5-membered n-heterocyclic compounds with hypoglycemic and hypolipidemic activity

专利摘要:
A compound of the formula (I) or a salt thereof, useful as a prophylactic or therapeutic agent for diabetes mellitus, (I) Wherein R 1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; X is a bond, an oxygen atom, a sulfur atom, or the formula -CO-, -CS-, -CR 4 (OR 5) - or -NR 6 - (wherein, each of R 4 and R 6 may be a hydrogen atom or a substituted And R < 5 > represents a hydrogen atom or a protecting group for a hydroxyl group; m represents an integer of 0 to 3; Y is an oxygen atom, a sulfur atom, or the formula -SO-, -SO 2 -, -NR 7 -, -CONR 7 - or -NR 7 CO- (wherein R 7 represents a hydrocarbon group which may be substituted or hydrogen atom) ≪ / RTI > Ring A represents an aromatic ring which may be further substituted with 1 to 3 substituents; n represents an integer of 1 to 8; Ring B represents a nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group; X 1 represents a bond, an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO 2 -, -O-SO 2 - or -NR 16 - (wherein R 16 represents a hydrogen atom or a hydrocarbon group which may be substituted) ≪ / RTI > R 2 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent hydrocarbon residue of 1 to 20 carbon atoms; R 3 is a group represented by the formula -OR 8 (wherein R 8 represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR 9 R 10 (each of R 9 and R 10 which may be the same or different is a hydrogen atom, a hydrocarbon group which may be substituted, A heterocyclic group which may be substituted, or an acyl group which may be substituted; R 9 and R 10 may bond together to form a ring; When Y is an oxygen atom, a sulfur atom, -NH- or -CONH-, R 1 is a heterocyclic group which may be substituted or R 2 may be substituted An aromatic hydrocarbon group or an optionally substituted heterocyclic group.
公开号:KR20020049044A
申请号:KR1020027006055
申请日:2000-11-09
公开日:2002-06-24
发明作者:모모세유；마에까와쯔요시；오다까히로유끼；기무라히로유끼
申请人:다케다 야쿠힌 고교 가부시키가이샤；
IPC主号:

专利说明:

5-MEMBERED N-HETEROCYCLIC COMPOUNDS WITH HYPOGLYCEMIC AND HYPOLIPIDEMIC ACTIVITY WITH HYPERGLYCLE DECREASE,
[4] JP-A 10-72434 discloses 2,4-substituted aniline derivatives of the following formula and herbicides containing them:
[5]
[6] Wherein R ¹ represents alkyl, haloalkyl, alkoxy and the like; R ² represents a hydrogen atom, alkyl, haloalkyl, etc.; R ³ represents alkyl, cycloalkyl, alkenyl or the like; X represents oxygen, sulfur, NR < ⁵ > or a single bond; Q represents an azole or the like].
[7] However, the above derivatives have not been reported to have a hypoglycemic effect or lipid lowering effect.
[8] Peroxisome proliferator-activated receptor gamma (PPARy), a member of the nuclear hormone receptor superfamily, which is typically exemplified by steroid hormone receptors and thyroid hormone receptors, is induced at the very early stages of lipid cell differentiation, It plays an important role as a master regulator in. PPARγ forms a dimer with the retinoid X receptor (RXR) by binding to the ligand and binds (activates) transcription efficiency directly to the responsive region of the target gene in the nucleus. Recently, it has been proposed that the metabolite of prostaglandin D ₂ , 15-deoxy-Δ ^12.14 prostaglandin J ₂ , acts as an endogenous ligand for PPARγ, and the family of insulin resistance enhancers typified by thiazolidinedione derivatives is PPARγ And its efficacy has been shown to be proportional to its hypoglycemic effect or lipid differentiation-promoting effect [Cell, vol. 83, p. 803 (1995): the Journal of Biological Chemistry, vol. 270, p. 12953 (1995); Journal of Medicinal Chemistry, vol. 39, p. 655 (1996)). In addition, recently, 1) PPARy is expressed in cultured cells of human liposarcoma origin, and the proliferation thereof is stopped by the addition of PPARy ligand (Proceedings of the National Academy of Sciences, vol. 94, p. 237 (1997)], 2) indomethacin and fenoprofen, the non-steroidal anti-inflammatory drugs typically exemplified have PPARγ ligand activity [the Journal of Biological Chemistry, vol. 272, p. 3406 (1997)], 3) high level expression in PPARγ-activated macrophages and the transcription of genes involved in inflammation is inhibited by the addition of its ligands [Nature, vol. 391, p. 79 (1998); 4) PPARγ ligand inhibits the production of inflammatory cytokines (TNFα, IL-1β, IL-6) by mononuclear cells [Nature, vol. 391, p. 82 (1998)].
[9] There is a demand for the development of novel compounds which are useful as preventive or therapeutic agents for diabetes mellitus, hypolipidemia, hyperglycemia, inflammatory diseases, arteriosclerosis and the like, and have pharmaceutical properties such as low side effects.
[1] The present invention relates to a novel nitrogen-containing 5-membered heterocyclic compound having an excellent hypoglycemic effect and a lipid lowering effect, and is useful as a prophylactic or therapeutic agent for diabetes mellitus, hypolipidemia, tolerance against diseases, inflammatory diseases, arteriosclerosis, Containing 5-membered heterocyclic compound.
[2] The present invention also relates to a prophylactic or therapeutic agent for diabetes mellitus, hyperlipidemia or tolerance to glucose tolerance, which contains a nitrogen-containing 5-membered heterocyclic compound.
[3] Further, the present invention relates to a retinoid-related receptor function modulator or an insulin resistance-improving agent containing a nitrogen-containing 5-membered heterocyclic compound.
[10] The present invention relates to the following (1) to (31):
[11] (1) A compound of formula (I) or a salt thereof:
[12]
[13] Wherein R ¹ represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
[14] X is a bond, an oxygen atom, a sulfur atom, or the formula ^{-CO-, -CS-, -CR 4 (OR} 5) - or -NR ⁶ - (wherein, each of R ⁴ and R ⁶ may be a hydrogen atom or a substituted And R < ⁵ > represents a hydrogen atom or a protecting group for a hydroxyl group;
[15] m represents an integer of 0 to 3;
[16] Y is an oxygen atom, a sulfur atom, or the formula ^{_{-SO-, -SO 2 -, -NR 7}} -, -CONR 7 - or -NR ⁷ CO- (wherein R ⁷ represents a hydrocarbon group which may be substituted or hydrogen atom) ≪ / RTI >
[17] Ring A represents an aromatic ring which may be further substituted with 1 to 3 substituents;
[18] n represents an integer of 1 to 8;
[19] Ring B represents a nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group;
[20] X ¹ represents a bond, an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO ₂ -, -O-SO ₂ - or -NR ¹⁶ - (wherein R ¹⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted) ≪ / RTI >
[21] R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
[22] W represents a bond or a divalent hydrocarbon residue of 1 to 20 carbon atoms;
[23] R ³ is a group represented by the formula -OR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR ⁹ R ¹⁰ (each of R ⁹ and R ¹⁰ which may be the same or different is a hydrogen atom, a hydrocarbon group which may be substituted, A heterocyclic group which may be substituted, or an acyl group which may be substituted; R ⁹ and R ¹⁰ may bond together to form a ring;
[24] When Y is an oxygen atom, a sulfur atom, -NH- or -CONH-, R ¹ is a heterocyclic group which may be substituted or R ² may be substituted An aromatic hydrocarbon group or an optionally substituted heterocyclic group;
[25] (2) a compound in which in (1), X ¹ is a bond and ring B is a nitrogen-containing 5-membered heterocyclic group;
[26] (3) a compound of the above (1) wherein R ¹ is a substituted cyclic hydrocarbon group or an optionally substituted cyclic hydrocarbon group;
[27] (4) a compound of the above-mentioned (1) wherein R ¹ is a substituted cyclic group;
[28] (5) a compound according to (1) above, wherein X is a bond;
[29] (6) The compound according to (1), wherein m is 1 or 2;
[30] (7) a compound wherein Y is an oxygen atom in the above-mentioned (1);
[31] (8) a compound according to (1), wherein ring A is a benzene ring or a pyridine ring, each of which may further have 1 to 3 substituents;
[32] (9) a compound of the above-mentioned (1), wherein n is an integer of 1 to 3;
[33] (10) a compound according to (1), wherein X < ¹ > is a bond or an oxygen atom;
[34] (11) a compound according to (1), wherein W is a divalent hydrocarbon residue having 1 to 8 carbon atoms;
[35] (12) a compound of the above-mentioned (1) wherein R ³ is a group of the formula -OR ⁸ (R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted);
[36] (13) In the above (1)
[37] Benzyl] -1H-pyrazol-4-yl] propionic acid, < RTI ID = 0.0 &
[38] Benzyl] -1H-pyrazol-4-yl] propionic acid, 3- [3-ethoxy-
[39] Benzyl] -1H-pyrazol-4-yl] propionic acid (prepared as described in example 1, ,
[40] Benzyl] -3- (2-thienyl) -lH-pyrazol-4-yl] propionic acid,
[41] 3- (2-thienyl) -1H-pyrazol-4-yl] propionic acid, or
[42] Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] propionic acid
[43] Phosphorus compounds;
[44] (14) a prodrug of the compound defined in (1) above;
[45] (15) A pharmaceutical composition comprising a compound of the formula (II), or a salt thereof or a prodrug thereof:
[46]
[47] Wherein R ¹ represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
[48] X is a bond, an oxygen atom, a sulfur atom, or the formula ^{-CO-, -CS-, -CR 4 (OR} 5) - or -NR ⁶ - (wherein, each of R ⁴ and R ⁶ may be a hydrogen atom or a substituted And R < ⁵ > represents a hydrogen atom or a protecting group for a hydroxyl group;
[49] m represents an integer of 0 to 3;
[50] Y is an oxygen atom, a sulfur atom, or the formula ^{_{-SO-, -SO 2 -, -NR 7}} -, -CONR 7 - or -NR ⁷ CO- (wherein R ⁷ represents a hydrocarbon group which may be substituted or hydrogen atom) ≪ / RTI >
[51] Ring A represents an aromatic ring which may be further substituted with 1 to 3 substituents;
[52] n represents an integer of 1 to 8;
[53] Ring B represents a nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group;
[54] X ¹ represents a bond, an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO ₂ -, -O-SO ₂ - or -NR ¹⁶ - (wherein R ¹⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted) ≪ / RTI >
[55] R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
[56] W represents a bond or a divalent hydrocarbon residue of 1 to 20 carbon atoms;
[57] R ³ is a group represented by the formula -OR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR ⁹ R ¹⁰ (each of R ⁹ and R ¹⁰ which may be the same or different is a hydrogen atom, a hydrocarbon group which may be substituted, A heterocyclic group which may be substituted, or an acyl group which may be substituted, and R ⁹ and R ¹⁰ may be bonded together to form a ring;
[58] (16) A composition according to (15), wherein X ¹ is a bond and ring B is a nitrogen-containing 5-membered heterocyclic group;
[59] (17) a prophylactic or therapeutic agent for diabetes mellitus containing a compound of the formula (II) or a salt thereof or a prodrug thereof;
[60] (18) a prophylactic or therapeutic agent for hyperlipidemia comprising a compound of the formula (II) or a salt thereof or a prodrug thereof;
[61] (19) a prophylactic or therapeutic agent for a tolerable disorder containing a compound of the formula (II) or a salt thereof or a prodrug thereof;
[62] (20) a retinoid-related receptor function modulator comprising a compound of formula (II) or a salt thereof or a prodrug thereof;
[63] (21) a modulator as described in (20) above, which is a ligand for a peroxisome proliferator-activated receptor;
[64] (22) the modulator according to (20), which is a ligand to the retinoid X receptor;
[65] (23) an insulin resistance-improving agent containing a compound of the formula (II) or a salt thereof or a prodrug thereof;
[66] (24) A method for preventing or treating diabetes mellitus in a mammal requiring prevention or treatment of diabetes mellitus comprising administering to said mammal an effective amount of a compound of formula (II) or a salt thereof or a prodrug thereof, ;
[67] (25) and a method for the prophylaxis or treatment of hyperlipidemia in a mammal requiring the prevention or treatment of lipidemia comprising administering to said mammal an effective amount of a compound of formula (II) or a salt thereof or a prodrug thereof, How to;
[68] (26), comprising the step of administering to said mammal an effective amount of a compound of formula (II) or a salt or prodrug thereof, as an effective amount for the prevention or treatment of impaired glucose tolerance in a mammal in need thereof How to;
[69] (27) A method of modulating retinoid-related receptor function in a mammal requiring modulation of retinoid-related receptor function comprising administering to said mammal an effective amount of a compound of formula (II) or a salt thereof or a prodrug thereof, How to;
[70] (28) the use of a compound of formula (II) or a salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the prophylaxis or treatment of diabetes mellitus;
[71] (29) and the use of a compound of formula (II) or a salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the prophylaxis or treatment of lipidemia;
[72] The use of a compound of formula (II) or a salt thereof or a prodrug thereof for the manufacture of a pharmaceutical preparation for the prophylaxis or treatment of a potency disorder in a subject (30);
[73] (31) Use of a compound of formula (II) or a salt thereof or a prodrug thereof, for the manufacture of a retinoid-related receptor function modulator.
[74] (1) Definition of R ¹
[75] (1-1) Definition of "hydrocarbon group" in R ¹
[76] Examples of the hydrocarbon group in the "hydrocarbon group which may be substituted" for R ¹ in the formulas (I) and (II) include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group, and an aromatic hydrocarbon group . The carbon number of such a hydrocarbon group is preferably 1 to 14.
[77] The aliphatic hydrocarbon group is preferably an aliphatic hydrocarbon group having 1 to 8 carbon atoms. Examples of the aliphatic hydrocarbon group include saturated aliphatic hydrocarbon groups (for example, alkyl groups) having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- , Isopentyl, neopentyl, hexyl, isohexyl, heptyl, and octyl; And an unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms (e.g., an alkenyl group having 2 to 8 carbon atoms, an alkadienyl group having 4 to 8 carbon atoms, an alkenylalkynyl group having 2 to 8 carbon atoms, Propenyl, 2-butenyl, 2-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, Pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, , 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, Pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadienyl, 5-hexynyl, 1-heptynyl, and 1-octynyl.
[78] The alicyclic hydrocarbon group is preferably an alicyclic hydrocarbon group having 3 to 7 carbon atoms. Examples of the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms (e.g., a cycloalkyl group) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; And an unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms (e.g., a cycloalkenyl group, a cycloalkadienyl group) such as 1-cyclopentenyl, 2-cyclopentenyl, 3- Hexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl.
[79] Examples of the alicyclic-aliphatic hydrocarbon group include those resulting from the bonding of the above-mentioned alicyclic hydrocarbon group and aliphatic hydrocarbon group (for example, a cycloalkyl-alkyl group, a cycloalkenyl-alkyl group) Alicyclic-aliphatic hydrocarbon groups are preferred. Examples of the alicyclic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, and cycloheptylethyl.
[80] The aromatic-aliphatic hydrocarbon group is preferably an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (for example, an aralkyl group having 7 to 13 carbon atoms or an arylalkenyl group having 8 to 13 carbon atoms). Examples of aromatic-aliphatic hydrocarbon groups include phenylalkyl of 7 to 9 carbon atoms, such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl; Naphthylalkyl having from 11 to 13 carbon atoms, such as -Naphthylmethyl, -Naphthylethyl, -Naphthylmethyl, and -Naphthylethyl; Phenylalkenyl having 8 to 10 carbon atoms, such as styryl; And naphthylalkenyl having 12 to 13 carbon atoms, such as 2- (2-naphthylvinyl).
[81] The aromatic hydrocarbon group is preferably an aromatic hydrocarbon group (for example, an aryl group) having 6 to 14 carbon atoms. Examples of the aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, and biphenyl, and phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
[82] Of the above-mentioned hydrocarbon groups, cyclic hydrocarbon groups such as alicyclic hydrocarbon groups and aromatic hydrocarbon groups are preferred. The hydrocarbon group is more preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, and phenyl, naphthyl and the like are preferable.
[83] (1-2) Definition of a "heterocyclic group" in R ¹
[84] The heterocyclic group in the "heterocyclic group which may be substituted" for R ¹ in the formulas (I) and (II) is preferably a heterocyclic group having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, A 5- to 7-membered monocyclic heterocyclic group, or a condensed heterocyclic group, which is contained as an atom to which a nitrogen atom is bonded. Examples of the condensed heterocyclic group include a 5- to 7-membered monocyclic heterocyclic group and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or a 5- And a group resulting from the condensation of the ring.
[85] Specifically, examples of the heterocyclic group include aromatic heterocyclic groups such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3- pyridyl, Pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2- pyrazinyl, 1- pyrrolyl, 2- pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazole, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, Thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-3-yl, Oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-1-yl , 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol- 1-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2- quinazolyl, 4- quinazolyl, 2- José Jolly, 2 Yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo [2,3 yl, lH-imidazo [4, < RTI ID = 0.0 > 5-c] pyridin-2-yl, 1H-imidazo [4,5-b] pyrazin-2-yl and benztriazol-1-yl; And non-aromatic heterocyclic groups such as 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin- Thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin- Dioxothiazolidin-3-yl, 1-oxo-phthalazin-2-yl and 2-oxo-2,3-dihydro-4H-1,4 -Benzothiazin-4-yl. ≪ / RTI >
[86] Preferably, the heterocyclic group is an aromatic group which may be condensed with a benzene ring (preferably a furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl) A heterocyclic group, more preferably a 5- or 6-membered aromatic heterocyclic group. Particularly preferred are furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, quinolyl and the like.
[87] (1-3) Definition of "Substituent" in R ¹
[88] Each hydrocarbon group and heterocyclic group for R < ¹ > in Formulas I and II may have 1 to 5 substituents, preferably 1 to 3 substituents, at substitutable positions. Examples of the substituent include "halogen atom", "nitro group", "aliphatic hydrocarbon group which may be substituted", "alicyclic hydrocarbon group which may be substituted", "aromatic hydrocarbon group which may be substituted" Aromatic heterocyclic group which may be substituted "," acyl group which may be substituted "," amino group which may be substituted "," hydroxy group which may be substituted "," A thiol group which may be substituted ", and " a carboxyl group which may be esterified ".
[89] Examples of " halogen atoms " include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
[90] Examples of the aliphatic hydrocarbon group in the " aliphatic hydrocarbon group which may be substituted " include linear or branched aliphatic hydrocarbon groups of 1 to 15 carbon atoms such as an alkyl group, an alkenyl group, and an alkynyl group.
[91] Preferable examples of the alkyl group include alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, t-butyl, pentyl, isopentyl, neopentyl, Propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl and decyl.
[92] Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, Hexyl, 1-hexenyl, 1-heptenyl, and 1-octenyl.
[93] Preferable examples of the alkynyl group include an alkynyl group having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, Pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, .
[94] Examples of the substituent in the "aliphatic hydrocarbon group which may be substituted" include a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl), an aromatic heterocyclic group For example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl), non-aromatic heterocyclic groups (for example, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, Mono-or di-substituted with an amino group, an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (e.g., an alkanoyl group) An acyl group having 2 to 8 carbon atoms (e.g., an alkanoyl group), a carbamoyl group, a carbamoyl group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, a sulfamoyl group , A sulfamoyl group which is mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, An alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine) An alkenyloxy group having 2 to 5 carbon atoms which may be substituted with one to three halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyl group having 7 to 9 carbon atoms An aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy), a thiol group, and 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) An alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (e.g., phenylthio or naphthylthio), a sulfo group, a cyano group, A nitro group, a nitroso group, and a halogen atom (e.g., fluorine, a salt , Bromine, iodine is included). The number of substituents is, for example, 1 to 3.
[95] Examples of the alicyclic hydrocarbon group in the " substitutable alicyclic hydrocarbon group " include saturated or unsaturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
[96] Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2 ] Octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, and bicyclo [4.3.1] do.
[97] Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 3 to 10 carbon atoms such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen- Hexen-1-yl.
[98] Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 4 to 10 carbon atoms such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, Cyclohexadien-1-yl.
[99] Preferable examples of the aromatic hydrocarbon group in the "aromatic hydrocarbon group which may be substituted" include aromatic hydrocarbon groups (for example, aryl groups) having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, phenanthryl, Phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
[100] Preferable examples of the aromatic heterocyclic group in the "aromatic heterocyclic group which may be substituted" include 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as an atom constituting a ring in addition to the carbon atom A 5- to 7-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl; And a condensed bicyclic or tricyclic aromatic heterocyclic group having 3 to 13 carbon atoms containing, as an atom constituting a ring, 1 to 5 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the carbon atom, For example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, lH-benzotriazolyl, quinolyl, Naphthyridinyl, furinyl, pteridinyl, carbazolyl, -Carbonyl, -Carbonyl, -Carbolinyl, isothiazolyl, quinolyl, quinoxalinyl, , Acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a A] pyridyl, imidazo [1, 2-b] pyridazinyl, imidazo [1, Piri Carbonyl, 1,2,4-triazolo [4,3-a] include the pyridyl, and 1,2,4-triazolo [4,3-b] pyridazinyl.
[101] Preferred examples of the non-aromatic heterocyclic group in the "non-aromatic heterocyclic group" include 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as an atom constituting a ring in addition to the carbon atom Aromatic heterocyclic groups having 2 to 10 carbon atoms, such as oxacanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholyl, Pyrrolidinyl, piperidino, morpholino, and thiomorpholino. ≪ / RTI >
[102] The term " aromatic hydrocarbon group which may be substituted ", " aromatic heterocyclic group which may be substituted ", and " non-aromatic heterocyclic group which may be substituted " Is an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, An alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl or naphthyl), an aromatic heterocyclic ring (For example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl), a non aromatic heterocyclic group (for example, tetrahydrofuryl, morpholino, thiomorpholino, piperidino , Pyrrolidinyl, piperazinyl), aralkyl of 7 to 9 carbon atoms An amino group which is mono- or di-substituted with an amino group, an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (such as an alkanoyl group), an amidino group, an acyl group having 2 to 8 carbon atoms A carbamoyl group, a carbamoyl group, a carbamoyl group which is mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, a sulfamoyl group, an alkyl group having 1 to 4 carbon atoms, A carbonyl group which may be substituted with a substituted sulfamoyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine) An alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a cycloalkyloxy group having 3 to 7 carbon atoms , Aralkyloxy groups having 7 to 9 carbon atoms, aryl groups having 6 to 14 carbon atoms An alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine), a cyano group (for example, phenyloxy or naphthyloxy) An aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (e.g., phenylthio or naphthylthio), a sulfo group, a cyano group, an azide group, a nitro group, And halogen atoms (e.g., fluorine, chlorine, bromine, iodine). The number of substituents may be, for example, from 1 to 3.
[103] The acyl group in the "acyl group which may be substituted" includes an acyl group having 1 to 13 carbon atoms, specifically formyl and a group represented by the formula -COR ¹¹ , -SO ₂ R ¹¹ , -SOR ¹¹ or -PO ₃ R ¹¹ R ¹² , Each of the same or different R ¹¹ and R ¹² represents a hydrocarbon group or an aromatic heterocyclic group.
[104] The hydrocarbon group for R ¹¹ or R ¹² is exemplified by the hydrocarbon groups mentioned for the above R ¹ . An alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, and an aryl group having 6 to 12 carbon atoms are particularly preferable.
[105] The aromatic heterocyclic group for R < ¹¹ > or R < ¹² > includes the aromatic heterocyclic groups mentioned for the above R < ¹ > Thienyl, furyl, pyridyl and the like are particularly preferable.
[106] Preferable examples of the acyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexane Carbonyl, cycloheptanecarbonyl, crotyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, and isonicotinoyl.
[107] The acyl group may have 1 to 3 substituents at substitutable positions. Examples of such substituents include a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, iodine), 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine , iodine), for C _1-6 alkoxy group, a halogen atom (for example, which may be substituted by, include fluorine, chlorine, bromine, iodine), nitro, hydroxy, and amino.
[108] Examples of the "amino group which may be substituted" include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, An amino group which may be mono- or di-substituted with an acyl group or an aryl group having 6 to 12 carbon atoms.
[109] Here, the acyl group is exemplified by the same acyl group as mentioned above, and an alkanoyl group having 2 to 10 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms and the like are preferable.
[110] Examples of substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, and N -Methyl-N-phenylamino. ≪ / RTI >
[111] Examples of the "hydroxy group which may be substituted" include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, an acyl group having 1 to 13 carbon atoms, Hydroxy group which may be substituted with an aryl group of 1 to 12 carbon atoms.
[112] The alkyl group having 1 to 10 carbon atoms, the alkenyl group having 2 to 10 carbon atoms, the aralkyl having 7 to 10 carbon atoms, the acyl group having 1 to 13 carbon atoms or the aryl group having 6 to 12 carbon atoms, Quot; which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine) _1-6 alkoxy groups, hydroxy, nitro, and amino. The number of substituents is, for example, 1 to 2.
[113] Examples of the substituted hydroxy group include an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group and an aryloxy group which may be substituted, respectively.
[114] Preferable examples of the alkoxy group include alkoxy groups having 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.butoxy, pentyloxy, iso Pentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
[115] Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenyloxy, and 2-cyclohexy ≪ / RTI >
[116] Preferable examples of the aralkyloxy group include aralkyloxy groups having 7 to 10 carbon atoms such as phenyl-C _1-4 alkyloxy (e.g., benzyloxy, phenethyloxy).
[117] Preferable examples of the acyloxy group include acyloxy groups having 2 to 13 carbon atoms and alkanoyloxy groups having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy) Do.
[118] Preferable examples of the aryloxy group include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
[119] The above-mentioned alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have 1 to 2 substituents at substitutable positions. Examples of such substituents include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C _1-6 alkoxy which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) Group, hydroxy, nitro, and amino. For example, examples of substituted aryloxy groups include 4-chlorophenoxy and 2-methoxyphenoxy.
[120] Examples of the thiol group which may be substituted include an alkyl group having 1 to 10 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, aralkyl having 7 to 10 carbon atoms, acyl having 2 to 13 carbon atoms, aryl having 6 to 14 carbon atoms, heteroaryl Lt; / RTI >
[121] Examples of substituted thiol groups include alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, and heteroarylthio.
[122] Preferred examples of the alkylthio group include alkylthio groups having 1 to 10 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, Thio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.
[123] Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, such as cyclobutylthio, cyclopentylthio, and cyclohexylthio.
[124] Preferable examples of the aralkylthio group include an aralkylthio group having 7 to 10 carbon atoms such as phenyl-C _1-4 alkylthio (e.g., benzylthio, phenethylthio).
[125] Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms and an alkanoylthio group having 2 to 4 carbon atoms (for example, acetylthio, propionylthio, butyrylthio, isobutyrylthio) desirable.
[126] Preferable examples of the arylthio group include arylthio groups having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
[127] Preferred examples of the heteroarylthio group include 2-pyridylthio, 3-pyridylthio, 2-imidazolylthio, and 1,2,4-triazol-5-ylthio.
[128] Examples of the esterified carboxyl group in the carboxyl group that can be esterified include an alkoxycarbonyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) , An aralkyloxycarbonyl group having 8 to 10 carbon atoms (e.g., benzyloxycarbonyl), and an aryloxycarbonyl group having 7 to 15 carbon atoms which may be substituted with one or two alkyl groups having 1 to 3 carbon atoms For example, phenoxycarbonyl, p-tolyloxycarbonyl) are exemplified.
[129] Amidated carboxyl group of the carboxyl group which may be amidated is the formula ^{-CON (R 13) (R 14} ) ( wherein, each of R ¹³ and R ¹⁴ the same or different is a hydrogen atom, a hydrocarbon group which may be substituted Or a heterocyclic group which may be substituted).
[130] Here, R ^13, and the hydrocarbon group in the "group which may be substituted with a hydrocarbon group" for R ¹⁴ is an aliphatic hydrocarbon group, alicyclic mentioned to illustrate a hydrocarbon group of the "group which may be substituted with a hydrocarbon group" for R ¹ Hydrocarbon group and aromatic hydrocarbon group are exemplified. Also, as the heterocyclic group in the "heterocyclic group which may be substituted" for R ¹³ and R ¹⁴ , mention may be made of, for example, a heterocyclic group in "a heterocyclic group which may be substituted" for R ¹ Substituted heterocyclic group are exemplified. Such a hydrocarbon group and a heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of each substituent is C _1-6 which may be substituted with a halogen atom (e.g., F, Cl, Br, I), 1 to 3 halogen atoms (e.g., F, Cl, Br, I) An alkyl group, a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy, and amino.
[131] The hydrocarbon group and the substituent in the heterocyclic group for R < ¹ > in the formulas (I) and (II) are preferably the following 1) to 4)
[132] 1) an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a halogen atom (e.g. fluorine, chlorine, bromine, iodine) An alkyl group having 1 to 10 (preferably 1 to 4) carbon atoms which may have 1 to 3 substituents selected from the group consisting of nitro, hydroxy and amino;
[133] 2) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, A cycloalkyl group having 3 to 10 carbon atoms (preferably 3 to 7 carbon atoms) which may have 1 to 10 carbon atoms;
[134] 3) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, An aromatic heterocyclic group (preferably, furyl, thienyl, pyridyl, pyrazinyl, etc.) which may have a substituent (s);
[135] 4) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, (Preferably phenyl, naphthyl, etc.) having 6 to 14 carbon atoms which may have a substituent. The number of substituents is, for example, 1 to 3, preferably 1 or 2.
[136] Preferably, the substituent is an alkyl group having 1 to 4 carbon atoms, furyl, thienyl, phenyl, naphthyl, and the like.
[137] (1-4) Preferable examples of R ¹
[138] In formulas (I) and (II), preferably, R ¹ is a heterocyclic group which may be substituted or a cyclic hydrocarbon group which may be substituted. More preferably, R ¹ is a heterocyclic group which may be substituted. Here, the heterocyclic group is preferably a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring (preferably a furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl , Thiazolyl, triazolyl, oxadiazolyl, pyrazolyl). Particularly preferred are furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, quinolyl, pyrazolyl and the like.
[139] Preferable examples of the substituents that the above-mentioned heterocyclic group or cyclic hydrocarbon group may have include the following 1) and 2):
[140] 1) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, Thienyl, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may have a substituent;
[141] 2) an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine) An alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group consisting of nitro, hydroxy and amino. The number of substituents is, for example, 1 or 2.
[142] Particularly preferably, R ¹ is a group selected from the group consisting of an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, furyl, thienyl, phenyl and naphthyl, each of which may have 1 or 2 substituents Pyridyl, oxazolyl, thiazolyl, triazolyl or pyrazolyl.
[143] (2) Definition of X
[144] In formula I and II, X is a bond, an oxygen atom, a sulfur atom, or the formula ^{-CO-, -CS-, -CR 4 (OR} 5) - or -NR ⁶ - (wherein, each of R ⁴ and R ⁶ is A hydrogen atom or a hydrocarbon group which may be substituted, and R ⁵ represents a hydrogen atom or a protecting group for a hydroxyl group; Preferably a bond, -CR ⁴ (OR ⁵ ) - or -NR ⁶ - (wherein the symbols have the same meanings as defined above), more preferably a bond or -NR ⁶ - (wherein the symbols have the same meanings as defined above )to be. Particularly preferably, X is a bond.
[145] Here, the "hydrocarbon group which may be substituted" for R ⁴ and R ⁶ includes the "hydrocarbon group which may be substituted" mentioned for exemplifying R ¹ above. The "hydrocarbon group which may be substituted" is preferably an alkyl group having 1 to 4 carbon atoms which may be substituted, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- to be. The alkyl group may have 1 to 3 substituents at substitutable positions. Examples of such substituents include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, (For example, an alkanoyl group having 1 to 4 carbon atoms, such as formyl, acetyl, and the like) having 1 to 4 carbon atoms, such as methoxy, ethoxy, sec.butoxy, t.butoxy), hydroxy, Propionyl).
[146] Preferably, R ⁴ and R ⁶ are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
[147] Examples of protecting groups for hydroxyl groups for R ⁵ include C _1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, C _7-10 aralkyl (E.g. benzyl), formyl, C _1-6 alkyl-carbonyl (e.g. acetyl, propionyl), benzoyl, C _7-10 aralkyl-carbonyl (E.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), and C _2-6 Alkenyl (for example, 1-allyl). These groups may be optionally substituted with one to three halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C _1-6 alkyl (e.g. methyl, ethyl, propyl), C _1-6 alkoxy Methoxy, ethoxy, propoxy), nitro, and the like.
[148] (3) Definition of m and Y
[149] In the formulas (I) and (II), m represents an integer of 0 to 3, preferably an integer of 1 to 3, more preferably 1 or 2.
[150] In formula I and II, Y is an oxygen atom, a sulfur atom, or the formula ^{_{-SO-, -SO 2 -, -NR 7}} -, -CONR 7 - or -NR ⁷ CO- (wherein R ⁷ is a hydrogen atom or optionally substituted And preferably represents an oxygen atom, a sulfur atom, -NR ⁷ - or -NR ⁷ CO- (wherein the symbols have the same meanings as defined above).
[151] Here, the "hydrocarbon group which may be substituted" for R ⁷ includes the "hydrocarbon group which may be substituted" mentioned for exemplifying R ⁴ and R ⁶ above. Preferably, R ⁷ is a hydrogen atom. Particularly preferably, Y is an oxygen atom.
[152] (4) Definition of ring A
[153] In the formulas I and II, " aromatic ring " in " aromatic ring which may have 1 to 3 substituents " for ring A includes benzene ring, condensed aromatic hydrocarbon ring, 5- or 6- And a condensed aromatic heterocycle are exemplified.
[154] Examples of the " condensed aromatic hydrocarbon ring " include condensed aromatic hydrocarbon rings having 9 to 14 carbon atoms. Specifically, naphthalene, indene, fluorene, anthracene and the like can be mentioned.
[155] Examples of the "5- or 6-membered aromatic heterocycle" include a 5- or 6-membered aromatic heterocycle containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the carbon atom do. Specific examples include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1 , 3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, furanaz and the like can be mentioned.
[156] Examples of the "condensed aromatic heterocycle" include a 9- to 14-membered (preferably 9- or 10-membered) ring containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom, Specific examples include benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline , Quinoline, indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalazine, naphthyridine, quinazoline, cinnoline, carbazole, -Carboline, acridine, phenazine, phthalimide May be mentioned.
[157] The "aromatic ring" is preferably a benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene etc.), a 5- or 6-membered aromatic heterocycle (preferably pyridine, isoxazole etc.) .
[158] Examples of the "substituent" in the "aromatic ring which may have 1 to 3 substituents" for Ring A include an aliphatic hydrocarbon group (preferably an alkyl group) which may be substituted, a hydroxy group which may be substituted, a halogen atom , An acyl group which may be substituted, a nitro group, and an amino group which may be substituted. All such substituents are those mentioned to illustrate substituents at R < ^{1 &} gt ;. The substituents are preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an aralkyloxy group (preferably benzyloxy) having 7 to 10 carbon atoms, or a halogen atom.
[159] The ring A is preferably a benzene ring or a pyridine ring each of which may further have 1 to 3 substituents, more preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, An aralkyloxy group having 7 to 10 carbon atoms, and a halogen atom, each of which may further have 1 to 3 substituents. Ring A is particularly preferably a benzene ring.
[160] (5) Definition of n
[161] In the formulas (I) and (II), n represents an integer of 1 to 8, preferably an integer of 1 to 3.
[162] (6) Definition of ring B
[163] In the formulas I and II, the "nitrogen-containing 5-membered heterocycle" in the "nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group" for ring B means that at least one nitrogen atom is bonded to a carbon atom And a 5-membered heterocyclic ring containing an atom constituting the ring and which may further contain 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
[164] Preferred examples of the nitrogen-containing 5-membered heterocycle include 5-membered aromatic heterocyclic rings such as pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,4- 1,2,3-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furanaz, 1,2,3-thiadiazole Sol, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and tetrazole; And a 5-membered non-aromatic heterocycle such as pyrrolidine, imidazolidine, and pyrazolidine. The nitrogen-containing 5-membered heterocyclic ring preferably contains at least one nitrogen atom in addition to the carbon atom as an atom constituting the ring and may further contain one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom 5-membered aromatic heterocycle such as pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, and isoxazole. Pyrrole, pyrazole, imidazole and the like are particularly preferable.
[165] The "alkyl group" in the "nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group" includes an alkyl group having 1 to 4 carbon atoms. Specifically, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl and the like can be mentioned, and methyl and ethyl are preferable.
[166] Preferably, ring B is pyrrole, pyrazole or imidazole, each of which may be further substituted with an alkyl group having from 1 to 4 carbon atoms. Particularly preferably ring B is pyrazole.
[167] (7) Definition of X ¹
[168] And in formula Ⅰ Ⅱ, X ¹ is a bond, an oxygen atom, a sulfur atom, or the formula _{-SO-, -SO 2 -, -O-} SO 2 - or -NR ¹⁶ - [wherein, R ¹⁶ is a hydrogen atom or a substituted A hydrocarbon group which may be substituted.
[169] Here, the "hydrocarbon group which may be substituted" for R ¹⁶ is exemplified by the "hydrocarbon group which may be substituted" mentioned for exemplifying R ⁴ and R ⁶ above.
[170] X ¹ is preferably a bond or an oxygen atom.
[171] (8) Definition of R ²
[172] In formula Ⅰ) and (Ⅱ, "optionally substituted hydrocarbon group" for R ^2, and "optionally substituted heterocyclic group" roneun mentioned to illustrate the R ¹ 'which may be substituted hydrocarbon group "and" substituted Quot; heterocyclic group which may be substituted ", respectively.
[173] (8-1) When X ^{1 in the} formulas (I) and (II) is a bond
[174] The hydrocarbon group in the " hydrocarbon group which may be substituted " for R ² is preferably an aliphatic hydrocarbon group (preferably an alkyl group) having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 14 carbon atoms, To 14 aromatic hydrocarbon groups (e.g., phenyl, naphthyl).
[175] The heterocyclic group in the "optionally substituted heterocyclic group" for R ² is preferably a 5- or 6-membered aromatic heterocyclic group (for example, furyl, thienyl, pyridyl).
[176] The substituents in the above-mentioned "hydrocarbon group which may be substituted" and "heterocyclic group which may be substituted" are preferably 1) a halogen atom (for example, fluorine, chlorine, bromine, iodine) (For example, methyl, trifluoromethyl, propyl, isopropyl) which may be substituted with at least one halogen atom (e.g. fluorine, chlorine, bromine, iodine) An alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, trifluoromethoxy) which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) (For example, benzyloxy), 5) an aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy), 6) an aromatic heterocyclic group (e.g., furyl, thienyl ).
[177] R ² is preferably 1) an aromatic hydrocarbon group having 6-14 carbon atoms which may be substituted (for example, phenyl, naphthyl), or 2) a 5- or 6-membered aromatic heterocyclic group For example, furyl, thienyl, pyridyl).
[178] R ² is more preferably 1) an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, phenyl or naphthyl) or 2) a 5- or 6-membered aromatic heterocyclic group (for example, Yl, pyridyl). Phenyl, furyl, thienyl and the like are particularly preferable.
[179] (8-2) a compound of the formula (I) wherein X ^{1 in the} formulas (I) and (II) is an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO ₂ -, -O-SO ₂ - or -NR ¹⁶ - Have the meaning].
[180] The hydrocarbon group in the "hydrocarbon group which may be substituted" for R ² is preferably an aliphatic hydrocarbon group (preferably an alkyl group (for example, methyl, ethyl, propyl, isopropyl) having 1 to 8 carbon atoms) (Preferably an aralkyl group such as benzyl) of 7 to 13, and an aromatic hydrocarbon group of 6 to 14 carbon atoms (e.g., phenyl, naphthyl).
[181] The heterocyclic group in the "optionally substituted heterocyclic group" for R ² is preferably a 5- or 6-membered aromatic heterocyclic group (for example, furyl, thienyl, pyridyl).
[182] The substituents in the above-mentioned "hydrocarbon group which may be substituted" and "heterocyclic group which may be substituted" are preferably 1) a halogen atom (for example, fluorine, chlorine, bromine, iodine) An alkyl group having 1 to 4 carbon atoms (e.g., methyl, ethyl, trifluoromethyl) which may be substituted with at least one halogen atom (e.g., fluorine, chlorine, bromine, iodine) 4) an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms (e.g., cyclohexyl), a furyl, a thienyl, a phenyl, and an aralkyloxy group (e.g., benzyloxy) A 5- or 6-membered aromatic heterocyclic group (for example, pyridyl, oxazolyl, thiazolyl, triazolyl) which may have 1 or 2 substituents selected from naphthyl, An alkoxy group (e.g., methoxy, ethoxy), 5) an aromatic heterocyclic group (e.g., furyl, An aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy), 7) a phenyl group substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) An alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, trifluoromethoxy), and the like. The number of substituents is, for example, 1 to 3.
[183] R ² is preferably an aliphatic hydrocarbon group (preferably an alkyl group (for example, methyl, ethyl, propyl, isopropyl) having 1 to 8 carbon atoms which may be substituted), an aromatic group having 7 to 13 carbon atoms - an aliphatic hydrocarbon group (preferably an aralkyl group (e.g. benzyl)), or a heterocyclic group which may be substituted (preferably a 5- or 6-membered aromatic heterocyclic group , Thienyl, pyridyl)).
[184] R ² is more preferably an aliphatic hydrocarbon group (preferably an alkyl group (e.g., methyl, ethyl, propyl, isopropyl) having 1 to 8 carbon atoms) or an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms Is an aralkyl group (e. G. Benzyl)).
[185] (9) Definition of W
[186] In formula (I) and (II), " divalent hydrocarbon residue having 1 to 20 carbon atoms " for W includes a divalent non-cyclic hydrocarbon residue, a divalent cyclic hydrocarbon residue and at least one divalent non- A divalent group obtained by combining at least one " divalent hydrocarbon residue " and at least one " divalent cyclic hydrocarbon residue "
[187] Examples of the "divalent non-cyclic hydrocarbon residue" include alkylene having 1 to 20 carbon atoms, alkenylene having 2 to 20 carbon atoms, and alkynylene having 2 to 20 carbon atoms.
[188] Examples of the "divalent cyclic hydrocarbon residue" include a cycloalkane having 5 to 20 carbon atoms, a cycloalkene having 5 to 20 carbon atoms or an aromatic hydrocarbon having 6 to 20 carbon atoms (for example, benzene, naphthalene, indene, anthracene) And a divalent group obtained by removing an arbitrarily selected hydrogen atom. Specific examples thereof include 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2- , 1,3-cycloheptylene, 1,4-cycloheptylene, 3-cyclohexene-1,4-ylene, 3-cyclohexene-1,2-ylene, 2,5-cyclohexadiene- Phenylene, 1,4-phenylene, 1,4-naphthylene, 1,6-naphthylene, 2,6-naphthylene, 2,7-naphthylene, Tylene, 1,5-indenylene, 2,5-indenylene, and the like can be mentioned.
[189] The compound wherein W in the formulas (I) and (II) is a divalent hydrocarbon residue having 1 to 20 carbon atoms has a stronger blood sugar lowering effect and lipid lowering effect than the compound wherein W is a bond. Therefore, it is preferable that W is a divalent hydrocarbon residue having 1 to 20 carbon atoms. W is more preferably " a divalent hydrocarbon residue having 1 to 8 carbon atoms ", and is preferably:
[190] (1) C _1-8 alkylene _{(e.g., -CH 2 -, - (CH} 2) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - (CH 2) 5 - _{, - (CH 2) 6 -} , - (CH 2) 7 -, - (CH 2) 8 -, -CH (CH 3) -, -C (CH 3) 2 -, - (CH (CH 3)) ₂ -, - (CH ₂ ) ₂ C (CH ₃ ) ₂ -, - (CH ₂ ) ₃ C (CH ₃ ) ₂ -);
[191] (2) C _2-8 alkenylene (for example, -CH═CH-, -CH ₂ -CH═CH-, -C (CH ₃ ) ₂ -CH═CH-, -CH ₂ -CH═CH- CH ₂ -, -CH ₂ -CH ₂ -CH = CH-, -CH = CH-CH = -, -CH = CH-CH ₂ -CH ₂ -CH ₂ -); or
[192] (3) C _2-8 alkynylene _{(e.g., -C≡C-, -CH 2 -C≡C-, -CH} 2 -C≡C-CH 2 -CH 2 -).
[193] W is particularly preferably -CH ₂ -, - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, -CH = CH- or the like.
[194] (10) Definition of R ³
[195] In the formulas (I) and (II), R ³ represents a group represented by the formula -OR ⁸ (R ⁸ represents a hydrogen atom or a hydrocarbon group of 10
[196] Or -NR ⁹ R ¹⁰ (each of the same or different R ⁹ and R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or an acyl group which may be substituted; R ⁹ and And R < ¹⁰ > may bond together to form a ring.
[197] The "hydrocarbon group which may be substituted" for R ⁸ includes the "hydrocarbon group which may be substituted" mentioned for the purpose of exemplifying R ¹ .
[198] The "hydrocarbon group which may be substituted" is preferably an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, and a halogen atom (for example, fluorine, chlorine, bromine, iodine) Quot; aryl group having 6 to 10 carbon atoms which may have 3 to 6 substituents " and the like. Examples of the "alkyl group having 1 to 4 carbon atoms" include methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl and the like. Chlorine is preferred as the " halogen atom ". Examples of the "aryl group having 6 to 10 carbon atoms" include phenyl and naphthyl, with phenyl being preferred.
[199] R ⁹ and the "optionally substituted hydrocarbon group" for R ^10, and "optionally substituted heterocyclic group" roneun mentioned to illustrate the R ¹ 'which may be substituted hydrocarbon group "and" heteroaryl which may be substituted Quot; and " cyclic group "
[200] The " substitutable acyl group " for R ⁹ and R ¹⁰ includes the "acyl group which may be substituted" mentioned for the purpose of exemplifying the substituent at R ¹ .
[201] Examples of rings formed by R ⁹ and R ¹⁰ bonded together are 5- to 7-membered cyclic amino groups, preferably 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 4- Polyno, 4-thiomorpholino, and the like.
[202] R ⁹ and R ¹⁰ are preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (e.g., methyl, ethyl).
[203] R ³ is preferably a group of the formula -OR ⁸ (wherein the symbols have the same meaning as defined above), and R ⁸ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl) .
[204] (11) Preferred compounds
[205] Preferable examples of the compounds of the formulas (I) and (II) include the following compounds.
[206] (A) wherein the symbols have the following meanings:
[207] R ¹ is a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring and which may have 1 or 2 substituents selected from 1) and 2) (preferably a furyl, thienyl, pyridyl , Pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) and:
[208] 1) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, A furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl each of which may have; And
[209] 2) an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine) An alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group consisting of nitro, hydroxy and amino;
[210] X is a bond or -NR ⁶ - (wherein R ⁶ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
[211] m is 1 or 2;
[212] Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-;
[213] Ring A further has 1 to 3 substituents each independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an aralkyloxy group having 7 to 10 carbon atoms, and a halogen atom A benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene etc.) or a 5- or 6-membered aromatic heterocycle (preferably pyridine, isoxazole etc.);
[214] n is an integer from 1 to 3;
[215] Ring B is a "5-membered aromatic heterocycle" which contains at least one nitrogen atom in addition to the carbon atom as a ring-constituting atom, and which may further contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom For example, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, which may be further substituted with an alkyl group having 1 to 4 carbon atoms;
[216] X ¹ is a bond;
[217] R ² is a group selected from the group consisting of 1) a halogen atom (for example, fluorine, chlorine, bromine, iodine), 2) a C 1-20 alkyl group which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine) 3) an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine), an alkyl group (e.g. methyl, trifluoromethyl, 4) an aralkyloxy group having 7 to 10 carbon atoms (e.g., benzyloxy); 5) an aryloxy group having 6 to 14 carbon atoms (for example, methoxy, trifluoromethoxy) An aliphatic hydrocarbon group having 1 to 8 carbon atoms, which may be substituted with 1 to 3 substituents each selected from the group consisting of, for example, phenoxy) and 6) aromatic heterocyclic groups (for example, furyl, thienyl) (Preferably an alkyl group), an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl , Naphthyl) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl);
[218] W is C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene;
[219] R ³ is selected from -OR ⁸ wherein R ⁸ is selected from a hydrogen atom, an "alkyl group having 1 to 4 carbon atoms" or an alkyl group having 1 to 4 carbon atoms and a halogen atom (for example, fluorine, chlorine, bromine, iodine) An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents ") or -NR ⁹ R ¹⁰ (each of the same or different R ⁹ and R ¹⁰ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) .
[220] (B) wherein the symbols have the following meanings:
[221] R ¹ is a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring and which may have 1 or 2 substituents selected from 1) and 2) (preferably a furyl, thienyl, pyridyl , Pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl) and:
[222] 1) an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino, A furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl each of which may have; And
[223] 2) an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine) An alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group consisting of nitro, hydroxy and amino;
[224] X is a bond or -NR ⁶ - (wherein R ⁶ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms);
[225] m is 1 or 2;
[226] Y is an oxygen atom, a sulfur atom, -NH- or -NHCO-;
[227] Ring A further has 1 to 3 substituents each independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an aralkyloxy group having 7 to 10 carbon atoms, and a halogen atom A benzene ring, a condensed aromatic hydrocarbon ring having 9 to 14 carbon atoms (preferably naphthalene etc.) or a 5- or 6-membered aromatic heterocycle (preferably pyridine, isoxazole etc.);
[228] n is an integer from 1 to 3;
[229] Ring B is a "5-membered aromatic heterocycle" which contains at least one nitrogen atom in addition to the carbon atom as a ring-constituting atom, and which may further contain one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom For example, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, which may be further substituted with an alkyl group having 1 to 4 carbon atoms;
[230] X ¹ is a bond;
[231] R ² is a group selected from the group consisting of 1) a halogen atom (for example, fluorine, chlorine, bromine, iodine), 2) a C 1-20 alkyl group which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine) 4) an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl or trifluoromethyl), 3) an aralkyloxy group having 7 to 10 carbon atoms (e.g., benzyloxy) A 5- or 6-membered aromatic heterocyclic group which may have one or two substituents selected from a cycloalkyl group having 3 to 7 carbon atoms (for example, cyclohexyl), furyl, thienyl, phenyl and naphthyl (For example, pyridyl, oxazolyl, thiazolyl, triazolyl)] - an alkoxy group having 1 to 6 carbon atoms such as methoxy and ethoxy, 5) an aromatic heterocyclic group 6) an aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy) and 7) 1 to 3 halogen atoms (e.g., (For example, methoxy, ethoxy, trifluoromethoxy), which may be substituted with fluorine, chlorine, bromine, iodine, and the like, with 1 to 3 substituents selected from the group consisting of An aliphatic hydrocarbon group (preferably an alkyl group (e.g., methyl, ethyl, propyl, isopropyl) having 1 to 8 carbon atoms which may be substituted, an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms Aralkyl group (e.g., benzyl)) or a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl);
[232] W is C _1-8 alkylene, C _2-8 alkenylene or C _2-8 alkynylene;
[233] R ³ is selected from -OR ⁸ wherein R ⁸ is selected from a hydrogen atom, an "alkyl group having 1 to 4 carbon atoms" or an alkyl group having 1 to 4 carbon atoms and a halogen atom (for example, fluorine, chlorine, bromine, iodine) An aryl group having 6 to 10 carbon atoms which may have 1 to 3 substituents ") or -NR ⁹ R ¹⁰ (each of the same or different R ⁹ and R ¹⁰ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) .
[234] (12) Salts
[235] The salt of the compound of the formula I or II (hereinafter also referred to as the compound (I) or the compound (II), respectively) is preferably a pharmacologically acceptable salt and may be a salt with an inorganic base, a salt with an organic base, Salts with organic acids, and salts with basic or acidic amino acids.
[236] Preferable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; Alkaline earth metal salts such as calcium salts and magnesium salts; And aluminum salts and ammonium salts.
[237] Preferable examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
[238] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
[239] Preferred examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like.
[240] Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
[241] Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
[242] Among these salts, sodium salt, potassium salt, hydrochloride salt and the like are preferable.
[243] (13) Pro Drugs, etc.
[244] The prodrug of the compound (II) is a compound which can be converted into the compound (II) by reactions such as enzymes and gastric juices under physiological conditions in vivo. More specifically, the prodrug of the compound (II) in enzymatic oxidation, reduction, , Or a compound which can be converted into compound (II) by hydrolysis with gastric juice or the like. Examples of prodrugs of the compound (II) include compounds derived by acylation, alkylation or phosphorylation of the amino group of the compound (II) (for example, eicosanoylation, alanylation, pentyl (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofurination, pyrrolidylmethylation, pivaloyloxymethylated or tert- butyl Lt; / RTI > Compounds which are induced by acylation, alkylation, phosphorylation or boration of the hydroxyl group of compound (II) (for example, by acetylation of the hydroxyl group of compound (II), palmitoylation, propanoylation, Compounds which are derived by an anion, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation); And compounds derived from the esterification or amidation of the carboxyl group of the compound (II) (for example, a compound in which the carboxyl group of the compound (II) is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethyl Esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, pivaloyloxymethyl esterification, Compounds derived by cyclohexyloxycarbonyl ethyl esterification or methyl amidation). These compounds can be prepared from compound (II) by a method known per se.
[245] The prodrug of compound (II) is described in " Iyakuhin No Kaihatsu (Development of Drugs) ", vol. 7, Molecular Designing, Hirokawa Shoten, 1990, pp. 163-198, under physiological conditions as described above.
[246] As the prodrug of the compound (I), the same prodrug as the compound (II) is exemplified.
[247] Compound (I) and compound (II) can also be labeled with isotopes (for example, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I).
[248] Further, the compound (I) and the compound (II) may be anhydrides or hydrates.
[249] (14) Formulation
[250] The compounds (I) and (II) and salts thereof (hereinafter also referred to as " the compounds of the present invention ") are low in toxicity and can be used in mammals (e.g., humans, mice, rats, rabbits, , Horses, pigs, and monkeys), as they are, or in the form of pharmaceutical compositions prepared by further mixing with a pharmacologically acceptable carrier or the like.
[251] Herein, pharmacologically acceptable carriers include various organic or inorganic carrier components commonly used as materials for pharmaceutical preparations, which are excipients, lubricants, binders and disintegrating agents for solid preparations; And solvents for liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffers, wetting agents and the like. In addition, other additional pharmaceutical preparations such as bactericides, antioxidants, colorants and sweeteners may be used if necessary.
[252] Preferred examples of excipients include lactose, saccharose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, gum arabic, dextrin, pullulan, Light anhydrous silicic acid, synthetic aluminum silicate, and magnesium metasilicate aluminate.
[253] Preferred examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
[254] Preferred examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, saccharose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose , Hydroxypropylmethylcellulose, and polyvinylpyrrolidone.
[255] Preferred examples of disintegrants include lactose, saccharose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.
[256] Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
[257] Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.
[258] Preferred examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and monostearoyl glycerol; Hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; And polysorbates and polyoxyethylene-hydrogenated castor oil.
[259] Preferred examples of isotonizing agents include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
[260] Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
[261] Preferable examples of the non-hydratizing agent include benzyl alcohol.
[262] Preferred examples of bactericides include p-oxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
[263] Preferable examples of the antioxidant include sulfite and ascorbate.
[264] Preferable examples of the coloring agent include water-insoluble tar pigments (for example, food color red No. 2 and No. 3, food color yellow No. 4 and No. 5, food color blue No. 1 and No. 2) (For example, aluminum salts of edible water-soluble tar coloring matter) and natural coloring matters (for example, beta -carotene, chlorophyll, red oxide).
[265] Preferred examples of sweeteners include saccharin sodium, dipotassium glycyrrhetinate, aspartame and stevia.
[266] (15) Dosage form
[267] Examples of dosage forms of the pharmaceutical compositions include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; (For example, a preparation for nasal administration, a transdermal preparation, ointment), suppositories (for example, rectal suppositories, intramuscular injections, intraperitoneal injections) Vaginal suppositories), pellets, drops, and non-oral preparations such as sustained release formulations. The formulations can each be administered orally or non-orally safely.
[268] The pharmaceutical composition may be prepared by a conventional method in the field of pharmaceutical production technology, for example, a method described in Japanese Pharmacopoeia. Specific preparation methods for the preparation are described in detail below.
[269] For example, oral preparations can be prepared by mixing the active ingredient with excipients such as excipients (e.g., lactose, saccharose, starch, D-mannitol), disintegrants (such as carboxymethylcellulose calcium), binders (e.g., (E.g., talc, magnesium stearate, polyethylene glycol 6000) is added, and the resulting mixture is compression-molded. Thereafter, a necessary If desired, by coating in a manner known per se, using a coating base for taste masking, enteric coating or sustained release.
[270] Examples of coating bases include sugar coating bases, water soluble film coating bases, enteric film coating bases, and sustained release film coating bases.
[271] Saccharose is used as the sugar coating base. In addition, one or two or more species selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like can be used in combination.
[272] Examples of water soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose; Synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trademark), Rhom Pharma] and polyvinylpyrrolidone; And polysaccharides such as pullulan.
[273] Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate; Methacrylic acid copolymer L [Eudragit L (trademark), Rhom Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 (trademark), Rhom Pharma], methacrylic acid copolymer S [Eudragit S Acrylic acid polymers such as Pharma; And natural products such as shellac.
[274] Examples of sustained-release film-coated bases include cellulosic polymers such as ethylcellulose; Acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trademark), Rhom Pharma] and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trademark), Rhom Pharma].
[275] More than one such coating base may be used as an additive mixture of suitable proportions. At the time of coating, a light-shielding agent such as titanium oxide, iron oxide red iron oxide may be used.
[276] The injectable solution may be prepared by dissolving the active ingredient in an aqueous solvent (for example, distilled water, physiological saline, Ringer's solution) or a solvent (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, For example, polysorbate 80, polyoxyethylene-cured castor oil 60), polyethylene glycol, carboxymethylcellulose, sodium alginate), preservative (methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol) For example, sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose) or the like. If desired, additives such as solubilizing agents (for example, sodium salicylate, sodium acetate), stabilizers (for example, human serum albumin), analgesic agents (for example, benzyl alcohol) may be used.
[277] (16) Pharmaceutical
[278] The compounds of the present invention can be used as an insulin resistance improving agent, an insulin sensitivity enhancer, a regulator of retinoid-related receptor function, a ligand for a peroxisome proliferator-activated receptor, and a ligand for a retinoid X receptor. The term " function modifier ", as used herein, refers to both an agonist and an antagonist. The function modulating agent may be a partial agonist or a partial antagonist.
[279] The compound of the present invention has a hypoglycemic effect, a lipid lowering effect, an insulin hypotensive effect, an insulin resistance improving effect, an insulin sensitivity enhancing effect, and a retinoid-related receptor function modulating effect. As used herein, the term " retinoid-related receptor " is a DNA-binding transcription factor that is classified as a nuclear receptor and in which the ligand is a signaling molecule, such as an avidity vitamin or the like, and includes any monomeric receptor, homodimeric receptor, and heterodimeric receptor .
[280] Examples of the monomer receptor include retinoid O receptor (hereinafter, abbreviated as ROR) (GenBank Accession No. L14611), ROR (GenBank Accession No. L14160), ROR (GenBank Accession No. U16997); Rev-erb (GenBank Accession No. M24898), Rev-erb (GenBank Accession No. L31785); ERR (GenBank Accession No. X51416), ERR (GenBank Accession No. X51417); Ftz-FI (GenBank Accession No. S65876), Ftz-FI (GenBank Accession No. M81385); TIx (GenBank Accession No. S77482); GCNF (GenBank Accession No. U14666).
[281] Examples of homodimeric receptors include retinoid X receptor (hereinafter also abbreviated as RXR) (GenBank Accession No. X52733), RXR (GenBank Accession No. M84820), RXR (GenBank Accession No. U38480); COUP (GenBank Accession No. X12795), COUP (GenBank Accession No. M64497), COUP (GenBank Accession No. X12794); TR2 (GenBank Accession No. M29960), TR2 (GenBank Accession No. L27586); Or homozymes formed by HNF4 (GenBank Accession No. X76930), HNF4 (GenBank Accession No. Z49826), and the like.
[282] (GenBank Accession No. X00614), RAR (GenBank Accession No. Y00291), retinoid A receptor (hereinafter abbreviated as RAR), retinoid X receptor (RXR , RXR Or RXT ) Mentioned above as examples of heterodimer receptors, , RAR gamma (GenBank Accession No. M24857); Thyroid hormone receptor (hereinafter also abbreviated as TR) (GenBank Accession No. M24748), TR (GenBank Accession No. M26747); Vitamin D receptor (VDR) (GenBank Accession No. J03258): Peroxisome proliferator-activated receptor (hereinafter abbreviated as PPAR) (GenBank Accession No. L02932), PPAR (PPAR ) (GenBank Accession No. U10375 ), PPARy (GenBank Accession No. L40904); LXR (GenBank Accession No. U22662), LXR (GenBank Accession No. U14534); FXR (GenBank Accession No. U18374); MB67 (GenBank Accession No. L29263); ONR (GenBank Accession No. X75163); And a heterodimer formed by one receptor selected from NUR (GenBank Accession No. L13740), NUR (GenBank Accession No. X75918) and NUR (GenBank Accession No. U12767).
[283] The compounds of the present invention exhibit particularly excellent ligand activity against retinoid X receptors (RXRa, RXRbeta, RXRgamma) and peroxisome-proliferator activating receptors (PPARa, PPARa (PPARdelta), PPARgamma) among the above mentioned retinoid- .
[284] In addition, the compounds of the present invention can be administered to a peroxisome proliferator-activated receptor in a heterodimeric receptor formed from a heterodimeric receptor formed from a retinoid X receptor and a peroxisome proliferator-activated receptor, preferably RXRa and PPARy ≪ / RTI >
[285] Thus, the retinoid-related receptor ligand of the present invention can be advantageously used as a ligand for a peroxisome proliferator-activated receptor or as a ligand for a retinoid X receptor.
[286] Among the compounds of the present invention, compounds having a divalent hydrocarbon residue of 1 to 20 carbon atoms relative to W (particularly alkylene such as methylene) can be preferably used as a PPAR gamma agonist or a PPAR gamma agonist.
[287] On the other hand, among the compounds of the present invention, a compound having a bond particularly to W can be preferably used as a PPARgamma antagonist or a PPARgamma partial antagonist.
[288] (17) Target disease
[289] The compound of the present invention and the pharmaceutical composition of the present invention can be used as a preventive or therapeutic agent for diabetes (for example, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus); And hyperlipidemia (for example, hyperglyceridemia, hypercholesterolemia, hypercholestero-lipoproteinemia, post-prandial hyperlipidemia); Insulin sensitivity enhancers; An insulin resistance-improving agent; A prophylactic or therapeutic agent for myogical disorder (IGT); And can be used as a prophylactic agent for the progression from inherited dysfunc- tion to diabetes mellitus.
[290] Regarding diagnostic criteria for diabetes mellitus, new diagnostic criteria were reported in 1998 by the Japan Diabetes Society.
[291] According to these reports, diabetes mellitus has been reported to have a fasting blood glucose level (glucose concentration in intravenous plasma) of 126 mg / dl or more, or a 2-hour value (glucose concentration in intravenous plasma) of 75 g oral glucose tolerance test (75 g OGTT) Is 200 mg / dl or more, or the non-fasting blood glucose level (glucose concentration in the intravenous plasma) is 200 mg / dl or more. It is also within the scope of the definition of intrinsic diabetes mellitus as described above and may be used to determine whether a fasting blood glucose level (glucose concentration in intravenous plasma) is less than 110 mg / dl or a 2-hour value of 75 g oral glucose tolerance test (75 g OGTT) (Glucose concentration in vein plasma) is less than 140 mg / dl " (steady state) is referred to as " border type ".
[292] Also, with respect to diagnostic criteria for diabetes mellitus, new diagnostic criteria were reported by the American Diabetic Association (ADA) in 1997, and WHO in 1998.
[293] According to the above report, diabetic patients had a fasting blood glucose level (glucose concentration in vein plasma) of 126 mg / dl or more, a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in intravenous plasma) of 200 mg / dl Or more.
[294] In addition, according to the report above, the tolerance to onset of glucose tolerance is defined as the fasting blood glucose level (glucose concentration in intravenous plasma) of less than 126 mg / dl and the 2-hour value of 75 g oral glucose tolerance test (glucose concentration in intravenous plasma) mg / dl to less than 200 mg / dl. According to the ADA report, IFG (fasting glucose deficiency) is defined as a state in which fasting blood glucose level (glucose concentration in intravenous plasma) is less than 110 mg / dl and less than 126 mg / dl. According to the WHO report, the status of IFG (impaired fasting glucose) with a 2-hour value (glucose concentration in intravenous plasma) of less than 140 mg / dl in a 75 g oral glucose tolerance test was compared with IFG : impaired fasting glycemia).
[295] The compounds of the present invention and the pharmaceutical composition of the present invention can be used as preventive or therapeutic agents for diabetes mellitus, borderline type, infertility disorder, IFG (fasting glucose disorder) and IFG (fasting glucose disorder) . In addition, the compounds of the present invention and the pharmaceutical compositions of the present invention can also be used to prevent the progression of borderline type, tolerance disorder, IFG (fasting glucose disorder) or IFG (fasting glucose insufficiency) to diabetes mellitus.
[296] The compounds of the present invention and the pharmaceutical compositions of the present invention may also be used for the treatment and / or prophylaxis of diabetic complications (for example, neuropathy, nephropathy, retinopathy, cataract, giant vasculopathy, osteopenia, diabetic hyperthermia, (Eg, respiratory infections, urinary tract infections, gastrointestinal infections, skin soft tissue infections, inferior limb infections), diabetic gangrene, dry mouth, hearing attenuation, cerebrovascular disease, peripheral circulatory disorders), obesity, osteoporosis, cachexia (Such as cancerous cachexia, tuberculous cachexia, diabetic cachexia, hemicritical disease cachexia, endocrine disease cachexia, infectious cachexia, cachexia caused by acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, For example, diabetic nephropathy, tetraspic nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive neuropathy, end stage renal disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disease (Eg, leukemia, breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory bowel disease, diabetes mellitus, (E.g., osteoarthritis, osteoarthritis, back pain, gout, post-surgical or traumatic inflammation, relief of swelling, neuralgia, sore throat, cystitis, hepatitis Hepatitis), pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis), visceral obesity syndrome, and the like.
[297] Since the compound of the present invention and the pharmaceutical composition of the present invention have a total cholesterol lowering action and enhance the plasma anti-arteriosclerosis index [(HDL cholesterol / total cholesterol) x 100], arteriosclerosis (for example, atherosclerosis) Of the present invention.
[298] In addition, the compounds of the present invention and the pharmaceutical compositions of the present invention can be used to improve the discomfort of stomach ulcers, acute or chronic gastritis, biliary dysentery, or cholecystitis, respectively associated with abdominal pain, nausea, vomiting or mildew.
[299] In addition, the compounds of the present invention and the pharmaceutical compositions of the present invention can control (enhance or inhibit) the appetite and food intake, and thus can be used for the treatment of dry skin and dietary phobia (weight gain when administered to a subject suffering from dry skin or diabetic phobias) Or as a therapeutic agent for obesity.
[300] The compounds of the present invention and the pharmaceutical composition of the present invention can also be used as a prophylactic or therapeutic agent for TNF-α mediated inflammatory diseases. TNF-α mediated inflammatory disease refers to an inflammatory disease that occurs in the presence of TNF-α and can be treated by the inhibition of TNF-α. Examples of such inflammatory diseases include diabetic complications (e.g. retinopathy, neuropathy, neuropathy, macular vasculopathy), rheumatoid arthritis, degenerative spondylitis, osteoarthritis, back pain, gout, postoperative or traumatic inflammation, Neuralgia, sore throat, cystitis, hepatitis, pneumonia, gastric mucosal injury (aspirin-induced gastric mucosal injury).
[301] The compound of the present invention and the pharmaceutical composition of the present invention have apoptosis inhibitory effect and can be used as a preventive or therapeutic agent for diseases mediated by the promotion of apoptosis. Examples of diseases mediated by the promotion of apoptosis include viral diseases (e.g., AIDS, hepatitis A), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, muscular atrophy, scleroderma, retinitis pigmentosa, cerebellum (Eg, hepatitis B, hepatitis C), joint disease (eg, atherosclerosis), atherosclerotic disease (eg, myelodysplastic syndrome) (For example, osteoarthritis), atherosclerosis, and the like.
[302] The compounds of the present invention and the pharmaceutical composition of the present invention are useful for the prevention and treatment of various diseases such as reduction of visceral fat, inhibition of accumulation of visceral fat, recovery of lipid metabolism, recovery of insulin resistance, inhibition of the production of oxidized LDL, The prevention or treatment of cardiovascular complications, the prevention or treatment of cardiovascular complications, the reduction of blood residues, the prevention or treatment of anovulation, the prevention or treatment of hypertelorism, the prevention or treatment of hyperandrogenism, and the like.
[303] The compounds of the present invention and the pharmaceutical compositions of the present invention may be used for the secondary prevention or inhibition of progression of the various diseases described above (e.g. cardiovascular events such as myocardial infarction, etc.).
[304] The compounds of the present invention and the pharmaceutical compositions of the present invention may be used in combination with midazolam, ketoconazole, and the like.
[305] The dosage of the compound of the present invention and the pharmaceutical composition of the present invention may vary depending on the subject to be administered, route of administration, target disease, clinical condition, etc. For example, for oral administration to adult diabetics, That is, a typical dose / dose of the compound of the present invention is about 1 to 100 mg / kg body weight, preferably 0.05 to 10 mg / kg body weight, more preferably 0.1 to 2 mg / kg body weight, It is preferable to administer it three times.
[306] (18) joint use of drugs
[307] The compounds of the present invention can be used for the treatment of diabetes mellitus, diabetic complications, antihyperlipidemic agents, antihypertensive agents, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, osteoporosis agents, anti-dementia agents, Or a treatment for the treatment of diabetes mellitus (hereinafter abbreviated as a co-drug). In this case, the time of administration of the compound of the present invention and the co-drug is not limited. They can be administered to the subject at the same time or at a time. The dose of the co-drug may be appropriately selected on the basis of the dose to be used clinically. The ratio of the compound of the present invention and the co-drug can be appropriately selected according to the administration subject, route of administration, target disease, clinical condition, combination, and other factors. When the subject to be administered is human, for example, the co-drug may be used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.
[308] Examples of therapeutic agents for diabetes mellitus include, but are not limited to, insulin preparations (for example, preparations extracted from the pancreas of cattle or pigs; human insulin preparations synthesized by gene engineering techniques using E. coli or yeast; insulin resistance-improving agents such as pioglitazone Glucosidase inhibitors (for example, hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011 and FK- , Insulin secretagogues (such as sulfonylureas (e.g., tolbutamide (for example, < RTI ID = 0.0 & , Glibenclamide, glyclazide, chloropropamide, tolazamide, acetohexamide, glycopyrimide, glimepiride, glipizide, glybuzole), repaglinide, senaglinide, nateglinide, Gliny (E.g., GLP-1 or its calcium salt hydrate, GLP-1), an amylin agonist (e.g., phamnnitide), a phosphotyrosine phosphatase inhibitor (such as vanadinic acid), a dipeptidyl peptidase IV inhibitor (Eg, NV-DPP-278, PT-100, P32 / 98), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, SB- (Eg, T-BMS-196085, AZ40140), your own inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), SGLT (sodium- 1095).
[309] Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (for example, tolestat, epalrestat, zenarestat, jopolrestat, myalestat, pidestest, SNK-860, CT-112), neurotrophic factor (E.g., NGF, NT-3, BDNF), PKC inhibitors (e.g., LY-333531), AGE inhibitors (e.g., ALT946, pimadine, pyratoxaline, N-phenacylthiazolium bromide (ALT766), EXO-226), active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., thiapuride, mexylin).
[310] Examples of anti-hyperlipidemic agents include statin compounds such as cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their salts (for example, sodium salt), which are cholesterol synthesis inhibitors , Squalene synthesis inhibitors or fibrate compounds having a triglyceride lowering action (for example, benazepibrate, clofibrate, simpibrate, clinopibrate).
[311] Examples of depressants include angiotensin converting enzyme inhibitors (e.g., captopfuril, enalapril, delapril), angiotensin II antagonists (e.g., losartan, candesartan cilexetil, losartan, , Valsartan, thermisartan, irbesartan, tosotaran), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), and clonidine.
[312] Examples of anti-obesity agents include anti-obesity agents that act on the central nervous system (for example, dexfenfluramine, fenfluramine, penttermin, sibutramine, anpepramone, dexamphetamine, margin stone, phenylpropanolamine, clobenzorex) , Pancreatic lipase inhibitors (e.g. orlistat), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 ), Anorexia peptides (e.g., leptin, CNTF (neurotrophic factor), and cholecystokinin agonists (e.g., lentil lift, FPL-15849) do.
[313] Examples of diuretics include, but are not limited to, xanthine derivatives (e.g., Tebremone and sodium salicylate, Teabromine and calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopentadiazide, (Such as thiazide, hydrochlorothiazide, hydrofluorometiazide, benzylhydrochlorothiazide, penflutzide, polythiazide, methiclothiazide), anti-aldosterone preparations (such as spironolactone, triamterene ), A carbonate dehydratase inhibitor (e.g., acetazolamide), a chlorobenzene sulfonamide preparation (e.g., chlortalidone, mefluxide, indapamide), azosemide, isosorbide, Acetic acid, acetic acid, succinic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid,
[314] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents (e.g., cyclophosphamide, ifosamide), metabolic antagonists (e.g., methotrexate, 5-fluorouracil), antitumor antibiotics (e.g., mitomycin, Adriamycin), plant-derived antineoplastic agents (e.g., vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide. Of these, 5-fluorouracil derivatives such as furthuron and neopur tulon are preferred.
[315] Examples of immunotherapeutic agents include, but are not limited to, microbial- or bacterial-derived components (such as muramylmethyl peptide derivatives, fisivanil, immunosuppressive polysaccharides (e.g., lentinan, shichofilament, cresstin), genetically modified cytokines IL-1, IL-2, IL-12, and the like, among which IL-1, IL-2, IL-12, and the like are included in the present invention (for example, interferon, interleukin .
[316] Examples of therapeutic agents for osteoporosis include alpha-calcide, calcitriol, elctatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, and incadronate disodium.
[317] Examples of anti-dementia agents include tacrine, donepezil, ribastigmine, and galantine.
[318] Examples of erectile dysfunction remedies include apomorphine, sildenafil citrate.
[319] Examples of incontinence or pneumonia treatment agents include plastisite hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride.
[320] In addition, the effects of cachexia recovery may be evaluated in animal models or in clinically identified agents, such as cyclooxygenase inhibitors (e.g., indomethacin) (Cancer Research, vol. 49, pp. 5935-5939, Progesterone derivatives (e.g., megestrol acetate) (Journal of Clinical Oncology, vol. 12, pp. 213-225, 1994), glucocorticoids (e.g. dexamethasone), metoclopramide drugs, 68, pp. 314-318, 1993), growth hormone, IGF-1 (e. G., Eicosapentaenoic acid) (British Journal of Cancer, , And antibodies against the cachexia-inducing factors TNF-a, LIF, IL-6 or oncostatin M may be used in combination with the compounds of the present invention.
[321] The co-drug is preferably an insulin preparation, an insulin resistance improving agent, an -Glucosidase inhibitor, a biguanide, an insulin secretion promoting agent (preferably a sulfonylurea) and the like.
[322] The co-drug may be used as a mixture of two or more species of suitable proportions. When two or more co-drugs are used, preferred combinations include:
[323] 1) an insulin resistance improving agent and an insulin preparation;
[324] 2) an insulin resistance improving agent and an insulin secretagogue (preferably a sulfonylurea);
[325] 3) insulin resistance improving agents and -Glucosidase inhibitors;
[326] 4) insulin resistance-improving agents and bigninoids;
[327] 5) insulin resistance improving agents, insulin preparations and bigninoids;
[328] 6) an insulin resistance improving agent, an insulin agent and an insulin secretagogue (preferably a sulfonylurea);
[329] 7) insulin resistance improving agents, insulin preparations and -Glucosidase inhibitors;
[330] 8) Insulin resistance improving agents, insulin secretagogues (preferably sulfonylureas) and biguanides;
[331] 9) an insulin resistance improving agent, an insulin secretagogue (preferably a sulfonylurea) and an -Glucosidase inhibitor; And
[332] 10) Insulin resistance improving agents, biguanides and -Glucosidase inhibitors.
[333] When the compound or pharmaceutical composition of the present invention is used in combination with a co-drug, the amount of each drug can be reduced to a safe range in consideration of their side effects. In particular, the dosage of an insulin resistance-improving agent, an insulin secretagogue (preferably a sulfonylurea) and an angiogenide may be reduced as compared with the usual dosage. Therefore, it is possible to safely prevent side effects that may be caused by the medicament. In addition, the dose of the drug, the anti-hyperlipemia drug and the pressure-reducing agent for diabetic complications can be reduced, so that side effects that can be caused by the drug can be effectively prevented.
[334] (19) Manufacturing method
[335] Methods for preparing compounds of the invention are described below. Since Compound (I) is contained in Compound (II), a method for producing Compound (II) is described.
[336] Compound (II) can be prepared by per se known methods, for example, any of the methods A to F and Method H, or a similar method.
[337] [Method A]
[338]
[339] Wherein Z represents a hydroxy group, a halogen atom or a group represented by the formula OSO ₂ R ¹⁵ wherein R ¹⁵ is an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms Lt; / RTI > Other symbols have the same meaning as above].
[340] Here, the "alkyl group having 1 to 4 carbon atoms" for R ^15, and alkyl groups of 1 to 4 carbon atoms in "an aryl group having 6 to 10 carbon atoms which may be substituted with a C 1 -C 4 alkyl" is methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, sec.-butyl and t-butyl are exemplified, and methyl is preferred.
[341] Examples of the aryl group having 6 to 10 carbon atoms in the "aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms" for R ¹⁵ include phenyl and naphthyl, with phenyl being preferred.
[342] In this way, compound (II) is prepared by the reaction of compound (III) with compound (IV).
[343] When Z is a hydroxy group, this reaction is carried out in a manner known per se, for example, by the method described in Synthesis, p. 1 (1981), or a similar method. That is, such a reaction can be conventionally carried out in the presence of an organic phosphorus compound and an electrophile, in a solvent which does not disturb the reaction.
[344] Examples of organophosphorus compounds include triphenylphosphine and tributylphosphine.
[345] Examples of the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate and azodicarbonyl piperazine.
[346] The amount of the organic phosphorus compound and the electrophile used is preferably about 1 to about 5 molar equivalents relative to compound (IV).
[347] Examples of the solvent that does not disturb the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; Halogenated hydrocarbons such as chloroform and dichloromethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Amides such as N, N-dimethylformamide; And sulfoxides such as dimethylsulfoxide. The solvents may be used as a mixture of suitable ratios.
[348] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[349] The reaction time is usually from about 0.5 to about 20 hours
[350] When Z is a halogen atom or a group of the formula OSO ₂ R ^15, the reaction is carried out in a solvent which does not disturb the presence of base, reaction.
[351] Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate and potassium carbonate; Amines such as pyridine, triethylamine, N, N-dimethylaniline and 1,8-diazobicyclo [5.4.0] undec-7-ene; Metal hydrides such as potassium hydride and sodium hydride, and alkali metal methoxide such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.
[352] The amount of base used is preferably about 1 to about 5 molar equivalents relative to compound (IV).
[353] Examples of the solvent which does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as tetrahydrofuran, dioxane and diethyl ether; Ketones such as acetone and 2-butanone; Halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide; And sulfoxides such as dimethylsulfoxide. These solvents can be used as a mixture of appropriate ratios.
[354] Such a reaction temperature is about -50 to about 150 캜, preferably about -10 to about 100 캜.
[355] The reaction time is usually from about 0.5 to about 20 hours.
[356] The compound (II) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[357] The compounds (III) and (IV) used as starting compounds in the above method A are known compounds. Compound (III) in which Z is a hydroxy group is described, for example, in EP-A 710659. Compound (III) is also described in EP-A 629624 (JP-A-7 (1995) -53555), WO 98/03505 and the like. Further, the compound (III) may be produced by a method similar to the method described in the patent publication.
[358] On the other hand, the compound (IV) can be obtained by, for example, the method described in Journal of Heterocyclic Chemistry, vol. 24, p. 1669 (1987); [Journal of Organic Chemistry, vol. 62, p. 2649 (1997); [Bioorganic & Medicinal Chemistry Letters, vol. 6, p. 1047 (1996)). Compound (IV) can also be prepared by a method similar to that described in the above publication.
[359] (II-2) or (II-3), respectively, wherein R ³ is OR ⁸ and W is -CH═CH- or - (CH ₂ ) ₂ - .
[360] [Method B]
[361]
[362] Wherein the symbols have the same meanings as defined above.
[363] (Step 1)
[364] This reaction is carried out by a conventional method in a solvent which does not interfere with the reaction in the presence of a reducing agent.
[365] Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, and diisobutyl aluminum hydride.
[366] The amount of reducing agent used is preferably about 0.5 to about 10 molar equivalents relative to compound (II-1).
[367] Examples of the solvent that does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as chloroform and dichloromethane; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; water; And alcohols such as methanol, ethanol, and isopropanol. The solvents can be used as a mixture of appropriate ratios.
[368] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[369] The reaction time is usually about 0.5 to about 20 hours.
[370] Compound (V) thus obtained can be isolated and purified by known methods of separation and purification, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[371] The compound (II-1) used as a starting compound in Step 1 of Method B can be produced, for example, by Method A described above. Further, the compound (II-1) can be produced by, for example, a method described in Journal of Heterocyclic Chemistry, vol. 24, p. 1669 (1987); [Journal of Organic Chemistry, vol. 62, p. 2649 (1997); [Bioorganic & Medicinal Chemistry Letters, vol. 6, p. 1047 (1996), or the like.
[372] (Step 2)
[373] The reaction is carried out in a conventional manner in the presence of an oxidizing agent in a solvent which does not interfere with the reaction.
[374] Examples of the oxidizing agent include metal oxidizing agents such as manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, and ruthenium oxide.
[375] The amount of oxidizing agent used is preferably about 1 to about 10 molar equivalents relative to compound (V).
[376] Examples of the solvent that does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; And halogenated hydrocarbons such as chloroform and dichloromethane. The solvents can be used as a mixture of appropriate ratios.
[377] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[378] The reaction time is usually about 0.5 to about 20 hours.
[379] Compound (VI) may also be prepared by adding a reaction reagent such as a sulfur trioxide-pyridine complex or oxalyl chloride to a compound (V) in a solvent mixture of dimethylsulfoxide or dimethylsulfoxide and halogenated hydrocarbons such as chloroform or dichloromethane, , ≪ / RTI > such as triethylamine or N-methylmorpholine.
[380] The amount of the reaction reagent is preferably about 1 to about 10 molar equivalents relative to compound (V).
[381] The amount of organic base used is preferably about 1 to about 10 molar equivalents relative to compound (V).
[382] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[383] The reaction time is usually about 0.5 to about 20 hours.
[384] The compound (VI) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[385] (Step 3)
[386] In this reaction, compound (II-2) is prepared by the reaction of organic phosphorus reagent and compound (VI).
[387] The reaction is carried out in a conventional manner in the presence of a base in a solvent which does not interfere with the reaction.
[388] Examples of the organic phosphorus reagent include methyldimethylphosphonoacetate, ethyldiethylphosphonoacetate, and ethyldimethylphosphonoacetate.
[389] The amount of organic phosphorus reagent used is preferably about 1 to about 10 molar equivalents relative to compound (VI).
[390] Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, and potassium carbonate; Amines such as pyridine, triethylamine, N, N-dimethylaniline, and 1,8-diazobicyclo [5.4.0] undec-7 ene; Metal hydrides such as potassium hydride and sodium hydride; And alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide.
[391] The amount of said base used is preferably about 1 to about 5 molar equivalents relative to compound (VI).
[392] Examples of the solvent that does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; Halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide; And sulfoxides such as dimethylsulfoxide. The solvents can be used as a mixture of appropriate ratios.
[393] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[394] The reaction time is usually about 0.5 to about 20 hours.
[395] Compound (II-2) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[396] (Step 4)
[397] The reaction is carried out in a conventional manner under a hydrogen atmosphere or in the presence of a hydrogen source (e.g., formic acid) and a metal catalyst in a solvent that does not interfere with the reaction.
[398] Examples of metal catalysts include transition metal catalysts such as palladium-carbon, palladium black, platinum oxide, Raney nickel, and Wilkinson's catalyst.
[399] The amount of the transition metal catalyst used is preferably about 0.01 to about 10 molar equivalents relative to compound (II-2).
[400] Examples of the solvent that does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; Halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide; And alcohols such as methanol, ethanol, and isopropanol. The solvents can be used as a mixture of appropriate ratios.
[401] The reaction temperature is usually about -50 to about 150 캜, preferably about -10 to about 100 캜.
[402] The reaction time is usually about 0.5 to about 20 hours.
[403] Compound (II-3) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[404] [Method C]
[405]
[406] Wherein Y 'represents an oxygen atom, a sulfur atom or a group of the formula -NR ⁷ - (wherein R ⁷ has the same meaning as defined above); Other symbols have the same meaning as above].
[407] In this method, compound (II-4) is produced by the reaction of compound (VII) with compound (VIII). The reaction is carried out in the same manner as the reaction of compound (III) with compound (IV) in method A.
[408] The thus obtained compound (II-4) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[409] Compound (VII) used as the starting compound in Method C is a known compound, for example, [Chemical and Pharmaceutical Bulletin, vol. 34, p. 2840 (1986); [Journal of Medicinal Chemistry, vol. 35, p. 2617 (1992); WO 98/03505 and the like. Further, the compound (VII) can be produced by a method similar to the method described in the above-mentioned document.
[410] [Method D]
[411]
[412] Wherein the symbols have the same meanings as above.
[413] In this method, compound (II-6) is prepared by hydrolysis of compound (II-5).
[414] The hydrolysis reaction is carried out in a conventional manner in the presence of an acid or base in a hydrating solvent.
[415] Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, and hydrobromic acid.
[416] Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; Alkali metal alkoxides such as sodium methoxide; And alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and lithium hydroxide.
[417] The amount of acid or base used is usually excessive in comparison with compound (II-5). Preferably, the amount of acid used is about 2 to about 50 equivalents relative to compound (II-5) and the amount of base used is about 1.2 to about 5 equivalents relative to compound (II-5).
[418] Examples of hydrating solvents include alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; A solvent mixture of water and at least one solvent selected from dimethylsulfoxide and acetone.
[419] The reaction temperature is usually about -20 to about 150 캜, preferably about -10 to about 100 캜.
[420] The reaction time is usually about 0.1 to about 20 hours.
[421] Compound (II-6) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[422] Compound (II-5) used as the starting material in Method D above is prepared, for example, by the above methods A to C.
[423] Compound (II-7) having NR ⁹ R ¹⁰ as R ³ in the formula (II) can also be prepared by the following method E.
[424] [Method E]
[425]
[426] Wherein the symbols have the same meanings as above.
[427] In this method, compound (II-7) is prepared by amidation of compound (II-6). This reaction is carried out by a known method itself, for example, a method in which the compound (II-6) and the compound (IX) are directly condensed by a condensing agent (for example, dicyclohexylcarbodiimide) A method in which the reactive derivative is reacted with the compound (IX), and the like. Examples of the reactive derivative of the compound (II-6) include acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides or mixed acid anhydrides (e.g., methoxycarboxylic acid, ethoxycarboxylic acid, Or an anhydride with isobutoxycarboxylic acid).
[428] When an acid halide is used, for example, the reaction is carried out in the presence of a base in a solvent which does not interfere with the reaction.
[429] Examples of the base include triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, and potassium carbonate.
[430] Examples of the solvent that does not disturb the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; Aromatic hydrocarbons such as benzene and toluene; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; Ethyl acetate, and water. The solvents can be used as a mixture of appropriate ratios.
[431] The amount of the compound (IX) to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to the compound (II-6).
[432] The reaction temperature is usually -30 to 100 占 폚.
[433] The reaction time is usually 0.5 to 20 hours.
[434] When a mixed acid anhydride is used, the compound (II-6) and the chlorocarboxylic acid ester (for example, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) For example, triethylamine, N-methylmorpholine, N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate) and further reacted with compound (IX).
[435] The amount of the compound (IX) to be used is usually 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to the compound (II-6).
[436] The reaction temperature is usually -30 to 100 占 폚.
[437] The reaction time is usually 0.5 to 20 hours.
[438] Compound (II-7) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[439] The compound (II-6) used as the starting compound in the above method E is prepared, for example, by the above methods A to D.
[440] [Method F]
[441]
[442] [Wherein X ² represents an oxygen atom, a sulfur atom or a group of the formula: -NR ¹⁶ - (wherein R ¹⁶ has the same meaning as defined above); Z ¹ represents a group of a hydroxy group, a halogen atom or a group of the formula OSO ₂ R ¹⁷ (wherein R ¹⁷ represents an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms); Other symbols have the same meaning as above].
[443] "Alkyl group of 1 to 4 carbon atoms" for R ^17, and "C 1 -C aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group of 4" is exemplified roneun things mentioned to illustrate the above R ^15.
[444] In this method, compound (II-9) is prepared by the reaction of compound (II-8) with compound (XI). The reaction is carried out in the same manner as the reaction of compound (III) with compound (IV) in method A.
[445] The thus obtained compound (II-9) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[446] Compound (II-8) used as the starting compound in Method F above can be obtained, for example, in Bioorganic & Medicinal Chemistry Letters, vol. 6, p. 1047 (1996)), or the like. Furthermore, the compound (II-8) can also be produced by the above methods A to E.
[447] Compound (VIII) used as the starting compound in Method C can be prepared, for example, by the following Method G.
[448] [Method G]
[449]
[450] Wherein the symbols have the same meanings as above.
[451] The reaction is carried out in the same manner as the reaction of compound (III) with compound (IV) in method A. The condensation reaction can be carried out by protecting the -Y'H moiety which can be deprotected after the reaction of compound (X). Useful protecting groups include a benzyl group, a methoxymethyl group, and a silyl group (e.g., trimethylsilyl group, tert-butyldimethylsilyl group).
[452] Compound (II-10) having OH for R ³ in formula (II) and -CH ₂ - for W can also be prepared by the following method H.
[453] [Method H]
[454]
[455] Wherein the symbols have the same meanings as above.
[456] (Step 5)
[457] Compound (XII) can be produced by reacting compound (VI) and p-toluenesulfonylmethylisocyanide in the presence of a base such as potassium t-butoxide, sodium hydride, and lithium hydride in a solvent that does not interfere with the reaction Can be produced by performing alcohol decomposition.
[458] The amount of p-toluenesulfonylmethylisocyanide used is preferably about 0.5 to about 10 molar equivalents relative to compound (VI).
[459] The amount of base used is preferably about 0.5 to about 20 molar equivalents relative to compound (VI).
[460] Examples of alcohols used for alcoholysis include methanol, ethanol, propanol, butanol, and isopropanol.
[461] Examples of the solvent that does not disturb the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as chloroform and dichloromethane; And ethers such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane. The solvents can be used as a mixture of appropriate ratios.
[462] The reaction temperature is usually about -100 to about 150 캜, preferably about -80 to about 100 캜.
[463] The reaction time is usually about 0.5 to about 20 hours.
[464] The compound (XII) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[465] Compound (VI) used as a starting compound in Step 5 of Method H can be prepared, for example, by Step 2 of Method B above.
[466] (Step 6)
[467] In this method, compound (II-10) is prepared by hydrolyzing compound (XII).
[468] The hydrolysis reaction is carried out in a conventional manner in the presence of an acid or base in a hydrating solvent.
[469] Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, and hydrobromic acid.
[470] Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate; Alkali metal alkoxides such as sodium methoxide; And alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and lithium hydride.
[471] The amount of acid or base used is usually excessive relative to compound (XII). Preferably, the amount of acid used is about 2 to about 50 equivalents relative to compound (XII) and the amount of base used is about 1.2 to about 5 equivalents relative to compound (XII).
[472] Examples of hydrating solvents include alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran, dioxane, and diethyl ether; A solvent mixture of water and at least one solvent selected from dimethylsulfoxide and acetone.
[473] The reaction temperature is usually about -20 to about 150 캜, preferably about -10 to about 100 캜.
[474] The reaction time is usually about 0.1 to about 20 hours.
[475] Compound (II-10) thus obtained can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
[476] When the starting compound has amino, carboxy, hydroxy, or carbonyl as a substituent in each of the reactions described above, the groups may have a protecting group commonly used in peptide chemistry and other fields introduced thereinto. If desired, the desired compound can be obtained by removing the protecting group after the reaction.
[477] Examples of protecting groups for amino include C _1-6 alkyl-carbonyl (e.g., acetyl, propionyl), C _1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar (E.g. benzyl, tert-butoxycarbonyl), benzoyl, _C7-10 aralkyl-carbonyl (for example benzylcarbonyl), _C7-14 aralkoxy-carbonyl (for example benzyloxycarbonyl, (For example, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, Butyl diethylsilyl), and C _2-6 alkenyl (e.g., 1-allyl). The group may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C _1-6 alkoxy (e.g., methoxy, ethoxy, propoxy)
[478] Examples of protecting groups for carboxy include C _1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), C _7-11 aralkyl (e.g., benzyl) Butyldimethylsilyl, tert-butyldimethylsilyl), and C _2-6 alkenyl (e.g., 1-allyl) can be used in the presence of a base such as triethylsilyl, triethylsilyl, triethylsilyl, dimethylphenylsilyl, . The group may be substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C _1-6 alkoxy (e.g., methoxy, ethoxy, propoxy)
[479] Examples of protecting groups for hydroxy include C _1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, C _7-10 aralkyl Benzyl), formyl, C _1-6 alkyl-carbonyl (for example acetyl, propionyl), benzoyl, C _7-10 aralkyl-carbonyl (for example benzylcarbonyl) Butyldimethylsilyl, tert-butyldiethylsilyl), and C _2-6 alkenyl (e.g., trimethylsilyl, trimethylsilyl, dimethylphenylsilyl, For example, 1-allyl). The group is optionally substituted with 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C _1-6 alkyl (e.g. methyl, ethyl, propyl), C _1-6 alkoxy Methoxy, ethoxy, propoxy), nitro, and the like.
[480] Examples of protecting groups for carbonyl include cyclic acetals (e.g., 1,3-dioxane) and acyclic acetals (e.g., di-C _1-6 alkyl acetals).
[481] The protecting groups may also be removed in a manner known per se, for example, by the methods described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980). For example, an acid, base, ultraviolet, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethyl Silyl bromide) or the like, a reduction method and the like can be used.
[482] When the compound (II) contains an optical isomer, stereoisomer, regioisomer, or rotamer, the isomers are also included in the compound (II) and can be obtained as a single substance by the known method of synthesis or separation, . For example, when an optical isomer is present in compound (II), an optical isomer separated from the compound is also included in compound (II).
[483] Optical isomers can be prepared by methods known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically separating a racemate of the final product in a conventional manner.
[484] Examples of optical separation methods include known methods themselves, such as fractional recrystallization methods, chiral column methods, and diastereoisomeric methods.
[485] 1) fractional recrystallization method
[486] (-) - mandelic acid, (+) - tartaric acid, (-) - tartaric acid, (+) - 1-phenethylamine, ) -I-phenethylamine, cinchinine, (-) - cinchonidine, brusin], the salt is separated by fractional recrystallization and the like, and, if desired, is subjected to a neutralization step to obtain a glass optical isomer How to.
[487] 2) Chiral column method
[488] Wherein the racemate or its salt is applied to a column (chiral column) for optical isomer separation. In the case of liquid chromatography, for example, the optical isomers can be prepared by adding the optical isomer mixture to a chiral column such as ENANTIO-OVM (Tosoh Corporation) or chiral series (DAICEL Chemical IND.), For example, a phosphate buffer solution), an organic solvent (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine), or a mixture of solvents thereof. In the case of gas chromatography, for example, chiral columns such as CP-Chirasil-DeX CB (manufactured by GL Science) are used to separate the optical isomers.
[489] 3) diastereomeric method
[490] The racemic mixture and the optically active reagent are chemically reacted to yield a diastereomeric mixture, followed by conventional separation methods (e. G., Fractional recrystallization, chromatography) to yield a single material, Acid hydrolysis to remove the optically active reagent moiety to obtain the desired optical isomer. For example, where the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound, an optically active organic acid (such as MTPA [ -Methoxy- - (trifluoromethyl) Phenylacetic acid], (-) - menthoxyacetic acid) and the like are condensed to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxyl group, the above compound and an optically active amine or alcohol reagent are condensed to obtain amide or diastereomer of an ester, respectively. The separated diastereoisomeric acid is subjected to hydrolysis or base hydrolysis to convert it into its optical isomer.
[491] The present invention will be described in more detail by way of the following Test Examples, Reference Examples, Examples and Preparation Examples, but the present invention is not limited thereto. In the following Reference Examples and Examples,% means weight percentage unless otherwise stated. Room temperature means a temperature of 1 to 30 캜.
[492] The bases, amino acids and other abbreviations used herein are based on the abbreviations specified in the IUPAC-IUB Commission on Biochemical Nomenclature or the abbreviations commonly used in the field. Some examples are shown below. Where an optical isomer can be present in an amino acid, it is in an L-stereoconstitution unless otherwise stated.
[493] In the present specification, the sequence numbers of the sequence listing show the corresponding sequences below.
[494] [SEQ ID NO: 1]
[495] The nucleotide sequence of the primer PAG-U used in Reference Example 1 is shown.
[496] [SEQ ID NO: 2]
[497] The base sequence of the primer PAG-L used in Reference Example 1 is shown.
[498] [SEQ ID NO: 3]
[499] The nucleotide sequence of the primer XRA-U used in Reference Example 2 is shown.
[500] [SEQ ID NO: 4]
[501] The nucleotide sequence of the primer XRA-L used in Reference Example 2 is shown.
[502] [SEQ ID NO: 5]
[503] The nucleotide sequence of the primer PPRE-U used in Reference Example 4 is shown.
[504] [SEQ ID NO: 6]
[505] The nucleotide sequence of the primer PPRE-L used in Reference Example 4 is shown.
[506] [SEQ ID NO: 7]
[507] The nucleotide sequence of the primer TK-U used in Reference Example 4 is shown.
[508] [SEQ ID NO: 8]
[509] The nucleotide sequence of the primer TK-L used in Reference Example 4 is shown.
[510] Test Example 1
[511] Reduction of blood sugar and lipid lowering effect in mice
[512] The test compound was dissolved in a 0.01% (compound of Example 12, 30, 89, 186), 0.005% (Example 7,80,82,181,182,184,256,262 , 283), 0.001% (compounds of Examples 9, 104, 110, 155, 156, 160, 167, 169, 172, 174, 176, 189), or 0.0003% Compound) and fed free of diet for 4 days in obese and KKA ^y mice of the type 2 diabetes model (9 to 12 weeks, 5 mice per group). During this period, water was also fed free. The blood was sampled from the orbit and the level of glucose and triglycerides in plasma isolated from the blood was measured using L-type Wako Glu2 (Wako Pure Chemical Industries, Ltd.) or L-type Wako TG.H (Wako Pure Chemical Industries, Ltd.) Were measured by using enzymes. The results are shown in Table 1.
[513] In the table, the values for each treatment group are expressed as the percentage reduction compared to the untreated group.
[514]
[515] These results indicate that the compounds of the present invention have strong hypoglycemic and lipid lowering effects. Therefore, it is proved that the compounds are useful as preventive or therapeutic agents for diabetes, hyperlipidemia (especially hypertriglyceridemia), tolerance to glucose, and the like.
[516] Test Example 2
[517] Total cholesterol lowering effect and plasma anti-arteriosclerosis index-enhancing effect in mouse
[518] The test compound was dissolved in a 0.01% (compound of Example 12, 30, 89), 0.005% (compound of Example 38, 40, 44, 181, 184, 262, 283) in powder feed (CE- Or 0.001% (compounds of Examples 9, 156, 167, 172, 174, 176, 189), and were administered to obese and type 2 diabetes models, KKA ^y mice (9-12 weeks old, ) For 4 days. During this period, water was also fed free. Blood was sampled from the orbit and the plasma was isolated. Total cholesterol levels were measured using L-type Wako Cholesterol (Wako Pure Chemical Industries, Ltd.). The precipitation reagent for apoB containing lipoproteins was added to a portion of plasma to precipitate non-HDL lipoproteins and the cholesterol (HDL cholesterol) in the resulting supernatant was measured. By the above cholesterol level, a plasma anti-arteriosclerosis index [(HDL cholesterol / total cholesterol) x 100] was calculated. The results are shown in Table 2.
[519] In the table, " total cholesterol lowering activity (%) " indicates a percentage reduction (%) of the total cholesterol level in the treatment group when the total cholesterol level in the untreated group is taken as 100%. "Plasma anti-arteriosclerosis index-enhancing effect (%)" indicates an increase percentage (%) of the plasma anti-arteriosclerosis index in the treated group when the plasma anti-arteriosclerosis index in the untreated group was taken as 100% .
[520]
[521] These results indicate that the compounds of the present invention possess a total cholesterol lowering and plasma anti-arteriosclerosis index-enhancing effect. Thus, compounds have proven useful as a preventive or therapeutic agent for arteriosclerosis by improving the plasma lipoprotein profile of hypercholesterolemia and / or low-HDL-cholesterol.
[522] Test Example 3
[523] (PPARγ-RXRα heterodimeric ligand activity)
[524] After incubation in HAM F12 medium (manufactured by NISSUISEIYAKU) containing 10% fetal bovine serum (manufactured by Life Technologies, Inc. (USA)), PPARγ: RXRα: 4 ERPP / CHO- Well plate (Corning Costar Corporation (USA)) at a density of 10 ⁴ cells / well and incubated overnight in a 37 ° C CO ₂ gas incubator.
[525] After washing the 96-well white plate with PBS (phosphate-buffered saline), 90 쨉 l of HAM F12 medium containing 0.1% non-fatty acid bovine serum albumin (BSA) and 10 쨉 l of the test compound were added and incubated in a 37 째 C CO ₂ gas incubator for 48 Lt; / RTI > After the medium was removed, 40 μl of PIKKAGENE 7.5 (manufactured by Wako Pure Chemical Industries, Ltd.) was added. After stirring, luciferase activity was measured using Lumistar (BMG Labtechnologies GmbH (Germany)).
[526] The luciferase activity in the untreated group was set at 1 and the fold induction was calculated based on the luciferase activity of each test compound. The test compound concentration values and the multiplication factor were analyzed using PRISM 2.01 (GraphPad Software Inc. (USA)) to calculate the EC ₅₀ value, the effective concentration of the test compound to obtain 50% of the maximum doubling induction. Table 3 shows the results.
[527]
[528] The results indicate that the compounds of the present invention have potent PPARγ-RXRα heterodimeric ligand activity.
[529] Reference Example 1
[530] (Human PPAR gamma gene cloning)
[531] PCR method using the primer set shown below, which was prepared with reference to the nucleotide sequence of the PPAR gamma gene reported in Greene et al. (Gene Expr., 1995, Vol.4 (4-5), pages 281 to 299) , And human PPAR gamma gene was cloned using heart cDNA (manufactured by Toyobo Co., Ltd., trade name: QUICK-Clone cDNA) as a template.
[532] PAG-U: 5'-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3 '(SEQ ID NO: 1)
[533] PAG-L: 5'-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3 '(SEQ ID NO: 2)
[534] The PCR reaction was carried out by Hot Start method using AmpliWax PCR Gem 100 (manufactured by TAKARA SHUZO CO., LTD.). First, 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterilized distilled water were mixed to obtain a bottom layer solution mixture. 1 μl of human heart cDNA (1 ng / ml) as templates, 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mM dNTP, 0.5 μl of TaKaRa LA Taq DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.), 24.5 [mu] l were mixed to obtain an upper layer solution mixture.
[535] To the above-described bottom layer solution mixture, 1 unit of AmpliWax PCR Gem 100 (manufactured by TAKARA SHUZO CO., LTD.) Was added and treated for 5 minutes on ice after 5 minutes at 70 ° C. The mixture of upper layer solutions was then added to the mixture to prepare a PCR reaction mixture. The tube containing the reaction mixture was set in a heat cycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating 35 cycles of 95 ° C for 15 seconds and 68 ° C for 2 minutes, the tubes were treated at 72 ° C for 8 minutes.
[536] The thus-obtained PCR product was electrophoresed on agarose gel (1%), and a 1.4 kb DNA fragment containing the PPARγ gene was recovered from the gel, and pT7 Blue-T vector (manufactured by TAKARA SHUZO CO., LTD. To obtain a plasmid pTBT-hPPAR .
[537] Reference Example 2
[538] (Human RXR alpha gene cloning)
[539] By a PCR method using the following primer set, which was prepared with reference to the nucleotide sequence of the RXRα gene reported in Mangelsdorf, DJ et al. (Nature, 1990, Vol. 345 (6272), pages 224 to 229) The human RXRa gene was cloned using renal cDNA (manufactured by Toyobo Co., Ltd., trade name: QUICK-Clone cDNA).
[540] XRA-U: 5'-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3 '(SEQ ID NO: 3)
[541] XRA-L: 5'-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3 '(SEQ ID NO: 4)
[542] The PCR reaction was carried out by the hot start method using AmpliWax PCR Gem 100 (manufactured by TAKARA SHUZO CO., LTD.). First, 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterilized distilled water were mixed to obtain a bottom layer solution mixture. 1 占 퐇 of human kidney cDNA (1 ng / ml) as template, 3 占 퐇 of 10 占 LA PCR buffer, 1 占 퐇 of 2.5 mM dNTP, 0.5 占 퐇 of TaKaRa LA Taq DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.), 24.5 [mu] l were mixed to obtain an upper layer solution mixture.
[543] To the above-described bottom layer solution mixture, 1 unit of AmpliWax PCR Gem 100 (manufactured by TAKARA SHUZO CO., LTD.) Was added and treated for 5 minutes on ice after 5 minutes at 70 ° C. The mixture of upper layer solutions was then added to the mixture to prepare a PCR reaction mixture. The tube containing the reaction mixture was set in a heat cycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating 35 cycles of 95 ° C for 15 seconds and 68 ° C for 2 minutes, the tubes were treated at 72 ° C for 8 minutes.
[544] The PCR product thus obtained was subjected to electrophoresis on agarose gel (1%), and a 1.4 kb DNA fragment containing the RXRα gene was recovered from the gel, and pT7 Blue-T vector (manufactured by TAKARA SHUZO CO., LTD. To obtain a plasmid pTBT-hRXR .
[545] Reference Example 3
[546] (Construction of Plasmids Expressing Human PPARgamma, RXRa)
[547] The 7.8 kb FspI-NotI fragment of the plasmid pVgRXR (Invitrogen (USA)) was ligated to a 0.9 kb FspI-NotI fragment containing the RXRa gene of the plasmid pTBT-hRXRα obtained in Reference Example 2. Subsequently, pVgRXR2 was digested with BstXI and then treated with T4 DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.) To obtain a blunt end. Subsequently, cleavage at KpnI yielded a 6.5 kb DNA fragment.
[548] On the other hand, the plasmid pTBT-hPPAR Obtained in Reference Example 1 was digested with Sal I and treated with T4 DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.) To obtain a blunt end. Followed by digestion with KpnI to obtain a 1.4 kb DNA fragment containing the human PPARy gene.
[549] Two DNA fragments were ligated to construct the plasmid pVgRXR2-hPPARγ.
[550] Reference Example 4
[551] (Construction of Reporter Plasmid)
[552] A DNA fragment containing the PPAR-reactive element (PPRE) of acyl CoA oxidase was prepared using the following 5'-terminal phosphorylated synthetic DNA.
[553] PPRE-U: 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3 '(SEQ ID NO: 5)
[554] PPRE-L: 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3 '(SEQ ID NO: 6)
[555] Primarily, PPRE-U and PPRE-L were annealed and inserted into the Sal I site of plasmid pBlue Script SK +. The nucleotide sequence of the inserted fragment was determined, and the plasmid pBSS-PPRE4 ligated in a line of 4 PPREs was selected.
[556] PCR using the primers shown below, prepared with reference to the nucleotide sequence of the promoter region of thymidine kinase reported in Luckow, B et al. (Nucleic Acids Res., 1987, Vol. 15 (13), p. , The HSV thymidine kinase promoter (TK promoter) region was cloned using the pRL-TK vector (Promega (USA)) as a template.
[557] TK-U: 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3 '(SEQ ID NO: 7)
[558] TK-L: 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3 '(SEQ ID NO: 8)
[559] The PCR reaction was carried out by the hot start method using AmpliWax PCR Gem 100 (TAKARA SHUZO CO., LTD.). First, 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10 μl of sterilized distilled water were mixed to obtain a bottom layer solution mixture. 1 μl of the template pRL-TK (Promega (USA)), 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mM dNTP, 0.5 μl of TaKaRa LA Taq DNA polymerase (manufactured by TAKARA SHUZO CO., LTD. 24.5 [mu] l of sterile distilled water was mixed to obtain an upper layer solution mixture.
[560] To the above-described bottom layer solution mixture, 1 unit of AmpliWax PCR Gem 100 (manufactured by TAKARA SHUZO CO., LTD.) Was added and treated for 5 minutes on ice after 5 minutes at 70 ° C. The mixture of upper layer solutions was then added to the mixture to prepare a PCR reaction mixture. The tube containing the reaction mixture was set in a heat cycler (Perkin Elmer, USA) and treated at 95 ° C for 2 minutes. After repeating 35 cycles of 95 ° C for 15 seconds and 68 ° C for 2 minutes, the tubes were treated at 72 ° C for 8 minutes.
[561] The PCR product thus obtained was subjected to electrophoresis on agarose gel (1%), a 140 b DNA fragment containing the TK promoter was recovered from the gel, and pT7 Blue-T vector (manufactured by TAKARA SHUZO CO., LTD. Lt; / RTI > The thus obtained plasmid was digested with restriction enzymes Bg1II and NcoI to obtain a fragment containing the TK promoter and ligated to the Bg1II-NcoI fragment of the plasmid pGL3-basic vector (Promega (USA)) to obtain the plasmid pGL3-TK ≪ / RTI >
[562] The 4.9 kb NheI-XhoI fragment of plasmid pGL3-TK thus obtained was ligated to the 200 b NheI-XhoI fragment of plasmid pBSS-PPRE4 to obtain plasmid pGL3-4 ERPP-TK.
[563] The thus obtained plasmid pGL3-4ERPP-TK was digested with BamHI (manufactured by TAKARA SHUZO CO., LTD.) And then treated with T4 DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.) To form a blunt end, DNA fragments were obtained.
[564] On the other hand, a blunt end was formed by digesting pGFP-C1 (manufactured by Toyobo Co., Ltd.) with Bsu36I (NEB) and then treating with T4 DNA polymerase (manufactured by TAKARA SHUZO CO., LTD.), ≪ / RTI >
[565] The two DNA fragments were ligated to obtain the reporter plasmid pGL3-4 ERPP-TK neo.
[566] Reference Example 5
[567] (Insertion of Human PPARγ- and RXRα-Expression Plasmid and Reporter Plasmid into CHO-K1 Cells and Construction of Expression Cells)
[568] CHO-K1 cultured in a 750 mL tissue culture flask (manufactured by Corning Costar Corporation (USA)) containing 10% fetal bovine serum (manufactured by Life Technologies, Inc. (USA)) containing HAM F12 medium (manufactured by NISSUI SEIYAKU) Cells were scraped by treatment with 0.5 g / L trypsin-0.2 g / L EDTA (Ethylenediaminetetraacetic acid) (Life Technologies, Inc. (USA)) and then cells were resuspended in PBS (phosphate-buffered saline) (USA)), centrifuged (1000 rpm, 5 minutes), and suspended in PBS. Subsequently, the DNA was introduced into the cells using the gene PULSER (Bio-Rad Laboratories (USA)) under the following conditions.
[569] That is, 8 x 10 ⁶ cells and 10 μg of the plasmid pVgRXR2-hPPARγ obtained in Reference Example 3 and 10 μg of the reporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 4 were added to the cuvette at intervals of 0.4 cm, and 960 μF Lt; RTI ID = 0.0 > 0.25 kV. ≪ / RTI > Then, the cells were transferred to HAM-F12 medium containing 10% fetal bovine serum and cultured for 24 hours. The cells were then re-scraped and centrifuged, and then transferred to 500 μg / ml geneticin (Life Technologies, Inc.). (USA)) and HEM F12 medium containing 10% fetal bovine serum supplemented with 250 μg / ml of Zeocin (manufactured by ZEOCIN, Invitrogen (USA)) and diluted to a density of 10 ⁴ cells / Well plates (manufactured by Corning Costar Corporation (USA)), and cultured in a 37 ° C CO ₂ gas incubator to obtain GENETICIN- and ZEOCIN-resistant transformants.
[570] Then, the thus obtained transformant cell line was cultured in a 24-well plate (manufactured by Corning Costar Corporation (USA)), and the cell line expressed and induced with luciferase by the addition of 10 μM of pioglitazone hydrochloride, that is, PPARγ: RXRα: 4 ERPP / CHO-K1 cells were selected.
[571] Reference Example 6
[572] Lithium aluminum hydride (2.53 g) was added to a solution of methyl 1- (4-benzyloxybenzyl) -4-phenylpyrrole-3-carboxylate (21.52 g) in tetrahydrofuran (100 ml) , And the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (30.00 g) and hexane (100 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain [1- (4-benzyloxybenzyl) -4-phenyl-3-pyrrolyl] methanol (19.68 g, yield: 98%) was dissolved in ethyl acetate- Lt; / RTI > as a colorless crystal. This was recrystallized from ethyl acetate-hexane. Melting point: 122 - 123 캜.
[573] Reference Example 7
[574] A mixture of [1- (4-benzyloxybenzyl) -4-phenyl-3-pyrrolyl] methanol (19.00 g), active manganese dioxide (41.19 g), and tetrahydrofuran (300 ml) was stirred at room temperature overnight . The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1- (4-benzyloxybenzyl) -4-phenylpyrrole-3-carbaldehyde (18.56 g, yield: 98%) in ethyl acetate- ) ≪ / RTI > as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 100 - 101 캜.
[575] Reference Example 8
[576] A mixture of ethyl (E) -3- [1- (4-benzyloxybenzyl) -4-phenyl-3-pyrrolyl] propanoate (19.50 g), 5% palladium- 200 mL) was stirred under hydrogen atmosphere at room temperature overnight. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (14.92 g, yield: 96% 1: 2, volume ratio) as an oily substance.
[577] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.44-2.58 (2H, m), 2.88-3.02 (2H, m), 4.08 (2H, q, J = 7.0 Hz), 4.93 (2H, s), 6.46-6.54 (1H, m), 6.66-6.84 (3H, m), 7.02-7.12 (2H, m), 7.14-7.44 (5H, m).
[578] Reference Example 9
[579] Lithium aluminum hydride (232 mg) was added to a solution of methyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4-phenylpyrrole- Ethyl ether (50 ml), and tetrahydrofuran (25 ml) at 0 ° C, and the mixture was stirred at 0 ° C for 3 hours. After water was added to the reaction mixture, the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel chromatography to obtain 2.37 g of [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] 86%) was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (2: 3, by volume).
[580] _{NMR (CDCl 3) δ: 2.43} (3H, s), 4.64 (2H, s), 4.99 (4H, s like), 6.73-6.77 (1H, m), 6.80-6.83 (1H, m), 7.04 (2H , d, J = 8.6Hz), 7.12-7.56 (10H, m), 7.98-8.04 (2H, m).
[581] Reference Example 10
[582] Benzyl] -4-phenyl-3-pyrrolyl] methanol (3.98 g), active manganese dioxide (8.00 g), and toluene ( 50 mL) was stirred at 80 < 0 > C for 10 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2.85 g of 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4-phenylpyrrole- 72%) was obtained as colorless crystals from the eluted fractions in ethyl acetate-hexane (2: 3, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 117 - 118 캜.
[583] Reference Example 11
[584] Lithium aluminum hydride (305 mg) was added at 0 ° C to a solution of methyl 1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl- -Phenyl-3-pyrrole carboxylate (1.78 g) in dichloromethane, and the mixture was stirred at room temperature for 6 hours. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain [1- [4- [2- [N-methyl- [N- (2-pyridyl) amino ] Ethoxy] benzyl] -4-phenyl-3-pyrrolyl] methanol (1.45 g, yield 87%) as an oily substance.
[585] _{NMR (CDCl 3) δ: 1.35-1.5} (1H, m), 3.15 (3H, s), 3.99 (2H, t, J = 5.5 Hz), 4.18 (2H, t, J = 5.5 Hz), 4.63 (2H d, J = 4.5 Hz), 4.96 (2H, s), 6.45-6.6 (2H, m), 6.73 (2H, d, J = 9.0 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.15-7.6 (6H, m), 8.1-8.2 (1H, m).
[586] Reference Example 12
[587] Benzyl] -4-phenyl-3-pyrrolyl] methanol (1.45 g), active manganese dioxide (4.0 g, ) And tetrahydrofuran (60 ml) was stirred for 3 hours at room temperature. The manganese dioxide was removed by filtration and the filtrate was concentrated to obtain 1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] Carbaldehyde (1.40 g, yield 97%) as an oily substance.
[588] _{NMR (CDCl 3) δ: 3.15} (3H, s), 3.99 (2H, t, J = 5.5 Hz), 4.19 (2H, t, J = 5.5 Hz), 5.02 (2H, s), 6.45-6.6 (2H (2H, d, J = 8.5 Hz), 7.2-7.5 (7H, m), 8.1 (2H, d, J = -8.2 (1 H, m), 9.84 (1 H, s).
[589] Reference Example 13
[590] Lithium aluminum hydride (0.258 g) was added to a solution of methyl 1- (6-benzyloxy-2-naphthylmethyl) -4-phenylpyrrole-3-carboxylate (3.04 g) in tetrahydrofuran (30 ml) And the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (2.19 g) and hexane (30 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to give [1- (6-benzyloxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] methanol (2.54 g, yield 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 116-117 [deg.] C.
[591] Reference Example 14
[592] A mixture of 2.39 g of [1- (6-benzyloxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] methanol, 4.80 g of active manganese dioxide and 50 ml of tetrahydrofuran was stirred for 1 hour Lt; / RTI > The manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to give l- (6-benzyloxy-2-naphthylmethyl) -4-phenylpyrrole-3-carbaldehyde (2.24 g, yield: 94%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 140-141 占 폚.
[593] Reference Example 15
[594] A mixture of ethyl (E) -3- [1- (6-benzyloxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] propanoate (1.46 g), 5% palladium- A mixture of ethanol (15 ml) and tetrahydrofuran (50 ml) was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- (6-hydroxy-2-naphthylmethyl) -4-phenyl-3 -Pyrrolyl] propanoate (1.08 g, yield 90%) as an oily substance.
[595] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.2 Hz), 2.53 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.6 Hz), 4.07 (2H, q, J = 7.2 Hz), 5.10 (2H, s), 5.57 (1H, br.s), 6.55 (1H, d, J = 2.4 Hz), 6.76 (1H, d, J = 2.4 Hz), 7.07-7.45 , < / RTI > m), 7.54 (1H, s), 7.60-7.71 (2H, m).
[596] Reference Example 16
[597] Lithium aluminum hydride (0.25 g) was added to a solution of ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4- (2- Pyridyl) pyrrole-3-carboxylate (2.40 g) in DMF (5 ml) and the mixture was stirred at 0 <0> C for 30 min. Sodium sulfate decahydrate (2.13 g) and hexane (30 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] - (2-pyridyl) -3-pyrrolyl] methanol (2.09 g, yield: 95%) as an oily substance.
[598] _{NMR (CDCl 3) δ: 2.44} (3H, s), 4.55 (2H, s), 4.99 (4H, s), 6.68 (1H, d, J = 2.2 Hz), 6.94-7.22 (6H, m), 7.36 -7.69 (5H, m), 7.96-8.08 (2H, m), 8.46-8.53 (1H, m).
[599] Reference Example 17
[600] Benzyl] -4- (2-pyridyl) -3-pyrrolyl] methanol (2.01 g), active manganese dioxide (5.09 g) And tetrahydrofuran (50 ml) was stirred at room temperature overnight. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] - 4- (2-pyridyl) pyrrole-3-carbaldehyde (1.71 g, yield: 85%) was obtained as an oily substance.
[601] _{NMR (CDCl 3) δ: 2.44} (3H, s), 5.00 (2H, s), 5.06 (2H, s), 6.96-7.28 (6H, m), 7.38-7.49 (4H, m), 7.62-7.74 ( 1H, m), 7.79-7.86 (1H, m), 7.96-8.08 (2H, m), 8.54-8.60 (1H, m), 10.16 (1H, s).
[602] Reference Example 18
[603] Methanesulfonyl chloride (5.03 ml) was slowly added to a mixture of 3,5-dibenzyloxybenzyl alcohol (16.0 g), triethylamine (9.06 ml) and tetrahydrofuran (200 ml) Lt; / RTI &gt; The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 3,5-dibenzyloxybenzylmethanesulfonate (22.20 g, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85-86 캜.
[604] Reference Example 19
[605] Lithium aluminum hydride (1.97 g) was added to a solution of methyl 1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrole carboxylate (26.2 g) in tetrahydrofuran (250 ml) And the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (16.1 g) and hexane (250 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] methanol (24.20 g, yield: 98%). This was recrystallized from ethyl acetate-hexane. Melting point: 115-116 [deg.] C.
[606] Reference Example 20
[607] A mixture of 23.8 g of [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] methanol, 50.00 g of active manganese dioxide and 200 ml of tetrahydrofuran was stirred at room temperature Lt; / RTI &gt; The manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain [1- (3,5-dibenzyloxybenzyl) -4-phenylpyrrole-3-carbaldehyde (23.10 g, yield: 97%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 117-118 [deg.] C.
[608] Reference Example 21
[609] A mixture of ethyl (E) -3- [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] propanoate (19.0 g), 5% palladium- 200 ml) and tetrahydrofuran (200 ml) was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- (3,5-dihydroxybenzyl) -4-phenyl-3-piperidinecarboxylate from a fraction eluted with ethyl acetate-hexane (3: Propionate (12.10 g, yield: 95%) was obtained as an oily substance.
[610] _{NMR (CDCl 3) δ: 1.13} (3H, t, J = 7.2 Hz), 2.49 (2H, t, J = 7.4 Hz), 2.93 (2H, t, J = 7.4 Hz), 4.01 (2H, q, J = 7.2 Hz), 4.77 (2H, s), 6.09 (2H, d, J = 2.2 Hz), 6.24 = 2.4 Hz), 6.65 (1H, d, J = 2.4 Hz), 7.14-7.37 (5H, m).
[611] Reference Example 22
[612] Lithium aluminum hydride (884 mg) was added to a solution of ethyl 1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylate (9.61 g) in tetrahydrofuran And the mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. After addition of water, the reaction mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to obtain [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-yl] methanol (23.10 g, yield 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 88-89 占 폚.
[613] Reference Example 23
[614] Thionyl chloride (1.83 ml) was added dropwise to a solution of [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-yl] methanol (8.43 g) in toluene And the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was dissolved in tetrahydrofuran (30 ml) and the solution was added at 0 C to a mixture of diethyl malonate (18.3 g), sodium hydride (60%, oil, 3.65 g) and tetrahydrofuran Lt; / RTI &gt; The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then at room temperature for 6 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain a diethyl 2- [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazole-3- carboxylic acid ethyl ester from the fraction eluted with ethyl acetate-hexane (1: 3, 4-yl] methylmalonate (9.50 g, yield: 81%) was obtained as an oily substance.
[615] _{NMR (CDCl 3) δ: 1.15} (6H, t, J = 7.1 Hz), 3.21 (2H, d, J = 8.0 Hz), 3.52 (1H, t, J = 8.0 Hz), 4.08 (4H, q, J = 7.1 Hz), 5.06 (2H, s), 5.21 (2H, s), 6.94 (2H, d, J = 8.8 Hz), 7.15-7.47 (11H, m), 7.60-7.66 (2H, m).
[616] Reference Example 24
[617] (500 mg), 5% palladium-carbon (1.00 g), and tetrahydrofuran (10 mg) were added to a solution of methyl 3- [1- (4-benzyloxybenzyl) ml) was stirred at room temperature under a hydrogen atmosphere for 18 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- [1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazole-4 -Yl] propionate (325 mg, yield 80%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 87-88 占 폚.
[618] Reference Example 25
[619] Methanesulfonyl chloride (3.37 g) was added to a solution of 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethan- g) and ethyl acetate (300 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The obtained crystals were collected by filtration to obtain 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl methanesulfonate (8.44 g, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 66-67 캜.
[620] Reference Example 26
[621] Phenoxymethyl] -5-methyl-2-phenyloxazole (1.62 g), phosphorus oxychloride (1.00 g) and N (2-methylpiperazin-1- , And N-dimethylformamide (20 ml) was stirred at room temperature for 5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 3,5-dimethyl-1- [4- (5-methyl-2-phenyl-4-oxazolyl Methoxy) benzyl] -1H-pyrazole-4-carbaldehyde (950 mg, yield 55%) as an oily substance.
[622] _{NMR (CDCl 3) δ: 2.43} (3H, s), 2.47 (6H, s), 4.97 (2H, s), 5.18 (2H, s), 6.98 (2H, d, J = 9 Hz), 7.10 (2H , d, J = 9 Hz), 7.4-7.5 (3H, m), 7.95-8.05 (2H, m), 9.92 (1H, s).
[623] Reference Example 27
[624] Lithium aluminum hydride (262 mg) was added to a solution of methyl 3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- Phenyl-lH-pyrazol-4-yl] propionate (3.50 g) and the mixture was stirred at 0 <0> C for 1 hour. After addition of water, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) Benzyl] -3-phenyl-1H-pyrazol-4-yl] propan-1-ol (3.04 g, yield 92%) as a colorless oily substance.
[625] _{NMR (CDCl 3) δ: 1.72-1.87} (2H, m), 2.44 (3H, s), 2.65-2.74 (2H, m), 3.63 (2H, t, J = 6.4 Hz), 4.99 (2H, s) , 5.25 (2H, s), 7.00 (2H, d, J = 8.8 Hz), 7.17-7.46 (9H, m), 7.62-7.68 (2H, m), 7.98-8.04 (2H, m).
[626] Reference Example 28
[627] Methanesulfonyl chloride (0.625 ml) was added at 0 ° C to a solution of 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] (2.98 g), triethylamine (1.74 ml) and ethyl acetate (50 ml), and the mixture was stirred for 30 minutes. The reaction mixture was then washed with water and saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was dissolved in acetone (50 ml), sodium iodide (1.86 g) was added, and the solution was stirred at 50 ° C for 3 hours. After removal of the solvent under reduced pressure, the residue was dissolved in water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 1- iodo-3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy ) Benzyl] -3-phenyl-1H-pyrazol-4-yl] propane (3.60 g, yield 98%) as a colorless oily substance.
[628] _{NMR (CDCl 3) δ: 1.96-2.08} (2H, m), 2.44 (3H, s), 2.69-2.77 (2H, m), 3.15 (2H, t, J = 6.8 Hz), 4.99 (2H, s) , 5.25 (2H, s), 7.01 (2H, d, J = 8.8Hz), 7.19-7.48 (9H, m), 7.60-7.66 (2H, m), 7.98-8.04 (2H, m).
[629] Reference Example 29
[630] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propane (1.75 g) was added to a solution of 1-iodo-3- [1- [4- , Sodium cyanide (291 mg) and dimethylsulfoxide (5 ml) was stirred at 60 ° C for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 4- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) Benzyl] -3-phenyl-1H-pyrazol-4-yl] butyronitrile (1.34 g, yield 92%) as a colorless oily substance.
[631] _{NMR (CDCl 3) δ: 1.76-1.92} (2H, m), 2.28 (2H, t, J = 7.0 Hz), 2.44 (3H, s), 2.78 (2H, t, J = 7.5 Hz), 4.99 (2H (2H, s), 5.25 (2H, s), 7.01 (2H, d, J = 8.8Hz), 7.19-7.47 (9H, m), 7.58-7.64 (2H, m), 7.98-8.04 (2H, m).
[632] Reference Example 30
[633] Sodium hydride (60%, oil, 476 mg) was added to a solution of diethyl malonate (2.37 g) in tetrahydrofuran (50 ml) at 0 C and the mixture was stirred for 30 minutes. To a solution of l-iodo-3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3-phenyl-lH- pyrazole- -Yl] propane (1.75 g) was added dropwise to the mixture, which was stirred at room temperature for 13 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain a diethyl 2- [3- [1- [4- (5-methyl-2-phenyl-4- Benzyl] -3-phenyl-1H-pyrazol-4-yl] propyl] malonate (1.63 g, yield 88%) as a colorless oily substance.
[634] _{NMR (CDCl 3) δ: 1.23} (6H, t, J = 7.1 Hz), 1.50-1.65 (2H, m), 1.86-1.98 (2H, m), 2.43 (3H, s), 2.63 (2H, t, J = 7.7 Hz), 3.29 (1H, t, J = 7.6 Hz), 4.15 (4H, q, J = 7.1 Hz), 4.99 (2H, s), 5.24 J = 8.8Hz), 7.17-7.47 (9H, m), 7.59-7.65 (2H, m), 7.98-8.04 (2H, m).
[635] Reference Example 31
[636] Lithium aluminum hydride (2.03 g) was added to a solution of ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazole-4-carboxylate (40.00 g) and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to give [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- [4- -Oxazolylmethoxy) benzyloxy] -1H-pyrazol-4-yl] methanol (35.91 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 157-158 占 폚.
[637] Reference Example 32
[638] Benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] - The mixture of 1H-pyrazol-4-yl] methanol (27.02 g), active manganese dioxide (52.29 g), chloroform (50 ml) and tetrahydrofuran (300 ml) was stirred at room temperature for 3 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- [4- Oxazolylmethoxy) benzyloxy] -1H-pyrazole-4-carbaldehyde (25.69 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 155-156 ° C.
[639] Reference Example 33
[640] Lithium aluminum hydride (0.98 g) was added to a solution of ethyl 1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3 -Benzyl] -1H-pyrazole-4-carboxylate (19.16 g) in anhydrous THF (5 ml) Stir at room temperature for 30 min. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to give [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- Methyl-4-oxazolylmethoxy] benzyloxy] -1H-pyrazol-4-yl] methanol (17.25 g, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 80-81 占 폚.
[641] Reference Example 34
[642] [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3- [ 4-yl] methanol (16.59 g), active manganese dioxide (35.19 g) and tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- ) -5-methyl-4-oxazolylmethoxy] benzyloxy] -1H-pyrazole-4-carbaldehyde (14.73 g, yield 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 109-110 占 폚.
[643] Reference Example 35
[644] Lithium aluminum hydride (0.58 g) was added to a solution of methyl 3-isopropyl-l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy] benzyl] - Pyrazole-4-carboxylate (9.02 g) and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate ., and extracted with ethyl acetate then washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), concentrated and the residue was purified by silica gel column chromatography, ethyl acetate-hexanes: with (1: 1, volume ratio) Benzyl] -1H-pyrazol-4-yl] methanol (8.20 g, yield: &lt; RTI ID = 97%) as a colorless oily substance which was recrystallized from ethyl acetate-hexane. Melting point: 98-99 [deg.] C.
[645] Reference Example 36
[646] A mixture of ethyl 3-oxohexanoate (15.80 g) and N, N-dimethylformamide dimethylacetal (17.9 g) was refluxed for 2.5 hours and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml) and after degassing, benzylhydrazine dihydrochloride (22.0 g) was added and the solution was refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and, after washed with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-5-propyl-1H-pyrazole-4-carboxylate (22.81 g, yield: : 84%) as a colorless oily substance.
[647] _{NMR (CDCl 3) δ: 0.92} (3H, t, J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz), 1.39-1.59 (2H, m), 2.84-2.92 (2H, m), 4.28 (2H, q, J = 7.2 Hz), 5.32 (2H, s), 7.08-7.13 (2H, m), 7.26-7.34 (3H, m), 7.92 (1H, s).
[648] Reference Example 37
[649] Lithium aluminum hydride (2.58 g) was added to a solution of ethyl 1-benzyl-5-propyl-lH-pyrazole-4-carboxylate (18.50 g) in tetrahydrofuran (300 ml) Was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (21.88 g) and hexane (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated to obtain (l-benzyl-5-propyl-1H-pyrazol-4-yl) methanol (14.99 g, yield: 96%) as a colorless oily substance .
[650] _{NMR (CDCl 3) δ: 0.90} (3H, t, J = 7.6 Hz), 1.38-1.57 (2H, m), 2.59 (2H, t, J = 7.6Hz), 4.52 (2H, s), 5.29 (2H , s), 7.06-7.11 (2H, m), 7.21-7.36 (3H, m), 7.51 (1H, s).
[651] Reference Example 38
[652] The mixture of (l-benzyl-5-propyl-lH-pyrazol-4-yl) methanol (14.99 g), active manganese dioxide (30.0 g) and tetrahydrofuran (300 ml) was stirred at room temperature for 3 days. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (10.69 g, yield: 72%) as a colorless oily substance.
[653] _{NMR (CDCl 3) δ: 0.93} (3H, t, J = 7.0 Hz), 1.43-1.58 (2H, m), 2.89 (2H, t, J = 8.0 Hz), 5.33 (2H, s), 7.11-7.16 (2H, m), 7.26-7.37 (3H, m), 7.96 (1H, s), 9.88 (1H, s).
[654] Reference Example 39
[655] Sodium hydride (60%, oil, 2.25 g) was added to a solution of 1-benzyl-5-propyl-lH- pyrazole-4-carbaldehyde (12.60 g), ethyldiethylphosphonoacetate , N-dimethylformamide (150 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E) -3- (1-benzyl-5-propyl-1 H-pyrazol-4-yl ) Propanoate (11.90 g, yield: 85%) as a colorless oily substance.
[656] _{NMR (CDCl 3) δ: 0.90} (3H, t, J = 7.2 Hz), 1.32 (3H, t, J = 7.2 Hz), 1.36-1.60 (2H, m), 2.65 (2H, t, J = 7.6 HZ ), 4.24 (2H, q, J = 7.2 Hz), 5.30 (2H, s), 6.17 (1H, d, J = 15.6 Hz), 7.07-7.12 (2H, m), 7.26-7.37 ), 7.50 (1H, d, J = 15.6Hz), 7.77 (1H, s).
[657] Reference Example 40
[658] (6.00 g), 5% palladium-carbon (12.0 g), formic acid (50 ml) and ethanol (10 ml) were added to a solution of ethyl (E) -3- (100 ml) was refluxed for 16 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate and saturated aqueous sodium bicarbonate solution and then washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- (3-propyl-1H-pyrazol-4-yl) propionate (3.45 g, Yield: 82%) as a colorless oily substance.
[659] _{NMR (CDCl 3) δ: 0.97} (3H, t, J = 7.2 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.56-1.76 (2H, m), 2.50-2.79 (6H, m), 4.13 (2H, q, J = 7.2 Hz), 7.34 (1H, s).
[660] Reference Example 41
[661] A mixture of ethyl benzoylacetate (20.0 g) and N, N-dimethylformamide dimethylacetal (18.59 g) was refluxed for 1.5 hours and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml) and after degassing, benzylhydrazine dihydrochloride (22.25 g) was added and the solution was refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and, after washed with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 1-benzyl-5-phenyl-1H-pyrazole-4-carboxylate (20.9 g, yield: : 66%) as colorless crystals. Melting point: 78-79 占 폚.
[662] Reference Example 42
[663] Lithium aluminum hydride (2.50 g) was added to a solution of ethyl 1-benzyl-5-phenyl-1H-pyrazole-4-carboxylate (20.2 g) in tetrahydrofuran (300 ml) Was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (21.23 g) and hexane (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography and fraction (1-benzyl-5-phenyl-1H-pyrazol-4-yl) methanol (17.4 g, yield: : 100%) as a colorless oily substance.
[664] _{NMR (CDCl 3) δ: 4.46} (2H, s), 5.25 (2H, s), 6.99-7.04 (2H, m), 7.23-7.32 (5H, m), 7.41-7.45 (3H, m), 7.69 ( 1H, s).
[665] Reference Example 43
[666] (9.76 g), active manganese dioxide (20.0 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 12 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.30 g, yield: 75%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 99-100 &lt; 0 &gt; C.
[667] Reference Example 44
[668] Sodium hydride (60%, oil, 1.28 g) was added to a solution of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.00 g), ethyldiethylphosphonoacetate , N-dimethylformamide (100 ml), and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and ethyl (E) -3- (1-benzyl-5-phenyl-1H-pyrazol-4-yl ) Propanoate (6.30 g, yield 71%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 62-63 캜.
[669] Reference Example 45
[670] (300 mg), 5% palladium-carbon (600 mg), formic acid (3 ml) and ethanol (5 ml) were added to a solution of ethyl (E) -3- (10 ml) was refluxed for 2 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate and saturated aqueous sodium bicarbonate solution and then washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- (3-phenyl-1H-pyrazol-4-yl] propionate (120 mg, Yield: 55%) as a colorless oily substance.
[671] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.2 Hz), 2.58 (2H, t, J = 7.6 Hz), 2.98 (2H, t, J = 7.6 Hz), 4.12 (2H, q, J = 7.2 Hz), 7.38-7.58 (6 H, m).
[672] Reference Example 46
[673] Lithium aluminum hydride (1.93 g) was added to a solution of ethyl 3-methyl-1- (2-pyridyl) -1H-pyrazole-4-carboxylate (15.00 g) in tetrahydrofuran And the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (21.03 g) and hexane (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give [3-methyl-1- (2-pyridyl) -1H-pyrazol-4-yl] methanol g). This was recrystallized from acetone-hexane. Melting point: 116-117 [deg.] C.
[674] Reference Example 47
[675] Sodium hydride (60%, oil, 0.80 g) was added to a solution of [3-methyl-1- (2-pyridyl) -lH- pyrazol- Methanol (3.20 g) in dichloromethane, and the mixture was stirred at room temperature for 1 hour. 4-Fluorobenzaldehyde (2 ml) was added to the reaction mixture, and the mixture was stirred at 50 占 폚 overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and 4- [3-methyl-1- (2-pyridyl) -1H-pyrazol-4-ylmethyl- Ethoxy] benzaldehyde (4.26 g, yield: 86%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 84-85 캜.
[676] Reference Example 48
[677] Sodium borohydride (0.25 g) was added to a solution of 4- [3-methyl- 1- (2-pyridyl) -1H-pyrazol-4-ylmethoxy] benzaldehyde (3.50 g), methanol (25 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted hydrochloric acid was added to the residue, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and 4- [3-methyl-1- (2-pyridyl) -1H-pyrazol-4-ylmethyl- Ethoxy] benzyl alcohol (3.41 g, yield: 97%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 83-84 캜.
[678] Reference Example 49
[679] Sodium hydride (60%, oil, 180 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (1.00 g), benzyl 4-chloromethylbenzoate ) And N, N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and a fraction eluted with ethyl acetate-hexane (1: 4, by volume) to give benzyl 4- [4- (3-ethoxy-3- -1H-pyrazol-1-ylmethyl] benzoate (1.68 g, yield: 88%) as a colorless oily substance.
[680] _{NMR (CDCl 3) δ: 1.18} (3H, t, J = 7.0 Hz), 2.53 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7.6 Hz), 4.07 (2H, q, J = 7.0 Hz), 5.35 (4H, s), 7.25-7.46 (11H, m), 7.60-7.66 (2H, m), 8.02-8.07 (2H, m).
[681] Reference Example 50
[682] Benzyl ester (1.67 g), 5% palladium-carbon (2.00 g, 0.35 mmol), and triethylamine ), And ethanol (50 ml) was stirred at room temperature under a hydrogen atmosphere for 5 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to give 1.08 g of 4- [4- (3-ethoxy-3-oxo-1-propyl) -3-phenyl-1H-pyrazol- 1- ylmethyl] Yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point 97-98 캜.
[683] Reference Example 51
[684] Sodium hydride (60%, oil, 850 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (4.69 g), benzyl 3-chloromethylbenzoate ) And N, N-dimethylformamide (50 ml), and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 4, by volume). The obtained oily substance, 5% palladium-carbon (12.0 g) and ethanol (200 ml) was stirred under a hydrogen atmosphere at room temperature for 5 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to give 2.41 g of 3- [4- (3-ethoxy-3-oxo-1-propyl) -3-phenyl-1H-pyrazol- 1- ylmethyl] benzoate Yield 33%). This was recrystallized from ethyl acetate-hexane. Melting point: 101-102 占 폚.
[685] Reference Example 52
[686] Thionyl chloride (4.35 g) was added dropwise at 0 ° C to a solution of (1-benzyl-5-phenyl-1H-pyrazol-4-yl) methanol (8.06 g) in toluene (100 ml) After stirring for 1 hour, it was refluxed for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g, yield: 96%) was obtained from the fraction eluted with ethyl acetate-hexane %) As a colorless oily substance.
[687] _{NMR (CDCl 3) δ: 4.44} (2H, s), 5.23 (2H, s), 6.99-7.04 (2H, m), 7.22-7.36 (5H, m), 7.42-7.47 (3H, m), 7.72 ( 1H, s).
[688] Reference Example 53
[689] A mixture of 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g), potassium cyanide (2.87 g) and N, N- dimethylformamide (100 ml) , Poured into water, and extracted with ethyl acetate. After washing the ethyl acetate layer with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated The residue was purified by silica gel column chromatography, ethyl acetate-hexanes: The eluted with (1: 2, volume ratio) fraction 5-phenyl-1H-pyrazol-4-yl) acetonitrile (3.50 g, yield 44%) as a colorless oily substance.
[690] _{NMR (CDCl 3) δ: 3.45} (2H, s), 5.21 (2H, s), 6.97-7.02 (2H, m), 7.19-7.30 (5H, m), 7.43-7.50 (3H, m), 7.67 ( 1H, s).
[691] Reference Example 54
[692] (3.50 g), 4N aqueous potassium hydroxide solution (16 ml) and ethanol (50 ml) was refluxed for 4 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give (l-benzyl-5-phenyl-lH- pyrazol-4- yl) acetic acid (3.70 g, Of an oily substance.
[693] _{NMR (CDCl 3) δ: 3.42} (2H, s), 5.22 (2H, s), 6.97-7.02 (2H, m), 7.22-7.26 (5H, m), 7.40-7.44 (3H, m), 7.65 ( 1H, s).
[694] Reference Example 55
[695] (3.70 g), concentrated sulfuric acid (0.5 ml) and ethanol (200 ml) was refluxed for 5 hours. The reaction mixture was basified with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and ethyl (1-benzyl-5-phenyl-1H-pyrazol-4-yl) acetate (3.62 g, Yield: 89%) as an oily substance.
[696] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 3.38 (2H, s), 4.11 (2H, q, J = 7.2 Hz), 5.21 (2H, s), 6.98-7.03 (2H m), 7.21-7.28 (5H, m), 7.37-7.44 (3H, m), 7.63 (1H, s).
[697] Reference Example 56
[698] A mixture of ethyl (l-benzyl-5-phenyl-lH-pyrazol-4-yl) acetate (3.60 g), 5% palladium- carbon (7.00 g), formic acid (40 ml) and ethanol Lt; / RTI &gt; After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated to give ethyl (3-phenyl -1H- pyrazol-4-yl) acetate (2.33 g , Yield: 90%) as a colorless oily substance.
[699] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.2 Hz), 3.61 (2H, s), 4.15 (2H, q, J = 7.2 Hz), 7.36-7.64 (6H, m).
[700] Reference Example 57
[701] Ethyl) -3-phenyl-1H-pyrazol-4-yl) acetate (800 mg), 5% palladium-carbon (1.50 g), tetrahydrofuran 20 ml) and ethanol (30 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [l- [2- (4-hydroxyphenyl) ethyl] -3-phenyl-lH-pyrazole from the fraction eluted with ethyl acetate-hexane (1: 4, Yl] acetate (400 mg, yield: 63%) was obtained as an oily substance.
[702] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.0 Hz), 3.11 (2H, t, J = 7.2 Hz), 3.57 (2H, s), 4.13 (2H, q, J = 7.0 Hz), (2H, m), 7.26-7.45 (4H, m), 7.58-7.28 (2H, m) 7.62 (2 H, m).
[703] Reference Example 58
[704] Lithium aluminum hydride (323 mg) was added to a solution of ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH- pyrazole- ), Diethyl ether (25 ml) and tetrahydrofuran (25 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, which was extracted with diethyl ether. D. After washing the ether layer with water and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were filtered to obtain 2.93 g (yield: 92%) of [1- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] ). This was recrystallized from ethyl acetate-hexane. Melting point: 100-101 占 폚.
[705] Reference Example 59
[706] Benzyl] -1H-pyrazol-4-yl] methanol (2.82 g), active manganese dioxide (6.00 g) and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and fraction eluted with ethyl acetate-hexane (1: 1, by volume) to obtain 1- [4- Pyrazole-4-carbaldehyde (2.63 g, yield 94%) as a colorless oily substance.
[707] _{NMR (CDCl 3) δ: 2.44} (3H, s), 5.00 (2H, s), 5.27 (2H, s), 7.03 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz ), 7.40-7.48 (3H, m), 7.84 (1H, s), 7.97-8.04 (3H, m), 9.82 (1H, s).
[708] Reference Example 60
[709] Sodium hydride (60%, oil, 880 mg) was added to a mixture of 3,5-dimethylpyrazole (2.11 g) and tetrahydrofuran (50 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. 4- (4-Chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (6.28 g) was added to the reaction mixture and the mixture was refluxed for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and the fraction eluted with ethyl acetate-hexane (1: 1, by volume) to give 3,5-dimethyl-1- [4- (5- Methoxy) benzyl] -1H-pyrazole (5.49 g, yield 74%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 86-87 캜.
[710] Reference Example 61
[711] A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11.53 g), benzyl bromide (18 ml), potassium carbonate (21.12 g) and N, N- dimethylformamide Lt; 0 &gt; C for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (13.52 g, Yield: 95%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 71-72 ° C.
[712] Reference Example 62
[713] Lithium aluminum hydride (6.64 g) was added to a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58.90 g) in tetrahydrofuran (500 ml) The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl) methanol (45.30 g, yield: 88%) was obtained as colorless crystals from the fraction eluted with ethyl acetate . This was recrystallized from ethyl acetate-hexane. Melting point: 79-80 占 폚.
[714] Reference Example 63
[715] The mixture of (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl) methanol (14.70 g), active manganese dioxide (30.00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to obtain 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (13.10 g, yield: 90%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 85-86 캜.
[716] Reference Example 64
[717] Benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), ethyldiethylphosphonoacetate (9.60 ml) and sodium hydride (60% Was added to a mixture of N, N-dimethylformamide (200 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to obtain ethyl (E) -3- (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl) propenoate (14.50 g, yield: 91% Respectively. This was recrystallized from ethyl acetate-hexane. Melting point: 88-89 占 폚.
[718] Reference Example 65
[719] Ethyl E) -3- (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl) propanoate (14.30 g), 5% palladium- carbon (28.00 g) The mixture of tetrahydrofuran (150 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to obtain ethyl 3- (1-benzyl-3-hydroxy-1H-pyrazol-4-yl) propionate (9.01 g, yield: 83%). This was recrystallized from ethyl acetate-hexane. Melting point: 75-76 占 폚.
[720] Reference Example 66
[721] Sodium hydride (60%, oil, 1.28 g) was added to a solution of ethyl 3- (1-benzyl-3-hydroxy-1H-pyrazol- Phonate (8.78 g) in tetrahydrofuran, and the mixture was stirred for 30 minutes. Iodoethane (2.82 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and then with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- (1-benzyl-3-ethoxy-1H-pyrazol-4-yl) propiopyranosyl chloride was obtained from the fraction eluted with ethyl acetate- (8.80 g, yield: 91%) was obtained as a colorless oily substance.
[722] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.48-2.55 (2H, m), 2.62-2.70 (2H, m), 4.09 (2H, m, J = 7.2 Hz), 4.22 (2H, q, J = 7.0 Hz), 5.07 (2H, s), 6.96 (1H, s), 7.13-7.18 3H, m).
[723] Reference Example 67
[724] (21.20 g), 5% palladium-carbon (40.00 g), ethanol (200 ml) and formic acid (100 ml) were added to a solution of ethyl 3- (1-benzyl-3-ethoxy-1H-pyrazol- ) Was refluxed for 1 hour. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, and this was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (10.70 g, , Yield: 72%) as a colorless oily substance.
[725] _{NMR (CDCl 3) δ: 1.24} (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.0 Hz), 2.51-2.59 (2H, m), 2.66-2.74 (2H, m), 4.12 (2H, q, J = 7.2 Hz), 4.24 (2H, q, J = 7.0 Hz), 7.18 (1H, s), 9.15 (1H, s).
[726] Reference Example 68
[727] (5.32 g), 5% palladium-carbon (3.45 g), and tetrahydrofuran (5 ml) were added to a solution of ethyl 3- [l- (4- benzyloxybenzyl) -3-ethoxy- 100 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- (4-hydroxybenzyl) -1H-pyrazole-1-carboxylate was obtained from the fraction eluted with ethyl acetate- 4-yl) propionate (3.56 g, yield 86%) as a colorless oily substance.
[728] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.4 Hz), 1.35 (3H, t, J = 7.4 Hz), 2.44-2.72 (4H, m), 4.03-4.29 (4H, m), 4.96 (2H, s), 6.58-6.68 (2H, m), 6.90-7.03 (3H, m).
[729] Reference Example 69
[730] Lithium aluminum hydride (1.52 g) was added to a solution of ethyl 1- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazole-4-carbaldehyde in 200 ml tetrahydrofuran (11.00 g) and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to give 7.11 g of [1- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazol- ). This was recrystallized from tetrahydrofuran-hexane. Melting point: 128-129 占 폚.
[731] Reference Example 70
[732] 4-yl] methanol (6.84 g), active manganese dioxide (14.00 g) and tetrahydrofuran (70 ml) in the same manner as in Example 1, except that 1-benzyloxy- ) Was stirred at room temperature for 1 hour. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The resulting crystals were collected by filtration to give 1- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazole-4-carbaldehyde (6.50 g, yield: 95% &Lt; / RTI &gt; This was recrystallized from tetrahydrofuran-hexane. Melting point: 138-139 占 폚.
[733] Reference Example 71
[734] 4-yl] propanoate (6.61 g), 5% palladium-on-charcoal solution of ethyl (E) -3- [1- (4-benzyloxybenzyl) -3- A mixture of carbon (13.00 g), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred under hydrogen atmosphere at room temperature for 1 hour. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to give ethyl 3- [1- (4-hydroxybenzyl) -3-hydroxy-1H-pyrazol-4-yl] propionate (2.98 g, &Lt; / RTI &gt; This was recrystallized from ethyl acetate-hexane. Melting point: 143-144 占 폚.
[735] Reference Example 72
[736] Sodium hydride (60%, oil, 2.40 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (9.46 g) in N, N- dimethylformamide (50 ml) The mixture was stirred for 15 minutes. A solution of methyl 2-chloro-4-pyridinecarboxylate (8.58 g) in tetrahydrofuran (50 ml) was added to the mixture. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and methyl 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridinecarboxylic acid was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, (2190 mg, yield: 14%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 106-107 占 폚.
[737] Reference Example 73
[738] Lithium aluminum hydride (228 mg) was added to methyl 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridinecarboxylate (1.95 g) in tetrahydrofuran (20 ml) And the mixture was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (1.93 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to give 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethanol (1.37 g, yield: 77%). This was recrystallized from ethyl acetate-hexane. Melting point: 100-101 占 폚.
[739] Reference Example 74
[740] A mixture of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethanol (1.19 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, then a saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine from the fraction eluted with ethyl acetate-hexane (1: 3, (680 mg, yield: 54%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 104-105 占 폚.
[741] Reference Example 75
[742] Methyl-2-phenyloxazole (13.40 g), potassium carbonate (8.90 g) and N, N-dimethylformamide (100 ml) was stirred overnight at 80 &lt; 0 &gt; C. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1: Carboxylate (12.42 g, yield 59%) as pale yellow crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 119-120 占 폚.
[743] Reference Example 76
[744] Lithium aluminum hydride (1.02 g) was added to methyl 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridinecarboxylate (10.70 g) in tetrahydrofuran (100 ml) And the mixture was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (8.93 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethanol (8.93 g, yield 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 111-112 占 폚.
[745] Reference Example 77
[746] A mixture of 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethanol (1.33 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, then a saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -pyridine as a colorless oil from a fraction eluted with tetrahydrofuran-hexane (1: 1, Pyridine (911 mg, yield 64%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 98-99 ° C.
[747] Reference Example 78
[748] Sodium borohydride (0.378 g) was added at room temperature to a solution of 4-methoxy-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde (3.23 g), tetrahydrofuran ml), which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give crystals of 4-methoxy-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol. This was recrystallized from tetrahydrofuran-hexane to give pale yellow flaky crystals (3.22 g, 99%). Melting point: 144-145 占 폚.
[749] Reference Example 79
[750] A mixture of 4-methoxy-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (3.22 g), thionyl chloride (0.73 ml) and toluene (50 ml) . The reaction mixture was concentrated, then a saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 4- (5-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (2.59 g, yield 75% Respectively. This was recrystallized from ethyl acetate-hexane. Melting point: 129-130 占 폚.
[751] Reference Example 80
[752] Sodium borohydride (378 g) was added at room temperature to a solution of 3-ethoxy-4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzaldehyde (3.37 g), tetrahydrofuran (50 ml) ml) and stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated by, ethoxy-4- (5-methyl-2-phenyl-4-oxazolyl methoxy) 3-benzyl alcohol (3.28 g, yield: : 97%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 130-131 占 폚.
[753] Reference Example 81
[754] (0.73 ml) was added to a solution of 3-ethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl alcohol (3.05 g), tetrahydrofuran 50 ml), which was stirred at 80 &lt; 0 &gt; C for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and concentrated to give 2.94 g of 4- (4-chloromethyl-2-ethoxyphenoxymethyl) , Yield: 91%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 138-139 占 폚.
[755] Reference Example 82
[756] Sodium hydride (60%, oil, 1.40 g) was added to a solution of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) in N, N-dimethylformamide (70 ml) It was stirred for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added to the mixture. After stirring at 60 [deg.] C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazole carboxylate (7.96 g, yield: 72% &Lt; / RTI &gt; This was recrystallized from tetrahydrofuran-hexane. Melting point: 123-124 占 폚.
[757] Reference Example 83
[758] (5-methyl-2-phenyl-4-oxazolylmethoxy) -5- (tert-butoxycarbonylamino) -thiophene in tetrahydrofuran (150 ml) was added dropwise to a solution of diisobutylaluminum hydride (1.0 M in tetrahydrofuran, Was added slowly to a solution of isoxazole carboxylate (7.86 g) which was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 5.93 g of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) : 86%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 99-100 &lt; 0 &gt; C.
[759] Reference Example 84
[760] Thionyl chloride (0.80 ml) was slowly added to a solution of 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5- isoxazolylmethanol (2.86 g) in toluene And this was stirred at reflux for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 5-chloromethyl-3- (5-methyl- Yield: 89%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 105-106 占 폚.
[761] Reference Example 85
[762] Sodium borohydride (620 mg) was added to a solution of 4- [2- [1-oxo-2 (1H) -phthaladiyl] ethoxy] benzaldehyde (4.90 g), methanol (20 ml) and tetrahydrofuran ml), which was stirred at room temperature for 30 minutes. Diluted hydrochloric acid was added to the reaction mixture, and the resulting colorless crystals were collected by filtration to give 4.53 g of 4- [2- [1-oxo-2 (1H) -phthaladinyl] ethoxy] benzyl alcohol, 92%). This was recrystallized from acetone-hexane. Melting point: 142-143 占 폚.
[763] Reference Example 86
[764] Sodium borohydride (600 mg) was added to a solution of 3- [2- [1-oxo-2 (1H) -phthaladyl] ethoxy] benzaldehyde (5.00 g), methanol (30 ml) and tetrahydrofuran ml), which was stirred at room temperature for 30 minutes. Diluted hydrochloric acid was added to the reaction mixture and the resulting colorless crystals were collected by filtration to give 4.80 g of 3- [2- [1-oxo-2 (1H) -phthaladinyl] ethoxy] benzyl alcohol, 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 133-134 占 폚.
[765] Reference Example 87
[766] Thionyl chloride (1 ml) was slowly added to a solution of 4- [2- [1-oxo-2 (1H) -phthaladinyl] ethoxy] benzyl alcohol (3.80 g) in toluene , Which was stirred at 90 &lt; 0 &gt; C for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 3.62 g (yield: 95%) as a colorless oily substance.
[767] _{NMR (CDCl 3) δ: 4.37-4.47} (2H, m), 4.54 (2H, s), 4.60-4.70 (2H, m), 6.86-6.96 (2H, m), 7.24-7.34 (2H, m), 7.66-7.86 (3H, m), 8.19 (1H, s), 8.40-8.48 (1H, m)
[768] Reference Example 88
[769] Thionyl chloride (1.3 ml) was slowly added to a solution of 3- [2- [1-oxo-2 (1H) -phthaladinyl] ethoxy] benzyl alcohol (4.59 g) in toluene , Which was stirred at 90 &lt; 0 &gt; C for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to obtain 4.39 g of 2- [2- (3-chloromethylphenoxy) ethyl] 95%) as a colorless oily substance.
[770] _{NMR (CDCl 3) δ: 4.40-4.48} (2H, m), 4.51 (2H, s), 4.62-4.70 (2H, m), 6.84-7.00 (3H, m), 7.18-7.26 (1H, m), 7.64-7.88 (3H, m), 8.19 (1H, s), 8.40-8.50 (1H, m).
[771] Reference Example 89
[772] Sodium hydride (60%, oil, 1.80 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (8.51 g) in tetrahydrofuran (100 ml) at 0 ° C, Lt; / RTI &gt; A solution of methyl 6-chloro-2-pyridinecarboxylate (7.72 g) in tetrahydrofuran (75 ml) was added to the mixture. After stirring at 40 &lt; 0 &gt; C for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated, methyl 6- (5-methyl-2-phenyl-4-oxazolyl methoxy) pyridine-2-carboxylate (7.41 g, Yield: 51%) as yellow crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97-98 캜.
[773] Reference Example 90
[774] Lithium aluminum hydride (759 mg) was added to methyl 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridinecarboxylate (6.49 g) in tetrahydrofuran (60 ml) And the mixture was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (6.44 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated. The mixture of the residue and thionyl chloride (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and a saturated aqueous sodium bicarbonate solution was added, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-chloromethyl-6- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (2.74 g, yield 44%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 85-86 캜.
[775] Reference Example 91
[776] Lithium aluminum hydride (2.43 g) was added to a solution of methyl 6-phenyl-3-pyridinecarboxylate (14.00 g) in tetrahydrofuran (200 ml) at 0 ° C and stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (22.50 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated to obtain 6-phenyl-3-pyridylmethanol (11.63 g, yield: 96%) as a pale yellow oily substance.
[777] _{NMR (CDCl 3) δ: 1.91} (1H, br.s), 4.78 (2H, d, J = 5.6 Hz), 7.34-7.54 (3H, m), 7.70-7.84 (2H, m), 7.93-8.04 ( 2H, m), 8.64-8.71 (1H, m).
[778] Reference Example 92
[779] Thionyl chloride (10 ml) was slowly added to a solution of 6-phenyl-3-pyridylmethanol (11.60 g) in toluene (100 ml) at room temperature and this was stirred at 100 ° C for 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 5-chloromethyl-2-phenylpyridine (11.49 g, yield 89%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 95-96 占 폚.
[780] Reference Example 93
[781] Sodium hydride (60%, oil, 2.88 g) was added to a solution of 2- (2-furyl) -5-methyl-4-oxazolylmethanol (10.80 g), methyl 2-chloro-4-pyridinecarboxylate g), tetrahydrofuran (100 ml) and N, N-dimethylformamide (100 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -4-pyridinecarboxylate (2.86 g, As colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 80-81 占 폚.
[782] Reference Example 94
[783] Lithium aluminum hydride (304 mg) was added to a solution of ethyl 2- 2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -4-pyridinecarboxylate in 30 ml tetrahydrofuran (2.63 g) in dichloromethane, and stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (2.58 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated. The mixture of the residue, thionyl chloride (10 ml) and toluene (5 ml) was stirred at room temperature for 1 hour. After concentrating the reaction mixture, a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-chloromethyl-2- [2- (2-furyl) -5-methyl-4-oxazolyl Methoxy] pyridine (1020 mg, yield: 42%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 107-108 占 폚.
[784] Reference Example 95
[785] Sodium hydride (60%, oil, 2.00 g) was added to a solution of 5-chloroimidazo [1,2-a] pyridin-2-ylmethanol (8.77 g), methyl 2-chloro-4-pyridinecarboxylate 8.24 g) and N, N-dimethylformamide (150 ml), which was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 2- (5-chloroimidazo [1,2-a] pyridin-2-ylmethoxy) -4-pyridinecarboxylate g, yield: 18%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 157-158 占 폚.
[786] Reference Example 96
[787] Diisobutyl aluminum hydride (1.0 M tetrahydrofuran solution, 30 mL) was added to a solution of methyl 2- (5-chloroimidazo [1,2-a] pyridin- 2- ylmethoxy) - 4-pyridinecarboxylate (3.97 g) at 0 C and stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (12.2 g) was added to the mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The resulting colorless crystals were collected by filtration to give 2- (5-chloroimidazo [1,2-a] pyridin-2-ylmethoxy) -4-pyridylmethanol (3.12 g, yield 86%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 143-144 占 폚.
[788] Reference Example 97
[789] A mixture of 2- (5-chloroimidazo [1,2-a] pyridin-2-ylmethoxy) -4-pyridylmethanol (2.90 g) and thienyl chloride (10 ml) was stirred at room temperature for 1 hour . After concentrating the reaction mixture, a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloro-2- (4-chloromethyl-2-pyridyloxymethyl) imidazo [l, 2-a] pyridine , Yield: 85%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 118-119 DEG C
[790] Reference Example 98
[791] Sodium hydride (60%, oil, 2.88 g) was added to a solution of methyl 5-hydroxy-3-pyridinecarboxylate (10.00 g) and N-phenyltrifluoromethanesulfonimide (24.00 g, ) At 0 &lt; 0 &gt; C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 5-trifluoromethanesulfonyloxy-3-pyridinecarboxylate (18.06 g, yield 97%) from a fraction eluted with ethyl acetate-hexane (1: 4 by volume) As a colorless oily substance.
[792] _{NMR (CDCl 3) δ: 4.01} (3H, s), 8.23 (1H, dd, J = 1.4, 2.6 Hz), 8.77 (1H, d, J = 2.6 Hz), 9.26 (1H, d, J = 1.4 Hz ).
[793] Reference Example 99
[794] Phenylboronic acid (7.88 g), tetrakis (triphenylphosphine) palladium (3.01 g), sodium carbonate (13.51 g), sodium carbonate A mixture of ethanol (80 mL), water (80 mL) and toluene (500 mL) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 5-phenyl-3-pyridinecarboxylate (8.63 g, yield 60%) as a colorless oily substance from the fraction eluted with ethyl acetate.
[795] _{NMR (CDCl 3) δ: 1.44} (3H, t, J = 6.8 Hz), 4.46 (2H, q, J = 6.8 Hz), 7.42-7.70 (5H, m), 8.44-8.56 (1H, m), 9.00 (1H, d, J = 2.2Hz), 9.20 (1H, d, J = 1.8Hz).
[796] Reference Example 100
[797] Lithium aluminum hydride (1.45 g) was added to a solution of ethyl 5-phenyl-3-pyridinecarboxylate (8.60 g) in tetrahydrofuran (100 ml) at 0 ° C and stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (13.40 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated. The resulting colorless crystals were collected by filtration to give 5-phenyl-3-pyridylmethanol (4.82 g, yield 69%). This was recrystallized from ethyl acetate-hexane. Melting point: 71-72 ° C
[798] Reference Example 101
[799] A mixture of 5-phenyl-3-pyridylmethanol (4.50 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and a saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5-phenylpyridine (4.28 g, yield 86%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from ethyl acetate-hexane. Melting point: 75-76 DEG C
[800] Reference Example 102
[801] A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g), 2-chloromethylquinoline hydrochloride (8.99 g), potassium carbonate (14.50 g) and N, N-dimethylformamide Was stirred at 60 &lt; 0 &gt; C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- (2-quinolylmethoxy) -5-isoxazole carboxylate (7.78 g, yield 78%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 133-134 占 폚.
[802] Reference Example 103
[803] Diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 mL) was added to a solution of methyl 3- (2-quinolylmethoxy) -5-isoxazole carboxylate (7.39 g) in tetrahydrofuran At 0 &lt; 0 &gt; C and stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 3- (2-quinolylmethoxy) -5-isoxazolylmethanol (4.95 g, yield 74%) as colorless crystals . This was recrystallized from tetrahydrofuran-hexane. Melting point: 111-112 DEG C
[804] Reference Example 104
[805] A mixture of 3- (2-quinolylmethoxy) -5-isoxazolylmethanol (1.54 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was extracted with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 2- (5-chloromethyl-3-isoxazolyloxymethyl) quinoline (1.61 g, yield 98%) as colorless crystals . This was recrystallized from ethyl acetate-hexane. Melting point: 126-127 DEG C
[806] Reference Example 105
[807] (1.7 M pentane solution, 15 mL) was slowly added to a solution of 5-chloro-2-phenylpyridine (4.70 g) in tetrahydrofuran (50 mL) at -78 <0> C under a nitrogen atmosphere, Lt; / RTI &gt; N, N-Dimethylformamide (2.3 mL) was added slowly to the mixture, and the mixture was stirred for 1 hour while the temperature was raised to room temperature. After addition of dilute hydrochloric acid, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with a saturated aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. Sodium borohydride (946 mg) was slowly added to the above mixture of the residue, tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloro-6-phenyl-2-pyridylmethanol (2.35 g, yield 43%) as a pale yellow crystal from an eluted fraction with ethyl acetate- . This was recrystallized from ethyl acetate-hexane. Melting point: 69-70 DEG C
[808] Reference Example 106
[809] A solution of 3-chloro-6-phenyl-2-pyridyl methanol (2.20 g), 5% palladium on carbon (1.10 g), triethylamine (1.4 ml), methanol (20 ml) and tetrahydrofuran The mixture was stirred at room temperature under a hydrogen atmosphere. The palladium-carbon was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-phenyl-2-pyridylmethanol (1.76 g, yield 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 5, .
[810] _{NMR (CDCl 3) δ: 4.20} (1H, t, J = 3.8 Hz), 4.82 (2H, d, J = 3.8 Hz), 7.16 (1H, dd, J = 0.8, 7.6 Hz), 7.38-7.54 (3H (1H, m), 7.64 (1H, dd, J = 0.8,7.6 Hz), 7.76 (1H, t, J = 7.6 Hz), 7.99-8.05 (2H, m).
[811] Reference Example 107
[812] A mixture of 3-chloro-6-phenyl-2-pyridylmethanol (2.20 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was concentrated to a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 3-chloro-2-chloromethyl-5-phenylpyridine (2.25 g, yield 94%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 74-75 DEG C
[813] Reference Example 108
[814] A mixture of 6-phenyl-2-pyridyl methanol (1.76 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-chloromethyl-5-phenylpyridine (1.91 g, yield 99%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 5, by volume) .
[815] _{NMR (CDCl 3) δ: 4.75} (2H, s), 7.36-7.52 (4H, m), 7.64 (1H, dd, J = 1.0, 7.6 Hz), 7.77 (1H, t, J = 7.6 Hz), 7.96 -8.02 (2 H, m).
[816] Reference Example 109
[817] Sodium hydride (60%, oil, 1.40 g) was added to a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate 6.01 g) at 0 &lt; 0 &gt; C, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. Lithium aluminum hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 mL) at 0 占 and stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 5.81 g of 6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethanol as a colorless crystal from the fraction eluted with tetrahydrofuran Respectively. This was recrystallized from tetrahydrofuran-hexane. Melting point: 134-135 DEG C
[818] Reference Example 110
[819] Sodium hydride (60%, oil, 1.58 g) was added to a solution of 2-quinolylmethanol (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78 g) in N, N- dimethylformamide At 0 &lt; 0 &gt; C, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. Lithium aluminum hydride (1.50 g) was added to the residue solution in tetrahydrofuran (150 ml) at 0 占 폚, which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2- (2-quinolylmethoxy) -5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from a fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124-125 DEG C
[820] Reference Example 111
[821] A mixture of 6- (2-quinolylmethoxy) -3-pyridylmethanol (2.66 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a fraction eluted with ethyl acetate-hexane (1: 1, by volume) to obtain 2- (5-chloromethyl-2-pyridyloxymethyl) quinoline (2.50 g, yield 88% Colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 118-119 DEG C
[822] Reference Example 112
[823] A mixture of 6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethanol (2.98 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloromethyl-2- (2-phenyl-4-thiazolylmethoxy) pyridine (2.40 g, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate . This was recrystallized from tetrahydrofuran-hexane. Melting point: 117-118 DEG C
[824] Reference Example 113
[825] A mixture of 3-methyl-1- (2-pyridyl) -lH-pyrazol-4-ylmethanol (3.00 g), thionyl chloride (2.5 mL) and toluene (50 mL) Respectively. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 4-chloromethyl-3-methyl-1- (2- pyridyl) -1H- pyrazole (3.10 g, 94% yield) Obtained as a colorless oily substance.
[826] _{NMR (CDCl 3) δ: 2.44} (3H, s), 4.58 (2H, s), 7.46-7.60 (1H, m), 8.18-8.42 (2H, m), 8.50-8.60 (1H, m), 9.43 ( 1H, s)
[827] Reference Example 114
[828] A mixture of 2-methyl-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (18.04 g), 3-chloroperbenzoic acid (18.85 g) and tetrahydrofuran Stir overnight and concentrate. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with tetrahydrofuran. A solution of the resulting colorless oily substance in acetic anhydride (100 mL) was slowly added to heated acetic anhydride (100 mL) heated at 130 &lt; 0 &gt; C, stirred for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 18.09 g (83% yield) of [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] acetate in ethyl acetate- 1: 2, volume ratio) as a colorless oily substance.
[829] _{NMR (CDCl 3) δ: 2.13} (3H, s), 2.45 (3H, s), 5.05 (2H, s), 5.16 (2H, s), 7.26-7.50 (5H, m), 7.94-8.05 (2H, m), 8.38-8.43 (1 H, m).
[830] Reference Example 115
[831] A mixture of 18.00 g of [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] acetate, 75 ml of 1N aqueous sodium hydroxide solution and 100 ml of methanol was stirred at room temperature Lt; / RTI &gt; for 3 hours and concentrated. The residue was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethanol (14.29 g, yield 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 125-126 DEG C
[832] Reference Example 116
[833] Sodium borohydride (835 mg) was added to a solution of 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) nicotinaldehyde (13.0 g) in tetrahydrofuran (150 ml) Lt; 0 &gt; C. After stirring for 30 minutes, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals of 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethanol. This was recrystallized from acetone-isopropyl ether to give colorless prism crystals (12.4 g, yield 95%). Melting point: 121-122 DEG C
[834] Reference Example 117
[835] (5.39 g) was added to a mixture of 6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethanol (12.2 g) and toluene (200 ml) Lt; / RTI &gt; for 1 hour. Ice water was added to the reaction mixture, which was washed with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (11.7 g, yield 90%) in ethyl acetate- , Volume ratio) as colorless crystals. This was recrystallized from ethyl acetate-hexane to give colorless prism crystals. Melting point: 86-87 DEG C
[836] Reference Example 118
[837] Sodium borohydride (410 mg) was added to a mixture of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] nicotinaldehyde (3.10 g), tetrahydrofuran (50 ml) At room temperature, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain 2.86 g of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] , Yield 92%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 120-121 DEG C
[838] Reference Example 119
[839] A mixture of 6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-pyridylmethanol (1.87 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour . The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloromethyl-2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] pyridine (1.41 g, yield 71% (1: 3, volume ratio) from the eluted fractions as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 95-96 DEG C
[840] Reference Example 120
[841] Lithium aluminum hydride (1.33 g) was added to a solution of ethyl 1- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -1H-pyrazole- g) at 0 &lt; 0 &gt; C, which was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (12.26 g) and hexane (100 mL) were added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was concentrated to give 1- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -1H-pyrazol-4-ylmethanol (12.9 g, yield 95% As colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 112-113 DEG C
[842] Reference Example 121
[843] A mixture of l- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -1H-pyrazol-4-ylmethanol (11.7 g), active manganese dioxide (20.0 g) and tetrahydrofuran Was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to obtain 10.9 g (yield 94%) of l- (4-benzyloxybenzyl) -3- (4-fluorophenyl) ) As colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97-98 DEG C
[844] Reference Example 122
[845] 5-methyl-2-phenyloxazole (15.20 g), potassium carbonate (15.98 g) and N, N-dimethylformamide (200 ml ) Was stirred at 80 &lt; 0 &gt; C for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-methyl-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (19.68 g, yield 96%) in tetrahydrofuran- , Volume ratio) as light yellow crystals. This was recrystallized from acetone-hexane. Melting point: 103-104 DEG C
[846] Reference Example 123
[847] Yl) propionate (2.02 g), 1,2-dibromoethane (20 ml), potassium carbonate &lt; RTI ID = 0.0 &gt; (1.68 g) and N, N-dimethylformamide (20 ml) was stirred at 90 占 폚 for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (2-bromoethoxy) benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (1530 mg, %) Was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 4, by volume).
[848] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.0 Hz), 2.46-2.58 (2H, m), 2.88-3.00 (2H, m), 3.59-3.70 (2H, m), 4.08 (2H, (2H, m), 7.16-7.52 (6H, m), 7.58-7.68 (2H, m) .
[849] Reference Example 124
[850] A solution of p-toluenesulfonylmethylisocyanide (12.3 g) in dimethoxyethane (60 ml) was added to a mixture of potassium t-butoxide (13.5 g) and dimethoxyethane (60 ml) at -78 < , And the product was stirred for 5 minutes. A solution of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (13.0 g) in dimethoxyethane (60 mL) was added to the mixture. After stirring at the same temperature for 1 hour, the mixture was stirred for 1 hour while raising the temperature. Methanol (180 mL) was added to the mixture and refluxed for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The resulting colorless oily substance, a mixture of 4N aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol (100 ml) was refluxed for 3 days. After cooling, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. A mixture of the residue, ethyl iodide (6.5 ml), potassium carbonate (14.9 g) and N, N-dimethylformamide (150 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The resulting oily substance, 5% palladium-carbon (30.0 g), formic acid (80 mL) and ethanol (160 mL) was refluxed for 1 hour. After cooling, the palladium-carbon was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and this saturated aqueous sodium bicarbonate solution, then washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-phenyl-1H-pyrazol-4-yl acetate (4.65 g, yield 34%) from the eluted fractions in ethyl acetate-hexane (1: 1, As an oily substance.
[851] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.0 Hz), 3.61 (2H, s), 4.14 (2H, q, J = 7.0 Hz), 7.32-7.47 (3H, m), 7.51-7.59 (3H, m), 11.38 (1H, br.
[852] Reference Example 125
[853] Lithium aluminum hydride (300 mg) was added to a solution of ethyl 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1H-pyrazole-4-carboxylate (1.56 g) in dichloromethane at 0 &lt; 0 &gt; C and stirred for 2 hours. Sodium sulfate decahydrate (3.40 g) was added to the reaction mixture and the precipitate was filtered. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to obtain 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] Pyrazol-4-ylmethanol (1.27 g, 89% yield) was obtained as a colorless oily substance from the fraction eluted with acetone-hexane (2: 3, by volume).
[854] _{NMR (CDCl 3) δ: 1.60} (1H, t, J = 5.5Hz), 2.48 (3H, s), 4.68 (2H, d, J = 5.5 Hz), 5.26 (2H, s), 5.30 (2H, s ), 6.82 (1H, d, J = 8.5 Hz), 7.25-7.5 (7H, m), 7.56 (1H, dd, J = 8.5,2 Hz), 7.7-7.8 (2H, m), 7.95-8.05 1H, m), 8.15 (1H, d, J = 2 Hz).
[855] Reference Example 126
[856] 3-phenyl-1H-pyrazol-4-yl methanol (1.25 g), active manganese dioxide ( 3.00 g) and ethyl acetate (80 mL) was stirred at room temperature for 3 hours. The manganese dioxide was separated by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] (1.20 g, yield 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[857] _{NMR (CDCl 3) δ: 2.48} (3H, s), 5.30 (2H, s), 5.31 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 7.4-7.6 (7H, m), 7.59 (1H, dd, J = 8.5, 2.5 Hz), 7.65-7.8 (2H, m), 7.97 (1H, s), 8.0-8.05 9.93 (1H, s).
[858] Reference Example 127
[859] A solution of p-toluenesulfonylmethylisocyanide (3.08 g) in dimethoxyethane (15 ml) was added to a mixture of potassium tert-butoxide (3.37 g) and dimethoxyethane (15 ml) at -78 < , And the product was stirred for 5 minutes. A solution of l- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -lH-pyrazole-4-carbaldehyde (5.80 g) in dimethoxyethane (30 mL) . After stirring at the same temperature, the mixture was stirred for 1 hour while raising the temperature. Methanol (45 mL) was added to the mixture, which was stirred for 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.52 g (yield 76%) of l- (4-benzyloxybenzyl) -3- (4- fluorophenyl) -1H- pyrazol-4-yl acetonitrile -Hexane &lt; / RTI &gt; (1: 2, volume ratio) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 86-87 DEG C
[860] Reference Example 128
[861] A mixture of ethyl 1- (4-phenoxybenzyl) -3- (4-phenoxybenzyloxy) -1H-pyrazole-4-carboxylate (21.50 g), 5% palladium- (300 mL) was stirred under a hydrogen atmosphere overnight. The palladium-carbon was removed by filtration and the filtrate was concentrated to give ethyl 3-hydroxy-1- (4-phenoxybenzyl) -1H-pyrazole-4-carboxylate (13.35 g, yield 96%) Colorless crystals. This was recrystallized from acetone-hexane. Melting point: 117-118 DEG C
[862] Reference Example 129
[863] Lithium aluminum hydride (205 mg) was added to a solution of methyl 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] -4-phenylpyridine in 40 ml of tetrahydrofuran Pyrrole-3-carboxylate (1.30 g) in tetrahydrofuran at 0 &lt; 0 &gt; C and the product was stirred for 3 hours. Sodium sulfate decahydrate (2.80 g) was added to the reaction mixture and the precipitate was removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to obtain [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) - pyrrolyl] methanol (1.15 g, yield 94%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (3: 2, by volume).
[864] NMR (CDCl ₃ ) : 2.48 (3H, s), 4.63 (2H, br s), 4.98 (2H, s), 5.30 (2H, s), 6.7-6.85 , &lt; / RTI &gt; m), 7.95-8.1 (3H, m).
[865] Reference Example 130
[866] 3-pyrrolyl] methanol (1.15 g), active manganese manganese (2.30 g, 0.35 mmol) ) And ethyl acetate (80 mL) was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to give 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) (1.06 g, yield 93%) as a colorless oily substance.
[867] _{NMR (CDCl 3) δ: 2.48} (3H, s), 5.04 (2H, s), 5.31 (2H, s), 6.75 (1H, d, J = 2 Hz), 6.84 (1H, d, J = 8.5 Hz ), 7.25-7.5 (10H, m), 7.95-8.15 (3H, m), 9.86 (1H, s).
[868] Reference Example 131
[869] A mixture of ethyl (E) -3- [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propionate (12.13 g), 5% palladium- After the palladium-carbon was removed by filtration, the filtrate was concentrated to give ethyl 3- [l- (4-hydroxybenzyl) -3-phenyl-thiophene- Pyrazol-4-yl] propionate (9.52 g, yield 98%) as a colorless oily substance.
[870] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.48-2.58 (2H, m), 2,88-3.00 (2H, m), 4.08 (2H, q, J = 7.2 Hz) , 5.19 (2H, s), 6.62-6.74 (2H, m), 6.98-7.10 (2H, m), 7.18-7.45 (4H, m), 7.56-7.66 (2H, m).
[871] Reference Example 132
[872] Yl) propionate (10.0 g), 5% palladium-on-charcoal (10.0 g) was added to a solution of ethyl (E) -3- [1- (20.0 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere for 1 hour. The palladium-carbon was removed by filtration and the filtrate was concentrated to obtain ethyl 3- [3- (4-fluorophenyl) -1- (4-hydroxybenzyl) -1H-pyrazol- (7.15 g, yield 88%) as a colorless oily substance.
[873] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.6 Hz), 2,90 (2H, t, J = 7.6 Hz), 4.08 (2H, q (2H, d, J = 8.4Hz), 6.97 (2H, d, J = 8.4Hz), 7.07 7.24 (1H, s), 7.56 (2H, dd, J = 5.4,8.8 Hz), 7.59 (1H, s).
[874] Reference Example 133
[875] A mixture of 5-phenyl-2-pyridylmethyl acetate (3.68 g), 1 N aqueous sodium hydroxide solution (30 mL), tetrahydrofuran (30 mL) and methanol (300 mL) was stirred at room temperature for 3 hours, . The residue was dissolved in ethyl acetate and the solution was then washed with water, then with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated. The residual colorless crystals were collected by filtration to give 5-phenyl-2-pyridylmethanol (2.84 g, yield 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 86-87 DEG C
[876] Reference Example 134
[877] A mixture of 5-phenyl-2-pyridyl methanol (1.98 g), thionyl chloride (1.6 ml) and toluene (30 ml) was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated, then a saturated aqueous sodium bicarbonate solution was added to the residue, which was washed with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The mixture of the residue, 4-hydroxybenzyl alcohol (1.37 g), potassium carbonate (3.18 g) and N, N-dimethylformamide (50 ml) was stirred at 80 占 폚 overnight. The reaction mixture was poured into water, which was washed with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.69 g (yield 86%) of 4- (5-phenyl-2-pyridylmethoxy) benzyl alcohol from the eluted fraction with ethyl acetate-hexane (1: 1, Crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 159-160 DEG C
[878] Reference Example 135
[879] Sodium borohydride (0.36 g) was added to a mixture of 4- (2-phenyl-4-oxazolylmethoxy) benzaldehyde (2.65 g) and methanol (50 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hour. Dilute hydrochloric acid and water were added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 4- (2-phenyl-4-oxazolylmethoxy) benzyl alcohol (2.43 g, yield 91%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 141-142 DEG C
[880] Reference Example 136
[881] A mixture of 4- (2-phenyl-4-oxazolylmethoxy) benzyl alcohol (2.39 g), thionyl chloride (0.69 ml) and toluene (50 ml) was stirred overnight at 40 & . A saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.34 g (yield 92%) of 4- (4-chloromethylphenoxymethyl) -2-phenyloxazole as a fraction eluted with ethyl acetate-hexane (1: 3, As colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 129-130 DEG C
[882] Reference Example 137
[883] Lithium aluminum hydride (320 mg) was added to a solution of methyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4-phenoxybenzyl) -lH-pyrazole in 30 ml of tetrahydrofuran Carboxylate (4.00 g) at 0 &lt; 0 &gt; C and stirred for 2 hours. Sodium sulfate decahydrate (2.95 g) was added to the reaction mixture and the precipitate was removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to obtain [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4-phenoxybenzyl) 4-yl] methanol (3.56 g, yield 97%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 103-104 DEG C
[884] Reference Example 138
[885] 4-yl] methanol (2.85 g), active manganese dioxide (8.42 g, 0.35 mmol), triethylamine ) And tetrahydrofuran (50 mL) was stirred at room temperature overnight. The manganese dioxide was separated by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4-phenoxybenzyl) -1H- pyrazole-4-carbaldehyde g, yield 92%) was obtained as colorless crystals from the eluted fractions in ethyl acetate-hexane (1: 1, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 129-130 DEG C
[886] Reference Example 139
[887] A mixture of 4- (2-bromoethoxy) benzaldehyde (4.97 g), 1 (2H) -phthalazinone (3.27 g), potassium carbonate (6.20 g) and N, N- dimethylformamide Lt; 0 &gt; C for 5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The ethylacetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give 4- [2- [1-oxo- 2 (lH) -phthalazinyl] ethoxy] benzaldehyde (5.36 g, As colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 126-127 DEG C
[888] Reference Example 140
[889] A mixture of 3- (2-bromoethoxy) benzaldehyde (6.00 g), 1 (2H) -phthalazine (4.21 g), potassium carbonate (7.24 g) and N, N- dimethylformamide Lt; 0 &gt; C for 5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated to give 3- [2- [1-oxo -2 (1H) -] phthalazine possess ethoxy] benzaldehyde (6.94 g, yield 90%) As colorless crystals. This was recrystallized from acetone-hexane. Melting point: 110-111 DEG C
[890] Reference Example 141
[891] (7.59 g), 2-chloropyridine (5 ml), sodium hydride (60%, oil, 2.32 g) and N, N-dimethylformamide ML) was stirred at 180 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-methyl-1- (2-pyridyl) -1H-pyrazole-4-carboxylate (prepared from ethyl 3-methyl- 8.31 g, yield 73%). This was recrystallized from ethyl acetate-hexane. Melting point: 79-80 DEG C
[892] Reference Example 142
[893] Sodium borohydride (0.45 g) was added to a mixture of 4- (2-phenyl-4-thiazolylmethoxy) benzaldehyde (6.35 g), tetrahydrofuran (30 ml) and methanol (20 ml) under ice- And stirred at room temperature for 30 minutes. The reaction mixture was neutralized with dilute hydrochloric acid and water to obtain a precipitate which was collected by filtration and air dried to give 4- (2-phenyl-4-thiazolylmethoxy) benzyl alcohol (5.76 g, yield 90% Crystals were obtained. This was recrystallized from ethyl acetate-hexane to give colorless needles. Melting point: 145-146 DEG C
[894] Reference Example 143
[895] A solution of thionyl chloride (1.5 mL) in toluene (5 mL) was added to a solution of 4- (2-phenyl-4-thiazolylmethoxy) benzyl alcohol (4.35 g), tetrahydrofuran (50 mL) Under ice-cooling, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium bicarbonate solution followed by a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give colorless crystals of 4- (4-chloromethylphenoxymethyl) -2-phenylthiazole (4.10 g, yield 89%). Melting point: 98-99 DEG C
[896] Reference Example 144
[897] A mixture of 4-chloromethyl-5-methyl-2-phenylthiazole (5.40 g), 4-hydroxybenzaldehyde (2.91 g), anhydrous potassium carbonate (4.95 g) and N, N-dimethylformamide Was stirred at 80 &lt; 0 &gt; C for 3 hours. The reaction mixture was poured into water and the precipitated solid was collected by filtration and air dried to give crystals of 4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzaldehyde (6.85 g, yield 93% &Lt; / RTI &gt; This was recrystallized from ethyl acetate-hexane to give a colorless prism. Melting point: 118-119 DEG C
[898] Reference Example 145
[899] Sodium borohydride (0.38 g) was added to a mixture of 4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzaldehyde (6.00 g), tetrahydrofuran (30 ml) and methanol (20 ml) And the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with dilute hydrochloric acid and water to give a precipitate which was collected by filtration and air dried to give 4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyl alcohol (5.68 g, 94%). &Lt; / RTI &gt; This was recrystallized from ethyl acetate-hexane to give a colorless prism. Melting point: 94-95 DEG C
[900] Reference Example 146
[901] A solution of thionyl chloride (1.5 mL) in toluene (5 mL) was added to a solution of 4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyl alcohol (4.50 g), tetrahydrofuran (50 mL) under ice-cooling, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution followed by a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crystals of 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenylthiazole (4.50 g, 94% yield). Melting point: 100-101 DEG C
[902] Reference Example 147
[903] A mixture of 4-chloromethyl-2-phenylthiazole (8.60 g), sodium acetate (10.1 g) and N, N-dimethylformamide (80 mL) was stirred at 80 ° C for 6 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue, a mixture of 4 N aqueous sodium hydroxide solution (25 mL), tetrahydrofuran (50 mL) and methanol (50 mL) was stirred at room temperature for 5 minutes, poured into water and rinsed with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-phenyl-4-thiazolylmethanol (7.05 g, yield 90%) as colorless crystals from an eluted fraction from ethyl acetate-hexane (1: 1, volume ratio). This was recrystallized from hexane. Melting point: 71-72 ° C
[904] Reference Example 148
[905] A mixture of 2-chloromethylquinoline hydrochloride (21.4 g), sodium acetate (32.8 g) and N, N-dimethylformamide (200 mL) was stirred at 60 ° C overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue, a mixture of 4N aqueous sodium hydroxide solution (50 mL), tetrahydrofuran (100 mL) and methanol (100 mL) was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-quinolylmethanol (14.0 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 68-69 캜
[906] Reference Example 149
[907] Sodium hydride (60%, oil, 5.01 g) was added to a solution of 5-hydroxy-2-methylpyridine (12.45 g) and N- phenyltrifluoromethanesulfonimide (40.80 g) in tetrahydrofuran At O &lt; 0 &gt; C, which was stirred at room temperature for 1 hour and concentrated. After dissolving the residue in ethyl acetate and wash it with saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 6-methyl-3-pyridyl trifluoromethanesulfonate (23.10 g, yield 84%) from a fraction eluted with ethyl acetate-hexane (1: 4, As an oily substance.
[908] _{NMR (CDCl 3) δ: 2.61} (3H, s), 7.27 (1H, d, J = 8.4 Hz), 7.52 (1H, dd, J = 2.8, 8.4 Hz), 8.47 (1H, d, J = 2.8 Hz ).
[909] Reference Example 150
[910] Palladium (5.00 g), sodium carbonate (22.43 g), ethanol (100 ml), and the mixture was stirred at room temperature for 3 hours. ML), water (100 mL) and toluene (500 mL) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-methyl-5-phenylpyridine (15.24 g, yield 94%) as a colorless oily substance from a fraction eluted with ethyl acetate.
[911] _{NMR (CDCl 3) δ: 2.61} (3H, s), 7.23 (1H, d, J = 8.0 Hz), 7.32-7.63 (5H, m), 7.78 (1H, dd, J = 2.6, 8.0 Hz), 8.73 (1 H, d, J = 2.6 Hz).
[912] Reference Example 151
[913] A mixture of 2-methyl-5-phenylpyridine (3.00 g), 3-chloroperbenzoic acid (4.79 g) and tetrahydrofuran (50 mL) was stirred at room temperature overnight and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with tetrahydrofuran. A solution of the resulting colorless oily substance (50 mL) in dry acetic acid was slowly added to heated acetic anhydride (50 mL) heated at 130 &lt; 0 &gt; C, which was stirred and concentrated for 2 h. The residue was dissolved in ethyl acetate and wash it with saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-phenyl-2-pyridylmethyl acetate (3.68 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 71-72 ° C
[914] Reference Example 152
[915] A solution of p-toluenesulfonylmethylisocyanide (10.3 g) in dimethoxyethane (50 ml) was added to a mixture of potassium t-butoxide mixture (11.2 g) and dimethoxyethane (50 ml) And the mixture was stirred for 5 minutes. A solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml) was added to this mixture. After stirring at the same temperature for 1 hour, the mixture was stirred for 1 hour while raising the temperature. Methanol (150 mL) was added to the mixture, which was refluxed for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 1-benzyl-3-benzyloxy-1H-pyrazol-4-yl acetonitrile (13.1 g, yield 86%) from a fraction eluted with ethyl acetate- %) As a colorless oily substance.
[916] _{NMR (CDCl 3) δ: 3.42} (2H, s), 5.11 (2H, s), 5.24 (2H, s), 7.18-7.24 (3H, m), 7.27-7.47 (8H, m).
[917] Reference Example 153
[918] A mixture of 1-benzyl-3-benzyloxy-1H-pyrazol-4-yl acetonitrile (13.0 g), 4N aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol Lt; / RTI &gt; After cooling, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. A mixture of the residue, ethyl iodide (5.2 mL), potassium carbonate (11.9 g) and N, N-dimethylformamide (100 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-yl acetate (14.9 g, yield 99%) from the fraction eluted with ethyl acetate-hexane (1: %) As a colorless oily substance.
[919] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 3.39 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 5.12 (2H, s), 5.24 (2H, s ), 7.17-7.26 (3H, m), 7.28-7.49 (8H, m).
[920] Reference Example 154
[921] A mixture of ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-yl acetate (14.9 g), 5% palladium- carbon (15.0 g), tetrahydrofuran (150 ml) and ethanol (150 ml) And stirred under a hydrogen atmosphere for 2 hours. The palladium-carbon was removed by filtration and the filtrate was concentrated to give ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-yl acetate (9.76 g, yield 88%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 156-157 DEG C
[922] Reference Example 155
[923] To a solution of ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-yl acetate (7.81 g) in N, N-dimethylformamide (100 ml) was added sodium hydride (60% At 0 [deg.] C, which was stirred at room temperature for 15 minutes. Ethyl iodide (2.40 mL) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-yl acetate (7.52 g, yield 87%) from the fraction eluted with ethyl acetate-hexane (1: 3, %) As a colorless oily substance.
[924] _{NMR (CDCl 3) δ: 1.25} (3H, t, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 3.36 (2H, s), 4.14 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0Hz), 5.10 (2H, s), 7.16-7.38 (6H, m).
[925] Reference Example 156
[926] A mixture of ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-yl acetate (7.50 g), 5% palladium- carbon (15.0 g), formic acid (50 ml) and ethanol (100 ml) Lt; / RTI &gt; After cooling, the palladium-carbon was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and this saturated aqueous sodium bicarbonate solution, then washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1H-pyrazol-4-yl acetate (2.79 g, yield 54%), which was eluted with ethyl acetate-hexane (1: 1, Lt; / RTI &gt;
[927] _{NMR (CDCl 3) δ: 1.27} (3H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.0 Hz), 3.41 (2H, s), 4.14 (2H, q, J = 7.2 Hz), 4.25 (2H, q, J = 7.0 Hz), 7.38 (1H, s), 9.38 (1H, br.s).
[928] Reference Example 157
[929] Lithium aluminum hydride (1100 mg) was added to a solution of ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -1H-pyrazole-4-carboxylate (14.39 g) in tetrahydrofuran at 0 &lt; 0 &gt; C and stirred for 30 minutes. Sodium sulfate decahydrate (12.14 g) was added to the reaction mixture and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography on silica gel to give [1- [4- (5-methyl-2-phenyl-4-oxazolyl Methoxy) benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] methanol (12.20 g, yield 93%) as a light yellow oily substance.
[930] _{NMR (CDCl 3) δ: 2.44} (3H, s), 4.69 (2H, d, J = 5.4 Hz), 4.99 (2H, s), 5.24 (2H, s), 6.96-7.13 (3H, m), 7.20 -7.34 (4H, m), 7.38-7.48 (4H, m), 7.96-8.06 (2H, m).
[931] Reference Example 158
[932] Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] methanol (12.15 g), active A mixture of manganese dioxide (37.03 g) and tetrahydrofuran (200 ml) was stirred at room temperature overnight. The manganese dioxide was removed by filtration, and the filtrate was concentrated to obtain 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) Sol-4-carbaldehyde (11.68 g, yield: 96%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 136-137 占 폚.
[933] Reference Example 159
[934] Lithium aluminum hydride (540 mg) was added to a solution of ethyl 1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) -1H-pyrazole in 50 ml of tetrahydrofuran Carboxylate (7.10 g) at O &lt; 0 &gt; C and stirred for 30 minutes. Sodium sulfate decahydrate (4.33 g) was added to the reaction mixture and the precipitate was removed by filtration. The filtrate was concentrated and the residue was chromatographed on silica gel column to give [1- [4- (2-phenyl-4-thiazolylmethoxy) benzyllthiazolylmethoxy) benzyl from the fraction eluted with ethyl acetate-hexane (1: 1, ] -3- (2-thienyl) -1H-pyrazol-4-yl] methanol (6.31 g, yield: 96%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 147-148 占 폚.
[935] Reference Example 160
[936] 4-yl] methanol (5.57 g), active manganese dioxide (16.11 g, 0.35 mmol), triethylamine ) And tetrahydrofuran (100 mL) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) (5.39 g, yield: 98%) of the title compound as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 115-116 [deg.] C.
[937] Reference Example 161
[938] A solution of p-toluenesulfonylmethylisocyanide (0.95 g) in dimethoxyethane (10 ml) was added to a mixture of potassium tert-butoxide (1.01 g) and dimethoxyethane (10 ml) at -78 < , And the mixture was stirred for 5 minutes. Benzyl] -3- (2-thienyl) -lH-pyrazole-4-carbaldehyde in 20 ml dimethoxyethane (20 ml) A solution of aldehyde (2.01 g) was added to the mixture, stirred at the same temperature for 1 hour, and stirred at room temperature for 1 hour. Methanol (40 ml) was added to the mixture and reflux was carried out for 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3 - (2-thienyl) -1 H-pyrazol-4-yl] acetonitrile (1.69 g, yield 78%) as a colorless oily substance.
[939] _{NMR (CDCl 3) δ: 2.44} (3H, s), 3.69 (2H, s), 4.99 (2H, s), 5.24 (2H, s), 6.96-7.48 (11H, m), 7.95-8.08 (2H, m).
[940] Reference Example 162
[941] Benzyl] -3- (2-thienyl) -1H-pyrazole-4-carbaldehyde (5.02 g), diethyl A mixture of malonate (2.12 g), piperidine (0.35 ml), benzoic acid (0.27 g) and toluene (50 ml) was azeotropically dehydrated for one hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). Sodium borohydride (170 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml) and tetrahydrofuran (20 ml) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -Yl] methyl malonate (6.08 g, yield 92%) as a light yellow oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[942] _{NMR (CDCl 3) δ: 1.14-1.35} (6H, m), 2.44 (3H, s), 3.24 (2H, d, J = 7.6 Hz), 3.61 (1H, t, J = 7.6 Hz), 4.05-4.18 (4H, m), 4.98 (2H, s), 5.20 (2H, s), 6.92-7.34 (8H, m), 7.38-7.48 (3H, m), 7.96-8.06 (2H, m).
[943] Reference Example 163
[944] Benzyl] -3- (2-thienyl) -1H-pyrazole-4-carbaldehyde (3.70 g), diethyl malonate (1.56 g), piperidine (0.25 mL), benzoic acid (0.20 g) and toluene (50 mL) was azeotropically dehydrated for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). Sodium borohydride (150 mg) was added to a mixture of the obtained colorless oily substance, ethanol (30 mL) and tetrahydrofuran (30 mL) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- ( Yl] methyl malonate (4.09 g, yield: 84%) was obtained as a pale yellow oily substance.
[945] _{NMR (CDCl 3) δ: 1.18} (6H, t, J = 7.0 Hz), 3.24 (2H, d, J = 7.6 Hz), 3.62 (1H, t, J = 7.6 Hz), 4.12 (4H, q, J = 7.0 Hz), 5.20 (2H, s), 5.26 (2H, s), 6.94-7.04 (2H, m), 7.09 (1H, dd, J = 3.6, 5.2 Hz), 7.15-7.36 , 7.40-7.48 (3H, m), 7.90-7.99 (2H, m).
[946] Reference Example 164
[947] Lithium aluminum hydride (210 mg) was added to a solution of ethyl 1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -1 H-pyrazole in 50 ml of tetrahydrofuran Carboxylate (2.73 g) in dichloromethane at 0 &lt; 0 &gt; C and stirred for 30 minutes. Sodium sulfate decahydrate (1.80 g) was added to the reaction mixture, then the precipitate was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain [l- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) Methanol (2.33 g, 94% yield) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 155-156 ° C.
[948] Reference Example 165
[949] 4-yl] methanol (2.03 g), active manganese dioxide (6.00 g, 0.35 mmol) ) And tetrahydrofuran (50 mL) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) (1.74 g, yield: 86%) of the title compound as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 153-154 &lt; 0 &gt; C.
[950] Reference Example 166
[951] Benzyl] -3- (2-thienyl) -1H-pyrazole-4-carbaldehyde (1.60 g), diethyl malonate (0.69 g), piperidine (0.12 mL), benzoic acid (0.09 g) and toluene (50 mL) was azeotropically dehydrated for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). Sodium borohydride (105 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml) and tetrahydrofuran (20 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel chromatography to obtain a diethyl 1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -1H- A colorless oily substance was obtained from the fraction eluted with malonate (1.76 g, yield: 83%) in ethyl acetate-hexane (1: 2, by volume).
[952] _{NMR (CDCl 3) δ: 1.18} (6H, t, J = 7.0 Hz), 3.24 (2H, d, J = 7.8 Hz), 3.61 (1H,, J = 7.8 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.12 (2H, q, J = 7.2 Hz), 5.07 (2H, d, J = 1.0 Hz), 5.20 (2H, s), 6.95-7.01 J = 5.0, 3.6 Hz), 7.17-7.32 (5H, m), 7.42-7.50 (3H, m), 7.73 (1H, J = 1.0 Hz), 8.02-8.08 (2H, m) .
[953] Reference Example 167
[954] A mixture of 2-acetylthiophene (50.75 g), sodium hydride (60%, oil, 16.33 g) and diethyl carbonate (500 ml) was stirred at 80 ° C for 1 hour. Water was added to the reaction mixture and the aqueous layer was neutralized with dilute hydrochloric acid. After stirring at room temperature for 30 minutes, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue and a mixture of N, N-dimethylformamide dimethylacetal (52.46 g) was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (500 mL). Hydrazine hydrate (20.09 g) was added to the solution and refluxed for 3 hours. The reaction mixture was concentrated and a saturated aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting crystals were collected by filtration to obtain ethyl 3- (2-thienyl) -1H-pyrazole-4-carboxylate (73.22 g, yield: 82%). This was recrystallized from ethyl acetate-hexane. Melting point: 123-124 占 폚.
[955] Example 1
[956] Sodium hydride (60%, oil, 2.55 g) was added to a solution of methyl 4-phenylpyrrole-3-carboxylate (11.61 g), 4- benzyloxybenzyl chloride (15.23 g) and N, N- dimethylformamide At O &lt; 0 &gt; C, and the mixture was stirred for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, and was concentrated after drying (MgSO _4). The residue was subjected to silica gel column chromatography to obtain methyl 1- (4-benzyloxybenzyl) -4-phenylpyrrole-3-carboxylate (22.16 g, , Yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 97-98 캜.
[957] Example 2
[958] Sodium hydride (60%, oil, 2.13 g) was added to a solution of 1- (4-benzyloxybenzyl) -4-phenylpyrrole-3-carbaldehyde (18.00 g), ethyldiethylphosphonoacetate N-dimethylformamide (150 ml) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [1- (4-benzyloxybenzyl) -4-phenyl-3- Pyrrolyl] propionate (20.16 g, yield: 94%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 111-112 占 폚.
[959] Example 3
[960] Sodium hydride (60%, oil, 298 mg) was added to a solution of methyl 4-phenylpyrrole-3-carboxylate (1.50 g) and 4- (4- chloromethylphenoxymethyl) 2.34 g) and N, N-dimethylformamide (15 mL) at 0 &lt; 0 &gt; C, and the mixture was stirred for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] piperazine from the fraction eluted with ethyl acetate-hexane (1: 3, -4-phenylpyrrole-3-carboxylate (3.12 g, yield: 88%) which was recrystallized from ethyl acetate-hexane. Melting point: 115-116 [deg.] C.
[961] Example 4
[962] Benzyl] -4-phenylpyrrole-3-carbaldehyde (2.37 g) was added to a solution of sodium hydride (60% , Ethyldiethylphosphonoacetate (1.1 ml) and tetrahydrofuran (30 ml) at 0 ° C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [1- [4- (5-methyl-2-phenyl- Oxazolylmethoxy) benzyl] -4-phenyl-3-pyrrolyl] propionate (2.13 g, yield 78%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 120-121 占 폚.
[963] Example 5
[964] Benzyl] -4-phenyl-3-pyrrolyl] propionate (600 mg), 1N The mixture of sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 60 ° C for 3 hours, 1N hydrochloric acid (7 ml) was added, and it was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give (E) -3- [1- [4- (5-methyl-2-phenyl- (521 mg, yield: 92%). This was recrystallized from ethyl acetate-hexane. Melting point: 154-155 占 폚.
[965] Example 6
[966] Benzyl] -4-phenyl-3-pyrrolyl] propionate (700 mg), 5 (5-methyl- % Palladium-carbon (1.00 g) and tetrahydrofuran (15 ml) was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) ) Benzyl] -4-phenyl-3-pyrrolyl] propionate (618 mg, yield 88%) as a colorless oily substance.
[967] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.47-2.56 (2H, m), 2.91-3.00 (2H, m), 4.08 (2H, q, D, J = 2.2 Hz), 6.98 (2H, d, J = 7.1 Hz), 4.95 (2H, s), 4.98 J = 8.8Hz), 7.10-7.47 (10H, m), 7.97-8.04 (2H, m).
[968] Example 7
[969] Benzyl] -4-phenyl-3-pyrrolyl] propionate (531 mg), lithium hydroxide monohydrate ( 128 mg), tetrahydrofuran (6 ml), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 2 hours and acidified by addition of 1N hydrochloric acid, which was washed with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were filtered to obtain 451 mg (yield: 45%) of 3- [1- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] 90%). This was recrystallized from ethyl acetate-hexane. Melting point: 124-125 占 폚.
[970] Example 8
[971] Pyrrolyl] propionate (1.01 g), 4-chloromethyl-2- (2-furyl) -5-methyloxazole ( 0.75 g), potassium carbonate (0.63 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. Water was added and the residue was acidified by the addition of 1N hydrochloric acid. The obtained colorless crystals were collected by filtration to give 3- [l- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] Propionic acid (1.02 g, yield: 73%). This was recrystallized from ethyl acetate-hexane. Melting point: 86-87 캜.
[972] Example 9
[973] Pyrrole] propionate (1.30 g), 4-chloromethyl-5-methyl-2- (2-thienyl) oxazole (0.95 g), potassium carbonate (1.20 g) and N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (10 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to acidify the residue. The obtained colorless crystals were collected by filtration to give 3- [1- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyl] (1.43 g, yield: 77%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 117-118 [deg.] C.
[974] Example 10
[975] Pyrrolyl] propionate (1.55 g), benzyl bromide (0.7 ml), potassium carbonate (0.92 g) and N, N-dimethyl Formamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 4, by volume). A mixture of the obtained oily substance, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to acidify the residue. The obtained colorless crystals were collected by filtration to give 3- [1- (4-benzyloxybenzyl) -4-phenyl-3-pyrrolyl] propionic acid (1.53 g, yield 84%). This was recrystallized from ethyl acetate-hexane. Melting point: 130-131 占 폚.
[976] Example 11
[977] Pyrrolyl] propionate (1.31 g), 2-picolyl chloride hydrochloride (0.73 g), potassium carbonate (0.69 g) and N, N-Dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). A mixture of the obtained oily substance, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to neutralize the residue. The obtained colorless crystals were collected by filtration to obtain 1.0 g of 3- [4-phenyl-1- [4- (2-pyridylmethoxy) benzyl] -3-pyrrolyl] propionic acid Respectively. This was recrystallized from ethanol-water. Melting point: 109-110 占 폚.
[978] Example 12
[979] Pyrrolyl] propionate (1.35 g), 3-picolyl chloride hydrochloride (0.76 g), potassium carbonate (0.85 g) and N, N-Dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). A mixture of the obtained oily substance, 1N aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to neutralize the residue. The obtained colorless crystals were collected by filtration to obtain 0.76 g (yield: 48%) of 3- [4-phenyl-1- [4- (3- pyridylmethoxy) benzyl] Respectively. This was recrystallized from ethanol-water. Melting point: 131-132 &lt; 0 &gt; C.
[980] Example 13
[981] Pyrrolyl] propionate (1.10 g), 4-picolyl chloride hydrochloride (0.60 g), potassium carbonate (0.88 g) and N, N-Dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to neutralize the residue. The obtained colorless crystals were collected by filtration to obtain 0.98 g (yield: 75%) of 3- [4-phenyl-1- [4- (4- pyridylmethoxy) benzyl] Respectively. This was recrystallized from acetone-hexane. Melting point: 124-125 占 폚.
[982] Example 14
[983] 2- (5-methyl-2-phenyl-4-oxazolyl) ethanol (2.48 g) was added to a solution of ethyl 3- [1- (4-hydroxybenzyl) g), triphenylphosphine (3.31 g) and tetrahydrofuran (25 ml) was slowly added dropwise at room temperature a toluene solution (5.66 g) of 40% diethyl azodicarboxylate. After the solution was stirred at room temperature for 2 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 4, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (15 ml), tetrahydrofuran (15 ml) and ethanol (15 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After addition of water, 1N hydrochloric acid was added to acidify the residue. The obtained colorless crystals were collected by filtration to give 3- [1- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl] ] Propionic acid (2.72 g, yield: 57%). This was recrystallized from ethanol-water. Melting point: 147-148 占 폚.
[984] Example 15
[985] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 2- (4-Chloromethyl-2-thiazolyl) pyrazine (349 mg) was added to the mixture and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- [2- (2-pyridyl) Yl) -4-thiazolylmethoxy] benzyl] -3-pyrrolyl] propionate (629 mg, yield 80%).
[986] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.96 (2H, s), 5.28 (2H, s), 6.51 (1H, d, J = 2.4 Hz), 6.72 = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.19-7.42 (5H, m), 7.50 (1H, s), 8.56 (1H, dd, J = , d, J = 2.4Hz), 9.43 (1H, d, J = 1.6Hz).
[987] Example 16
[988] Benzyl] -3-pyrrolyl] propionate (629 mg) and 1N aqueous sodium hydroxide solution (10 ml) were added to a solution of ethyl 3- [4-phenyl-1- [4- [2- (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred overnight at room temperature, 1N hydrochloric acid (2.5 ml) was added and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [4-phenyl-1- [4- [2- (2-pyrazinyl) ] Propionic acid (523 mg, yield: 88%). This was recrystallized from ethanol. Melting point: 137-138 占 폚.
[989] Example 17
[990] A mixture of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (699 mg), 3-furanmethanol (0.172 ml), triphenylphosphine (577 mg) A solution of 40% diethyl azodicarboxylate in toluene (1.04 g) was slowly added dropwise to a mixture of hydrofuran (20 ml) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (3-furylmethoxy) benzyl] -4- (4-methoxyphenyl) propanoic acid as an oily substance from a fraction eluted with ethyl acetate- Phenyl-3-pyrrolyl] propionate (385 mg, yield 45%).
[991] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.0 Hz), 2.51 (2H, t, J = 7.8 Hz), 2.94 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.91 (2H, s), 4.94 (2H, s), 6.48 (1H, d, J = 1.8 Hz), 6.50 = 2.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.16-7.43 (5H, m), 7.49 (1H, d, J = 1.8 Hz).
[992] Example 18
[993] 3-pyrrolyl] propionate (382 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and tetrahydrofuran ml) and ethanol (4 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated.
[994] The obtained colorless crystals were collected by filtration to give 257 mg (yield: 72%) of 3- [1- [4- (3-furylmethoxy) benzyl] -4-phenyl-3-pyrrolyl] Respectively. This was recrystallized from ethanol-hexane. Melting point: 110-111 占 폚.
[995] Example 19
[996] (873 mg), 2-thiophenemethanol (0.237 ml), triphenylphosphine (984 mg) and a mixture of ethyl 3- [1- (4-hydroxybenzyl) To a mixture of tetrahydrofuran (20 ml) was slowly added dropwise a toluene solution of 40% diethyl azodicarboxylate (1.74 g) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (2-thienylmethoxy) benzyl] -4- (2-pyridylmethoxy) benzene as an oily substance from a fraction eluted with ethyl acetate- Phenyl-3-pyrrolyl] propionate (620 mg, yield: 56%).
[997] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.3 Hz), 2.51 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.94 (2H, s), 5.20 (2H, s), 6.50 (1H, d, J = 2.2 Hz), 6.70 (1H, d, J = 2.2 Hz), 6.90-7.02 ), 7.14-7.25 (4H, m), 7.30-7.41 (5H, m).
[998] Example 20
[999] 3-pyrrolyl] propionate (620 mg), 1N aqueous sodium hydroxide solution (3 ml) and tetrahydrofuran (6 ml) were added to a solution of ethyl 3- [4-phenyl- ml) and ethanol (6 ml) was stirred at room temperature for 7 hours, 1N hydrochloric acid (3 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated.
[1000] The obtained colorless crystals were collected by filtration to obtain 272 mg (yield: 47%) of 3- [4-phenyl-1- [4- (2- Respectively. This was recrystallized from ethyl acetate-hexane. Melting point: 127-128 占 폚.
[1001] Example 21
[1002] A mixture of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (873 mg), 3-thiophenemethanol (0.236 ml), triphenylphosphine To a mixture of tetrahydrofuran (20 ml) was slowly added dropwise a toluene solution of 40% diethyl azodicarboxylate (1.74 g) at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (3-thienylmethoxy) benzyl] -4- (4-methoxyphenyl) propanoic acid as an oily substance from a fraction eluted with ethyl acetate- Phenyl-3-pyrrolyl] propionate (629 mg, yield: 56%).
[1003] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.51 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.93 (2H, s), 5.05 (2H, s), 6.50 (1H, d, J = 2.2 Hz), 6.71 = 8.8 Hz), 7.08-7.22 (4H, m), 7.31-7.41 (6H, m).
[1004] Example 22
[1005] (624 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and tetrahydrofuran (6 ml) were added to a solution of ethyl 3- [4- phenyl- ml) and ethanol (6 ml) was stirred at room temperature for 5 hours, 1N hydrochloric acid (3 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 421 mg (yield: 72%) of 3- [4-phenyl-1- [4- (3-thienylmethoxy) benzyl] -3-pyrrolyl] Respectively. This was recrystallized from ethyl acetate-hexane. Melting point: 118-119 占 폚.
[1006] Example 23
[1007] (873 mg), furfuryl alcohol (0.216 ml), triphenylphosphine (984 mg) and tetrahydrofuran (2 ml) were added to a solution of ethyl 3- [1- Furan (20 ml) was slowly added dropwise a toluene solution (1.74 g) of 40% diethyl azodicarboxylate at room temperature. After the solution was stirred at room temperature overnight, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (2-furylmethoxy) benzyl] -4- (2-pyridinylmethoxy) benzene as an oily substance from a fraction eluted with ethyl acetate- Phenyl-3-pyrrolyl] propionate (624 mg, yield 58%).
[1008] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.94 (2H, s), 4.99 (2H, s), 6.38 (1H, dd, J = 3.2, 1.4 Hz), 6.43 J = 2.4 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.10-7.45 (8H, m).
[1009] Example 24
[1010] (624 mg), 1N aqueous sodium hydroxide solution (3 ml) and tetrahydrofuran (6 ml) were added to a solution of ethyl 3- [1- [4- (2-furylmethoxy) benzyl] ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3- [l- [4- (2-furylmethoxy) benzyl] -4-phenyl-2-pyrrolidone as an oily substance from a fraction eluted with ethyl acetate- -3-pyrrolyl] propionic acid (386 mg, yield 66%).
[1011] _{NMR (CDCl 3) δ: 2.58} (2H, t, J = 7.8 Hz), 2.96 (2H, t, J = 7.8 Hz), 4.94 (2H, s), 4.98 (2H, s), 6.37 (1H, dd , 6.94 (1H, d, J = 2.4 Hz), 6.94 (1H, d, J = , J = 8.8Hz), 7.12 (2H, d, J = 8.8Hz), 7.19-7.44 (8H, m).
[1012] Example 25
[1013] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (212 mg) was added to the mixture and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (2-methyl-3-pyridylmethoxy) benzyl ester as an oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, ] -4-phenyl-3-pyrrolyl] propionate (581 mg, yield 85%).
[1014] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.59 (3H, s), 2.96 (2H, t, J = 7.8 Hz), (2H, s), 6.51 (1H, d, J = 2.6 Hz), 6.72 (1H, d, J = 2.6 Hz), 4.08 (1H, d, J = 7.8, 1.8 Hz), 8.48 (1H, d, J = , dd, J = 4.8, 1.8 Hz).
[1015] Example 26
[1016] 3-pyrrolyl] propionate (568 mg), 1N aqueous sodium hydroxide solution (3 ml), tetra (2-methylpyridylmethoxy) A mixture of hydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 4 hours, 1N hydrochloric acid (3 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 465 mg (yield: 87%) of 3- [1- [4- (2-methyl-3-pyridylmethoxy) benzyl] %). This was recrystallized from ethyl acetate-hexane. Melting point: 158-159 占 폚.
[1017] Example 27
[1018] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenylthiazole (336 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-thia Benzyl] -4-phenyl-3-pyrrolyl] propionate (690 mg, yield: 86%).
[1019] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.51 (2H, t, J = 7.8 Hz), 2.52 (3H, s), 2.95 (2H, t, J = 7.8 Hz), (2H, s), 6.50 (1H, d, J = 2.4Hz), 6.71 M), 7.86-7.91 (2H, m), 7.30 (2H, d, J = 8.8 Hz) .
[1020] Example 28
[1021] Benzyl] -4-phenyl-3-pyrrolyl] propionate (671 mg), 1N aqueous sodium hydroxide solution ( 2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyl] -4-phenyl-3-pyrrolyl] mg, yield: 78%). This was recrystallized from ethyl acetate-hexane. Melting point: 157-158 占 폚.
[1022] Example 29
[1023] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (315 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- (2-phenyl-4-thia Benzyl] -3-pyrrolyl] propionate (717 mg, yield 91%).
[1024] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.95 (2H, s), 5.25 (2H, s), 6.51 (1H, d, J = 2.4 Hz), 6.71 = 8.8 Hz), 7.13 (2H, d, J = 8.8Hz), 7.18-7.25 (1H, m), 7.30-7.49 (8H, m), 7.91-7.99 (2H, m).
[1025] Example 30
[1026] Benzyl] -3-pyrrolyl] propionate (706 mg), 1N aqueous sodium hydroxide solution (2.5 ml), and a mixture of ethyl 3- [4- phenyl- A mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 6 hours, 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 619 mg (yield: 99%) of 3- [4-phenyl-1- [4- 93%). This was recrystallized from ethanol-hexane. Melting point: 111-112 占 폚.
[1027] Example 31
[1028] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2- (2-pyridyl) thiazole (316 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- [2- (2-pyridyl) -1H-pyrazole as colorless crystals from a fraction eluted with ethyl acetate- ) -4-thiazolylmethoxy) benzyl] -3-pyrrolyl] propionate (590 mg, yield 75%). This was recrystallized from ethyl acetate-hexane. Melting point: 81-82 占 폚.
[1029] Example 32
[1030] Benzyl] -3-pyrrolyl] propionate (471 mg), a 1N aqueous solution of sodium hydroxide (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred overnight at room temperature, 1N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [4-phenyl-1- [4- [2- (2-pyridyl) -4-thiazolylmethoxy) benzyl] -3-pyrrolyl] 408 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 117-118 [deg.] C.
[1031] Example 33
[1032] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2- (4-pyridyl) thiazole (316 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- [2- (4-pyridyl) ) -4-thiazolylmethoxy) benzyl] -3-pyrrolyl] propionate (867 mg, yield 89%).
[1033] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.51 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.95 (2H, s), 5.27 (2H, s), 6.51 (1H, d, J = 2.4 Hz), 6.71 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.18-7.26 (1H, m), 7.29-7.41 4.8, 1.4 Hz), 8.71 (2H, dd, J = 4.8, 1.4 Hz).
[1034] Example 34
[1035] Benzyl] -3-pyrrolyl] propionate (864 mg) and 1N aqueous sodium hydroxide solution (1 ml) were added to a solution of ethyl 3- [4-phenyl-1- [4- [2- (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred overnight at room temperature, 1 N hydrochloric acid (3 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [4-phenyl-1- [4- [2- (4-pyridyl) -4-thiazolylmethoxy) benzyl] -3-pyrrolyl] 771 mg, yield: 94%). This was recrystallized from ethanol. Melting point: 149-150 占 폚.
[1036] Example 35
[1037] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 2- (3-Chloromethylphenyl) pyrazine (307 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated to residue was purified by silica gel column chromatography, ethyl acetate-hexanes: oily substance from the fraction eluted with (1: 1, volume ratio) Benzyl] -3-pyrrolyl] propionate (647 mg, yield: 83%) was obtained as a colorless oil.
[1038] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.94 (2H, s), 5.15 (2H, s), 6.51 (1H, d, J = 2.2 Hz), 6.71 (2H, m), 7.92-8.00 (1H, m), 8.10 (1H, s), 7.18-7.41 , 8.52 (1H, d, J = 2.6 Hz), 8.64 (1H, dd, J = 2.6, 1.4 Hz), 9.04 (1H, d, J = 1.4 Hz).
[1039] Example 36
[1040] Benzyl] -3-pyrrolyl] propionate (647 mg), 1N aqueous sodium hydroxide solution (2.5 ml), and a mixture of ethyl 3- [4-phenyl-1- [4- [3- A mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, and 1 N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 470 mg (yield: &lt; RTI ID = 0.0 &gt; 77%). This was recrystallized from ethyl acetate-hexane. Melting point: 91-92 占 폚.
[1041] Example 37
[1042] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethylphenyl-2- (2-furyl) thiazole (299 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- [2- (2-furyl) -4-thiae Benzyl] -4-phenyl-3-pyrrolyl] propionate (643 mg, yield 84%).
[1043] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.95 (2H, s), 5.23 (2H, s), 6.52-6.55 (2H, m), 6.71 (1H, d, J = 2.2 Hz), 6.96 ), 7.01 (1H, d, J = 2.2 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.16-7.41 (6H, m), 7.51 (1H, dd, J = 1.8, 0.6 Hz).
[1044] Example 38
[1045] Benzyl] -4-phenyl-3-pyrrolyl] propionate (641 mg), 1N aqueous sodium hydroxide solution ( 2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 5 hours, 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- [2- (2-furyl) -4-thiazolylmethoxy] benzyl] -4-phenyl-3-pyrrolyl] mg, yield: 78%). This was recrystallized from ethanol-hexane. Melting point: 114-115 [deg.] C.
[1046] Example 39
[1047] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2- (2-thienyl) thiazole (324 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- [2- (2-thienyl) ethyl] -amine as an oily substance from a fraction eluted with ethyl acetate- ) -4-thiazolylmethoxy] benzyl] -3-pyrrolyl] propionate (590 mg, yield 74%).
[1048] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.94 (2H, s), 5.22 (2H, s), 6.51 (1H, d, J = 2.2 Hz), 6.70 = 8.8 Hz), 7.03-7.40 (10H, m), 7.52 (1H, dd, J = 3.6, 1.0 Hz).
[1049] Example 40
[1050] Benzyl] -3-pyrrolyl] propionate (582 mg) and 1N aqueous sodium hydroxide solution (10 ml) were added to a solution of ethyl 3- [4-phenyl-1- [4- [2- (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred overnight at room temperature, 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [4-phenyl-1- [4- [2- (2-thienyl) -4-thiazolylmethoxy] benzyl] -3-pyrrolyl] 421 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 106-107 占 폚.
[1051] Example 41
[1052] A mixture of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (349 mg), 4-chloromethyl-2-methylthiazole hydrochloride (276 mg) (276 mg) and N, N-dimethylformamide (5 ml) was stirred at 90 占 폚 for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (2-methyl-4-thiazolylmethoxy) ethyl] -amine as an oily substance from a fraction eluted with ethyl acetate-hexane (1: Benzyl] -4-phenyl-3-pyrrolyl] propionate (373 mg, yield 81%).
[1053] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.73 (3H, s), 2.95 (2H, t, J = 7.8 Hz), (2H, s), 6.50 (1H, d, J = 2.2 Hz), 6.71 (1H, d, J = 2.2 Hz), 4.08 (2H, q, J = 7.2 Hz) 6.95 (2H, d, J = 8.8Hz), 7.12 (2H, d, J = 8.8Hz), 7.14-7.41 (6H, m).
[1054] Example 42
[1055] Benzyl] -4-phenyl-3-pyrrolyl] propionate (368 mg), 1N aqueous sodium hydroxide solution (2 ml), and a mixture of ethyl 3- [1- [4- The mixture of tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 4 hours, 1N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution were washed, dried (MgSO _4), and concentrated. the obtained colorless and crystals are collected by filtration, 3- [1- [4- (2-methyl-4-thiazolyl methoxy] benzyl] -4 Phenyl-3-pyrrolyl] propionic acid (251 mg, yield 73%) which was recrystallized from ethanol-hexane.
[1056] Example 43
[1057] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenyloxazole (290 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- (2-phenyl-4-oxa Benzyl] -3-pyrrolyl] propionate (550 mg, yield 72%).
[1058] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.95 (2H, s), 5.07 (2H, s), 6.51 (1H, d, J = 2.4 Hz), 6.71 = 8.8 Hz), 7.01-7.50 (10H, m), 7.73 (1H, s), 8.01-8.10 (2H, m).
[1059] Example 44
[1060] Benzyl] -3-pyrrolyl] propionate (532 mg), 1N aqueous sodium hydroxide solution (2.5 ml), and a mixture of ethyl 3- [4- phenyl- The mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred overnight at room temperature, 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution , dried (MgSO _4), and concentrated. the colorless crystals obtained by collecting by filtration, 3- [4-phenyl-1- [4- (2-phenyl-4-oxazolyl methoxy] benzyl] -3-pyrrolyl] propionic acid (428 mg, yield: 85%) which was recrystallized from ethanol-hexane.
[1061] Example 45
[1062] To a solution of ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (524 mg) in N, N-dimethylformamide (10 ml) at 0 ° C was added sodium hydride (60%, oil, 60.0 mg) was added and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2- (3-pyridyl) thiazole (316 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [4- [2- (3-pyridyl) ) -4-thiazolylmethoxy] benzyl] -3-pyrrolyl] propionate (657 mg, yield 84%).
[1063] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.96 (2H, s), 5.27 (2H, s), 6.51 (1H, d, J = 2.4 Hz), 6.71 = 8.6 Hz), 7.02-7.42 (9H, m), 8.24 (1H, ddd, J = 8.2,2.0,1.2 Hz), 8.66 (1H, dd, J = 4.8,1.2 Hz), 9.17 J = 2.0 Hz).
[1064] Example 46
[1065] Benzyl] -3-pyrrolyl] propionate (655 mg) and 1N aqueous sodium hydroxide solution (100 ml) were added to a solution of ethyl 3- [4-phenyl- (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 6 hours and 1N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. a saturated aqueous sodium chloride and washed with an aqueous solution, (MgSO _4), then dried and concentrated. the obtained colorless and crystals are collected by filtration, 3- [4-phenyl-1- [4- [2- (3-pyridyl 3-pyrrolyl] propionic acid (537 mg, yield 92%). This was recrystallized from ethanol. Melting point: 118-119 占 폚.
[1066] Example 47
[1067] To a solution of 4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl alcohol (1.50 g) in toluene (40 ml) at 0 ° C was added dropwise thionyl chloride (830 mg) Respectively. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue and methyl 4-phenylpyrrole-3-carboxylate (1.40 g) were dissolved in N, N-dimethylformamide (40 ml). Sodium hydride (60%, oil, 465 mg) was added to the solution at 0 ° C and stirred at room temperature for 3 days. The reaction mixture was poured into a saturated aqueous sodium chloride solution and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1- [4- [2- [N-methyl-N- (2-pyridyl) ) Amino] ethoxy] benzyl] -4-phenylpyrrole-3-carboxylate (1.80 g, yield 70%).
[1068] _{NMR (CDCl 3) δ: 3.15} (3H, s), 3.70 (3H, s), 3.99 (2H, t, J = 5.0 Hz), 4.19 (2H, t, J = 5.0 Hz), 4.97 (2H, s ), 6.5-6.6 (2H, m), 6.64 (1H, d, J = 2.5 Hz), 6.88 (7H, m), 8.1-8.2 (1 H, m).
[1069] Example 48
[1070] To a solution of ethyl diethylphosphonoacetate (1.10 g) and l- [4- [2- [N-methyl-N- (2-pyridyl) amino] (60%, oil, 200.0 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. After washing the ethyl acetate layer with water followed by saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [1- [4- [2- [N-methyl-N - (2-pyridyl) amino] ethoxy] benzyl] -4-phenyl-3-pyrrolyl] propanoate (1.35 g, yield 85%).
[1071] _{NMR (CDCl 3) δ: 1.26} (3H, t, J = 7 Hz), 3.16 (3H, s), 3.95-4.25 (6H, m), 4.98 (2H, s), 6.05 (1H, d, J = (1H, d, J = 6 Hz), 6.56-6.6 (2H, m), 6.69 (1H, d, J = 2.5 Hz) (2H, d, J = 9Hz), 7.2-7.55 (6H, m), 7.69 (2H, d, J = 16 Hz), 8.1-8.2 (1H, m).
[1072] Example 49
[1073] Ethyl E) -3- [1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] -4-phenyl-3-pyrrolyl] propanoate 1.32 g), 5% palladium on carbon (1.0 g), tetrahydrofuran (40 ml) and ethanol (40 ml) was carried out at room temperature and atmospheric pressure. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in a mixed solution of tetrahydrofuran (10 ml) and ethanol (10 ml), and then a 1N aqueous sodium hydroxide solution (10 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid (10 ml), and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] (900 mg, yield: 72%) was obtained. This was recrystallized from acetone-ethyl acetate. Melting point: 110-111 占 폚.
[1074] Example 50
[1075] 3-phenoxybenzyl chloride (11.32 g) and ethyl 3-phenyl-1H-pyrazole-4-carboxylate (11.30 g) were dissolved in N, N-dimethylformamide (100 ml). Sodium hydride (60%, oil, 2.49 g) was added to the solution at 0 ° C and the solution was stirred at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous sodium chloride solution and extracted with ethyl acetate. After washing the ethyl acetate layer with water followed by saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain an oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). A mixture of the obtained oily substance, potassium hydroxide (8.53 g) and ethanol (150 ml) was refluxed for 5 hours. After removing the reaction solvent under reduced pressure, water was added to the mixture, and the mixture was then acidified using 1N hydrochloric acid. The obtained colorless crystals were collected by filtration to obtain 14.83 g (yield: 77%) of 1- (3-phenoxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylic acid. This was recrystallized from acetone-hexane. Melting point: 148-149 占 폚.
[1076] Example 51
[1077] To a mixture of methyl 4-phenylpyrrole-3-carboxylate (1.81 g), 6-benzyloxy-2-chloromethylnaphthalene (2.54 g) and N, N- dimethylformamide (35 ml) , Oil, 0.36 g) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water followed by saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1- (6-benzyloxy-2-naphthylmethyl) -4-phenylpyrrole as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1: 2, -3-carboxylate (3.20 g, yield: 80%). This was recrystallized from ethyl acetate-hexane. Melting point: 109-110 占 폚.
[1078] Example 52
[1079] Sodium hydride (60%, oil, 0.20 g) was added to a mixture of ethyldiethylphosphonoacetate (0.992 ml) and tetrahydrofuran (20 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. A solution of l- (6-benzyloxy-2-naphthylmethyl) -4-phenylpyrrole-3-carbaldehyde (2.09 g) in tetrahydrofuran (20 ml) was slowly added dropwise to the mixture, Lt; / RTI &gt; The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain ethyl (E) -3- [1- (6-benzyloxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] propanoate Yield: 68%). This was recrystallized from ethyl acetate-hexane. Melting point: 119-120 占 폚.
[1080] Example 53
[1081] To a solution of ethyl 3- [1- (6-hydroxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] propionate (360 mg) in N, N- dimethylformamide (10 ml) Was added sodium hydride (60%, oil, 36.0 mg) and the mixture was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (207 mg) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [6- (5-methyl-2-phenyl-4-oxa 2-naphthylmethyl] -4-phenyl-3-pyrrolyl] propionate (304 mg, yield 59%).
[1082] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.0 Hz), 2.47 (3H, s), 2.52 (2H, t, J = 7.8 Hz), 2.97 (2H, t, J = 7.8 Hz), (2H, s), 6.56 (1H, d, J = 2.2Hz), 6.77 (1H, d, J = 2.2Hz), 4.06 (2H, q, J = 7.0Hz) 7.15-7.48 (11H, m), 7.56 (1H, s), 7.71 (2H, d, J = 8.8Hz), 7.99-8.06 (2H, m).
[1083] Example 54
[1084] Phenyl-3-pyrrolyl] propionate (304 mg) was added to a solution of ethyl 3- [1- [6- A mixture of 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, 1N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate . After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-naphthylmethyl] (243 mg, yield: 84%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 122-123 占 폚.
[1085] Example 55
[1086] To a solution of ethyl 3- [1- (6-hydroxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] propionate (360 mg) in N, N- dimethylformamide (10 ml) Was added sodium hydride (60%, oil, 36.0 mg) and the mixture was stirred at room temperature for 15 minutes. 2-Fluorobenzyl chloride (0.119 ml) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [6- (2-fluorobenzyloxy) -2-naphthoquinone as an oily substance from a fraction eluted with ethyl acetate-hexane (1: 3, Ylmethyl] -4-phenyl-3-pyrrolyl] propionate (404 mg, yield 88%).
[1087] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.96 (2H, t, J = 7.8 Hz), 4.06 (2H, q, J = 7.2 Hz), 5.12 (2H, s), 5.24 (2H, s), 6.55 (1H, d, J = 2.4 Hz), 6.76 (1H, d, J = 2.4 Hz), 7.06-7.43 ), 7.51-7.59 (2H, m), 7.68-7.75 (2H, m).
[1088] Example 56
[1089] 3-pyrrolyl] propionate (401 mg) and 1N aqueous sodium hydroxide solution (2 ml) were added to a solution of ethyl 3- [1- [6- (2- fluorobenzyloxy) , Tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, 1N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 289 mg of 3- [1- [6- (2-fluorobenzyloxy) -2-naphthylmethyl] -4-phenyl-3-pyrrolyl] : 76%). This was recrystallized from ethanol-hexane. Melting point: 143-144 占 폚.
[1090] Example 57
[1091] 3-pyrrol yl] propionate (599 mg) in N, N-dimethylformamide (10 ml) Was added sodium hydride (60%, oil, 60.0 mg) and the mixture was stirred at room temperature for 15 minutes. 3-Picolyl chloride (230 mg) was added to the mixture and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4-phenyl-1- [6- (3-pyridylmethoxy) - Naphthylmethyl] -3-pyrrolyl] propionate (647 mg, yield 88%).
[1092] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.6 Hz), 4.06 (2H, q, J = 7.0 Hz), 5.13 (2H, s), 5.19 (2H, s), 6.56 (1H, d, J = 2.6 Hz), 6.76 (1H, d, J = 2.6 Hz), 7.16-7.43 ), 7.57 (1H, s), 7.68-7.84 (3H, m), 8.60 (1H, d, J = 4.4 Hz), 8.74 (1H, s).
[1093] Example 58
[1094] 3-pyrrolyl] propionate (638 mg), 1N aqueous sodium hydroxide solution (2.5 ml), and a mixture of ethyl 3- [4-phenyl-1- [6- (3- pyridylmethoxy) A mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, and 1 N hydrochloric acid (2.5 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 508 mg (yield: 50%) of 3- [4-phenyl-1- [6- (3-pyridylmethoxy) -2-naphthylmethyl] 84%). This was recrystallized from ethanol. Melting point: 158-159 占 폚.
[1095] Example 59
[1096] To a solution of ethyl 3- [1- (6-hydroxy-2-naphthylmethyl) -4-phenyl-3-pyrrolyl] propionate (799 mg) in N, N- dimethylformamide (10 ml) Was added sodium hydride (60%, oil, 80.0 mg) and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (283 mg) was added to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [6- (2-methyl-3-pyridylmethoxy) - 2-naphthylmethyl] -4-phenyl-3-pyrrolyl] propionate (959 mg, yield: 95%).
[1097] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.63 (3H, s), 2.97 (2H, t, J = 7.8 Hz), (2H, s), 6.56 (1H, d, J = 2.6 Hz), 6.77 (1H, d, J = 7.14-7.48 (9H, m), 7.57 (1H, s), 7.69-7.79 (3H, m), 8.49 (1H, dd, J = 4.8, 1.8 Hz).
[1098] Example 60
[1099] 3-pyrrolyl] propionate (959 mg) and 1N aqueous sodium hydroxide solution (100 mg) were added to a solution of ethyl 3- [1- [6- 4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred overnight at room temperature, 1N hydrochloric acid (4 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [6- (2-methyl-3-pyridylmethoxy) -2-naphthylmethyl] -4-phenyl-3-pyrrolyl] mg, yield: 83%). This was recrystallized from ethanol. Melting point: 163-164 占 폚.
[1100] Example 61
[1101] To a solution of ethyl 4- (2-pyridyl) pyrrole-3-carboxylate (1.10 g), 4- (4-chloromethylphenoxymethyl) -5- Sodium hydride (60%, oil, 0.22 g) was added to a mixture of N, N-dimethylformamide (25 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water followed by saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethyl) -1H-pyrazole as an oily substance from a fraction eluted with tetrahydrofuran-hexane (1: 1, Benzyl] -4- (2-pyridyl) pyrrole-3-carboxylate (2.43 g, yield 97%).
[1102] _{NMR (CDCl 3) δ: 1.28} (3H, t, J = 7.2 Hz), 2.44 (3H, s), 4.22 (2H, q, J = 7.2 Hz), 4.99 (2H, s), 5.02 (2H, s ), 6.94-7.24 (6H, m), 7.35-7.48 (4H, m), 7.60-7.72 (1H, m), 7.84-7.92 (1H, m), 7.96-8.08 (1 H, m).
[1103] Example 62
[1104] Sodium hydride (60%, oil, 0.17 g) was added to a mixture of ethyl diethylphosphonoacetate (1.00 g) and N, N-dimethylformamide (5 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes Lt; / RTI &gt; Benzyl] -4-phenylpyrrole-3-carbaldehyde (1.65 g) in N, N-dimethylformamide (10 ml) Was slowly added to the mixture and stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [1- [4- (5-methyl-2-phenylpyridin- -4-oxazolylmethoxy) benzyl] -4- (2-pyridyl) -3-pyrrole] propanoate (1.83 g, yield: 96%).
[1105] _{NMR (CDCl 3) δ: 1.29} (3H, t, J = 7.2 Hz), 2.44 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 4.99 (2H, s), 5.02 (2H, s ), 6.14 (1H, d, J = 16.0 Hz), 6.94-7.24 (7H, m), 7.34-7.52 (4H, m), 7.58-7.72 (1H, m), 7.86-8.16 8.58-8.66 (1 H, m).
[1106] Example 63
[1107] Ethyl (E) -3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4- (2-pyridyl) -3-pyrrolyl] propanoate 1.80 g), 5% palladium-carbon (2.32 g) and tetrahydrofuran (30 ml) was stirred at room temperature in a hydrogen atmosphere overnight. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxa Benzyl] -4- (2-pyridyl) -3-pyrrolyl] propionate (1.61 g, yield 89%).
[1108] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 2.43 (3H, s), 2.56-2.66 (2H, m), 3.04-3.16 (2H, m), 4.09 (2H, q, (2H, s), 6.51 (1H, d, J = 2.6 Hz), 6.92-7.18 (6H, m), 7.34-7.66 7.94-8.04 (2H, m), 8.50-8.56 (1H, m).
[1109] Example 64
[1110] Benzyl] -4- (2-pyridyl) -3-pyrrolyl] propionate (1.46 g), ethyl 3- [1- [4- A mixture of 1N sodium hydroxide aqueous solution (6 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for 5 hours, 1N hydrochloric acid (6 ml) was added to the mixture and extracted with ethyl acetate . After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -4- (2- (1.20 g, yield: 87%) was obtained. This was recrystallized from N, N-dimethylformamide-water. Melting point: 155-156 ° C.
[1111] Example 65
[1112] To a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.10 g), 3,5-dibenzyloxybenzyl methanesulfonate (21.9 g) and N, N-dimethylformamide (200 ml) Sodium (60%, oil, 2.20 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water followed by saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1- (3,5-dibenzyloxybenzyl) -4-phenylpyrrole-3 as an oily substance from a fraction eluted with tetrahydrofuran-hexane (1: 2, -Carboxylate (26.4 g, yield: 95%).
[1113] _{NMR (CDCl 3) δ: 3.72} (3H, s), 4.95 (2H, s), 4.99 (4H, s), 6.41 (1H, d, J = 2.6 Hz), 6.56 (1H, t, J = 2.2 Hz ), 6.64 (1H, d, J = 2.6Hz), 7.21-7.42 (15H, m), 7.44-7.50 (2H, m).
[1114] Example 66
[1115] Sodium hydride (60%, oil, 2.11 g) was added to a mixture of ethyldiethylphosphonoacetate (10.5 ml) and tetrahydrofuran (150 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes. A solution of 1- (3,5-dibenzyloxybenzyl) -4-phenylpyrrole-3-carbaldehyde (22.7 g) in tetrahydrofuran (20 ml) was slowly added to the mixture and stirred at room temperature for 1 hour Respectively. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 21.9 g of ethyl (E) -3- [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] propanoate %). This was recrystallized from ethyl acetate-hexane. Melting point: 98-99 ° C.
[1116] Example 67
[1117] A solution of ethyl (E) -3- [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] propanoate (544 mg), 1N aqueous sodium hydroxide solution (2 ml) and tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred overnight at 50 <0> C, then 1 N hydrochloric acid (2 ml) was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were filtered to obtain 479 mg (yield: 93%) of E-3- [1- (3,5-dibenzyloxybenzyl) -4-phenyl-3-pyrrolyl] propenoic acid. This was recrystallized from ethanol. Melting point: 182-183 占 폚.
[1118] Example 68
[1119] A solution of ethyl 3- [1- (3,5-dihydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (4.93 g) in N, N-dimethylformamide (50 ml) Was added sodium hydride (60%, oil, 0.54 g), and the solution was stirred at room temperature for 15 minutes. 2- (4-Chloromethyl-2-thiazolyl) pyrazine (2.86 g) was added to the solution and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-hydroxy-5- [2- (2-pyrazinyl) -4-thiazolylmethoxy] benzyl] - pyrrolyl] propionate (2.00 g, yield: 27%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 156-157 占 폚.
[1120] Example 69
[1121] Benzyl] -4-phenyl-pyrrolyl] propionate (324 mg), 1N (2-methyl- A mixture of sodium hydroxide aqueous solution (1.5 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at 50 ° C for 2 hours, 1N hydrochloric acid (1.5 ml) was added to the mixture and extracted with ethyl acetate . After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [3-hydroxy-5- [2- (2-pyrazinyl) -4- thiazolylmethoxy] benzyl] ] Propionic acid (277 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 206-207 ° C.
[1122] Example 70
[1123] To a solution of ethyl 3- [1- [3-hydroxy-5- [2- (2-pyrazinyl) -4-thiazolylmethoxy] benzyl] -4 -Phenyl-3-pyrrolyl] propionate (378 mg) was added sodium hydride (60%, oil, 28.0 mg), and the mixture was stirred at room temperature for 15 minutes. Iodomethane (0.0523 ml) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-methoxy-5- [2- (2-pyrazol- 4-phenyl-3-pyrrolyl] propionate (361 mg, yield: 93%).
[1124] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.96 (2H, t, J = 7.8 Hz), 3.77 (3H, s), (2H, s), 6.36 (1H, s), 6.43 (1H, s), 6.52 (1H, t, J = 2.2 Hz, ), 6.53 (1H, d, J = 2.2 Hz), 6.73 (1H, d, J = 2.2 Hz), 7.16-7.42 (5H, m), 7.48 2.6, 1.4 Hz), 8.61 (1H, d, J = 2.6 Hz), 9.43 (1H, d, J = 1.4 Hz).
[1125] Example 71
[1126] Benzyl] -4-phenyl-3-pyrrolyl] propionate (361 mg) was added to a solution of ethyl 3- [1- [3-methoxy- , 1N sodium hydroxide aqueous solution (1.5 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 4 hours, 1N hydrochloric acid (1.5 ml) was added to the mixture and extracted with ethyl acetate Respectively. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [3-methoxy-5- [2- (2-pyrazinyl) Pyrrolyl] propionic acid (338 mg, yield: 99%). This was recrystallized from ethanol-hexane. Melting point: 111-112 占 폚.
[1127] Example 72
[1128] To a solution of ethyl 3- [1- [3-hydroxy-5- [2- (2-pyrazinyl) -4-thiazolylmethoxy] benzyl] -4 -Phenyl-3-pyrrolyl] propionate (378 mg) was added sodium hydride (60%, oil, 28.0 mg), and the mixture was stirred at room temperature for 15 minutes. Iodoethane (0.0672 ml) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-ethoxy-5- [2- (2-pyrazol- 4-phenyl-3-pyrrolyl] propionate (385 mg, yield 97%).
[1129] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.96 (2H, t, J (2H, s), 6.35 (1H, s), 4.94 (2H, s) (1H, s), 6.42 (1H, s), 6.50-6.53 (2H, m), 6.73 (1H, d, J = 2.6 Hz), 7.16-7.42 J = 2.4, 1.2 Hz), 8.61 (1H, d, J = 2.4 Hz), 9.42 (1H, d, J = 1.2 Hz).
[1130] Example 73
[1131] Benzyl] -4-phenyl-3-pyrrolyl] propionate (370 mg) was added to a solution of ethyl 3- [1- [3-ethoxy- , 1N sodium hydroxide aqueous solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred under refluxing overnight, then 1N hydrochloric acid (6 ml) was added to the mixture, And extracted. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [3-ethoxy-5- [2- (2- pyrazinyl) -4- thiazolylmethoxy] benzyl] Pyrrol yl] propionic acid (210 mg, yield 60%). This was recrystallized from ethanol. Melting point: 97-98 캜.
[1132] Example 74
[1133] To a solution of ethyl 3- [1- [3-hydroxy-5- [2- (2-pyrazinyl) -4-thiazolylmethoxy] benzyl] -4 -Phenyl-3-pyrrolyl] propionate (378 mg) was added sodium hydride (60%, oil, 28.0 mg), and the mixture was stirred at room temperature for 15 minutes. Benzyl bromide (0.10 ml) was added to the mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-benzyloxy-5- [2- (2-pyrazol- Yl) -4-thiazolylmethoxy] benzyl] -4-phenyl-3-pyrrolyl] propionate (419 mg, yield 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 126-127 占 폚.
[1134] Example 75
[1135] Benzyl] -4-phenyl-3-pyrrolyl] propionate (347 mg) was added to a solution of ethyl 3- [1- [3- benzyloxy- (5 ml), 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred under refluxing overnight, then 1N hydrochloric acid (5 ml) And extracted. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [3-benzyloxy-5- [2- (2-pyrazinyl) Pyrrolyl] propionic acid (274 mg, yield: 83%). This was recrystallized from ethanol-hexane. Melting point: 109-110 占 폚.
[1136] Example 76
[1137] To a mixture of 4-benzyloxybenzyl chloride (10.8 g), ethyl 3-phenyl-1H-pyrazole-4-carboxylate (10.0 g) and N, N-dimethylformamide (50 ml) was added sodium hydride (60%, oil, 1.85 g) was added and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain ethyl 1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylate (15.3 g, yield 80%). This was recrystallized from ethyl acetate-diisopropyl ether. Melting point: 102-103 占 폚.
[1138] Example 77
[1139] (9.41 g), 4N aqueous potassium hydroxide solution (30 ml), and ethanol (30 ml) were added to a solution of 4-amino-2- ) Was refluxed for 1 hour. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was dissolved in pyridine (20 ml) and stirred at 110 [deg.] C for 2 hours. After removal of the solvent under reduced pressure, the residue was extracted with ethyl acetate. Dilute hydrochloric acid, the ethyl acetate layer was then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to give 7.52 g (yield: 99%) of 3- [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propionic acid. This was recrystallized from ethyl acetate-hexane. Melting point: 147-148 占 폚.
[1140] Example 78
[1141] (7.01 g), iodomethane (2.12 ml), potassium carbonate (4.70 g) and N, N (3-benzyloxybenzyl) -Dimethylformamide (30 ml) was stirred at room temperature for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- [l- (4-benzyloxybenzyl) -3-phenyl-lH-pyrazole as an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, Yl] propionate (6.51 g, yield: 90%).
[1142] _{NMR (CDCl 3) δ: 2.48-2.57} (2H, m), 2.90-2.98 (2H, m), 3.61 (3H, s), 5.06 (2H, s), 5.23 (2H, s), 6.95 (2H, d, J = 8.8 Hz), 7.17-7.46 (11H, m), 7.59-7.66 (2H, m).
[1143] Example 79
[1144] (4-hydroxybenzyl) -3-phenyl-1H-pyrazol-4-yl] -2-methyl- A mixture of propionate (500 mg), potassium carbonate (397 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- [l- [4- [2- (2-furyl) -5-methylpyridinium chloride was obtained as an oily substance from a fraction eluted with ethyl acetate-hexane (5: 6, -4-oxazolylmethoxy] benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (687 mg, yield 87%).
[1145] _{NMR (CDCl 3) δ: 2.42} (3H, s), 2.49-2.58 (2H, m), 2.90-2.99 (2H, m), 3.61 (3H, s), 4.98 (2H, s), 5.24 (2H, s), 6.51-6.54 (1H, m), 6.94-7.02 (3H, m), 7.18-7.46 (6H, m), 7.52-7.55 (1H, m), 7.60-7.66 (1H, m).
[1146] Example 80
[1147] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (610 mg) was added to a solution of methyl 3- [1- [4- [2- The mixture of lithium hydroxide monohydrate (154 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours and 1N hydrochloric acid (3.7 ml) And extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The colorless crystals were collected by filtration to give 3- [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -Propionic acid (583 mg, yield: 98%). This was recrystallized from ethyl acetate-hexane. Melting point: 152-153 &lt; 0 &gt; C.
[1148] Example 81
[1149] (338 mg) and methyl 3- [1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazol-4-yl ] Propionate (500 mg), potassium carbonate (397 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- [1- [4- [5-methyl-2- (2-thienyl) ) -4-oxazolylmethoxy] benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (715 mg, yield 88%).
[1150] _{NMR (CDCl 3) δ: 2.41} (3H, s), 2.49-2.58 (2H, m), 2.90-2.99 (2H, m), 3.61 (3H, s), 4.96 (2H, s), 5.24 (2H, s), 6.98 (2H, d, J = 8.8Hz), 7.06-7.12 (1H, m), 7.17-7.46 (7H, m), 7.60-7.66 (3H, m).
[1151] Example 82
[1152] Methyl 3- [1- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate The mixture of lithium hydroxide monohydrate (155 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours and 1N hydrochloric acid (3.7 ml) Was added to the mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- [5-methyl-2- (2-thienyl) -4-oxazolylmethoxy] benzyl] Yl] propionic acid (581 mg, yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 159-160 &lt; 0 &gt; C.
[1153] Example 83
[1154] Diethyl azodicarboxylate (40% in toluene, 753 mg) was added to a solution of methyl 3- [1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propionate ) Was slowly added dropwise at room temperature to a mixture of 5-methyl-2- (4-pyridyl) -4-oxazolyl] methanol (274 mg), triphenylphosphine (414 mg) and tetrahydrofuran Respectively. After stirring at room temperature for 4 hours, the reaction solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (3: 1, by volume). The obtained oily substance, a mixture of lithium hydroxide monohydrate (181 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, Was added to the mixture, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [l- [4- [5-methyl-2- (4-pyridyl) -4-oxazolylmethoxy] benzyl] -4-yl] propionic acid (470 mg, yield 68%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 154-155 占 폚.
[1155] Example 84
[1156] 3-Chloromethyl-5-phenyl-1,2,4-oxadiazole (307 mg) and methyl 3- [1- (4- hydroxybenzyl) A mixture of propionate (500 mg), potassium carbonate (397 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- [3-phenyl-1- [4- (5-phenyl-1,2,4-oxadiazol-3-ylmethoxy) benzyl] Yl] propionate (651 mg, yield 89%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio) as a colorless oily substance.
[1157] _{NMR (CDCl 3) δ: 2.49-2.57} (2H, m), 2.90-2.99 (2H, m), 3.61 (3H, s), 5.25 (4H, s), 7.04 (2H, d, J = 8.8 Hz) , 7.18-7.66 (11H, m), 8.13-8.19 (2H, m).
[1158] Example 85
[1159] Benzyl] -1H-pyrazol-4-yl] propionate (560 mg) was added to a solution of methyl 3- [3-phenyl- The mixture of lithium hydroxide monohydrate (139 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours and 1N hydrochloric acid &Lt; / RTI &gt; and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-phenyl-1- [4- (5-phenyl-1,2,4-oxadiazol-3- ylmethoxy) benzyl] 4-yl] propionic acid (529 mg, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 166-167 占 폚.
[1160] Example 86
[1161] Diethyl azodicarboxylate (40% in toluene, 1.00 g) was added to a solution of methyl 3- [1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propionate Was slowly added dropwise at room temperature to a mixture of (2,5-dimethyl-4-oxazolyl] methanol (275 mg), triphenylphosphine (585 mg) and tetrahydrofuran (10 ml) After stirring for a time, the reaction solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 3- [1- [4- (2,5-dimethyl-4-oxazolylmethoxy) benzyl] (288 mg, 44% yield) was obtained from the eluted fraction as an oily substance in ethyl acetate-hexane (6: 5, by volume).
[1162] _{NMR (CDCl 3) δ: 2.31} (3H, s), 2.41 (3H, s), 2.49-2.58 (2H, m), 2.90-2.99 (2H, m), 3.62 (3H, s), 4.86 (2H, s), 5.24 (2H, s), 6.97 (2H, d, J = 8.8Hz), 7.18-7.47 (6H, m), 7.59-7.66 (2H, m).
[1163] Example 87
[1164] Benzyl] 3-phenyl-1H-pyrazol-4-yl] propionate (254 mg), lithium hydroxide monohydrate (69.9 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours and 1N hydrochloric acid (1.7 ml) . After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated to give 3- [1- [4- (2,5-dimethyl-4-oxazolyl-methoxy) benzyl] 3-phenyl -1H -Pyrazol-4-yl] propionic acid (243 mg, yield: 99%) as an amorphous substance.
[1165] _{NMR (CDCl 3) δ: 2.30} (3H, s), 2.41 (3H, s), 2.54 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.4 Hz), 4.85 (2H, s ), 5.21 (2H, s), 6.94 (2H, d, J = 8.4Hz), 7.15-7.47 (6H, m), 7.61 (2H, d, J = 7.0Hz).
[1166] Example 88
[1167] Methyl-2-phenyloxazole (324 mg) and methyl 3- [1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propionate 500 mg), potassium carbonate (397 mg) and N, N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] ] Propionate (657 mg, yield 90%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio) as a colorless oily substance.
[1168] _{NMR (CDCl 3): δ2.43 (} 3H, s), 2.49-2.58 (2H, m), 2.95 (2H, t, J = 7.7 Hz), 3.61 (3H, s), 4.99 (2H, s), 5.24 (2H, s), 7.00 (2H, d, J = 8.8Hz), 7.18-7.47 (9H, m), 7.60-7.66 (2H, m), 7.98-8.04 (2H, m).
[1169] Example 89
[1170] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (640 mg), hydroxy A mixture of lithium monohydrate (363 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (9 ml) This was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Propionic acid (592 mg, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 179-180 占 폚.
[1171] Example 90
[1172] 4-ylmethoxy] benzyl alcohol (400 mg) was added to thionyl chloride (1 ml) at 0 &lt; 0 & And stirred for 1 hour. After thionyl chloride was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated. Sodium hydride (60%, oil, 60 mg) was added to a residue, ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (320 mg) and N, N-dimethylformamide ), And the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3- [1- [4- [3-methyl-1- (2-pyridyl) -1H-pyrazol- Pyrazol-4-yl] propionate (340 mg, yield 50%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, volume ratio) as a colorless oily substance.
[1173] _{NMR (CDCl 3): δ 1.18} (3H, t, J = 7.2 Hz), 2.39 (3H, s), 2.52 (2H, t, J = 7.7 Hz), 2.94 (2H, t, J = 7.7 Hz), (2H, s), 6.94-6.99 (2H, m), 7.11-7.45 (7H, m), 7.61-7.65 (2H, m), 7.74-7.82 (1H, m), 7.91 (1H, d, J = 8.4 Hz), 8.36-8.39 (1H, m), 8.53 (1H, s).
[1174] Example 91
[1175] 3-phenyl-1H-pyrazol-4-yl] propionate (300 mg), potassium carbonate ( 357 mg) and N, N-dimethylformamide (5 ml) was stirred at 50 &lt; 0 &gt; C for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from a fraction eluted with ethyl acetate. The obtained oily substance, a mixture of lithium hydroxide monohydrate (108 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, Was added to the mixture, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to obtain 279 mg (yield 78%) of 3- [3-phenyl-1- [4- (3- pyridylmethoxy) benzyl] -1H- ). This was recrystallized from acetone-hexane. Melting point: 112-113 [deg.] C.
[1176] Example 92
[1177] A mixture of ethyl 1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylate (1.79 g), potassium hydroxide (0.75 g) and ethanol (30 ml) . After removing the solvent under reduced pressure, water was added to the reaction mixture, and the mixture was then acidified with 1N hydrochloric acid. The obtained crystals were collected by filtration to give 1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylic acid (1.36 g, yield: 82%). This was recrystallized from acetone-hexane. Melting point: 152-153 &lt; 0 &gt; C.
[1178] Example 93
[1179] (2.40 g), ethyl 1- (4-hydroxybenzyl) -3-phenyl-1H-pyrazole-4-carboxylate (3.40 g), carbonic acid A mixture of potassium (2.51 g) and N, N-dimethylformamide (50 ml) was stirred at 80 &lt; 0 &gt; C overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue, a mixture of potassium hydroxide (1.78 g) and ethanol (50 ml) was refluxed for 5 hours. After removing the reaction solvent under reduced pressure, water was added to the reaction mixture, and then the mixture was acidified with 1N hydrochloric acid. The obtained crystals were collected by filtration to obtain 1.66 g of 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yield: 75%). This was recrystallized from acetone-hexane. Melting point: 165-166 ° C.
[1180] Example 94
[1181] Pyrazole-4-carboxylate (1.65 g) and potassium carbonate (1.18 g, 0.36 mmol) in tetrahydrofuran ) And N, N-dimethylformamide (25 ml) was stirred overnight at 80 &lt; 0 &gt; C. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue, a mixture of potassium hydroxide (0.93 g) and ethanol (50 ml) was refluxed for 5 hours. After removing the reaction solvent under reduced pressure, water was added to the reaction mixture, and then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to give 3-phenyl-1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -lH-pyrazole-4-carboxylic acid (1.82 g, %). This was recrystallized from acetone-hexane. Melting point: 119-120 占 폚.
[1182] Example 95
[1183] Thionyl chloride (1 ml) was added to a solution of [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] In methanol (3.01 g) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated. The residue was dissolved in N, N-dimethylformamide (50 ml). Sodium cyanide (0.82 g) was added to the solution at 0 &lt; 0 &gt; C and the solution was then stirred at 70 &lt; 0 &gt; C overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with water, then washed with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and the amorphous substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The resulting amorphous material, a mixture of 4N aqueous potassium hydroxide solution (10 ml) and ethanol (20 ml) was refluxed overnight. After removal of the solvent, water was added to the mixture, and the mixture was then acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to give [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyll-3-phenyl-lH-pyrazol- g, yield: 74%). This was recrystallized from ethyl acetate-hexane. Melting point: 156-157 占 폚.
[1184] Example 96
[1185] Benzyl] -3-phenyl-1H-pyrazol-4-yl] butyronitrile (1.27 g), 4N hydroxysuccinimide A mixture of potassium aqueous solution (5 ml) and ethanol (10 ml) was refluxed for 18 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 4- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Butanoic acid (709 mg, yield: 54%). This was recrystallized from ethyl acetate-hexane. Melting point: 118-119 占 폚.
[1186] Example 97
[1187] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propyl] malonate (prepared from diethyl 2- [3- [1- [4- 1.56 g), 4N aqueous potassium hydroxide solution (5 ml) and ethanol (10 ml) was refluxed for 30 minutes. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue and a mixture of pyridine (10 ml) was stirred at 110 &lt; 0 &gt; C for 2 hours. After removal of the solvent under reduced pressure, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 5- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Pentanoic acid (857 mg, yield 65%). This was recrystallized from ethyl acetate-hexane. Melting point: 109-110 占 폚.
[1188] Example 98
[1189] Tetrakis (triphenolphosphine) palladium (120 mg) was added to a solution of ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3-trifluoromethanesulfonyl 4-trifluoromethylphenylboronic acid (0.46 g), 2N aqueous sodium carbonate solution (2.6 ml), ethanol (3 ml) and toluene (50 ml ). &Lt; / RTI &gt; The mixture was refluxed under an argon atmosphere for 13 hours. After ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from an eluted fraction with ethyl acetate-hexane (1: 3, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained colorless crystals were collected by filtration to give 3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (4-trifluoromethylphenyl) Pyrazol-4-yl] propionic acid (250 mg, yield: 22%). This was recrystallized from ethyl acetate-hexane. Melting point: 149-150 占 폚.
[1190] Example 99
[1191] Tetrakis (triphenolphosphine) palladium (130 mg) was added to a solution of ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- trifluoromethanesulfonyl (1.31 g), 4-fluorophenylboronic acid (0.31 g), 2N aqueous sodium carbonate solution (2.9 ml), ethanol (3 ml) and toluene (50 ml) Lt; / RTI &gt; The mixture was refluxed in an argon atmosphere for 13 hours. After ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium chloride solution, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (4-fluorophenyl) -1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Pyrazol-4-yl] propionate (540 mg, yield 45%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 93-94 占 폚.
[1192] Example 100
[1193] Benzyl] -1H-pyrazol-4-yl] propionate &lt; / RTI &gt; (500 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (3 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (4-fluorophenyl) -1- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (330 mg, yield 69%). This was recrystallized from ethyl acetate-hexane. Melting point: 139-140 占 폚.
[1194] Example 101
[1195] Tetrakis (triphenylphosphine) palladium (790 mg) was added to a solution of ethyl 3- [1- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] -3-trifluoromethanesulfonyl 4-methoxyphenylboronic acid (0.77 g), 2N aqueous sodium carbonate solution (5.0 ml), ethanol (5 ml) and toluene (100 ml) were added to a solution of 2- Lt; / RTI &gt; The mixture was refluxed in an argon atmosphere for 13 hours. After ethyl acetate was added to the reaction mixture, washing it with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (4-methoxyphenyl) -1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Pyrazol-4-yl] propionate (450 mg, yield: 24%) was obtained from the eluted fraction as an oily substance in ethyl acetate-hexane (1: 1, by volume).
[1196] _{NMR (CDCl 3): δ 1.19} (3H, t, J = 7.0 Hz), 2.44 (3H, s), 2.51 (2H, t, J = 7.5 Hz), 2.92 (2H, t, J = 7.5 Hz), (3H, s), 4.08 (2H, q, J = 7.0 Hz), 4.99 (2H, s), 5.22 (2H, s), 6.93-7.02 (4H, m), 7.16-7.26 , 7.52-7.59 (2H, m), 7.99-8.04 (2H, m).
[1197] Example 102
[1198] Ethyl 3- [3- (4-methoxyphenyl) -1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate (450 mg), 1N sodium hydroxide aqueous solution (2 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (4-methoxyphenyl) -1- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] Zol-4-yl] propionic acid (350 mg, yield: 81%). This was recrystallized from ethyl acetate-hexane. Melting point: 137-138 占 폚.
[1199] Example 103
[1200] Tetrakis (triphenylphosphine) palladium (990 mg) was added to a solution of ethyl 3- [1- [4- [2- (2-furyl) -5- methyl-4-oxazolylmethoxy) benzyl] -3- 4-trifluoromethylphenylboronic acid (1.23 g), 2N sodium carbonate aqueous solution (6.5 ml), ethanol (7 ml) and water (10 ml) Was added to a mixture of toluene (100 ml). The mixture was refluxed in an argon atmosphere for 13 hours. After ethyl acetate was added to the reaction mixture, washing it with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from an eluted fraction with ethyl acetate-hexane (1: 3, by volume). The obtained oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [l- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy) benzyl] -3- (4-trifluoromethylphenyl ) -1H-pyrazol-4-yl] propionic acid (680 mg, yield 29%). This was recrystallized from ethyl acetate-hexane. Melting point: 92-93 占 폚.
[1201] Example 104
[1202] Tetrakis (triphenylphosphine) palladium (878 mg) was added to a solution of ethyl 3- [1- [4- [2- (2-furyl) -5- methyl-4-oxazolylmethoxy) benzyl] -3- 4-yl] propionate (2.22 g), 4-fluorophenylboronic acid (798 mg), a 2N aqueous solution of sodium carbonate (10 ml), ethanol (10 ml) and toluene (30 ml). The mixture was refluxed under an argon atmosphere for 13 hours. After ethyl acetate was added to the reaction mixture, washing it with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (4-fluorophenyl) -1- [4- [2- (2-furyl) -5-methyl- 4- oxazolylmethoxy] benzyl ] -1H-pyrazol-4-yl] propionate (350 mg, yield 17%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio) as colorless oily substance.
[1203] _{NMR (CDCl 3): δ 1.19} (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.51 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6 Hz), (2H, s), 6.53 (1H, dd, J = 3.4, 1.8 Hz), 6.96-7.01 (3H, m), 7.05 -7.23 (5 H, m), 7.53 - 7.63 (2 H, m).
[1204] Example 105
[1205] Methyl-4-oxazolylmethoxy) benzyl] -lH-pyrazol-4-yl &lt; / RTI &gt; ] Propionate (350 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (4 ml) and tetrahydrofuran (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (4-fluorophenyl) -1- [4- [2- (2-furyl) -5-methyl- -1H-pyrazol-4-yl] propionic acid (150 mg, yield 45%). This was recrystallized from ethyl acetate-hexane. Melting point: 125-126 ° C.
[1206] Example 106
[1207] Methyl-2-phenyloxazole (7.13 g), ethyl 3-isopropyl-1H-pyrazole-4-carboxylate (6.17 g) and potassium carbonate 4.72 g) and N, N-dimethylformamide (70 ml) was stirred at 80 占 폚 overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue, a mixture of potassium hydroxide (4.83 g) and ethanol (150 ml) was refluxed for 5 hours. After removal of the reaction solvent under reduced pressure, water was added to the mixture, and the mixture was then acidified with dilute hydrochloric acid. The crystals obtained were collected by filtration to give 3-isopropyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH- pyrazole- g, yield: 78%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 194-195 占 폚.
[1208] Example 107
[1209] Benzyl] -1H-pyrazole-4-carboxylic acid (10.09 g), iodomethane (2 ml ), Potassium carbonate (4.83 g) and N, N-dimethylformamide (50 ml) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3-isopropyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazole- (9.80 g, yield: 94%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 90-91 占 폚.
[1210] Example 108
[1211] Methanesulfonyl chloride was reacted with [3-isopropyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol- Was added dropwise at 0 [deg.] C to a mixture of triethylamine (0.8 ml) and ethyl acetate (30 ml), which was stirred for 3 hours at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was dissolved in tetrahydrofuran (20 ml). This solution was added dropwise at 0 ° C to a tetrahydrofuran solution (30 ml) of sodium diethyl malonate prepared separately using diethyl malonate (2.35 g) and sodium hydride (60%, oil, 0.55 g). The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was dissolved in ethanol (50 ml), and then a 1N aqueous sodium hydroxide solution (15 ml) was added to the solution, which was stirred at 60 ° C for 2 hours. After removal of the reaction solvent under reduced pressure, water was added to the mixture and it was acidified with dilute hydrochloric acid. The obtained crystals were filtered and washed with water, and then the crystals were dissolved in pyridine (50 ml), and this was stirred at 120 ° C for 2 hours. After removal of the pyridine under reduced pressure, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, then with saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated. The resulting crystals were collected by filtration to give 3- [3-isopropyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Propionic acid (1.23 g, yield: 55%). This was recrystallized from ethyl acetate-hexane. Melting point: 97-98 캜.
[1212] Example 109
[1213] 5-methyl-2-phenyloxazole (910 mg), ethyl 3- (3-propyl-1H-pyrazol- Pyrazol-4-yl) propionate (500 mg) and N, N-dimethylformamide (10 ml) and stirred for 12 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] ] Propionate (620 mg, yield 53%) as a colorless oily substance.
[1214] _{NMR (CDCl 3): δ 0.97} (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 1.60-1.75 (2H, m), 2.43 (3H, s), 2.45-2.59 (4H, m), 2.66-2.75 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 4.98 (2H, s), 5.14 (2H, s), 6.94-7.04 7.11-7.16 (2H, m), 7.42-7.45 (3H, m), 7.98-8.04 (2H, m).
[1215] Example 110
[1216] Benzyl] -3-propyl-1H-pyrazol-4-yl] propionate (610 mg), 1N A mixture of sodium hydroxide aqueous solution (2.6 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3-propyl-lH-pyrazol- (480 mg, yield: 80%). This was recrystallized from ethyl acetate-hexane. Melting point: 153-154 &lt; 0 &gt; C.
[1217] Example 111
[1218] From the eluted fraction after the elution of the compound of Example 109 in the silica gel column chromatography in Example 109, ethyl 3- [1- [4- (5-methyl-2-phenyl- Methoxy) benzyl] -5-propyl-1H-pyrazol-4-yl] propionate (240 mg, yield 21%).
[1219] _{NMR (CDCl 3): δ 0.89} (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.35-1.47 (2H, m), 2.42 (3H, s), 2.43-2.58 (4H, m), 2.67-2.75 (2H, m), 4.13 (2H, q, J = 7.2 Hz), 4.96 (2H, s), 5.20 7.33 (1H, s), 7.41-7.45 (3H, m), 7.98-8.03 (2H, m).
[1220] Example 112
[1221] Benzyl] -5-propyl-1H-pyrazol-4-yl] propionate (210 mg), 1N A mixture of aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -5-propyl-lH-pyrazol-4-yl] (170 mg, yield: 85%). This was recrystallized from ethyl acetate-hexane. Melting point: 158-159 占 폚.
[1222] Example 113 Synthesis of
[1223] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (prepared as described in 340 mg), 1N sodium hydroxide aqueous solution (1.5 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hour. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [l- [4- (3-methyl-1- (2-pyridyl) -1H- pyrazol-4-ylmethoxy] benzyl] 4-yl] propionic acid (320 mg, yield 88%). This was recrystallized from ethyl acetate-hexane. Melting point: 131-132 &lt; 0 &gt; C.
[1224] Example 114
[1225] Sodium hydride (60%, oil, 200 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (1.04 g) in N, N-dimethylformamide At 0 &lt; 0 &gt; C, which was stirred for 30 minutes at 0 &lt; 0 &gt; C. 4- [2- (4-chloromethylphenoxy) ethyl] -5-methyl-2-phenyloxazole (1.43 g) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography and an oily substance was obtained from an eluted fraction with ethyl acetate-hexane (1: 2, by volume). The resulting material, a mixture of 1N aqueous sodium hydroxide solution (4 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred for 2 hours at room temperature. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [l- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) epoxy] benzyl] Yl] propionic acid (930 mg, yield: 71%). This was recrystallized from acetone-hexane. Melting point: 142-143 占 폚.
[1226] Example 115
[1227] Sodium hydride (60%, oil, 170 mg) was added to a N, N-dimethylformamide solution (50 ml) of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate At 0 &lt; 0 &gt; C and the mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. 2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl methanesulfonate (2.79 g) was added to the reaction mixture and stirred at 90 占 폚 for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] Yl] propionate (1.19 g, yield: 62%) was obtained as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 81-82 占 폚.
[1228] Example 116
[1229] Ethyl] -3-phenyl-1H-pyrazol-4-yl] propionate (prepared as described in 900 mg), a 1N sodium hydroxide aqueous solution (3.4 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [l- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] 4-yl] propionic acid (860 mg, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85-86 캜.
[1230] Example 117
[1231] Thionyl chloride (0.31 ml) was added dropwise at 0 占 폚 to a toluene solution (30 ml) of 4- [2- [N-methyl-N- (2- pyridyl) amino] ethoxy] benzyl alcohol . The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in ethyl acetate and washing it with saturated sodium bicarbonate, then washed with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue and ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (860 mg) were dissolved in N, N-dimethylformamide (15 ml). Sodium hydride (60%, oil, 100 mg) was added to the solution, which was then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous sodium chloride solution, which was extracted with ethyl acetate. After washing the ethyl acetate layer with water, then washed with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] Yl] propionate (0.75 g, yield: 68%) was obtained as a colorless oily substance.
[1232] _{NMR (CDCl 3): δ 1.17} (3H, t, J = 7.0 Hz), 2.46-2.54 (2H, m), 2.89-2.97 (2H, m), 3.16 (3H, s), 3.99 (2H, t, J = 5.4 Hz), 4.06 (2H, q, J = 7.0 Hz), 4.19 (2H, t, J = 5.4 Hz), 5.21 (2H, s), 6.51-6.59 (2H, m), 6.83-6.89 2H, m), 7.15-7.51 (7H, m), 7.59-7.64 (2H, m), 8.13-8.17 (1H, m).
[1233] Example 118
[1234] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (prepared as described in Example 1) was reacted with ethyl 3- [1- [4- [2- [N-methyl- 750 mg), 1N aqueous sodium hydroxide solution (3 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 1 hour. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [1- [4- [2- [N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] -4-yl] propionic acid (610 mg, yield 90%). This was recrystallized from ethyl acetate-hexane. Melting point: 110-111 占 폚.
[1235] Example 119
[1236] (3-phenyl-1H-pyrazol-4-yl] propionate (390 mg) was dissolved in N, N-dimethylformamide Sodium hydride (60%, oil, 70 mg) was added to the solution at 0 ° C and stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium chloride solution, The residue was purified by column chromatography on silica gel, eluting with ethyl 3- [1- ( ₄ -fluorophenyl) -lH-imidazol-4- Pyrazol-4-yl] propionate (0.58 g, yield: 72%) was obtained as a colorless oily substance from 4- [6- (2- fluorobenzyloxy) -2-naphthylmethyl] Obtained from the fraction eluted with ethyl acetate-hexane (1: 4, volume ratio).
[1237] _{NMR (CDCl 3): δ 1.14} (3H, t, J = 7.0 Hz), 2.47-2.50 (2H, m), 2.91-2.98 (2H, m), 4.04 (2H, q, J = 7.0 Hz), 5.25 (2H, s), 7.06-7.77 (16H, m).
[1238] Example 120
[1239] 4-yl] propionate (580 mg) and 1N aqueous sodium hydroxide solution (5 ml) were added to a solution of ethyl 3- [1- [6- (2-fluorobenzyloxy- 2.2 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, and the resulting colorless crystals were collected by filtration, Pyrazol-4-yl] propionic acid (450 mg, yield 85%) as a colorless oil. 0.0 &gt; 152-153 C. &lt; / RTI &gt;
[1240] Example 121
[1241] (500 mg), 4-trifluoromethylbenzylamine (250 mg), and 1- (4-fluorophenyl) -1H- A mixture of hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [4- (4-trifluoromethylbenzylaminocarbonyl) benzyl] -1H-pyrazol-4-yl] propionate (550 mg, yield: 77%) was obtained as an colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (3: 1, by volume).
[1242] _{NMR (CDCl 3): δ 1.18} (3H, t, J = 7.0 Hz), 2.47 (3H, s), 2.53 (2H, t, J = 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), (2H, s), 6.83 (1H, br.s), 7.24-7.47 (9H, m), 7.60 (2H, -7.65 (2H, m), 7.76-7.81 (2H, m), 7.96-8.01 (2H, m).
[1243] Example 122
[1244] Benzyl] -1H-pyrazol-4-yl] propionate (680 mg) and a 1N aqueous solution of sodium hydroxide ( 1.7 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration to obtain 620 mg (yield, 40%) of 3- [3-phenyl-1- [4- (4- trifluoromethylbenzylaminocarbonyl) benzyl] -1H- , Yield: 94%). This was recrystallized from ethyl acetate-hexane. Melting point: 151-152 占 폚.
[1245] Example 123
[1246] Methyl-benzoic acid (500 mg), (5-methyl-2-phenyl-4-oxazolyl) methyl The mixture of amine (260 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The obtained yellow crystals were collected by filtration and recrystallized from ethyl 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl) benzyl] 4-yl] propionate (600 mg, yield: 87%). This was recrystallized from ethyl acetate-hexane. Melting point: 190-191 占 폚.
[1247] Example 124
[1248] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (550 mg) was added to a solution of ethyl 3- [1- [4- (5- , A 1N sodium hydroxide aqueous solution (1.3 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl) benzyl] Yl] propionic acid (500 mg, yield: 96%). This was recrystallized from acetone-methanol. Melting point: 177-178 占 폚.
[1249] Example 125
[1250] (700 mg), 4-trifluoromethylbenzylamine (390 mg), and 1- (4-fluorobenzyloxy) -lH-pyrazol- A mixture of hydroxybenzotriazole monohydrate (340 mg), WSC (430 mg) and N, N-dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [3- (4-trifluoromethylbenzylaminocarbonyl) benzyl] -1H-pyrazol-4-yl] propionate (900 mg, yield: 91%) was dissolved in acetone-hexane (1: 2, volume ratio) to give an oily substance.
[1251] _{NMR (CDCl 3): δ 1.13} (3H, t, J = 7 Hz), 2.52 (2H, t, J = 7.3 Hz), 2.96 (2H, t, J = 7.3 Hz), 3.98 (2H, q, J M), 7.7-7.8 (1 H, m), 7.25-7.65 (13H, m) .
[1252] Example 126
[1253] Benzyl] -1H-pyrazol-4-yl] propionate (870 mg), 1N aqueous sodium hydroxide solution ( 2 ml), ethanol (6 ml) and tetrahydrofuran (4 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, then 1 N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to obtain 730 mg (yield: 95%) of 3- [3-phenyl-1- [3- (4- trifluoromethylbenzylaminocarbonyl) benzyl] -1H- pyrazol-4-yl] , Yield: 89%). This was recrystallized from acetone-isopropyl ether. Melting point: 165-166 ° C.
[1254] Example 127
[1255] (300 mg), 2-picolylamine (95 mg) and 1-hydroxybenzoic acid (100 mg) were added to a solution of 4- [4- A mixture of triazole monohydrate (130 mg), WSC (170 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [3- (2-picolylaminocarbonyl) benzyl] -1H-pyrazol-4-yl] propionate , Yield: 54%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-methanol (50: 1, by volume).
[1256] _{NMR (CDCl 3): δ 1.17} (3H, t, J = 7.2 Hz), 2.53 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7.6 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.76 (2H, d, J = 4.8 Hz), 5.36 (2H, s), 7.18-7.49 (7H, m), 7.61-7.84 4.0 Hz).
[1257] Example 128
[1258] (180 mg) and 1N aqueous sodium hydroxide solution (0.77 ml) were added to a solution of ethyl 3- [3-phenyl- 1- [3- (2-picolylaminocarbonyl) benzyl] , Ethanol (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (0.77 ml) was added to the reaction mixture, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration, and 120 mg (yield: &lt; RTI ID = 0.0 &gt; 71%). This was recrystallized from ethyl acetate-hexane. Melting point: 83-85 C (decomposition).
[1259] Example 129
[1260] (400 mg), 2-aminopyridine (120 mg) and 1-hydroxybenzotriazole (100 mg) were added to a solution of 4- A mixture of the sol monohydrate (200 mg), WSC (250 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and then washed with a saturated aqueous sodium chloride solution, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [3- (2-pyridylaminocarbonyl) benzyl] -1H-pyrazol-4-yl] propionate , Yield: 40%) was obtained from the fraction eluted with ethyl acetate-hexane (5: 1, by volume) as colorless oily substance.
[1261] _{NMR (CDCl 3): δ 1.18} (3H, t, J = 7.0 Hz), 2.54 (2H, t, J = 7.4 Hz), 2.97 (2H, t, J = 7.4 Hz), 4.08 (2H, q, J = 7.0 Hz), 5.37 (2H, s), 7.05-7.12 (1H, m), 7.26-7.86 (11H, m), 8.30-8.39 (2H, m), 8.56 (1H, br s).
[1262] Example 130
[1263] (200 mg) and 1N sodium hydroxide aqueous solution (0.88 ml) were added to a solution of ethyl 3- [3-phenyl-1- [3- (2- pyridylaminocarbonyl) benzyl] , Ethanol (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (0.88 ml) was added to the reaction mixture, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The obtained crystals were collected by filtration, and 110 mg (yield: 100%) of 3- [3-phenyl-1- [3- (2- pyridylaminocarbonyl) benzyl] 58%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 187-188 占 폚.
[1264] Example 131
[1265] (400 mg) and 2- (2-pyridyl) ethylamine (170 mg) were added to a solution of 4- [4- (2- ethoxycarbonylethyl) A mixture of 1-hydroxybenzotriazole monohydrate (200 mg), WSC (250 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3- [3-phenyl-1- [3- [2- (2-pyridyl) ethylaminocarbonyl) benzyl] -1H-pyrazol- (460 mg, yield: 87%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-methanol (50: 1, by volume).
[1266] _{NMR (CDCl 3): δ 1.17} (3H, t, J = 7.0 Hz), 2.52 (2H, t, J = 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), 3.08 (2H, t, J = 6.0 Hz), 3.85 (2H, q, J = 6.0 Hz), 4.06 (2H, q, J = 7.0 Hz), 5.33 (2H, s), 7.07-7.72 , J = 4.0 Hz).
[1267] Example 132
[1268] Benzyl] -1H-pyrazol-4-yl] propionate (450 mg), 1N sodium hydroxide A mixture of aqueous solution (2 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (2 ml) was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 3- [3-phenyl-1- [3- [2- (2-pyridyl) ethylaminocarbonyl] benzyl] -1H- pyrazol-4-yl] 400 mg, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 166-167 占 폚.
[1269] Example 133
[1270] (400 mg), 3-aminopyridine (160 mg) and 1-hydroxybenzotriazole (100 mg) were added to a solution of 4- A mixture of sol monohydrate (200 mg), WSC (250 mg) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and then washed with a saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [3- (3-pyridylaminocarbonyl) benzyl] -1H-pyrazol-4-yl] propionate , Yield: 56%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-methanol (50: 1, by volume). Melting point: 111-112 占 폚.
[1271] Example 134
[1272] (230 mg) and 1N sodium hydroxide aqueous solution (1.2 ml) were added to a solution of ethyl 3- [3-phenyl-1- [3- (3- pyridylaminocarbonyl) benzyl] , Ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hour. After adding 1N hydrochloric acid (1.2 ml) to the reaction mixture, the reaction mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to obtain 190 mg (yield: Yield: 95%) of 3- [3-phenyl-1- [3- (3- pyridylaminocarbonyl) benzyl] 86%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 131-132 &lt; 0 &gt; C.
[1273] Example 135
[1274] Methanesulfonyl chloride (790 mg) was added dropwise at 0 ° C to a mixture of 2- (4-benzyloxyphenyl) ethanol (1.19 g), triethylamine (700 mg) and ethyl acetate (30 ml) Lt; / RTI &gt; for 2 h. The reaction mixture was washed with water, saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, then was washed with a saturated aqueous sodium chloride solution, dried (MgSO _4), and concentrated. Sodium hydride (60%, oily, 190 mg) was added to a mixture of the residue, ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (1.0 g) and N, N- dimethylformamide At 0 &lt; 0 &gt; C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.45 g of ethyl [1- [2- (4-benzyloxyphenyl) ethyl] -3-phenyl-1H-pyrazol- To give a fraction eluted with diethyl ether-hexane (2: 3, by volume) as a colorless oily substance.
[1275] _{NMR (CDCl 3): δ 1.22} (3H, t, J = 7.0 Hz), 3.15 (2H, t, J = 7.4 Hz), 3.57 (2H, s), 4.13 (2H, q, J = 7.0 Hz), (2H, m), 7.02-7.07 (2H, m), 7.31-7.47 (9H, m), 7.58-7.64 (2H, 2H, m).
[1276] Example 136
[1277] To a solution of ethyl 1- [2- (4-hydroxyphenyl) ethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (400 mg) in N, N- dimethylformamide (10 ml) Sodium (60%, oil, 50 mg) was added at 0 &lt; 0 &gt; C and the solution was stirred at room temperature for 30 minutes. To this solution, 4-chloromethyl-5-methyl-2-phenyloxazole (290 mg) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] Yl] acetate (260 mg, yield 46%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 3, volume ratio) as a colorless oily substance.
[1278] _{NMR (CDCl 3): δ 1.22} (3H, t, J = 7.0 Hz), 2.43 (3H, s), 3.15 (2H, t, J = 7.4 Hz), 3.57 (2H, s), 4.13 (2H, q (2H, m), 7.03-7.08 (2H, m), 7.26-7.45 (7H, m) m), 7.58-7.63 (2H, m), 7.99-8.04 (2H, m).
[1279] Example 137
[1280] Ethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (260 mg) was dissolved in a mixture of ethyl [1- [2- [4- A mixture of 1N aqueous sodium hydroxide solution (1 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hour. After adding 1N hydrochloric acid (1 ml) to the reaction mixture, the reaction mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with aqueous saturated sodium chloride, dried (MgSO _4), and concentrated. The crystals obtained were collected by filtration to give 1- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] Acetic acid (170 mg, yield 68%). This was recrystallized from ethyl acetate-hexane. Melting point: 104-105 占 폚.
[1281] Example 138
[1282] Pyrazole-4-carboxylate (1.50 g), potassium carbonate (2.76 g), and N (4-chloromethylphenoxy) , N-dimethylformamide (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with water, then washed with saturated aqueous sodium chloride, dried (MgSO _4), and concentrated. The resulting crystals were collected by filtration and dried under reduced pressure to obtain ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazole- : 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 108-109 占 폚.
[1283] Example 139
[1284] Sodium hydride (60%, oil, 336 mg) was added to a solution of ethyl diethylphosphonoacetate (1.67 ml) in tetrahydrofuran (20 ml) at 0 ° C and stirred at 0 ° C for 30 minutes. Benzyl] -1H-pyrazole-4-carbaldehyde (2.61 g) in tetrahydrofuran (20 ml) Was added dropwise at 0 &lt; 0 &gt; C, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate layer with saturated sodium chloride solution, dried (MgSO _4), and concentrated. The resulting crystals were collected by filtration to obtain ethyl (E) -3- [1- [4- (5-methyl-2-phenyl- ] Propanoate (2.78 g, yield: 90%). This was recrystallized from ethyl acetate-hexane. Melting point: 112-113 [deg.] C.
[1285] Example 140
[1286] Benzyl] -lH-pyrazol-4-yl] propanoate (887 mg), 1N (5-methyl- A mixture of sodium hydroxide aqueous solution (4 ml), ethanol (8 ml) and tetrahydrofuran (8 ml) was stirred at 40 ° C for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and the obtained crystals were collected by filtration to give (E) -3- [1- [4- (5-methyl-2-phenyl- Pyrazol-4-yl] propenoic acid (672 mg, yield 81%). Which was recrystallized from ethanol. Melting point: 186-187 占 폚.
[1287] Example 141
[1288] Benzyl] -1H-pyrazol-4-yl] propanoate (1.78 g), 5 (5-methyl- A mixture of% palladium-carbon (2.0 g), ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred under hydrogen atmosphere at room temperature for 1 hour. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [1- [4- (5-methyl-2-phenyl-4-phenyl- -Oxazolylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate (1.57 g, yield: 88%).
[1289] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 2.42 (3H, s), 2.52 (2H, t, J = 7.2 Hz), 2.77 (2H, t, J = 7.2 Hz), D, J = 8.6 Hz), 7.15 (1H, s), 7.18 (2H, s), 4.98 (2H, , J = 8.6Hz), 7.36 (1H, s), 7.39-7.46 (3H, m), 7.97-8.03 (2H, m).
[1290] Example 142 [
[1291] Benzyl] -1H-pyrazol-4-yl] propionate (1.34 g) and a 1N aqueous solution of sodium hydroxide ( 6 ml), ethanol (12 ml), and tetrahydrofuran (12 ml) was stirred at room temperature for 2 hours. After adding 1N hydrochloric acid (6 ml) to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The crystals obtained were collected by filtration to give 1.21 g (0.14 mmol) of 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol- , Yield: 97%). This was recrystallized from ethanol-hexane. Melting point: 124-125 DEG C
[1292] Example 143
[1293] Dimethyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole-4-carbaldehyde in N, N-dimethylformamide Sodium hydride (60%, oil, 200 mg) was added at 0 ° C to a solution of the aldehyde (900 mg) and ethyldiethylphosphonoacetate (1.10 g) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and concentrated. The crystals obtained were collected by filtration to give ethyl (E) -3- [3,5-dimethyl-1- [4- (5- Pyrazol-4-yl] propanoate (740 mg). After concentrating the mother liquor, the residue was subjected to silica gel column chromatography, and 150 mg of crystals were further obtained from the fraction eluted with ethyl acetate-hexane (2: 3, by volume). (Yield: 87%). This was recrystallized from ethyl acetate-isopropyl ether. Melting point: 98-99 DEG C
[1294] Example 144
[1295] Ethyl (E) -3- [3,5-dimethyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol-4-yl] propanoate (800 mg), 5% palladium-carbon (400 mg), ethanol (30 ml), and tetrahydrofuran (10 ml) was stirred under hydrogen atmosphere at room temperature for 1 hour. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3,5-dimethyl-1- [4- (5-methylpyridin-2-ylmethyl) Benzyl] -1 H-pyrazol-4-yl] propionate (770 mg, yield: 96%).
[1296] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7 Hz), 2.09 (3H, s), 2.22 (3H, s), 2.35-2.5 (5H, m), 2.6-2.75 (2H, m) (2H, d, J = 9 Hz), 4.09 (2H, q, J = 7 Hz), 4.96 , 7.4-7.5 (3H, m), 7.95-8.1 (2H, m).
[1297] Example 145
[1298] Benzyl] -1 H-pyrazol-4-yl] propionate (760 mg) was added to a solution of ethyl 3- [3,5-dimethyl- , A 1N sodium hydroxide aqueous solution (5 ml), ethanol (5 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. This was recrystallized from methanol-ethyl acetate to give 3- [3,5-dimethyl-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (550 mg, yield: 77%). Melting point: 170-171 DEG C
[1299] Example 146
[1300] (440 mg), 1N aqueous sodium hydroxide solution (2 ml) and ethanol (2 ml) were added to a solution of ethyl [1- [2- (4- benzyloxyphenyl) ethyl] , And tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with IN hydrochloric acid. The resulting crystals were collected by filtration to give [1- [2- (4-benzyloxyphenyl) ethyl] -3-phenyl-1H-pyrazol-4-yl] acetic acid (350 mg, %). This was recrystallized from tetrahydrofuran-hexane. Melting point: 199-200 ° C
[1301] Example 147
[1302] 5-methyl-2-phenyloxazole (55.11 g), potassium carbonate ((4-chloromethylphenoxymethyl) 25.52 g), and N, N-dimethylformamide (300 ml) was stirred at 90 占 폚 for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -pyrrolidinone as colorless crystals from a fraction eluted with ethyl acetate-hexane (1: 1, ) Benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H-pyrazole-4-carboxylate (48.16 g, yield 87% Respectively. This was recrystallized from acetone-hexane. Melting point: 118-119 占 폚.
[1303] Example 148
[1304] Benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] -1H (60%, oil-based, 1.68 g) was added to a mixture of 2-methyl-pyrazole-4-carbaldehyde (25.20 g), ethyldiethylphosphonoacetate (9.50 g), and N, N- g) was added at 0 &lt; 0 &gt; C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water and the obtained crystals were collected by filtration to give ethyl (E) -3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) Benzyloxy] -1H-pyrazol-4-yl] propanoate (25.58 g, yield: 92%) was obtained as colorless crystals of 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] This was recrystallized from tetrahydrofuran-hexane. Melting point: 148 - 149 캜
[1305] Example 149
[1306] Benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolyl) (24.15 g), 5% palladium-carbon (34.22 g), and tetrahydrofuran (400 ml) was hydrogenated under a hydrogen atmosphere at room temperature And stirred overnight. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-hydroxy-1- [4- (5-methyl-2- Phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazol-4-yl] propionate (13.93 g, yield 92%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 137 - 138 캜
[1307] Example 150
[1308] Benzyl] -1 H-pyrazol-4-yl] propionate (650 mg), and ethyl 3- [3-hydroxy- After stirring a mixture of 1N sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (560 mg, yield: 91%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 197-198 DEG C
[1309] Example 151
[1310] To a solution of ethyl 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazol- To the solution of propionate (1.00 g) was added sodium hydride (60%, oil, 100 mg) at 0 ° C and the solution was stirred for 30 minutes. N-phenyltrifluoromethanesulfonimide (930 mg) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. After washing the ethyl acetate with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, washed with saturated sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-methyl-2-phenyl-4-phenyl-isoxazol- -Oxazolylmethoxy) benzyl] -3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl] propionate (1.31 g, yield: 100%).
[1311] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.43 (3H, s), 2.48-2.56 (2H, m), 2.69-2.76 (2H, m), 4.09 (2H, q, M), 7.42-7.46 (3H, m), 7.99-8.04 (2H, m), 7.99-8.04 (2H, m).
[1312] Example 152
[1313] To a solution of ethyl 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole- (60%, oil, 40.0 mg) was added at 0 占 폚, and the solution was stirred at room temperature for 30 minutes. Iodomethane (0.187 ml) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-methoxy-1- [4- (5-methyl-thiophene- Benzyl] -1H-pyrazol-4-yl] propionate (382 mg, yield 80%).
[1314] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 2.43 (3H, s), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 3.90 (3H, s) (1H, s), 4.09 (2H, q, J = 7.2 Hz), 4.98 (2H, s), 5.01 d, J = 8.8Hz), 7.40-7.47 (3H, m), 7.99-8.04 (2H, m).
[1315] Example 153
[1316] Benzyl] -1H-pyrazol-4-yl] propionate (380 mg), and ethyl 3- [3-methoxy- A mixture of 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (2 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-methoxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (319 mg, yield: 89%). This was recrystallized from ethanol-hexane. Melting point: 127-128 DEG C
[1317] Example 154
[1318] To a solution of ethyl 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole- (60%, oil, 40.0 mg) was added at 0 占 폚, and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and ethyl 3- [3-ethoxy-1- [4- (5-methyl-pyridin- 2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazol-4-yl] propionate (452 mg, yield 92%).
[1319] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.43 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.98 (2H, s), 5.00 , 6.97 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.40-7.47 (3H, m), 7.97-8.06 (2H, m).
[1320] Example 155
[1321] Benzyl] -1H-pyrazol-4-yl] propionate (441 mg) was obtained as colorless crystals from ethyl 3- [3-ethoxy- A mixture of 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (2 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (328 mg, yield: 79%). This was recrystallized from ethanol-hexane. Melting point: 96-97 占 폚.
[1322] Example 156
[1323] To a solution of ethyl 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole- (60%, oil, 72.0 mg) was added at 0 ° C and the solution was stirred at room temperature for 30 minutes. Iodopropane (0.33 g) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained oily substance, a mixture of 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (3 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [l- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3-propyloxy- Yl] propionic acid (0.59 g, yield: 81%). This was recrystallized from acetone-hexane. Melting point: 108-109 占 폚.
[1324] Example 157
[1325] Benzyl] -1H-pyrazol-4-yl] propionate (700 mg), ethyl 3- [3-hydroxy- A mixture of potassium carbonate (250 mg), iodo isopropane (1.03 g), and N, N-dimethylformamide (15 ml) was stirred at 80-90 占 폚 for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-isopropoxy-1- [4- (5-methylpyridin-2-ylmethyl) Benzyl] -1H-pyrazol-4-yl] propionate (460 mg, yield: 60%).
[1326] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7 Hz), 1.32 (6H, d, J = 6 Hz), 2.43 (3H, s), 2.45-2.7 (4H, m), 4.09 (2H (2H, d, J = 7 Hz), 4.75-4.95 (1H, m), 4.98 (2H, s), 5.00 , 7.14 (2H, d, J = 9Hz), 7.4-7.5 (3H, m), 7.95-8.1 (2H, m).
[1327] Example 158
[1328] Benzyl] -1H-pyrazol-4-yl] propionate (440 mg) was added to a solution of ethyl 3- [3- isopropoxy- , 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 1 hour, diluted with 1N hydrochloric acid (5 ml) and extracted with ethyl acetate . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-isopropoxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -Propionic acid (380 mg, yield: 91%). This was recrystallized from acetone-isopropyl ether. Melting point: 106-107 占 폚.
[1329] Example 159
[1330] Benzyl] -lH-pyrazol-4-yl] propionate (500 mg) and ethyl 3- [3-hydroxy-1- [4- A mixture of potassium carbonate (165 mg), benzyl bromide (205 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 ° C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-benzyloxy-1- [4- (5-methyl-piperidin- Benzyl] -1H-pyrazol-4-yl] propionate (385 mg, yield 64%).
[1331] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7 Hz), 2.44 (3H, s), 2.45-2.7 (4H, m), 4.07 (2H, q, J = 7 Hz), 4.99 (2H (2H, d, J = 9 Hz), 7.31 (2H, s), 5.04 -7.5 (8H, m), 7.95-8.1 (2H, m).
[1332] Example 160
[1333] Benzyl] -1 H-pyrazol-4-yl] propionate (380 mg), and ethyl 3- [3- benzyloxy- The mixture of 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for 1 hour and then diluted with 1N hydrochloric acid (5 ml) , Which were collected by filtration. This was recrystallized from ethyl acetate-hexane to give 3- [3-benzyloxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] ] Propionic acid (300 mg, yield: 83%). Melting point: 108-109 占 폚.
[1334] Example 161
[1335] To a solution of ethyl 3- [3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole- (60%, oil, 100 mg) was added at 0 占 폚 and the solution was stirred at room temperature for 30 minutes. 2-Chloro-5-trifluoromethylpyridine (0.45 g) was added to the reaction mixture and stirred at 90 캜 for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). The obtained oily substance, a mixture of 1N sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature overnight, diluted with 1N hydrochloric acid (5 ml) . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (5- Pyridyloxy) -1H-pyrazol-4-yl] propionic acid (960 mg, Yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 107-108 DEG C
[1336] Example 162
[1337] 4- (4-chloromethylphenoxymethyl) -2- (2-furyl) -5-methyloxazole (22.85 g), ethyl 3- , Potassium carbonate (15.11 g) and N, N-dimethylformamide (200 ml) was stirred at 90 占 폚 for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and ethyl 1- [4- [2- (2-furyl) -5-methyl-4- (4- Oxazolylmethoxy] benzyl] -1H-pyrazole-4-carboxylate (19.96 g, , Yield: 82%). This was recrystallized from ethyl acetate-hexane. Melting point: 133-134 占 폚.
[1338] Example 163
[1339] Methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- (2-furyl) To a mixture of 4-methoxybenzyloxy-1H-pyrazole-4-carbaldehyde (14.09 g), ethyldiethylphosphonoacetate (5.88 g), and N, N-dimethylformamide (100 ml) Sodium (60%, oil, 1.01 g) was added at 0 &lt; 0 &gt; C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the obtained crystals were collected by filtration to give ethyl (E) -3- [1- [4- [2- (2-furyl) -5- Benzyl] -3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyloxy] -1H-pyrazol-4-yl] propanoate (13.91 g , Yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 138-139 DEG C
[1340] Example 164
[1341] 3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- (20.5 g), 5% palladium-carbon (20.0 g), ethanol (200 ml), and tetra (4-methoxybenzyloxy) A mixture of hydrofuran (200 ml) was stirred under hydrogen atmosphere at room temperature for 7 hours. After removal of the catalyst by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to obtain ethyl 3- [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3-hydroxy- Yl] propionate (4.40 g, yield: 56%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 145-146 占 폚.
[1342] Example 165
[1343] To a solution of ethyl 3- [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3-hydroxy-1H- pyrazole- (60%, oil, 420 mg) was added at 0 占 폚 and the solution was stirred for 10 minutes. N-phenyltrifluoromethanesulfonimide (3.75 g) was added to the reaction mixture and stirred at 0 &lt; 0 &gt; C for 20 min. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [1- [4- [2- (2-furyl) -5 (trifluoromethyl) phenyl] propanoic acid was obtained as a colorless oily substance from a fraction eluted with ethyl acetate- -Methyl-4-oxazolylmethoxy] benzyl] -3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl] propionate (5.02 g, yield 91%).
[1344] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.53 (2H, t, J = 7.0 Hz), 2.73 (2H, t, J = 7.0 Hz), (2H, s), 6.52 (1H, dd, J = 3.6, 1.8 Hz), 6.96-7.01 (3H, m), 7.12 (1H, s), 7.17 (2H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 1.8, 0.8 Hz).
[1345] Example 166
[1346] To a solution of ethyl 3- [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3-hydroxy-1H (60%, oil, 40.0 mg) was added at 0 占 폚 and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [4- [2- (2 (phenylmethoxy) -Furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -1H-pyrazol-4-yl] propionate (348 mg, yield 73%).
[1347] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.47 (3H, s), 2.48-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J = 7.0Hz), 4.22 (2H, q, J = 7.0Hz), 4.97 J = 3.6, 2.0 Hz), 6.92-6.99 (4H, m), 7.13 (2H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 2.0, 0.6 Hz).
[1348] Example 167
[1349] Ethyl 3- [3-ethoxy-1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -1H-pyrazol-4-yl] propionate 381 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 4 hours, diluted with 1N hydrochloric acid (2 ml) . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] Yl] propionic acid (327 mg, yield: 91%) which was recrystallized from ethanol-hexane. Melting point: 129-130 占 폚.
[1350] Example 168
[1351] To a solution of ethyl 3- [1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3-hydroxy-1H (60%, oil, 40.0 mg) was added at 0 占 폚 and the solution was stirred at room temperature for 30 minutes. Benzyl bromide (0.178 ml) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-benzyloxy-1- [4- [2- (2 (1-benzyloxy- -Furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -1H-pyrazol-4-yl] propionate (383 mg, yield 71%).
[1352] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.47-2.55 (2H, m), 2.63-2.71 (2H, m), 4.07 (2H, q, (2H, s), 5.23 (2H, s), 6.52 (1H, dd, J = 3.6, 1.8 Hz), 6.90-6.99 7.13 (2H, d, J = 8.4Hz), 7.27-7.47 (5H, m), 7.54 (1H, dd, J = 1.8, 1.0Hz).
[1353] Example 169
[1354] Ethyl 3- [3-benzyloxy-1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -1H-pyrazol-4-yl] propionate The mixture was stirred at room temperature for 5 hours, diluted with 1N hydrochloric acid (2 ml), extracted with ethyl acetate (5 ml), and the mixture was extracted with ethyl acetate . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-benzyloxy-1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] Yl] propionic acid (299 mg, yield: 83%). This was recrystallized from ethanol-hexane. Melting point: 104-105 占 폚.
[1355] Example 170
[1356] (1.59 g), 4-benzyloxy-3-methoxybenzyl chloride (1.97 g), and N, N-dimethylformamide (30%) was added sodium hydride (60%, oil, 0.30 g) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and ethyl 3- [1- (4-benzyloxy-3-methoxybenzyl) - (4- 3-ethoxy-1H-pyrazol-4-yl] propionate (2.93 g, yield 89%).
[1357] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 3.84 (2H, s), 4.06 (2H, q, J = 7.2 Hz), 4.22 (2H, q, J = 7.0 Hz), 4.97 J = 8.4, 2.0 Hz), 6.76 (1H, d, J = 2.0 Hz), 6.81 (1H, d, J = 8.4 Hz), 6.93 (1H, s), 7.28-7.44 (5H, m).
[1358] Example 171
[1359] Ethyl 3- [3-ethoxy-1- (4-hydroxy-3-methoxybenzyl) -1H-pyrazol-4-yl] propionate (505 (60%, oil, 58.0 mg) at 0 &lt; 0 &gt; C, the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (301 mg) was added to the reaction mixture, which was stirred for 1 hour at 60 deg. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [3-methoxy-4- (4-methoxy- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate (661 mg, yield 88%).
[1360] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82 (3H, s), 4.09 (2H, q, J = 7.2 Hz), 4.23 (2H, q, J = 7.2 Hz), 5.00 , 6.72 (1H, dd, J = 8.2,2.2 Hz), 6.76 (1H, d, J = 2.2 Hz), 6.95 3H, m), 7.98-8.03 (2H, m).
[1361] Example 172
[1362] Ethyl 3- [3-ethoxy-1- [3-methoxy-4- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol-4- yl] propionate (660 mg), 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (3 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Pyrazol-4-yl] propionic acid (510 mg, yield 82%). This was recrystallized from ethanol-hexane. Melting point: 122-123 占 폚.
[1363] Example 173
[1364] Ethyl 3- [3-ethoxy-1- (4-hydroxy-3-methoxybenzyl) -1H-pyrazol-4-yl] propionate (505 (60%, oil, 58.0 mg) at 0 &lt; 0 &gt; C, the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-2- (2-furyl) -5-methyloxazole (573 mg) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [4- [2- (2-methylpiperidin- -Furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxybenzyl] -1H-pyrazol-4-yl] propionate (564 mg, yield 76%).
[1365] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82 (3H, s), 4.09 (2H, q, J = 7.2 Hz), 4.23 (2H, q, J = 7.2 Hz), 4.99 Dd, J = 3.6, 1.8 Hz), 6.71 (1H, dd, J = 8.2,2.0Hz), 6.75 (1H, d, J = 2.0Hz), 6.94 (1H, d, J = 8.2 Hz), 6.96 (1H, dd, J = 3.6, 0.8 Hz), 7.53 (1H, dd, J = 1.8, 0.8 Hz).
[1366] Example 174
[1367] Ethyl 3- [3-ethoxy-1- [4- [2- (2-furyl) -5-methyl-4- oxazolylmethoxy] -3- methoxybenzyl] ] Propionate (561 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours and diluted with 1N hydrochloric acid Diluted and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [2- (2-furyl) -5-methyl-4- oxazolylmethoxy] ] -1H-pyrazol-4-yl] propionic acid (506 mg, yield: 96%). This was recrystallized from ethanol-hexane. Melting point: 133-134 &lt; 0 &gt; C.
[1368] Example 175
[1369] Ethyl 3- [3-ethoxy-1- (4-hydroxy-3-methoxybenzyl] -lH-pyrazol-4-yl] propionate (505 (60%, oil, 58.0 mg) at 0 ° C, the solution was stirred at room temperature for 30 minutes. To a solution of 4-chloromethyl-5-methyl- The reaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was washed with water and then with a saturated aqueous sodium chloride solution (1: 1) to give the title compound . ethyl 3- [3 as a colorless oily substance from the fraction eluted with a (1, 1 by volume) of hexane-washed, dried (MgSO ₄₎ and concentrated and the residue was purified by silica gel column chromatography to ethyl acetate Benzyl] -1H-pyrazol-4-yl] propionate (500 mg) was added to a solution of mg, Yield: 66% ).
[1370] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82 (3H, s), 4.09 (2H, q, J = 7.2 Hz), 4.23 (2H, q, J = 7.2 Hz) D, J = 8.0, 2.2 Hz), 6.75 (1H, d, J = 2.2 Hz), 6.94 (1H, s), 6.96 dd, J = 4.8, 3.6 Hz), 7.39 (1H, dd, J = 4.8, 1.2 Hz), 7.62 (1H, dd, J = 3.6, 1.2 Hz).
[1371] Example 176
[1372] Ethyl 3- [3-ethoxy-1- [3-methoxy-4- [5-methyl- 2- (2- thienyl) -4-oxazolylmethoxy] benzyl] (499 mg), 1N sodium hydroxide aqueous solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 3 hours and washed with 1N hydrochloric acid (2 ml) &Lt; / RTI &gt; and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3-methoxy-4- [5-methyl- 2- (2- thienyl) -4-oxazolylmethoxy] Benzyl] -1H-pyrazol-4-yl] propionic acid (392 mg, yield 83%). This was recrystallized from ethanol-hexane. Melting point: 123-124 占 폚.
[1373] Example 177
[1374] Pyrazol-4-yl] propionate (505 mg), 3-picolyl chloride hydrochloride (476 mg) was added to a solution of ethyl 3- [3-ethoxy- mg), potassium carbonate (601 mg), and N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [3-methoxy-4- (3-pyridylmethoxy) benzyl] piperidine as a colorless oily substance from a fraction eluted with ethyl acetate. -1H-pyrazol-4-yl] propionate (531 mg, yield: 83%).
[1375] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.84 (2H, s), 4.08 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 4.99 (1H, d, J = 8.0, 2.2 Hz), 6.77 (1H, d, J = 2.2 Hz), 6.84 Hz), 7.79 (1H, dt, J = 8.0, 1.8 Hz), 8.57 (1H, d, J = 4.8 Hz), 8.67 (1H, s).
[1376] Example 178
[1377] Benzyl] -1H-pyrazol-4-yl] propionate (527 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (2.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3-methoxy-4- (3-pyridylmethoxy) benzyl] -1H-pyrazol-4-yl] 381 mg, yield: 77%). This was recrystallized from ethanol-hexane. Melting point: 124-125 占 폚.
[1378] Example 179
[1379] (1.50 g), 4-benzyloxybenzyl chloride (1.81 g) and N, N-dimethylformamide (30 ml) were added to a solution of ethyl 3- [3-ethoxy-1H-pyrazol- To the mixture was added sodium hydride (60%, oil, 0.35 g) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [1- (4-benzyloxybenzyl) -3-ethoxy-benzoic acid methyl ester was obtained as a colorless oily substance from a fraction eluted with ethyl acetate-hexane (1: 4, Pyrazol-4-yl] propionate (2.76 g, yield: 96%).
[1380] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.44-2.70 (4H, m), 4.09 (2H, q, J = 7.0 Hz (2H, s), 5.05 (2H, s), 6.88-6.98 (3H, m), 7.09-7.19 (2H, m), 7.30-7.48 5H, m).
[1381] Example 180
[1382] (490 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and tetrahydrofuran (5 ml) were added to a solution of ethyl 3- [1- ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (3 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to obtain 430 mg (yield: 94%) of 3- [1- (4-benzyloxybenzyl) -3-ethoxy-1H-pyrazol- Respectively. This was recrystallized from acetone-hexane. Melting point: 115-116 [deg.] C.
[1383] Example 181
[1384] (1.55 g), 4-chloromethyl-2-phenylthiazole (1.05 g) and ethyl 3- [3-ethoxy- , Potassium carbonate (1.30 g), and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained oily substance, a mixture of 1N sodium hydroxide aqueous solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (10 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -1H- pyrazol-4-yl] 1.60 g, yield: 73%). This was recrystallized from acetone-hexane. Melting point: 114-115 [deg.] C.
[1385] Example 182
[1386] 4-yl] propionate (1.20 g), 4-chloromethyl-5-methyl-2-phenylthiazole (0.95 g), potassium carbonate (1.06 g), and N, N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography to obtain a fraction eluted with ethyl acetate-hexane (1: 2, To give a colorless oily substance. The obtained oily substance, a mixture of 1N sodium hydroxide aqueous solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (10 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (5-methyl-2-phenyl-4-thiazolylmethoxy) benzyl] Yl] propionic acid (1.46 g, yield: 81%). This was recrystallized from ethyl acetate-hexane. Melting point: 73-74 占 폚.
[1387] Example 183
[1388] (3-ethoxy-lH-pyrazol-4-yl) propionate (318 mg), 5-chloromethyl- (60%, oil, 60.0 mg) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes, to which was then added sodium hydride . The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [2- (5-methyl-pyridin- Pyridylmethyl] -1H-pyrazol-4-yl] propionate (651 mg, yield 88%).
[1389] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.47-2.55 (5H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 4.21 (2H, q, J = 7.0 Hz), 4.98 (2H, s), 5.28 (1H, s), 7.39-7.46 (4H, m), 7.98-8.04 (3H, m).
[1390] Example 184
[1391] Ethyl 3- [3-ethoxy-1- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridylmethyl] -1H-pyrazol-4-yl] propionate (638 mg), 1N sodium hydroxide aqueous solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (2.5 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [2- (5-methyl-phenyl-4-oxazolylmethoxy) -5-pyridylmethyl] -1H-pyrazole -4-yl] propionic acid (495 mg, yield: 82%). This was recrystallized from ethanol-hexane. Melting point: 143-144 占 폚.
[1392] Example 185
[1393] (4-chloromethylphenoxymethyl) -2-phenyloxazole (450 mg), and N (3-ethoxy-lH- pyrazol-4-yl) propionate (60%, oil, 60.0 mg) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to obtain ethyl 3- [3-ethoxy-1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -1H- (616 mg, yield: 86%). This was recrystallized from ethyl acetate-hexane. Melting point: 80-81 占 폚.
[1394] Example 186
[1395] Benzyl] -1H-pyrazol-4-yl] propionate (523 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (2.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol-4-yl] 456 mg, yield: 93%). This was recrystallized from ethanol-hexane. Melting point: 135-136 占 폚.
[1396] Example 187
[1397] 3- (4-chloromethylphenoxymethyl) pyridine (554 mg), and N, N-dimethylformamide To the mixture of amide (10 ml) was added sodium hydride (60%, oil, 80.0 mg) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (3-pyridyl) methanone as a colorless oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, Ethoxy) benzyl] -1H-pyrazol-4-yl] propionate (340 mg, yield 55%).
[1398] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 4.22 (2H, q, J = 7.0 Hz), 5.00 (2H, s), 5.07 (1H, s), 7.14 (2H, d, J = 8.8 Hz), 7.32 (1H, dd, J = 7.4, 4.8 Hz), 7.77 dd, J = 4.8, 2.0 Hz), 8.68 (1H, d, J = 2.0 Hz).
[1399] Example 188
[1400] 4-yl] propionate (340 mg), 1N aqueous sodium hydroxide solution (2 ml), and a mixture of ethyl 3- [3-ethoxy- A mixture of tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (2 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to obtain 260 mg (yield: 300 mg) of 3- [3-ethoxy-1- [4- (3- pyridylmethoxy) benzyl] -1H- 82%). This was recrystallized from ethanol-hexane. Melting point: 120-121 占 폚.
[1401] Example 189
[1402] Pyrazol-4-yl) propionate (300 mg), 4- (4-chloromethylphenoxymethyl) -5-methyl-2- (2- Sodium hydride (60%, oil, 70.0 mg) was added at 0 占 폚 to a mixture of 4-methyl-lH-imidazole (450 mg) and N, N- dimethylformamide (5 ml) Lt; / RTI &gt; The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained colorless crystals, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, diluted with 1N hydrochloric acid (5 ml) . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [5-methyl-2- (2- Pyrazol-4-yl] propionic acid (460 mg, yield 70%). This was recrystallized from acetone-hexane. Melting point: 156-157 占 폚.
[1403] Example 190
[1404] Ethyl] -N-methylamino] - &lt; / RTI &gt; Sodium hydride (60%, oil, 80.0 mg) was added to a mixture of pyridine (554 mg) and N, N-dimethylformamide (10 ml) at 0 ° C and the mixture was stirred at room temperature for 30 minutes Respectively. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [4- [2- [N [N (2-pyridyl) amino] ethoxy] benzyl] -1H-pyrazol-4-yl] propionate (771 mg, yield 85%).
[1405] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.47-2.54 (2H, m), 2.59-2.67 (2H, m), 3.14 (3H, s), 3.97 (2H, t, J = 5.6 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.17 D, J = 8.6 Hz), 4.97 (2H, s), 6.49-6.58 (2H, m), 6.84 , 7.45 (1H, ddd, J = 8.6, 7.2, 1.8 Hz), 8.15 (1H, ddd, J = 5.0, 1.8, 1.0 Hz).
[1406] Example 191
[1407] Ethyl 3- [3-ethoxy-1- [4- [2- [N-methyl-N- (2- pyridyl) amino] ethoxy] benzyl] -1H-pyrazol-4-yl] propionate (769 mg), 1N sodium hydroxide aqueous solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (4 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain 3- [3-ethoxy-1- [4- [2- [N-methyl-N- (2-pyridyl ) Amino] ethoxy] benzyl] -1H-pyrazol-4-yl] propionic acid (402 mg, yield 56%).
[1408] _{NMR (CDCl 3) δ: 1.34} (3H, t, J = 7.0 Hz), 2.50-2.68 (4H, m), 3.12 (3H, s), 3.94 (2H, t, J = 5.4 Hz), 4.15 (2H (2H, m, J = 5.4 Hz), 4.21 (2H, q, J = 7.0 Hz), 4.97 (1H, s), 7.08 (2H, d, J = 8.8 Hz), 7.45 (1H, ddd, J = 8.6, 7.2, 2.0 Hz), 8.15 (1H, ddd, J = 7.2, 2.0, 1.0 Hz).
[1409] Example 192
[1410] Yl) propionate (318 mg), 2- [4- (4-chloromethylphenoxy) piperidin- 1 -yl] Sodium hydride (60%, oil, 60.0 mg) was added at 0 ° C to a mixture of N, N-dimethylformamide (10 mg) and N, N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [4- [1- (2 (phenylmethyl) Yloxy] benzyl] -1H-pyrazol-4-yl] propionate (609 mg, yield 85%).
[1411] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 1.76-1.93 (2H, m), 1.98-2.12 (2H, m), 2.48 (2H, m), 2.61-2.69 (2H, m), 3.39-3.49 (2H, m), 3.85-3.97 (1H, d, J = 7.0 Hz), 4.46-4.57 (1H, m), 4.99 (2H, s), 6.60 (1H, ddd, J = 7.0, 5.0, 0.8 Hz) (1H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 6.93 ), 8.19 (1H, ddd, J = 5.0, 1.8, 0.8 Hz).
[1412] Example 193
[1413] Benzyl] -lH-pyrazol-4-yl] propionate (598 mg, 0.35 mmol) was added to a solution of ethyl 3- [3-ethoxy- ), 1N sodium hydroxide aqueous solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (2.5 ml), extracted with ethyl acetate Respectively. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [1- (2-pyridyl) piperidin-4-yloxy] benzyl] -1H- -Propionic acid (408 mg, yield: 72%). This was recrystallized from ethanol-hexane. Melting point: 142-143 占 폚.
[1414] Example 194
[1415] (314 mg) and 2- [2- (4-chloromethylphenoxy) ethyl] -5-ethylpyridine (414 mg) were added to a solution of ethyl 3- (3-ethoxy- (60%, oil, 60.0 mg) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [4- [2- (5 (trifluoromethyl) -Ethyl-2-pyridyl) ethoxy] benzyl] -1H-pyrazol-4-yl] propionate (520 mg, yield 77%).
[1416] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.6 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.46-2.54 (2H, m (2H, q, J = 7.0 Hz), 4.33 (2H, s), 2.57-2.68 (4H, m), 3.22 (2H, d, J = 6.6 Hz), 4.97 (2H, s), 6.85 d, J = 7.8 Hz), 7.45 (1H, dd, J = 7.8, 2.0 Hz), 8.39 (1H, d, J = 2.0 Hz).
[1417] Example 195
[1418] Ethyl 3- [3-ethoxy-1- [4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl] -1H-pyrazol-4-yl] propionate (519 mg) A mixture of 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (2.5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [2- (5-ethyl-2- pyridyl) ethoxy] benzyl] Yl] propionic acid (228 mg, yield 47%). This was recrystallized from ethanol-hexane. Melting point: 89-90 캜.
[1419] Example 196
[1420] (3-ethoxy-lH-pyrazol-4-yl) propionate Sodium hydride (60%, oil, 130 mg) was added at 0 ° C to a mixture of diisopropylethylamine (1.05 g) and N, N-dimethylformamide (20 ml) Lt; / RTI &gt; The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The obtained colorless oily substance, a mixture of 1N sodium hydroxide aqueous solution (6 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (6 ml) , And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [2- (5-methyl-2- phenyl-4-oxazolyl) ethoxy] benzyl] Yl] propionic acid (1.09 g, yield: 72%). This was recrystallized from acetone-hexane. Melting point: 142-143 占 폚.
[1421] Example 197
[1422] To a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (780 mg) in N, N-dimethylformamide (50 ml) was added sodium hydride (60% mg) at 0 &lt; 0 &gt; C, and the solution was stirred at room temperature for 30 minutes. After adding 2- [4- (5-methyl-2-phenyl-4-oxazolyl) methoxy] phenyl] ethyl methanesulfonate (2.17 g) to the reaction mixture at 0 ° C, Lt; / RTI &gt; The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [2- [4- (5 (trifluoromethyl) Phenyl] ethyl] -1H-pyrazol-4-yl] propionate (1.08 g, yield 58%).
[1423] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 2.43 (3H, s), 2.49-2.65 (4H, m), 3.00 (2H J = 7.0 Hz), 4.04 (2H, t, J = 7.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.24 ), 6.78 (1H, s), 6.89-7.01 (4H, m), 7.42-7.46 (3H, m), 7.99-8.04 (2H, m).
[1424] Example 198
[1425] Phenyl] ethyl] -1H-pyrazol-4-yl] propionate &lt; / RTI &gt; (1.08 g), 1N sodium hydroxide aqueous solution (4.2 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (5 ml) Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting crystals were collected by filtration to give 3- [3-ethoxy-1- [2- [4- (5-methyl-2- phenyl-4-oxazolylmethoxy) phenyl] ethyl] Yl] propionic acid (880 mg, yield: 88%). This was recrystallized from ethyl acetate-hexane. Melting point: 110-111 占 폚.
[1426] Example 199
[1427] (509 mg) and 4- (2-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole (753 mg) were added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol- ) And N, N-dimethylformamide (10 ml), sodium hydride (60%, oil, 96.0 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- [2- (5-methyl-pyridin- Benzyl] -1H-pyrazol-4-yl] propionate (1.09 g, yield: 93%).
[1428] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 4.08 (2H, q, J = 7.2 Hz), 4.20 (2H, q, J = 7.2 Hz), 5.03 (2H, s), 5.11 m), 7.01-7.06 (2H, m), 7.22-7.31 (1H, m), 7.41-7.48 (3H, m), 7.98-8.05 (2H, m).
[1429] Example 200
[1430] Benzyl] -1H-pyrazol-4-yl] propionate (1.09 g), and ethyl 3- [3-ethoxy- A mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, diluted with 1N hydrochloric acid (5 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (834 mg, yield: 82%). This was recrystallized from ethanol-hexane. Melting point: 127-128 占 폚.
[1431] Example 201
[1432] To a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (509 mg) and 4- (3- chloromethylphenoxymethyl) -5- ) And N, N-dimethylformamide (10 ml), sodium hydride (60%, oil, 96.0 mg) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, washed with saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and ethyl 3- [3-ethoxy-1- [3- (5-methyl-pyridin- Benzyl] -1H-pyrazol-4-yl] propionate (809 mg, yield 69%).
[1433] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.48-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), 4.95 m), 6.91-6.97 (2H, m), 7.25 (1H, t, J = 7.8 Hz), 7.42-7.45 (3H, m), 7.99-8.04 (2H, m).
[1434] Example 202
[1435] Benzyl] -1H-pyrazol-4-yl] propionate (808 mg), and ethyl 3- [3-ethoxy- A mixture of 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml), and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1N hydrochloric acid (4 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography and a fraction eluted with ethyl acetate-methanol (5: 1, by volume) to give 3- [3-ethoxy-1- [3- Benzyl] -1H-pyrazol-4-yl] propionic acid (709 mg, yield 93%).
[1436] _{NMR (CDCl 3) δ: 1.35} (3H, t, J = 7.0 Hz), 2.48 (3H, s), 2.67 (4H, s), 4.21 (2H, q, J = 7.0 Hz), 4.96 (2H, s (1H, s), 5.11 (2H, s), 6.42 (1H, s), 6.84-6.91 m), 7.94-7.99 (2H, m).
[1437] Example 203
[1438] Benzyl] -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxy] - A mixture of 1H-pyrazole-4-carboxylate (2.84 g), 5% palladium-carbon (5.00 g), ethanol (25 ml), and tetrahydrofuran (25 ml) Lt; / RTI &gt; After removal of the catalyst by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to give ethyl 3-hydroxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazole- (968 mg, yield: 56%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 152-153 &lt; 0 &gt; C.
[1439] Example 204
[1440] 4-carboxylate (10.30 g), 4-benzyloxybenzyl chloride (18.60 g), potassium carbonate (16.60 g), and N, N-dimethylformamide ) Was stirred at 100 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazole-4-carbaldehyde as colorless crystals from a fraction eluted with ethyl acetate (11.90 g, yield: 54%). This was recrystallized from ethyl acetate-hexane. Melting point: 124-125 占 폚.
[1441] Example 205
[1442] To the solution of ethyl diethylphosphonoacetate (2.74 ml) in tetrahydrofuran (50 ml) was added sodium hydride (60%, oil, 552 mg) at 0 ° C and the solution was stirred at room temperature for 30 minutes Respectively. To the reaction mixture was added a solution of l- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazole-4-carbaldehyde (6.31 g) in tetrahydrofuran (100 ml) Was slowly added and the solution was stirred at room temperature for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained crystals were collected by filtration to give ethyl 3- [1- (4-benzyloxybenzyl) -3- (4-benzyloxybenzyloxy) -1H-pyrazol-4-yl] propionate , Yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 98-99 ° C.
[1443] Example 206
[1444] To a solution of ethyl 3- [3-hydroxy-1- (4-hydroxybenzyl) -1H-pyrazol-4-yl] propionate (435 mg) in N, N- dimethylformamide , Sodium hydride (60%, oil, 120 mg) at 0 ° C, and the solution was stirred at room temperature for 30 minutes. 3-Picolyl chloride (574 mg) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, washed with a saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (3-pyridylmethoxy) -1- [4- (3-pyridylmethoxy) benzyl] piperidine as a colorless oily substance from a fraction eluted with ethyl acetate, -1H-pyrazol-4-yl] propionate (533 mg, yield 75%).
[1445] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.46-2.54 (2H, m), 2.62-2.70 (2H, m), 4.07 (2H, q, J = 7.2 Hz), 5.01 (2H, s), 5.07 (2H, s), 5.25 (2H, s), 6.93 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.26-7.36 m), 7.74-7.80 (2H, m), 8.55-8.60 (2H, m), 8.69 (2H, s).
[1446] Example 207
[1447] Benzyl] -1H-pyrazol-4-yl] propionate (529 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 1 hour, diluted with 1N hydrochloric acid (3 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The obtained colorless crystals were collected by filtration to give 3- [3- (3-pyridylmethoxy) -1- [4- (3-pyridylmethoxy) benzyl] -1H-pyrazol-4-yl] 427 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 116-117 [deg.] C.
[1448] Example 208
[1449] 3-ethoxy-1H-pyrazol-4-yl] propionate (2.92 g), 5% palladium- carbon (6.00 g) , Ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred under hydrogen atmosphere at room temperature for 1 hour. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- [3-ethoxy-1- (4-hydroxy-3- (2- Methoxybenzyl) -1H-pyrazol-4-yl] propionate (2.04 g, yield 89%).
[1450] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.85 (2H, s), 4.08 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.97 d, J = 8.0 Hz), 6.73 (1H, s), 6.86 (1H, d, J = 8.0 Hz), 6.93 (1H, s).
[1451] Example 209
[1452] 4-yl] propionate (360 mg), 2-chloromethylquinoline hydrochloride (270 mg) and potassium carbonate (300 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 占 폚 for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5 ml) The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 420 mg of 3- [3-ethoxy-1- [4- (2-quinolylmethoxy) benzyl] -1H-pyrazol-4-yl] : 86%). This was recrystallized from acetone-hexane. Melting point: 140-141 占 폚.
[1453] Example 210
[1454] Sodium hydride (60%, oil, 60.0 mg) was added to ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide Was added at 0 ° C to a solution of 4-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (472 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [2- (5-methyl-imidazol- 4-pyridylmethyl] -1H-pyrazol-4-yl] propionate (640 mg, yield 87%).
[1455] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.46 (3H, s), 2.49-2.57 (2H, m), 2.62-2.70 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 5.01 (2H, s), 5.27 , 6.63 (1H, d, J = 5.2 Hz), 7.03 (1H, s), 7.39-7.46 (3H, m), 7.97-8.04 (2H, m), 8.09 (1H,
[1456] Example 211
[1457] Ethyl 3- [3-ethoxy-1- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethyl] -1H-pyrazol-4-yl] propionate (638 mg), 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, and 1N hydrochloric acid (3 ml) The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -4-pyridylmethyl] Pyrazol-4-yl] propionic acid (495 mg, yield 82%). This was recrystallized from ethanol-hexane. Melting point: 114-115 [deg.] C.
[1458] Example 212
[1459] Sodium hydride (60%, oil, 60.0 mg) was added to ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide Was added at 0 ° C to a solution of 3-chloromethyl-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (472 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethyl) -3-pyridylmethyl] -1H-pyrazol-4-yl] propionate (616 mg, yield 84%).
[1460] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.43 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 5.00 (2H, s), 5.07 , 7.14 (1H, dd, J = 1.4, 3.0 Hz), 7.41-7.47 (3H, m), 7.97-8.03 , J = 3.0 Hz).
[1461] Example 213
[1462] Ethyl 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] -1H-pyrazol-4-yl] propionate (613 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] Yl] propionic acid (532 mg, yield: 92%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 133-134 占 폚.
[1463] Example 214
[1464] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide mg) and 4- (5-chloromethyl-2-methoxyphenoxymethyl) -5-methyl-2-phenyloxazole (516 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4-methoxy-3- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] Yl) propionate (647 mg, yield 83%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 109-110 占 폚.
[1465] Example 215
[1466] Ethyl 3- [3-ethoxy-1- [4-methoxy-3- (5-methyl-2- phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol-4-yl] propionate (572 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4-methoxy-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (498 mg, yield 92%). This was recrystallized from ethanol-hexane. Melting point: 136-137 占 폚.
[1467] Example 216
[1468] Sodium hydride (60%, oil, 50.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (265 mg) and 4- (4-chloromethyl-2-ethoxyphenoxymethyl) -5-methyl-2-phenyloxazole (447 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [3-ethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl) propionate (548 mg, yield 82%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1469] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz), 2.43 (3H, s), (2H, q, J = 7.0 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = (2H, s), 6.70 (1H, d, J = 1.8, 8.0 Hz) , 6.98 (1H, d, J = 8.0Hz), 7.40-7.49 (3H, m), 7.96-8.03 (2H, m).
[1470] Example 217
[1471] Ethyl 3- [3-ethoxy-1- [3-ethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -1H- pyrazol-4-yl] propionate (544 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3-ethoxy-4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] Yl] propionic acid (466 mg, yield 90%). This was recrystallized from ethanol-hexane. Melting point: 105-106 占 폚.
[1472] Example 218
[1473] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide mg) and 5-chloromethyl-3- (5-methyl-2-phenyl-4-oxazolylmethoxy) isoxazole (457 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5- isoxazolylmethyl] Pyrazol-4-yl] propionate (653 mg, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). This was recrystallized from ethyl acetate-hexane. Melting point: 82-83 캜.
[1474] Example 219
[1475] Ethyl 3- [3-ethoxy-1- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-isoxazolylmethyl] -1H-pyrazol- After stirring the mixture at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture (5 ml), and the mixture was stirred at room temperature for 3 hours. And then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5- isoxazolylmethyl] Pyrazol-4-yl] propionic acid (459 mg, yield 94%). This was recrystallized from ethanol-hexane. Melting point: 142-143 占 폚.
[1476] Example 220
[1477] Sodium hydride (60%, oil, 90.3 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (400 mg) in N, N- dimethylformamide mg) and 2- [2- (4-chloromethylphenoxy) ethyl] -1 (2H) -phthalazinone (650 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). After stirring a mixture of colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) at room temperature for 2 hours, 1N hydrochloric acid (5 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- [2- [1 -oxo phthalazin-2 (1H) -yl] ethoxy] benzyl] Yl] propionic acid (730 mg, yield 84%). This was recrystallized from acetone-hexane. Melting point: 152-153 &lt; 0 &gt; C.
[1478] Example 221
[1479] Sodium hydride (60%, oil, 90.3 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (400 mg) in N, N- dimethylformamide mg) and 2- [2- (3-chloromethylphenoxy) ethyl] -1 (2H) -phthalazinone (650 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance (1: 1, by volume) from a fraction eluted with ethyl acetate-hexane. The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (5ml), tetrahydrofuran (5ml) and ethanol (5ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5ml) And the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3- [2- [1 -oxo phthalazin-2 (1H) -yl] ethoxy] benzyl] Yl] propionic acid (690 mg, yield: 79%). This was recrystallized from acetone-hexane. Melting point: 146-147 占 폚.
[1480] Example 222
[1481] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide mg) and 2-chloromethyl-6- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (472 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] Yl) propionate (656 mg, yield 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1482] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.47 (3H, s), 2.51-2.59 (2H, m), 2.66-2.74 (2H, m), 4.11 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 5.11 (2H, s), 5.28 J = 7.2 Hz), 6.70 (1H, d, J = 8.0 Hz), 7.13 (1H, s), 7.41-7.46 (3H, m), 7.48 8.05 (2 H, m).
[1483] Example 223
[1484] Ethyl 3- [3-ethoxy-1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] -1H-pyrazol-4-yl] propionate (652 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] Yl] propionic acid (522 mg, yield: 85%). This was recrystallized from ethanol-hexane. Melting point: 144-145 占 폚.
[1485] Example 224
[1486] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- [3-ethoxy- 1- (4-hydroxybenzyl) -1H-pyrazole Chloromethylimidazo [l, 2-a] pyridine (302 mg) and the mixture was stirred at room temperature for 1 hour Respectively. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- [l- [4- (5-chloroimidazo [1,2-a] pyridin- 2- ylmethoxy) benzyl] -3-ethoxy- 4-yl] propionate (625 mg, yield 86%) was obtained as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 69-70 캜.
[1487] Example 225
[1488] Benzyl] -3-ethoxy-1H-pyrazol-4-yl] propionate (prepared as described in After stirring the mixture at room temperature for 3 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [l- [4- (5-chloroimidazo [l, 2-a] pyridin- 2- ylmethoxy) benzyll-3-ethoxy-lH-pyrazole -4-yl] propionic acid (448 mg, yield 94%). This was recrystallized from ethanol. Melting point: 153-154 &lt; 0 &gt; C.
[1489] Example 226
[1490] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- [3-ethoxy- 1- (4-hydroxybenzyl) -1H-pyrazole 4-yl] propionate (478 mg) and 2-chloromethyl-5-ethoxyimidazo [1,2-a] pyridine (316 mg) and the mixture was stirred at room temperature for 1 hour Respectively. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (5-ethoxyimidazo [1,2- a] pyridin- 2- ylmethoxy) benzyl] Yl] propionate (442 mg, yield 60%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
[1491] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 1.55 (3H, t, J = 7.0 Hz), 2.47-2.54 (2H, m Q, J = 7.0 Hz), 4.29 (2H, q, J = 7.0 Hz), 2.99-2.68 (2H, m), 4.08 d, J = 2.0, 6.2 Hz), 6.92 (1H, s), 7.00 (2H, d, J = 8.8 Hz), 7.13 J = 8.8 Hz), 7.18-7.25 (2H, m), 7.71 (1H, s).
[1492] Example 227
[1493] Ethyl 3- [3-ethoxy-l- [4- (5-ethoxyimidazo [1,2- a] pyridin- 2- ylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate (441 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (2 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (5-ethoxyimidazo [1,2- a] pyridin- 2- ylmethoxy) benzyl] Yl] propionic acid (335 mg, yield: 81%). This was recrystallized from ethanol-hexane. Melting point: 197-198 占 폚.
[1494] Example 228
[1495] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- [3-ethoxy- 1- (4-hydroxybenzyl) -1H-pyrazole -4-yl] propionate (478 mg) and 1-chloromethyl-1H-benzotriazole (251 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (1H-benzotriazol-1-ylmethoxy) benzyl] -3-ethoxy-1H-pyrazol-4-yl] propionate (652 mg, yield 97%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1496] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.45-2.53 (2H, m), 2.59-2.67 (2H, m), 4.08 (2H, s), 6.90 (1H, s), 7.01-7.11 (4H, s), 4.96 ddd, J = 1.2, 7.0, 8.4 Hz), 7.53 (1H, ddd, J = 1.2, 7.0, 8.4 Hz), 7.69 (1H, dd, J = 1.2,8.4 Hz).
[1497] Example 229
[1498] Benzyl] -3-ethoxy-1H-pyrazol-4-yl] propionate (652 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [l- [4- (lH-benzotriazol-l-ylmethoxy) benzyl] -3-ethoxy-lH- pyrazol- mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 136-137 占 폚.
[1499] Example 230
[1500] (690 mg), 5-chloromethyl-2-phenylpyridine (470 mg), and 3-ethoxy-3- A mixture of potassium carbonate (450 mg) and N, N-dimethylformamide (10 mL) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) Was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resultant colorless crystals were collected by filtration to obtain 900 mg (yield: 65%) of 3- [3-ethoxy-1- [4- , Yield: 91%). This was recrystallized from acetone-hexane. Melting point: 140-141 占 폚.
[1501] Example 231
[1502] Benzyl] -3-ethoxy-1H-pyrazol-4-yl] propionate (prepared as described in (3 ml), water (3 ml), and toluene (15 ml) were added to a solution of the compound of formula (2) (676 mg), phenyl boronic acid (195 mg), tetrakis (triphenylphosphine) palladium (40.4 mg), sodium carbonate (339 mg) The mixture was refluxed under an argon atmosphere overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (5-phenylimidazo [1,2- a] pyridin- 2- ylmethoxy) benzyl] Yl] propionate (707 mg, yield: 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. This was purified by crystallization with ethyl acetate-hexane. Melting point: 104-105 占 폚.
[1503] Example 232
[1504] Phenyl] imidazo [1,2-a] pyridin-2-ylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate (551 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (5-phenylimidazo [1,2- a] pyridin- 2- ylmethoxy) benzyl] Yl] propionic acid (469 mg, yield 90%). This was recrystallized from ethanol-hexane. Melting point: 160-161 占 폚.
[1505] Example 233
[1506] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) in N, N- dimethylformamide was added to a solution of 4-chloromethyl-2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] pyridine (457 mg) and the mixture was stirred at room temperature for 1 hour . The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [2- [2- (2-furyl) -5- methyl-4-oxazolylmethoxy] Pyrazol-4-yl] propionate (643 mg, yield 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1507] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.46 (3H, s), 2.49-2.57 (2H, m), 2.63-2.71 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 4.20 (2H, q, J = 7.0 Hz), 5.01 (2H, s), 5.25 Dd, J = 0.8, 3.4 Hz), 6.63 (1H, dd, J = 1.8, 5.4 Hz), 6.97 7.03 (1H, s), 7.52 (1H, dd, J = 0.6, 1.8 Hz), 8.08 (1H, dd, J = 0.6, 5.4 Hz).
[1508] Example 234
[1509] Ethyl 3- [3-ethoxy-1- [2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -4-pyridylmethyl] ] Propionate (639 mg), 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, and then 1N hydrochloric acid (3 ml) Was added to the mixture, and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [2- [2- (2-furyl) -5-methyl-4- oxazolylmethoxy] -1H-pyrazol-4-yl] propionic acid (569 mg, yield 94%). This was recrystallized from ethanol-hexane. Melting point: 138-139 占 폚.
[1510] Example 235
[1511] Sodium hydride (60%, oil, 160 mg) was added to a solution of ethyl 3- (3-ethoxy-lH-pyrazol-4-yl) propionate (849 mg) in N, N- dimethylformamide pyridyloxymethyl) imidazo [l, 2-a] pyridine (1230 mg) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 1 hour Respectively. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [2- (5-chloroimidazo [1,2- a] pyridin-2-ylmethoxy) -1H-pyrazol-4-yl] propionate (1570 mg, yield 81%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
[1512] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.50-2.58 (2H, m), 2.63-2.71 (2H, m), 4.11 (2H, q, J = 7.2 Hz), 4.20 (2H, q, J = 7.2 Hz), 5.04 (2H, s), 5.56 (1H, d, J = 7.2, 9.2 Hz), 6.65 (1H, dd, J = 1.4, 5.2 Hz), 6.89 Hz), 7.55-7.60 (1H, m), 7.84 (1H, d, J = 0.8Hz), 8.12 (1H, dd, J = 0.6,5.2Hz).
[1513] Example 236
[1514] 4-pyridylmethyl] -3-ethoxy-lH-pyrazol-4-yl &lt; / RTI &gt; ] Propionate (605 mg), 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, and then 1N hydrochloric acid (3 ml) Was added to the mixture, and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [2- (5-chloroimidazo [1,2-a] pyridin- 2- ylmethoxy) -LH-pyrazol-4-yl] propionic acid (534 mg, yield 94%). This was recrystallized from ethanol-hexane. Melting point: 160-161 占 폚.
[1515] Example 237
[1516] 4-pyridylmethyl] -3-ethoxy-lH-pyrazol-4-yl &lt; / RTI &gt; ] Propionate (968 mg), phenylboronic acid (280 mg), tetrakis (triphenylphosphine) palladium (57.8 mg), sodium carbonate (488 mg), ethanol (3 ml), water (3 ml) (15 mL) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [2- (5-phenylimidazo [1,2- a] pyridin- 2- ylmethoxy) ] -1H-pyrazol-4-yl] propionate (1040 mg, yield 99%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
[1517] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.49-2.56 (2H, m), 2.62-2.70 (2H, m), 4.10 (2H, s, J = 7.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 5.01 (2H, s), 5.49 J = 5.2 Hz), 6.74 (1H, d, J = 7.0 Hz), 7.02 (1H, s), 7.27 (1H, dd, J = 7.0,9.2 Hz), 7.42-7.72 1H, d, J = 5.2 Hz).
[1518] Example 238
[1519] Phenyl] imidazo [l, 2-a] pyridin-2-ylmethoxy) -4-pyridylmethyl] -1H-pyrazol-4- The mixture was stirred at room temperature for 3 hours, and then 1 N hydrochloric acid (4 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Was added to the mixture, and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [2- (5-phenylimidazo [1,2- a] pyridin- 2- ylmethoxy) ] -1H-pyrazol-4-yl] propionic acid (922 mg, yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 177-178 占 폚.
[1520] Example 239
[1521] (700 mg) and 3-chloromethyl-5-phenylpyridine (500 mg) were added to a solution of ethyl 3- [3-ethoxy- A mixture of potassium carbonate (500 mg) and N, N-dimethylformamide (10 mL) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (5-phenyl-3-pyridylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate 720 mg, yield: 67%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1522] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.45-2.70 (4H, m), 4.09 (2H, q, J = 7.0 Hz ), 4.22 (2H, q, J = 7.0 Hz), 5.01 (2H, s), 5.13 (2H, s), 6.88-7.02 (2H, m), 7.10-7.22 5H, m), 7.96 (1H, t, J = 2.2 Hz), 8.65 (1H, d, J = 2.2 Hz), 8.82 (1H, d, J = 2.2 Hz).
[1523] Example 240
[1524] Benzyl] -1H-pyrazol-4-yl] propionate (700 mg) and a 1N aqueous solution of sodium hydroxide ( 3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to obtain 560 mg (yield: 95%) of 3- [3-ethoxy-1- [4- , Yield: 85%). This was recrystallized from acetone-hexane. Melting point: 92-93 占 폚.
[1525] Example 241
[1526] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (371 mg) in N, N- dimethylformamide mg) and 2- (5-chloromethyl-3-isoxazolylmethyl) quinoline (481 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [3- (2-quinolylmethoxy) -5-isoxazolylmethyl] -1H-pyrazol- (722 mg, yield 92%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1527] _{NMR (CDCl 3) δ: 1.23} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.49-2.57 (2H, m), 2.62-2.70 (2H, m), 4.11 (2H, s, J = 7.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 5.06 (2H, s), 5.54 , 7.51-7.60 (2H, m), 7.73 (1H, ddd, J = 1.6, 7.0, 8.6 Hz), 7.83 (1H, dd, J = 1.6, 8.0 Hz), 8.06-8.12 (1H, d, J = 8.6 Hz).
[1528] Example 242
[1529] 1 H-pyrazol-4-yl] propionate (721 mg), 1N hydroxysuccinimide The mixture of sodium aqueous solution (3 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 mL) was added to the mixture and then the mixture was extracted with ethyl acetate And extracted. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [3- (2-quinolylmethoxy) -5-isoxazolylmethyl] -1H-pyrazol-4-yl] (608 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 123-124 占 폚.
[1530] Example 243
[1531] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- [3-ethoxy- 1- (4-hydroxybenzyl) -1H-pyrazole -4-yl] propionate (478 mg) and 3-chloro-2-chloromethyl-6-phenylpyridine (357 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (3-chloro-6-phenyl-2-pyridylmethoxy) benzyl] -3-ethoxy-1H-pyrazol- Propionate (740 mg, yield 95%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 3, by volume).
[1532] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 4.09 (2H, d, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), 5.00 (2H, s), 5.34 J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.37-7.51 (3H, m), 7.67 , 7.91-7.98 (2H, m).
[1533] Example 244
[1534] Benzyl] -3-ethoxy-1H-pyrazol-4-yl] propionate (738 mg), 1N The mixture of sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [l- [4- (3-chloro-6-phenyl-2-pyridylmethoxy) benzyl] -3-ethoxy-lH- pyrazol- Propionic acid (669 mg, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 120-121 占 폚.
[1535] Example 245
[1536] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of ethyl 3- [3-ethoxy- 1- (4-hydroxybenzyl) -1H-pyrazole -4-yl] propionate (478 mg) and 2-chloromethyl-6-phenylpyridine (306 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (6-phenyl-2-pyridylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate 689 mg, yield: 95%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1537] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.46-2.55 (2H, m), 2.60-2.68 (2H, m), 4.12 (2H, d, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), 5.00 (2H, s), 5.28 J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.38-7.53 (4H, m), 7.64 (1H, dd, J = Hz), 7.97-8.03 (2H, m).
[1538] Example 246
[1539] Benzyl] -1H-pyrazol-4-yl] propionate (685 mg), 1N aqueous sodium hydroxide solution ( 3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 482 mg (yield: 48%) of 3- [3-ethoxy-1- [4- , Yield: 75%). This was recrystallized from ethanol-hexane. Melting point: 95-96 占 폚.
[1540] Example 247
[1541] (600 mg) and 2-chloromethyl-1-methyl-1H-benzimidazole (100 mg) were added to a solution of ethyl 3- [3-ethoxy- (360 mg), potassium carbonate (550 mg) and N, N-dimethylformamide (10 mL) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (1 -methyl-1 H-benzimidazol-2-ylmethoxy) benzyl] ] Propionate (730 mg, yield 84%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1542] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.44-2.68 (4H, m), 3.88 (3H, s), 4.08 (2H (1H, s, J = 7.0 Hz), 4.21 (2H, q, J = 7.0 Hz), 4.98 (2H, s), 5.38 , 7.23-7.41 (3 H, m), 7.72-7.82 (1 H, m).
[1543] Example 248
[1544] Benzyl] -1H-pyrazol-4-yl] propionate (700 mg), and ethyl 3- [3-ethoxy- After stirring a mixture of 1N sodium hydroxide aqueous solution (3 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) at room temperature for 2 hours, 1N hydrochloric acid (3 mL) was added to the mixture, Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] ] Propionic acid (520 mg, yield: 79%). This was recrystallized from ethanol-water. Melting point: 177-178 占 폚.
[1545] Example 249
[1546] A mixture of 5-phenyl-2-pyridyl methanol (300 mg), thionyl chloride (0.25 mL) and toluene (10 mL) was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crystals were filtered and washed with hexane. The resulting crystals, 500 mg of ethyl 3- [3-ethoxy-1- (4-hydroxybenzyl) -1H-pyrazol-4-yl] propionate, potassium carbonate (420 mg) -Dimethylformamide &lt; / RTI &gt; (10 mL) was stirred at 70 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- (5-phenyl-2-pyridylmethoxy) benzyl] -1H-pyrazol-4-yl] propionate 730 mg, yield: 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1547] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.44-2.70 (4H, m), 4.09 (2H, q, J = 7.0 Hz (2H, s), 4.22 (2H, s), 4.22 (2H, 6H, m), 7.91 (1H, dd, J = 2.2, 8.0 Hz), 8.82 (1H, d, J = 2.2 Hz).
[1548] Example 250
[1549] Benzyl] -1H-pyrazol-4-yl] propionate (700 mg) and a 1N aqueous solution of sodium hydroxide ( 3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 620 mg (yield: 65%) of 3- [3-ethoxy-1- [4- , Yield: 94%). This was recrystallized from acetone-hexane. Melting point: 127-128 占 폚.
[1550] Example 251
[1551] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of 2- (5-chloromethyl-2-pyridyloxymethyl) quinoline (498 mg) in ethyl N, N- dimethylformamide - (3-ethoxy-1H-pyrazol-4-yl) propionate (371 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [6- (2-quinolylmethoxy) -3-pyridylmethyl] -1H-pyrazol- (733 mg, yield 91%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1552] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.47-2.55 (2H, m), 2.60-2.68 (2H, m), 4.09 (2H, s), 6.87 (1H, dd, J = 0.8,8.4 Hz), 4.21 (2H, q, J = 7.0 Hz), 4.98 , 6.97 (1H, s), 7.48 (1H, dd, J = 2.6,8.4 Hz), 7.53 (1H, ddd, J = 1.4, 7.0, 8.4 Hz), 7.57 Dd, J = 1.4, 7.0, 8.4 Hz), 7.81 (1H, dd, J = 1.4,8.4 Hz), 8.00 (1H, dd, J = 0.8, 2.6 Hz), 8.07-8.13 m), 8.15 (1 H, d, J = 8.6 Hz).
[1553] Example 252
[1554] Pyrazol-4-yl] propionate (732 mg), 1 N sodium hydroxide The mixture of aqueous solution (3 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 mL) was added to the mixture and then the mixture was extracted with ethyl acetate Respectively. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [6- (2-quinolylmethoxy) -3-pyridylmethyl] -1H-pyrazol-4-yl] 629 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 133-134 占 폚.
[1555] Example 253
[1556] Sodium hydride (60%, oil, 60.0 mg) was added to a solution of 5-chloromethyl-2- (2-phenyl-4-thiazolylmethoxy) pyridine (475 mg, ), Ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (318 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethyl] (657 mg, yield 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2: 3, by volume).
[1557] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.47-2.56 (2H, m), 2.61-2.69 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.0 Hz), 5.00 (2H, s), 5.54 8.4 Hz), 7.31 (1H, t, J = 0.8 Hz), 7.40-7.49 (4H, m), 7.92-8.01 (2H, m), 8.04 (1H, d, J = 2.6 Hz).
[1558] Example 254
[1559] Pyrazol-4-yl] propionate (655 mg) was added to a solution of ethyl 3- [3-ethoxy-1- [6- , 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, And extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [6- (2-phenyl-4-thiazolemethoxy) -3-pyridylmethyl] ] Propionic acid (569 mg, yield 92%). This was recrystallized from ethanol-hexane. Melting point: 121-122 占 폚.
[1560] Example 255
[1561] (350 mg) and ethyl 3- [3-ethoxy-1- (4-hydroxybenzyl) -1H-pyrazole 4-yl] propionate (500 mg), potassium carbonate (500 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [4- [3-methyl- 1- (2-pyridyl) -1H-pyrazol-4-ylmethoxy] benzyl] Pyrazol-4-yl] propionate (700 mg, yield 91%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1562] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 2.44-2.71 (4H, m), 4.09 (2H (3H, s), 6.88-6.98 (3H, m), 7.08-7.20 (3H, s, J = 7.0 Hz), 4.22 m), 7.72-7.82 (1H, m), 7.86-7.94 (1H, m), 8.35-8.40 (1H, m), 8.53 (1H, s).
[1563] Example 256
[1564] Ylmethoxy] benzyl] -1H-pyrazol-4-yl] -1H-pyrazol-3- The mixture of propionate (680 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) &Lt; / RTI &gt; and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [4- (3-methyl-1- (2-pyridyl) -1H-pyrazol-4-ylmethoxy] benzyl] Pyrazol-4-yl] propionic acid (620 mg, yield 97%) which was recrystallized from acetone-hexane.
[1565] Example 257
[1566] A mixture of 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethanol (550 mg) and thionyl chloride (10 ml) was stirred at 0 ° C for 2 hours, Was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution and saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. To a solution of the resulting residue, ethyl 3- (3-ethoxy-1H-pyrazol-4-yl) propionate (400 mg), potassium carbonate (510 mg) and N, N-dimethylformamide The mixture was stirred at 80 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] Yl) propionate (730 mg, yield 80%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2: 1, by volume).
[1567] _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.44 (3H, s), 2.47-2.75 (4H, m), 4.03-4.28 (1H, m), 5.02 (2H, s), 5.15 (2H, s), 6.93 (1H, d, J = 8.8 Hz), 7.09 Hz), 7.38-7.50 (3H, m), 7.94-8.06 (2H, m), 8.35 (1H, d, J = 3.0Hz).
[1568] Example 258
[1569] Ethyl 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] -1H-pyrazol-4-yl] propionate (730 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-ethoxy-1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] Yl] propionic acid (650 mg, yield: 95%). This was recrystallized from acetone-hexane. Melting point: 133-134 占 폚.
[1570] Example 259
[1571] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of 4- (4-chloromethylphenoxymethyl) -5-methyl-2-phenyloxazole mg), ethyl 3-ethoxy-1H-pyrazol-4-yl acetate (347 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] mg, yield: 74%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1572] _{NMR (CDCl 3) δ: 1.25} (3H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.0 Hz), 2.43 (3H, s), 3.36 (2H, s), 4.14 (2H, q J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.98 (2H, s), 5.04 (2H, s), 6.98 ), 7.17 (1H, d, J = 8.8Hz), 7.40-7.50 (3H, m), 7.97-8.04 (2H, m).
[1573] Example 260
[1574] Benzyl] -lH-pyrazol-4-yl acetate (618 mg), 1N aqueous sodium hydroxide solution (3 &lt; Ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3-ethoxy-1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -lH-pyrazol- mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 125-126 ° C.
[1575] Example 261
[1576] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of 5-chloromethyl-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) Pyridine (551 mg) and ethyl 3-ethoxy-1H-pyrazol-4-yl acetate (347 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] -Acetic acid (608 mg, yield: 73%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1577] _{NMR (CDCl 3) δ: 1.25} (3H, t, J = 7.2 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.47 (3H, s), 3.36 (2H, s), 4.15 (2H, q (2H, s), 6.78 (1H, d, J = 8.4 Hz), 7.19 (1H, s), 7.22 ), 7.39-7.49 (4H, m), 7.98-8.07 (3H, m).
[1578] Example 262
[1579] 3-pyridylmethyl] -1H-pyrazol-4-yl acetate (605 mg), 1N After stirring a mixture of sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3-ethoxy-1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] Yl) acetic acid (518 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 126-127 占 폚.
[1580] Example 263
[1581] Sodium hydride (60%, oil, 39.4 mg) was added to a solution of 5-chloromethyl-2- [2- (2-furyl) -5- (300 mg) and ethyl 3-ethoxy-1H-pyrazol-4-yl acetate (195 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1- [6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] Pyrazol-4-yl acetate (364 mg, yield 79%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume).
[1582] _{NMR (CDCl 3) δ: 1.25} (3H, t, J = 7.2 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.46 (3H, s), 3.66 (2H, s), 4.14 (2H, q (2H, s), 6.52 (1H, dd, J = 1.8, 3.2 Hz), 6.76 (1H, dd, J = 8.6 Hz), 6.98 (1H, dd, J = 0.8,3.2 Hz), 7.19 (1H, s), 7.46 J = 0.8, 1.8 Hz), 8.05 (1H, d, J = 2.4 Hz).
[1583] Example 264
[1584] Methyl-4-oxazolylmethoxy] -3-pyridylmethyl] -1H-pyrazol-4-yl acetate (364 The mixture of 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (2 ml) The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3-ethoxy-1- [6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] Pyrazol-4-ylacetic acid (308 mg, yield 90%). This was recrystallized from ethanol-hexane. Melting point: 155-156 &lt; 0 &gt; C.
[1585] Example 265
[1586] Sodium hydride (60%, oil, 0.30 g) was added to a solution of ethyl 3- [1- (3,5-dihydroxybenzyl) -4-phenyl- Pyrrolyl] propionate (1.83 g) in tetrahydrofuran, and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (1.05 g) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3,5-bis (2-phenyl-4-thiazolemethoxy) benzyl] -4-phenyl-3-pyrrolyl] propionate , Yield: 14%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1587] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.2 Hz), 2.52 (2H, t, J = 7.8 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.08 (2H, q, J = 7.2 Hz), 4.95 (2H, s), 5.21 (4H, s), 6.47 (2H, d, J = 2.2 Hz), 6.52 = 2.2 Hz), 6.72 (1H, d, J = 2.4 Hz), 7.16-7.46 (13H, m), 7.90-7.97 (4H, m).
[1588] Example 266
[1589] Benzyl] -4-phenyl-3-pyrrolyl] propionate (498 mg) and 1N aqueous sodium hydroxide solution (2 ml) were added to a solution of ethyl 3- [1- [3,5- ), Tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 378 mg of 3- [1- [3,5-bis (2-phenyl-4-thiazolemethoxy) benzyl] -4-phenyl-3-pyrrolyl] : 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 78-79 占 폚.
[1590] Example 267
[1591] Sodium hydride (60%, oil, 190 mg) was added to a solution of 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3- -Pyridylmethyl] -4-phenyl-3-pyrrolecarbaldehyde (1.05 g) and ethyl diethylphosphonoacetate (1.05 g) and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was poured into water and the precipitated crystals were collected by filtration to give (E) -3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) ] -4-phenyl-3-pyrrolyl] propanoate. The crystals were dissolved in ethanol (80 mL) and hydrogenated over 5% palladium-carbon (800 mg) at room temperature under standard pressure. The catalyst was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] ] Propionate (1.05 g, yield: 86%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1592] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7 Hz), 2.48 (3H, s), 2.4-2.55 (2H, m), 2.9- 3.0 (2H, m), 4.08 (2H, q, J = 7 Hz), 4.94 (2H, s), 5.29 (2H, s), 6.51 (1H, d, J = 2.5 Hz), 6.70 J = 8.5 Hz), 7.15-7.5 (9H, m), 7.95-8.1 (3H, m).
[1593] Example 268
[1594] Pyridylmethyl] -4-phenyl-3-pyrrolyl] propionate (1.03 g), ethyl 3- [1- [6- A mixture of 1N aqueous sodium hydroxide solution (8 ml), ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature. The reaction mixture was poured into water, neutralized with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) Propionic acid was obtained from the fraction eluted with acetone-hexane (1: 1, volume ratio). This was crystallized from ethyl acetate-hexane to give colorless prism (740 mg, yield: 74%). Melting point: 123-124 占 폚.
[1595] Example 269
[1596] Sodium hydride (60%, oil, 0.56 g) was added to a solution of ethyl 3- [1- (3,5-dihydroxybenzyl) -4-phenyl- Pyrrol] propionate (5.12 g) in DMF (5 ml) and the mixture was stirred at room temperature for 15 minutes. Ethyl iodide (1.12 mL) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- (3,5-diethoxybenzyl) -4-phenyl-3-pyrrolyl] propionate (1040 mg, yield: 24% Hexane as a colorless oily substance from the fraction eluted with hexane (1: 2, volume ratio).
[1597] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.38 (6H, t, J = 7.0 Hz), 2.48-2.56 (2H, m), 2.91-2.99 (2H, m), 3.97 (2H, q, J = 7.0 Hz), 4.08 (4H, q, J = 7.0 Hz), 4.91 2.2 Hz), 6.51 (1H, d, J = 2.4 Hz), 6.72 (1H, d, J = 2.4 Hz), 7.15-7.25 (1H, m), 7.29-7.42 (4H, m).
[1598] Example 270
[1599] Phenyl-3-pyrrolyl] propionate (2040 mg, yield: 90%) was obtained in silica gel column chromatography described in Example 269, 37%) was obtained as a colorless oily substance from the fraction eluted with the compound described in Example 269.
[1600] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 2.47-2.55 (2H, m), 2.92-3.00 (2H, m), 3.96 (2H, q, J = 7.0 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.89 (2H, s), 5.67 (1H, s), 6.06 m), 6.50 (1H, d, J = 2.4Hz), 6.71 (1H, d, J = 2.4Hz), 7.15-7.41 (5H, m).
[1601] Example 271
[1602] Sodium hydride (60%, oil, 50.0 mg) was added to a solution of ethyl 3- [1- (3-ethoxy-5-hydroxybenzyl) -4-phenyl- 3-pyrrolyl] propionate (492 mg), and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (260 mg) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-ethoxy-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] ] Propionate (622 mg, yield 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 3, by volume).
[1603] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 2.41 (3H, s), 2.47-2.55 (2H, m), 2.91-2.99 (2H, m), 3.98 (2H, q, J = 7.0 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.93 (4H, s), 6.34 (1H, m), 6.51 (1H, s), 6.52 (1H, d, J = 2.4 Hz), 6.72 (1H, d, J = 2.4 Hz).
[1604] Example 272
[1605] Benzyl] -4-phenyl-3-pyrrolyl] propionate (621 mg) was added to a solution of ethyl 3- [1- [3-ethoxy- After stirring a mixture of 1N sodium hydroxide aqueous solution (2.5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) at room temperature for 2 hours, 1N hydrochloric acid (2.5 mL) was added to the mixture, Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [3-ethoxy-5- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] ] Propionic acid (439 mg, yield 74%). This was recrystallized from ethanol-hexane. Melting point: 126-127 占 폚.
[1606] Example 273
[1607] Sodium hydride (60%, oil, 50.0 mg) was added to a solution of ethyl 3- [1- (3-ethoxy-5-hydroxybenzyl) -4-phenyl- 3-pyrrolyl] propionate (492 mg), and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (262 mg) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-ethoxy-5- (2-phenyl-4-thiazolemethoxy) benzyl] -4-phenyl-3-pyrrolyl] propionate 601 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 3, by volume).
[1608] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 2.48-2.56 (2H, m), 2.91-2.99 (2H, m), 3.97 (2H, s, J = 7.0 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.93 (2H, s), 5.20 , 6.50 (1H, d, J = 2.4 Hz), 6.52 (1H, s), 6.72 (1H, d, J = 2.4 Hz), 7.15-7.46 (9H, m), 7.92-7.96 (2H, m).
[1609] Example 274
[1610] Benzyl] -4-phenyl-3-pyrrolyl] propionate (595 mg), 1N aqueous sodium hydroxide solution ( 2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 538 mg (yield: 53%) of 3- [1- [3-ethoxy-5- , Yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 109-110 占 폚.
[1611] Example 275
[1612] Sodium hydride (60%, oil, 50.0 mg) was added to a solution of ethyl 3- [1- (3-ethoxy-5-hydroxybenzyl) -4-phenyl- 3-pyrrolyl] propionate (492 mg), and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2- (2-thienyl) thiazole (270 mg) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [3-ethoxy-5- [2- (2-thienyl) -4-thiazolemethoxy) benzyl] ] Propionate (657 mg, yield 92%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 3, by volume).
[1613] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 2.48-2.56 (2H, m), 2.91-2.99 (2H, m), 3.97 (2H, q, J = 7.0 Hz), 4.08 (2H, q, J = 7.0 Hz), 4.92 (2H, s), 5.16 , 6.48 (1H, d, J = 2.2 Hz), 6.51 (1H, d, J = 2.4 Hz) , 7.19-7.25 (2H, m), 7.29-7.40 (5H, m), 7.50 (1H, dd, J = 1.2, 3.6 Hz).
[1614] Example 276
[1615] Benzyl] -4-phenyl-3-pyrrolyl] propionate (653 mg) was dissolved in a mixture of ethyl 3- [1- [3-ethoxy-5- [2- After stirring a mixture of 1N sodium hydroxide aqueous solution (2.5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) at room temperature for 2 hours, 1N hydrochloric acid (2.5 mL) was added to the mixture, and it extracted with acetate. the ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [3-ethoxy-5- [2- (2-thienyl) -4- thiazolemethoxy) benzyl] ] Propionic acid (545 mg, yield: 88%). This was recrystallized from ethanol-hexane. Melting point: 104-105 占 폚.
[1616] Example 277
[1617] (600 mg), 5-chloromethyl-2-phenylpyridine (370 mg) and potassium carbonate (450 mg, ) And N, N-dimethylformamide (10 mL) was stirred at 80 &lt; 0 &gt; C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from a fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (5ml), tetrahydrofuran (5ml) and ethanol (5ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5ml) And the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to obtain 820 mg (yield: 98%) of 3- [4-phenyl-1- [4- ). This was recrystallized from acetone-hexane. Melting point: 185-186 &lt; 0 &gt; C.
[1618] Example 278
[1619] A mixture of 5-phenyl-2-pyridine methanol (390 mg), thionyl chloride (0.3 mL) and toluene (10 mL) was stirred at 80 <0> C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crystals were filtered and washed with hexane. The resulting crystals were recrystallized from ethyl 3- [1- (4-hydroxybenzyl) -4-phenyl-3-pyrrolyl] propionate (790 mg), potassium carbonate (700 mg) and N, N-dimethylformamide 15 mL) was stirred at 70 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (5-phenyl-2-pyridylmethoxy) benzyl] -4-phenyl-3-pyrrolyl] propionate (1050 mg, 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume).
[1620] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.46-2.58 (2H, m), 2.88-3.00 (2H, m), 4.08 (2H, q, J = 7.0 Hz), 4.95 (2H, s), 5.25 (2H, s), 6.51 (1H, d, J = 2.6 Hz), 6.71 (1H, d, J = 2.6 Hz), 6.94-7.04 13H, m), 7.91 (1H, dd, J = 2.2, 8.0 Hz), 8.82 (1H, d, J = 2.2 Hz).
[1621] Example 279
[1622] Benzyl] -4-phenyl-3-pyrrolyl] propionate (1020 mg), 1N aqueous sodium hydroxide solution (4 ml), tetra The mixture of hydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (4 ml) was added to the mixture, and the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to obtain 930 mg (yield 97%) of 3- [1- [4- (5-phenyl-2-pyridylmethoxy) benzyl] ). This was recrystallized from acetone-hexane. Melting point: 169-170 &lt; 0 &gt; C.
[1623] Example 280
[1624] Pyrazole-4-carboxylate (11.70 g), potassium carbonate (13.80 g) and N, N-dimethylformamide Amide (150 mL) was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give ethyl 1- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -1H-pyrazole-4-carboxylate (16.90 g, &Lt; / RTI &gt; This was recrystallized from ethyl acetate-hexane. Melting point: 103-104 占 폚.
[1625] Example 281
[1626] Sodium hydride (60%, oil, 1.10 g) was added to a solution of l- (4-benzyloxybenzyl) -3- (4- fluorophenyl) -lH- pyrazole 4-carbaldehyde (9.66 g) and ethyl diethylphosphonoacetate (5.46 ml) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 2 hours. Ice water was poured into the reaction mixture and the resulting crystals were collected by filtration. After drying, recrystallization from ethyl acetate-hexane gave ethyl (E) -3- [1- (4-benzyloxybenzyl) -3- (4- fluorophenyl) -1H- pyrazol- (10.60 g, yield: 93%). Melting point: 113-114 占 폚.
[1627] Example 282
[1628] Sodium hydride (60%, oil, 140 mg) was added to a solution of 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3- Pyrazole-4-carbaldehyde (1.20 g) and ethyl diethylphosphonoacetate (780 mg) in dichloromethane (5 ml) and the mixture was stirred at 0 ° C for 2 hours Respectively. The reaction mixture was poured into water and the precipitated crystals were collected by filtration to give ethyl (E) -3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) Methyl] -3-phenyl-1H-pyrazol-4-yl] propionate. The crystals were dissolved in ethanol (100 mL) and hydrogenated over 5% palladium on carbon (1.0 g) at room temperature under standard pressure. The catalyst was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] Yl] propionate (1.20 g, yield: 86%) was obtained as a colorless oily substance.
[1629] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7 Hz), 2.47 (3H, s), 2.52 (2H, t, J = 7.5 Hz), 2.94 (2H, t, J = 7,5 Hz ), 4.08 (2H, q, J = 7 Hz), 5.23 (2H, s), 5.29 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 7.2-7.65 -8.15 &lt; / RTI &gt; (3H, m).
[1630] Example 283
[1631] Methyl-3-phenyl-1H-pyrazol-4-yl] propionate (prepared as described in 1.20 g), 1N aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and neutralized with 1N hydrochloric acid and the precipitated 3- [1- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridylmethyl] Pyrazol-4-yl] propionic acid was collected by filtration. This was recrystallized from ethyl acetate to give colorless prism crystals (810 mg, yield: 71%). Melting point: 172-173 [deg.] C.
[1632] Example 284
[1633] The mixture of 1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-ylmethanol (26.39 g), active manganese dioxide (70.26 g) and tetrahydrofuran (300 ml) Respectively. The manganese dioxide was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). Sodium hydride (60%, oil, 3.20 g) was added to a solution of the resulting colorless oily substance and ethyl diethylphosphonoacetate (18.19 g) in N, N-dimethylformamide (100 ml) The mixture was stirred at room temperature for 2 hours. Ice water was poured into the reaction mixture and the resulting crystals were collected by filtration. Dried and then recrystallized from ethyl acetate-hexane to obtain ethyl (E) -3- [1- (4-benzyloxybenzyl) -3-phenyl-1H-pyrazol-4-yl] propanoate (26.71 g, Yield: 86%). Melting point: 94-95 占 폚.
[1634] Example 285
[1635] 4-yl] propionate (600 mg), 2-chloromethylquinoline hydrochloride (380 mg), and potassium carbonate ((3-fluorophenyl) 360 mg) and N, N-dimethylformamide (10 mg) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid was added to the mixture, The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 660 mg of 3- [3-phenyl-1- [4- (2-quinolylmethoxy) benzyl)] 1H-pyrazol-4-yl] : 83%). This was recrystallized from acetone-hexane. Melting point: 147-148 占 폚.
[1636] Example 286
[1637] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (1050 mg), 1 (2H) -phthalazinone (530 mg), potassium carbonate (1000 mg) and N, N-dimethylformamide (15 ml) was stirred at 90 占 폚 for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, then 1N hydrochloric acid (5 ml) And the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [4- [2- [1-oxopthalazin-2 (1H) -yl] ethoxy] benzyl] Yl] propionic acid (1460 mg, yield 90%). This was recrystallized from acetone-hexane. Melting point: 155-156 ° C.
[1638] Example 287
[1639] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (883 mg), 2H-1,4-benzothiazine 3 (4H) -one (320 mg), potassium carbonate (530 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 2, by volume). The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours and then 1N hydrochloric acid (5 ml) And the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated to give 3- [1- [4- [2- (3-oxo-2,3-dihydro -4H-1,4- benzothiazol Yl) propionic acid (680 mg, yield 69%) was obtained as a colorless amorphous substance.
[1640] Example 288
[1641] 4-yl] propionate (600 mg), 5-chloromethyl-2-phenylpyridine (350 mg), carbonic acid A mixture of potassium (460 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 &lt; 0 &gt; C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1: 1, by volume). The resulting colorless oily substance, a mixture of 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours and then 1N hydrochloric acid (3 ml) And the mixture was then extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resultant colorless crystals were collected by filtration to give 710 mg (0.15 mmol) of 3- [3-phenyl- 1- [4- (6-phenyl-3-pyridylmethoxy) benzyl] -1H- , Yield: 85%). This was recrystallized from acetone-hexane. Melting point: 155-156 ° C.
[1642] Example 289
[1643] 4-yl] propionate (840 mg), 3-chloromethyl-5-phenylpyridine (550 mg), and carbonic acid A mixture of potassium (500 mg) and N, N-dimethylformamide (10 ml) was stirred at 80 &lt; 0 &gt; C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [4- (5-phenyl-3-pyridylmethoxy) Benzyl] -1H-pyrazol-4-yl] propionate (1010 mg, yield 81%) as a colorless oily substance.
[1644] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.0 Hz), 2.46-2.56 (2H, m), 2.88-3.00 (2H, m), 4.12 (2H, q, J = 7.0 Hz), 5.15 (2H, s), 5.25 (2H, s), 6.92-7.04 (2H, m), 7.16-7.67 (13H, m), 7.94-7.99 ), 8.82 (1H, d, J = 2.2 Hz).
[1645] Example 290
[1646] 4-yl] propionate (980 mg) and 1N aqueous sodium hydroxide solution (4 &lt; RTI ID = 0.0 & ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to obtain 760 mg (yield: 95%) of 3- [3-phenyl-1- [4- , Yield: 82%). This was recrystallized from acetone-hexane. Melting point: 161-162 占 폚.
[1647] Example 291
[1648] 4-yl] propionate (460 mg), 2-chloromethyl-1-methyl-1H-benzimidazole ( 250 mg), potassium carbonate (360 mg) and N, N-dimethylformamide (15 ml) was stirred at 80 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [4- (1-methyl-1H-benzimidazol-2-ylmethoxy) ) Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (550 mg, yield 85%) as a colorless oily substance.
[1649] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.0 Hz), 2.45-2.56 (2H, m), 2.86-2.98 (2H, m), 3.89 (3H, s), 4.06 (2H, q, J = 7.0 Hz), 5.22 (2H, s), 5.39 (2H, s), 7.01-7.10 (2H, m), 7.16-7.47 (9H, m), 7.58-7.66 (1 H, m).
[1650] Example 292
[1651] Benzyl] -3-phenyl-1H-pyrazol-4-yl] propionate (520 mg), 1N After stirring a mixture of sodium hydroxide aqueous solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [4- (1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] ] Propionic acid (420 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 225-226 占 폚.
[1652] Example 293
[1653] 4-yl] propionate (950 mg), 2-chloromethylquinoline hydrochloride (600 mg, mg), potassium carbonate (700 mg) and N, N-dimethylformamide (15 ml) was stirred at 60 ° C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (4-fluorophenyl) -1- [4- (2-quinolyl) Methoxy) benzyl] -1H-pyrazol-4-yl] propionate (1210 mg, yield 92%) as a colorless oily substance.
[1654] _{NMR (CDCl 3) δ: 1.18} (3H, t, J = 7.0 Hz), 2.45-2.56 (2H, m), 2.83-2.96 (2H, m), 4.07 (2H, q, J = 7.0 Hz), 5.21 (2H, s), 5.38 (2H, s), 6.94-7.26 (7H, m), 7.50-7.88 (6H, m), 8.04-8.13 (1H, m), 8.16-8.24 (1H, m).
[1655] Example 294
[1656] Benzyl] -1H-pyrazol-4-yl] propionate (1150 mg), 1 N sodium hydroxide The mixture of aqueous solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5 ml) was added to the mixture and then the mixture was extracted with ethyl acetate Respectively. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (4-fluorophenyl) -1- [4- (2-quinolylmethoxy) benzyl] -1H-pyrazol-4-yl] (1010 mg, yield: 93%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 178-179 占 폚.
[1657] Example 295
[1658] A mixture of 5-phenyl-2-pyridine methanol (330 mg), thionyl chloride (0.3 ml) and toluene (10 ml) was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crystals were filtered and washed with hexane. The resulting crystals, 650 mg of ethyl 3- [3- (4-fluorophenyl) -1- (4-hydroxybenzyl) -1H-pyrazol-4-yl] propionate and 550 mg ) And N, N-dimethylformamide (10 ml) was stirred at 70 占 폚 overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (4-fluorophenyl) -1- [4- (5-phenyl-isobutyramide) from the fraction eluted with ethyl acetate- Benzyl] -1H-pyrazol-4-yl] propionate (850 mg, yield 90%) was obtained as a colorless oily substance.
[1659] _{NMR (CDCl 3) δ: 1.18} (3H, t, J = 7.0 Hz), 2.44-2.56 (2H, m), 2.85-2.97 (2H, m), 4.07 (2H, q, J = 7.0 Hz), 5.22 (2H, s), 5.25 (2H, s), 6.94-7.26 (8H, m), 7.34-7.68 (7H, m), 7.91 (1H, dd, J = 2.2,8.4Hz) , J = 2.2 Hz).
[1660] Example 296
[1661] Benzyl] -1H-pyrazol-4-yl] propionate (800 mg) was dissolved in a mixture of ethyl 3- [3- (4-fluorophenyl) After stirring a mixture of 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) at room temperature for 5 hours, 1N hydrochloric acid (3 ml) was added to the mixture, Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (4-fluorophenyl) -1- [4- (5-phenyl-2-pyridylmethoxy) benzyl] Yl] propionic acid (700 mg, yield: 93%). This was recrystallized from ethanol-water. Melting point: 162-163 占 폚.
[1662] Example 297
[1663] Sodium hydride (60%, oil, 70.0 mg) was added to ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (428 mg), 2 - (5-chloromethyl-2-pyridyloxymethyl) quinoline (498 mg) at 0 ° C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [6- (2-quinolylmethoxy) -3- Pyridylmethyl] -1H-pyrazol-4-yl] propionate (651 mg, yield 76%) as a colorless oily substance.
[1664] _{NMR (CDCl 3) δ: 1.18} (3H, t, J = 7.2 Hz), 2.48-2.56 (2H, m), 2.90-2.98 (2H, m), 4.07 (2H, q, J = 7.2 Hz), 5.22 (2H, s), 5.68 (2H, s), 6.89 (1H, d, J = 8.8 Hz), 7.23 (1H, s), 7.29-7.65 , 7.0, 8.4 Hz), 7.72 (1H, ddd, J = 1.8, 6.8,8.4 Hz), 7.81 (1H, dd, J = 1.8,8.2 Hz), 8.08-8.18 (3H, m).
[1665] Example 298
[1666] Pyrazol-4-yl] propionate (650 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) was added to the mixture and then the mixture was extracted with ethyl acetate . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-phenyl-1- [6- (2-quinolylmethoxy) -3-pyridylmethyl] -1H-pyrazol-4-yl] 489 mg, yield: 80%). This was recrystallized from acetone-hexane. Melting point: 166-167 占 폚.
[1667] Example 299
[1668] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (428 mg) in 5 ml N, N- dimethylformamide -Chloromethyl-2- (2-phenyl-4-thiazolylmethoxy) pyridine (554 mg) at 0 ° C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [6- (2-phenyl-4-thiazolylmethoxy) Yl) propionate (678 mg, yield 74%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 88-89 占 폚.
[1669] Example 300
[1670] Pyrazol-4-yl] propionate (603 mg), ethyl 3- [3-phenyl-1- [2- After stirring a mixture of 1N sodium hydroxide aqueous solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, And extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-phenyl-1- [6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethyl] Yl] propionic acid (500 mg, yield: 88%). This was recrystallized from acetone-hexane. Melting point: 107-108 占 폚.
[1671] Example 301
[1672] A mixture of 4- (5-phenyl-2-pyridylmethoxy) benzyl alcohol (600 mg), thionyl chloride (0.35 ml) and toluene (30 ml) was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The solution was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. Sodium hydride (60%, oil, 92.0 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (510 mg) in N, N- dimethylformamide At 0 &lt; 0 &gt; C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [4- (5-phenyl-2-pyridylmethoxy) Benzyl] -1H-pyrazol-4-yl] propionate (970 mg, yield 91%) was obtained as a colorless oily substance.
[1673] _{NMR (CDCl 3) δ: 1.18} (3H, t, J = 7.4 Hz), 2.47-2.57 (2H, m), 2.90-3.00 (2H, m), 4.07 (2H, q, J = 7.4 Hz), 5.24 (2H, s), 5.26 (2H, s), 7.00 (2H, d, J = 8.8 Hz), 7.19-7.68 (14H, m), 7.91 1H, &lt; / RTI &gt; d, J = 2.2 Hz).
[1674] Example 302
[1675] 4-yl] propionate (970 mg), 1N sodium hydroxide solution (5 ml), and a solution of 5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 820 mg (0.15 mmol) of 3- [3-phenyl-1- [4- , Yield: 90%). This was recrystallized from acetone-hexane. Melting point: 149-150 占 폚.
[1676] Example 303
[1677] Sodium hydride (60%, oil, 110 mg) was added to a solution of ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (580 mg) in N, N- dimethylformamide - (4-chloromethylphenoxymethyl) -2-phenylthiazole (760 mg) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-phenyl-1- [4- (2-phenyl-4-thiazolylmethoxy) ) Benzyl] -1H-pyrazol-4-yl] propionate (1110 mg, yield 89%) as a colorless oily substance.
[1678] _{NMR (CDCl 3) δ: 1.19} (3H, t, J = 7.0 Hz), 2.47-2.57 (2H, m), 2.89-3.00 (2H, m), 4.07 (2H, q, J = 7.0 Hz), 5.24 (2H, s), 5.27 (2H, s), 6.96-7.05 (2H, m), 7.18-7.49 (10H, m), 7.59-7.68 (2H, m), 7.90-7.99 (2H, m).
[1679] Example 304
[1680] Benzyl] -1H-pyrazol-4-yl] propionate (1110 mg), 1N sodium hydroxide solution ( 5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate . The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-phenyl-1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -lH-pyrazol-4-yl] mg, yield: 60%). This was recrystallized from acetone-hexane. Melting point: 132-133 &lt; 0 &gt; C.
[1681] Example 305
[1682] A mixture of 5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridinemethanol (630 mg) and thionyl chloride (10 ml) was stirred at 0 ° C for 2 hours, Concentrate under reduced pressure. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution and saturated aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. A mixture of the resulting crystals, ethyl 3- (3-phenyl-1H-pyrazol-4-yl) propionate (520 mg), potassium carbonate (590 mg) and N, N- dimethylformamide Stir at 80 &lt; 0 &gt; C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) Pyrazol-4-yl] propionate (950 mg, yield 85%) as a colorless oily substance.
[1683] _{NMR (CDCl 3) δ: 1.20} (3H, t, J = 7.0 Hz), 2.44 (3H, s), 2.48-2.58 (2H, m), 2.92-3.03 (2H, m), 4.09 (2H, q, J = 7.0 Hz), 5.02 (2H, s), 5.38 (2H, s), 7.08 (1H, d, J = 8.4 Hz), 7.20-7.54 (8H, m), 7.60-7.68 7.95-8.08 (2H, m), 8.38 (1H, d, J = 2.6 Hz).
[1684] Example 306
[1685] Methyl-3-phenyl-1H-pyrazol-4-yl] propionate ( 930 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [5- (5-methyl-2-phenyl-4-oxazolylmethoxy) -2-pyridylmethyl] Yl] propionic acid (830 mg, yield 94%). This was recrystallized from acetone-hexane. Melting point: 175-176 占 폚.
[1686] Example 307
[1687] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (403 mg) and 5-chloromethyl- Was added at 0 <0> C to a solution of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (551 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) - 3-pyridylmethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (513 mg, yield 58%) as a colorless oily substance.
[1688] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 2.48 (3H, s), 3.60 (2H, s), 4.13 (2H, q, J = 7.0 Hz), 5.26 (2H, s ), 5.30 (2H, s), 6.81 (1H, d, J = 8.8 Hz), 7.30-7.47 (7H, m), 7.53-7.62 (3H, m), 7.98-8.05 1H, &lt; / RTI &gt; d, J = 2.2 Hz).
[1689] Example 308
[1690] 3-phenyl-1H-pyrazol-4-yl] acetate (509 mg), and ethyl [1- [6- After stirring a mixture of 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, And extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give [1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3-pyridylmethyl] 4-yl] acetic acid (408 mg, yield: 85%). This was recrystallized from acetone-hexane. Melting point: 144-145 占 폚.
[1691] Example 309
[1692] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (403 mg) and 5-chloromethyl- Was added at 0 [deg.] C to a solution of 2- (2-phenyl-4-thiazolylmethoxy) pyridine (554 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [3-phenyl-1- [6- (2-phenyl-4-thiazolylmethoxy) - 3-pyridylmethyl] -1H-pyrazol-4-yl] acetate (594 mg, yield 66%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 75-76 占 폚.
[1693] Example 310
[1694] Pyrazol-4-yl] acetate (536 mg), 1 N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (2 ml) was added to the mixture and then the mixture was extracted with ethyl acetate Respectively. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give [3-phenyl-1- [6- (2-phenyl-4-thiazolylmethoxy) -3-pyridylmethyl] -1H- Acetic acid (459 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 118-119 占 폚.
[1695] Example 311
[1696] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (403 mg) and 5-chloromethyl- Was added at 0 ° C to a solution of 2- (5-methyl-2-phenyl-4-thiazolylmethoxy) pyridine (579 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1- [6- (5-methyl-2-phenyl-4-thiazolylmethoxy) - 3-pyridylmethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (476 mg, yield 52%) as a colorless oily substance.
[1697] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.2 Hz), 2.56 (3H, s), 3.60 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 5.26 (2H, s ), 5.44 (2H, s), 6.82 (1H, d, J = 8.0 Hz), 7.29-7.47 (7H, m), 7.53-7.62 (3H, m), 7.86-7.92 1H, &lt; / RTI &gt; d, J = 2.2 Hz).
[1698] Example 312
[1699] 3-phenyl-1H-pyrazol-4-yl] acetate (475 mg) was added to a solution of ethyl [1- [6- After stirring a mixture of 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, And extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give [1- [6- (5-methyl-2-phenyl-4-thiazolylmethoxy) -3-pyridylmethyl] 4-yl] acetic acid (402 mg, yield 89%). This was recrystallized from ethanol-hexane. Melting point: 140-141 占 폚.
[1700] Example 313
[1701] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (403 mg) and 5-chloromethyl- Was added at 0 ° C to a solution of 2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (575 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1- [6- [2- (5-methyl-2-phenyl-4-oxazolyl) 3-phenyl-1H-pyrazol-4-yl] acetate (575 mg, yield 63%) as a colorless oily substance.
[1702] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 2.34 (3H, s), 2.98 (2H, t, J = 6.8 Hz), 3.59 (2H, s), 4.12 (2H, q (1H, m, J = 7.0 Hz), 4.56 (2H, t, J = 6.8 Hz), 5.24 (2H, s), 6.71 (1H, d, J = 8.4 Hz), 7.29-7.47 (3H, m), 7.94-8.01 (2H, m), 8.12 (1H, d, J = 2.6 Hz).
[1703] Example 314
[1704] Ethyl] -3-pyridylmethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (prepared from ethyl [1- [6- [2- After stirring the mixture at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture and the mixture was stirred at room temperature for 2 hours. , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give [l- [6- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -3-pyridylmethyl] -Pyrazol-4-yl] acetic acid (466 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 148-149 占 폚.
[1705] Example 315
[1706] Sodium hydride (60%, oil, 70.0 mg) was added to a solution of ethyl (3-phenyl-1H-pyrazol-4-yl) acetate (403 mg) and 5-chloromethyl- Was added at 0 [deg.] C to a solution of 2- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] pyridine (533 mg) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1- [6- [2- (2-furyl) -5-methyl-4-oxazolyl Methoxy] -3-pyridylmethyl] -3-phenyl-1H-pyrazol-4-yl] acetate (581 mg, yield 67%) as a colorless oily substance.
[1707] _{NMR (CDCl 3) δ: 1.21} (3H, t, J = 7.0 Hz), 2.46 (3H, s), 3.60 (2H, s), 4.13 (2H, q, J = 7.0 Hz), 5.26 (2H, s ), 5.28 (2H, s), 6.51 (1H, dd, J = 1.8, 3.6 Hz), 6.79 (1H, d, J = 8.4 Hz), 6.98 -7.46 (4 H, m), 7.52-7.61 (4 H, m), 8.14 (1 H, d, J = 2.2 Hz).
[1708] Example 316
[1709] 3-phenyl-lH-pyrazol-4-yl] acetate (prepared from ethyl [l- [6- [2- (2- furyl) -5- methyl-4-oxazolylmethoxy] 578 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) , Then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give [1- [6- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-pyridylmethyl] -Pyrazol-4-yl] acetic acid (467 mg, yield 86%). This was recrystallized from acetone-hexane. Melting point: 135-136 占 폚.
[1710] Example 317
[1711] 4-yl] acetonitrile (4.37 g), 4N sodium hydroxide solution (20 ml) and tetrahydrofuran (5 ml) were added to a solution of 20 ml), and ethanol (20 ml) was refluxed for 2 days. After cooling, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated to give [1- (4-benzyloxybenzyl) -3- (4- fluorophenyl) (4.37 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 194-195 占 폚.
[1712] Example 318
[1713] 4-yl] acetic acid (4.16 g), methyl iodide (0.95 ml) and potassium carbonate (2.76 g, ), And N, N-dimethylformamide (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl [1- (4-benzyloxybenzyl) -3- (4-fluorophenyl) -lH- Pyrazol-4-yl] acetate (4.21 g, yield 98%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 58-59 DEG C
[1714] Example 319
[1715] 4-carboxylate (8.95 g), 4-phenoxybenzyl chloride (25.35 g), potassium carbonate (31.88 g) and N, N-dimethylformamide (200 ml) Was stirred at 90 &lt; 0 &gt; C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-4- (phenoxybenzyl) -3- (4-phenoxybenzyloxy) -1H-1-indan- Pyrazole-4-carboxylate (22.71 g, yield: 76%) as a colorless oily substance.
[1716] _{NMR (CDCl 3) δ: 1.31} (3H, t, J = 7.4 Hz), 4.25 (2H, q, J = 7.4 Hz), 5.09 (2H, s), 5.31 (2H, s), 6.93-7.50 (18H , &lt; / RTI &gt; m), 7.67 (1H, s).
[1717] Example 320
[1718] (500 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (1 ml) and tetrahydrofuran (2 ml) were added to a solution of ethyl 4- (phenoxybenzyl) 5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, then 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 450 mg (yield: 95%) of 1-4- (phenoxybenzyl) -3- (4-phenoxybenzyloxy) ). This was recrystallized from acetone-hexane. Melting point: 141-142 占 폚.
[1719] Example 321
[1720] Carboxylate (3.00 g), 4- (4-chloromethyl-2-methoxyphenoxymethyl) -2- (4-fluorophenyl) 5-methyloxazole (3.00 g), potassium carbonate (2.52 g) and N, N-dimethylformamide (30 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethyl- 3-methoxybenzyloxy] -1- (4-phenoxybenzyl) -1H-pyrazole-4-carboxylate (5.30 g, yield 94%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 98-99 ° C.
[1721] Example 322
[1722] Methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1- (4-phenoxybenzyl) -lH-pyrazole- A mixture of 4-carboxylate (1500 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours and then 1N hydrochloric acid ) Was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3- methoxybenzyloxy] Phenoxybenzyl) -1H-pyrazole-4-carboxylic acid (1330 mg, yield: 93%). This was recrystallized from acetone-hexane. Melting point: 153-154 &lt; 0 &gt; C.
[1723] Example 323
[1724] Methyl-4-oxazolylmethoxy] -3-methoxybenzyloxy] -1- (4-phenoxybenzyl) -1H-pyrazole-4 -Carbamic acid (0.80 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.22 g), 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride 0.28 g), and N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy ] -3-methoxybenzyloxy] -1- (4-phenoxybenzyl) -1H-pyrazole-4-carbamide (0.75 g, yield 94%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 105-106 占 폚.
[1725] Example 324
[1726] Carboxylate (3.00 g) and 4- (4-chloromethyl-2-methoxyphenoxymethyl) -5- (4-fluorophenyl) A mixture of methyl-2-phenyloxazole (3.06 g), potassium carbonate (2.50 g), and N, N-dimethylformamide (30 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and aqueous sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazolyl Methoxy) benzyloxy] -1- (4-phenoxybenzyl) -1H-pyrazole-4-carboxylate (5.43 g, yield 95%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 127-128 占 폚.
[1727] Example 325
[1728] Benzyloxy-l- (4-phenoxybenzyl) -lH-pyrazole-4-carboxyl &lt; / RTI &gt; (750 mg), 1 N sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours and 1N hydrochloric acid And the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3-methoxy-4- (5-methyl-2-phenyl-4-oxazylmethoxy) benzyloxy] -1H-pyrazole-4-carboxylate (680 mg, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 176-177 占 폚.
[1729] Example 326
[1730] Methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- (2-furyl) (250 mg), 1 N sodium hydroxide solution (1 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature For 2 h, 1 N hydrochloric acid (1 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 1- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] benzyl] -3- [4- [2- Furyl) -5-methyl-4-oxazolylmethoxy] benzyloxy] -1H-pyrazole-4-carboxylic acid (230 mg, yield 93%). This was recrystallized from acetone-hexane. Melting point: 144-145 占 폚.
[1731] Example 327
[1732] Sodium hydride (60%, oil, 310 mg) was added to a solution of methyl 4-phenyl-3-pyrrole carboxylate (1.20 g), 5-chloromethyl- ) Pyridine (1.88 g), and N, N-dimethylformamide (50 ml) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) -3- -Pyridylmethyl] -4-phenyl-1H-pyrrole-4-carboxylate (2.74 g, yield: 96%) as a colorless oily substance.
[1733] _{NMR (CDCl 3) d: 2.48} (3H, s), 3.72 (2H, s), 5.00 (2H, s), 5.30 (2H, s), 6.66 (1H, d, J = 1.5 Hz), 6.82 (1H , d, J = 8.5Hz), 7.2-7.5 (10H, m), 7.95-8.15 (3H, m).
[1734] Example 328
[1735] Sodium hydride (60%, oil, 270 mg) was added to a solution of ethyl 3-phenyl-1H-pyrazole-4-carboxylate (1.20 g), 5-chloromethyl- Oxazolylmethoxy) pyridine (1.75 g), and N, N-dimethylformamide (50 ml) at 0 ° C, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [6- (5-methyl-2-phenyl-4-oxazolylmethoxy) - 3-phenyl-1H-pyrazole-4-carboxylate (1.56 g, yield 57%) as a colorless oily substance.
[1736] _{NMR (CDCl 3) d: 1.14} (3H, t, J = 7 Hz), 2.45 (3H, s), 4.13 (2H, q, J = 7 Hz), 5.10 (2H, s), 5.25 (2H, s ), 6.72 (1H, d, J = 8.5 Hz), 7.2-7.5 (9H, m), 7.80 (1H, d, J = 2 Hz), 7.95-8.05 (3H, m).
[1737] Example 329
[1738] 4-Chloromethyl-5-methyl-2-phenyloxazole (2.58 g), ethyl 4-chloro- A mixture of potassium carbonate (1.73 g) and N, N-dimethylformamide (30 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4 - phenoxybenzyl) -1H-pyrazole-4-carboxylate (5.86 mg, yield: 96%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 96-97 占 폚.
[1739] Example 330
[1740] Carboxylate (1600 mg), 1 N sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 1 hour. 5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4- phenoxybenzyl) -lH-pyrazole- (1470 mg, yield: 97%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 222-223 [deg.] C.
[1741] Example 331
[1742] (0.75 g), &lt; RTI ID = 0.0 &gt; 1H-1, 2-benzyloxy- (0.26 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.33 g) and N, N-dimethylformamide (10 ml ) Was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- ( 4-phenoxybenzyl) -1H-pyrazole-4-carbamide (0.70 g, yield 94%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 158-159 占 폚.
[1743] Example 332
[1744] Sodium hydride (60%, oil, 220 mg) was added to a solution of ethyl diethylphosphonoacetate (1.06 g) and 3- (5-methyl- Methoxy) -1- (4-phenoxybenzyl) -lH-pyrazole-4-carbaldehyde (2.00 g) at 0 ° C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethyl) Pyrazol-4-yl] propanoate (2.19 g, yield: 95%) was obtained as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 93-94 占 폚.
[1745] Example 333
[1746] Ethyl E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4- phenoxybenzyl) -1H- pyrazol-4-yl] propanoate 450 mg), 1N sodium hydroxide solution (1.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 50 ° C for 2 hours and then 1N hydrochloric acid (1.5 ml) And the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) Yl] propenoic acid (410 mg, yield: 96%) was obtained. This was recrystallized from acetone-hexane. Melting point: 210-211 占 폚.
[1747] Example 334
[1748] Ethyl E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4- phenoxybenzyl) -1H- pyrazol-4-yl] propanoate 1100 mg), 5% palladium-carbon (390 mg), and tetrahydrofuran (30 ml) was stirred at room temperature under a hydrogen atmosphere for 5 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) - 1 - (4-phenoxybenzyl) -1H-pyrazol-4-yl] propionate (980 mg, yield 95%) as a colorless oily substance.
[1749] _{NMR (CDCl 3) δ: 1.17} (3H, t, J = 7.0 Hz), 2.39 (3H, s), 2.45-2.72 (4H, m), 4.06 (2H, q, J = 7.0 Hz), 5.05 (2H , s), 5.15 (2H, s), 6.90-7.46 (13H, m), 7.94-8.06 (2H, m).
[1750] Example 335
[1751] Yl) propionate (800 mg) was added to a solution of ethyl 3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) After stirring a mixture of 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, Acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) -1- (4- phenoxybenzyl) Yl] propionic acid (740 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 120-121 占 폚.
[1752] Example 336
[1753] (10.23 g), 4- (4-chloromethylphenoxy) methyl-5-methyl-2-phenyloxazole (14.66 g) was added to a solution of ethyl 3- (2-thienyl) , Potassium carbonate (13.09 g) and N, N-dimethylformamide (100 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -1H-pyrazole-4-carboxylate (19.88 g, yield 87%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 113-114 占 폚.
[1754] Example 337
[1755] Benzyl] -3- (2-thienyl) -1H-pyrazole-4-carboxylate (900 mg), 1N A mixture of sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 80 ° C for 5 hours. After cooling, 1 N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -Carboxylic acid (750 mg, yield: 88%). This was recrystallized from acetone-hexane. Melting point: 204-205 占 폚.
[1756] Example 338
[1757] Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] acetonitrile (1.69 g), 4N Sodium hydroxide solution (10 ml), and ethanol (10 ml) was refluxed overnight. After cooling, 1 N hydrochloric acid (40 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) -Yl] acetic acid (1.13 g, yield: 64%). This was recrystallized from acetone-hexane. Melting point: 98-99 ° C.
[1758] Example 339
[1759] Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] methylmalonate (6.08 g, ), 4N sodium hydroxide solution (10 ml), and ethanol (10 ml) was refluxed for 1 hour. After cooling, 1 N hydrochloric acid (40 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless oily substance was dissolved in pyridine (50 ml) and stirred at 110 ° C for 2 hours. After the pyridine was removed under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) Yl] propionic acid (4.02 g, yield: 80%). This was recrystallized from acetone-hexane. Melting point: 172-173 [deg.] C.
[1760] Example 340
[1761] Sodium hydride (60%, oil, 150 mg) was added to a solution of ethyl diethylphosphonoacetate (0.82 g) and 1- [4- (2-phenyl-4-thiazolylmethyl) Benzyl] -3- (2-thienyl) -1H-pyrazole-4-carbaldehyde (1.54 g) in dichloromethane at 0 &lt; 0 &gt; C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl (E) -3- [1- [4- (2-phenyl-4-thiazolylmethoxy) Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] propanoate (1.65 g, yield 93%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 104-105 占 폚.
[1762] Example 341
[1763] Ethyl (E) -3- [1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] propanoate After stirring the mixture at 50 占 폚 for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture (1.25 g), 1N sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (5 ml), and ethanol And then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give (E) -3- [1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) Yl] propenoic acid (970 mg, yield: 82%). This was recrystallized from ethyl acetate-hexane. Melting point: 137-138 占 폚.
[1764] Example 342
[1765] 4-yl] methylmalonate (4.09 g), 1N-hydroxynaphthalene-2-carboxylate A mixture of sodium aqueous solution (30 ml), tetrahydrofuran (30 ml), and ethanol (10 ml) was refluxed for 1 hour. After cooling, 1 N hydrochloric acid (30 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless oily substance was dissolved in pyridine (50 ml) and stirred at 110 ° C for 2 hours. After the pyridine was removed under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) Yl] propionic acid (3.25 g, yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 133-134 占 폚.
[1766] Example 343
[1767] (1.88 g) and potassium carbonate (1.88 g) in the same manner as in Reference Example 1, but using ethyl 3- (2-thienyl) -1H-pyrazole- 1.30 g), and N, N-dimethylformamide (30 ml) was stirred at 80 ° C for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Washed with aqueous solution of sodium chloride, the ethyl acetate layer, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- ( Thienyl) -1H-pyrazole-4-carboxylate (2.81 g, yield 92%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 114-115 [deg.] C.
[1768] Example 344
[1769] Yl] methylmalonate (1.75 g), 2N (2-phenyl-4-oxazolylmethoxy) Sodium hydroxide solution (10 ml), and ethanol (10 ml) was refluxed for 2 hours. After cooling, 1 N hydrochloric acid (20 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless oily substance was dissolved in pyridine (30 ml) and stirred at 110 ° C for 2 hours. After the pyridine was removed under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 3- [1- [4- (2-phenyl-4-oxazolylmethoxy) benzyl] -3- (2-thienyl) Yl] propionic acid (1.24 g, yield: 85%). This was recrystallized from ethyl acetate-hexane. Melting point: 145-146 占 폚.
[1770] Example 345
[1771] (5.96 g), ethyl 4- (4-chloromethylphenoxy) methyl-2-phenylthiazole (7.96 g), potassium carbonate 6.98 g), and N, N-dimethylformamide (75 ml) was stirred at 80 占 폚 for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- ( Thienyl) -1H-pyrazole-4-carboxylate (10.93 g, yield 87%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 94-95 占 폚.
[1772] Example 346
[1773] (750 mg) and a 1N aqueous solution of sodium hydroxide ((2-thienylmethoxy) benzyl] -3- 3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 80 ° C for 5 hours. After cooling, 1 N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride, dried (MgSO ₄₎ and concentrated. The resulting colorless crystals were collected by filtration to give 1- [4- (2-phenyl-4-thiazolylmethoxy) benzyl] -3- (2-thienyl) -1H-pyrazole- (640 mg, yield: 90%). This was recrystallized from acetone-hexane. Melting point: 187-188 占 폚.
[1774] Preparation Example 1 (Preparation of capsules)
[1775] 1) Compound of Example 4 30 mg
[1776] 2) microparticulate cellulose 10 mg
[1777] 3) Lactose 19 mg
[1778] 4) Magnesium stearate 1 mg
[1779] Total 60 mg
[1780] 1), 2), 3) and 4) are added and mixed in a gelatin capsule.
[1781] Preparation Example 2 (Preparation of tablet)
[1782] 1) 30 g of the compound of Example 4
[1783] 2) Lactose 50 g
[1784] 3) Corn starch 15 g
[1785] 4) Carboxymethylcellulose calcium 44 g
[1786] 5) Magnesium stearate 1 g
[1787] 1000 tablets 140 g
[1788] Total amounts of 1), 2) and 3) and 30 g of 4) were kneaded together with water, dried in vacuo and granulated. The granulation mixture was further mixed with 14 g of 4) and 1 g of 5) and the resulting mixture was tableted using a tablet machine to obtain 1000 tablets each containing 30 mg of the compound of Example 4.
[1789] The compounds of the present invention and the pharmaceutical composition of the present invention have low toxicity and are useful as preventive or therapeutic agents for diabetes (for example, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus); And hyperlipidemia (for example, hyperglyceridemia, hypercholesterolemia, hypercholestero-lipoproteinemia, post-prandial hyperlipidemia); Insulin sensitivity enhancers; An insulin resistance-improving agent; A prophylactic or therapeutic agent for myogical disorder (IGT); And can be used as a prophylactic agent for the progression from inherited dysfunc- tion to diabetes mellitus.
[1790] The compounds of the present invention and the pharmaceutical compositions of the present invention can be used in the treatment of diabetic complications (for example, neuropathy, nephropathy, retinopathy, cataract, macular vasculopathy, osteopenia, diabetic hyperthermia, Diabetic gangrene, dry mouth, hearing loss, cerebrovascular disease, peripheral circulatory disorder, etc.), obesity, osteoporosis, cachexia (e. G., Gastrointestinal disorders such as respiratory infections, urinary tract infections, gastrointestinal tract infections, skin soft tissue infections, Diabetic cachexia, hemicellular disease cachexia, endocrine disease cachexia, infectious cachexia, cachexia caused by acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, renal disease (for example, diabetic Myocardial infarction, angina pectoris, cerebrovascular disease (e.g., cerebral infarction, cerebral apoplexy), cerebral apoplexy, cerebral infarction, (Eg, leukemia, breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (eg, diabetic nephropathy, diabetic nephropathy, (Including, for example, fatty liver disease such as non-alcoholic fatty liver disease), chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, back pain, gout, postoperative or traumatic inflammation, relief of swelling, neuralgia, sore throat, cystitis, , Pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis), visceral obesity syndrome, arteriosclerosis (e.g., atherosclerosis), and the like.
[1791] In addition, the compounds of the present invention and the pharmaceutical compositions of the present invention can be used to improve discomfort in stomach ulcers, acute or chronic gastritis, biliary anomalies, or abdominal pain, nausea, vomiting,
[1792] In addition, the compounds of the present invention and the pharmaceutical compositions of the present invention can control (enhance or inhibit) the appetite and food intake, and thus can be used for the treatment of dry skin and dietary phobia (weight gain when administered to a subject suffering from dry skin or diabetic phobias) Or as a therapeutic agent for obesity.

权利要求:
Claims (31)
[1" claim-type="Currently amended] Claims 1. Compounds of the general formula (I)
(I)

Wherein R ¹ represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
X is a bond, an oxygen atom, a sulfur atom, or the formula ^{-CO-, -CS-, -CR 4 (OR} 5) - or -NR ⁶ - (wherein, each of R ⁴ and R ⁶ may be a hydrogen atom or a substituted And R &lt; ⁵ &gt; represents a hydrogen atom or a protecting group for a hydroxyl group;
m represents an integer of 0 to 3;
Y is an oxygen atom, a sulfur atom, or the formula ^{_{-SO-, -SO 2 -, -NR 7}} -, -CONR 7 - or -NR ⁷ CO- (wherein R ⁷ represents a hydrocarbon group which may be substituted or hydrogen atom) &Lt; / RTI &gt;
Ring A represents an aromatic ring which may be further substituted with 1 to 3 substituents;
n represents an integer of 1 to 8;
Ring B represents a nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group;
X ¹ represents a bond, an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO ₂ -, -O-SO ₂ - or -NR ¹⁶ - (wherein R ¹⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted) &Lt; / RTI &gt;
R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
W represents a bond or a divalent hydrocarbon residue of 1 to 20 carbon atoms;
R ³ is a group represented by the formula -OR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR ⁹ R ¹⁰ (each of R ⁹ and R ¹⁰ which may be the same or different is a hydrogen atom, a hydrocarbon group which may be substituted, A heterocyclic group which may be substituted, or an acyl group which may be substituted; R ⁹ and R ¹⁰ may bond together to form a ring;
When Y is an oxygen atom, a sulfur atom, -NH- or -CONH-, R ¹ is a heterocyclic group which may be substituted or R ² may be substituted An aromatic hydrocarbon group or an optionally substituted heterocyclic group.
[2" claim-type="Currently amended] The compound according to claim 1, wherein X ¹ is a bond and ring B is a nitrogen-containing 5-membered heterocyclic group.
[3" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ is a heterocyclic group which may be substituted or a cyclic hydrocarbon group which may be substituted.
[4" claim-type="Currently amended] 2. The compound according to claim 1, wherein R &lt; ¹ &gt; is a heterocyclic group which may be substituted.
[5" claim-type="Currently amended] 2. The compound according to claim 1, wherein X is a bond.
[6" claim-type="Currently amended] The compound according to claim 1, wherein m is 1 or 2.
[7" claim-type="Currently amended] 2. The compound according to claim 1, wherein Y is an oxygen atom.
[8" claim-type="Currently amended] The compound according to claim 1, wherein Ring A is a benzene ring or a pyridine ring, each of which may further have 1 to 3 substituents.
[9" claim-type="Currently amended] The compound according to claim 1, wherein n is an integer of 1 to 3.
[10" claim-type="Currently amended] 2. The compound according to claim 1, wherein X &lt; ¹ &gt; is a bond or an oxygen atom.
[11" claim-type="Currently amended] The compound according to claim 1, wherein W is a divalent hydrocarbon residue having 1 to 8 carbon atoms.
[12" claim-type="Currently amended] The compound according to claim 1, wherein R ³ is a group of the formula -OR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted).
[13" claim-type="Currently amended] The method according to claim 1,
Benzyl] -1H-pyrazol-4-yl] propionic acid, &lt; RTI ID = 0.0 &
Benzyl] -1H-pyrazol-4-yl] propionic acid, 3- [3-ethoxy-
Benzyl] -1H-pyrazol-4-yl] propionic acid (prepared as described in example 1, ,
Benzyl] -3- (2-thienyl) -lH-pyrazol-4-yl] propionic acid,
3- (2-thienyl) -1H-pyrazol-4-yl] propionic acid, or
Benzyl] -3- (2-thienyl) -1H-pyrazol-4-yl] propionic acid
/ RTI &gt;
[14" claim-type="Currently amended] A prodrug of a compound as defined in claim 1.
[15" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (II), or a salt or prodrug thereof,
&Lt; RTI ID = 0.0 &

Wherein R ¹ represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
X is a bond, an oxygen atom, a sulfur atom, or the formula ^{-CO-, -CS-, -CR 4 (OR} 5) - or -NR ⁶ - (wherein, each of R ⁴ and R ⁶ may be a hydrogen atom or a substituted And R &lt; ⁵ &gt; represents a hydrogen atom or a protecting group for a hydroxyl group;
m represents an integer of 0 to 3;
Y is an oxygen atom, a sulfur atom, or the formula ^{_{-SO-, -SO 2 -, -NR 7}} -, -CONR 7 - or -NR ⁷ CO- (wherein R ⁷ represents a hydrocarbon group which may be substituted or hydrogen atom) &Lt; / RTI &gt;
Ring A represents an aromatic ring which may be further substituted with 1 to 3 substituents;
n represents an integer of 1 to 8;
Ring B represents a nitrogen-containing 5-membered heterocycle which may be further substituted with an alkyl group;
X ¹ represents a bond, an oxygen atom, a sulfur atom or a group represented by the formula -SO-, -SO ₂ -, -O-SO ₂ - or -NR ¹⁶ - (wherein R ¹⁶ represents a hydrogen atom or a hydrocarbon group which may be substituted) &Lt; / RTI &gt;
R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
W represents a bond or a divalent hydrocarbon residue of 1 to 20 carbon atoms;
R ³ is a group represented by the formula -OR ⁸ (wherein R ⁸ represents a hydrogen atom or a hydrocarbon group which may be substituted) or -NR ⁹ R ¹⁰ (each of R ⁹ and R ¹⁰ which may be the same or different is a hydrogen atom, a hydrocarbon group which may be substituted, A heterocyclic group which may be substituted, or an acyl group which may be substituted, and R ⁹ and R ¹⁰ may bond together to form a ring.
[16" claim-type="Currently amended] 16. The composition of claim 15 wherein X &lt; ¹ &gt; is a bond and ring B is a nitrogen-containing 5-membered heterocyclic group.
[17" claim-type="Currently amended] A prophylactic or therapeutic agent for diabetes mellitus comprising a compound of the formula (II) or a salt thereof or a prodrug thereof:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[18" claim-type="Currently amended] A prophylactic or therapeutic agent for hyperlipidemia comprising a compound of the formula (II) or a salt thereof or a prodrug thereof:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[19" claim-type="Currently amended] A prophylactic or therapeutic agent for a tolerable disorder comprising a compound of the formula (II) or a salt thereof or a prodrug thereof:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[20" claim-type="Currently amended] A retinoid-related receptor function modulator comprising a compound of formula (II) or a salt thereof or a prodrug thereof:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[21" claim-type="Currently amended] 21. The modulator of claim 20, which is a ligand to a peroxisome proliferator-activated receptor.
[22" claim-type="Currently amended] 21. The modulator of claim 20, which is a ligand to the retinoid X receptor.
[23" claim-type="Currently amended] An insulin resistance-improving agent comprising a compound of the formula (II) or a salt thereof or a prodrug thereof:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[24" claim-type="Currently amended] A method for preventing or treating diabetes mellitus in a mammal in need of such prevention or treatment of diabetes mellitus comprising the step of administering to said mammal an effective amount of a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt;
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[25" claim-type="Currently amended] A method for preventing or treating hyperlipidemia in a mammal in need of such prevention or treatment of hyperlipidemia comprising administering to said mammal an effective amount of a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; :
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[26" claim-type="Currently amended] Comprising administering to said mammal an effective amount of a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; / RTI &gt; or a salt or prodrug thereof, for the prevention or treatment of impaired glucose tolerance in a mammal in need thereof, :
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[27" claim-type="Currently amended] A method of modulating retinoid-related receptor function in a mammal in need of modulation of retinoid-related receptor function comprising administering to said mammal an effective amount of a compound of formula II, or a salt or prodrug thereof, :
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[28" claim-type="Currently amended] Use of a compound of formula (II), or a salt or prodrug thereof, for the manufacture of a pharmaceutical formulation for the prophylaxis or treatment of diabetes mellitus:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[29" claim-type="Currently amended] Use of a compound of the formula II: or a salt or prodrug thereof, for the manufacture of a pharmaceutical preparation for the prophylaxis or treatment of lipidemia:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[30" claim-type="Currently amended] The use of a compound of formula II: or a salt or prodrug thereof, for the manufacture of a pharmaceutical formulation for the prophylaxis or treatment of myelastic disorders:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.
[31" claim-type="Currently amended] Use of a compound of formula (II) or a salt thereof, or a prodrug thereof, for the manufacture of a retinoid-related receptor function modulating agent:
&Lt; RTI ID = 0.0 &

Wherein the symbols have the same meanings as in claim 15.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-11-10|Priority to JPJP-P-1999-00320317

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1999-11-10|Priority to JP32031799

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1999-12-10|Priority to JP35223799

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1999-12-10|Priority to JPJP-P-1999-00352237

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2000-11-09|Application filed by 다케다 야쿠힌 고교 가부시키가이샤

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2002-06-24|Publication of KR20020049044A

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2005-10-04|Application granted

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2005-10-04|Publication of KR100518142B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-1999-00320317|1999-11-10|

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JP32031799|1999-11-10|

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JP35223799|1999-12-10|

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JPJP-P-1999-00352237|1999-12-10|