Tetrahydroquinoline derivatives

专利摘要:
The present invention relates to a tetrahydroquinoline derivative of formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising such derivatives and to the use of such derivatives for modulating modifications. Formula I In the above formula, R 1 is formyl, (1-6C) alkylcarbonyl or (1-6C) alkylsulfonyl; R 2 and R 3 are H or (1-4C) alkyl; R 4 is phenyl; R 5 is (1-4C) alkyl; YX is C (O) -O, S (O) 2 -O, NHC (O) -O, NHC (S) -O, OC (O) -O, Bond-O, C (O) -NH, S (O) 2 -NH, NHC (O) -NH, NHC (S) -NH, OC (O) -NH, bond-NH, NH-C (O), OC (O), NH-S (O) 2 or OS (O) 2 or YX is a bond; R 6 is H, trifluoromethyl, (1-6C) alkyl, 1- or 2-adamantyl (1-4C) alkyl, (2-6C) alkenyl, (3-9C) heteroaryl, (3 -6C) cycloalkyl, (2-6C) heterocycloalkyl, (1-4C) alkylthio (1-4C) alkyl, (6-10C) aryl (1-4C) alkyl, (3-9C) heteroaryl ( 1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, R 8 , R 9 -aminocarbonyl (1-4C) alkyl , R 8 , R 9 -amino (1-4C) alkyl, R 8 -oxycarbonyl (1-4C) alkyl, R 8 -oxy (1-4C) alkyl, R 8 -carbonyl (1-4C) alkyl Or (6-10C) aryl; R 7 is H, (1-4C) alkyl, (1-4C) alkoxy, halogen, trifluoromethyl, cyano, nitro, hydroxyl; R 8 and / or R 9 is H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (6-10C) aryl, (3-9C) heteroaryl, (6 -10C) aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1- 4C) alkyl, (1-4C) (di) alkylamino (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylthio (1-4C) alkyl, (1 -4C) alkylcarbonylamino (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) alkoxycarbonylamino (1-4C) alkyl, (3-6C) Or cycloalkyl, (2-6C) heterocycloalkyl, or R 8 and R 9 may be bonded in (2-6C) heterocycloalkyl.
公开号:KR20040030714A
申请号:KR10-2003-7017088
申请日:2002-06-25
公开日:2004-04-09
发明作者:반스트라텐니콜코린르네；반소머렌루돌프기즈스베르투스；슐츠주르겐
申请人:악조 노벨 엔.브이.；
IPC主号:

专利说明:

Tetrahydroquinoline derivatives {TETRAHYDROQUINOLINE DERIVATIVES}
[1] The present invention relates to compounds having FSH (follicular stimulating hormone) modulating activity, in particular tetrahydroquinoline derivatives, pharmaceutical compositions comprising the same, and the use of such compounds in pharmaceutical treatment.
[2] Gonadotropin performs important functions in various body functions, including metabolism, temperature control, and reproductive processes. Gonadotropin acts on specific germ cell types to initiate ovarian and testicular differentiation and steroid formation. Pituitary gonadotropin FSH, for example, plays a central role in stimulating follicle formation and maturation, while LH (luteinizing hormone) induces ovulation. Sharp, RM Clin Endocrinol . 33: 787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res . 35: 301-342, 1979. Typically, FSH is combined with LH to induce in vitro fertilization (IVF) and ovulation in ovarian stimulation, such as ovarian hyperstimulation in infertile ovulation women [Insler, V., Int. J. Fertility 33: 85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5: 3-13, 1988], as well as clinically applied to hypogonadism in men and infertility in men.
[3] Konadotropin FSH is released from the anterior pituitary gland under the influence of gonadotropin releasing hormone and estrogen and from the placenta during pregnancy. In women, FSH acts on the ovary to stimulate follicle formation and is a major hormone that regulates the release of estrogens. In men, FSH results in the integration of the tubules, which act on sertoli cells to support reproductive development. Purified FSH is used clinically for infertility treatment in women and certain types of spermatogenesis failure in men. The gonadotropin used for therapeutic purposes can be isolated from human urine sources, which is of low purity. Morse et al, Amer. J. Reproduct. Immunol. and Microbiology 17: 143, 1988]. Alternatively, they can be produced as recombinant gonadotropins. Recombinant human FSH is commercially available and is used to aid reproduction. Olijve et al. Mol. Hum. Reprod. 2: 371, 1996; Devroey et al. Lancet 339: 1170, 1992].
[4] The action of the FSH hormone is regulated by specific plasma membrane receptors that are members of a large line of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and can interact with the Gs protein to induce activation of adenylate cyclase.
[5] FSH receptors are highly specific targets in ovarian follicle growth and are expressed only in the ovaries. Blocking of these receptors, or the inhibition of signals that are commonly induced after FSH regulated receptor activation, interferes with follicle formation, thus preventing ovulation and fertilization. Thus, low molecular weight FSH antagonists can form the basis of novel contraceptive methods. Such FSH antagonists can cause reduced follicle formation (ovulation) with sufficient estergen production remaining to avoid deleterious effects on bone weight.
[6] The present invention relates to the production of low molecular weight hormone analogs that selectively have regulatory activity on the FSH receptor. The compounds of the present invention can be used as (partial) agonists or (partial) antagonists of FSH-receptors.
[7] Thus, it was found that the following types of tetrahydroquinoline compounds of formula (I) or pharmaceutically acceptable salts thereof have FSH modulating activity.
[8]
[9] In the above formula,
[10] R ¹ is formyl, (1-6C) alkylcarbonyl or (1-6C) alkylsulfonyl;
[11] R ² and R ³ are H or (1-4C) alkyl;
[12] R ⁴ is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, Phenyl optionally substituted with one or more substituents selected from the group of (1-4C) (di) alkylamino. Substitution is preferably at the para-position.
[13] R ⁵ is (1-4C) alkyl;
[14] YX is C (O) -O, S (O) ₂ -O, NHC (O) -O, NHC (S) -O, OC (O) -O, Bond-O, C (O) -NH, S (O) ₂ -NH, NHC (O) -NH, NHC (S) -NH, OC (O) -NH, bond-NH, NH-C (O), OC (O), NH-S (O) ₂ or OS (O) ₂ or XY is a bond;
[15] R ⁶ is H, trifluoromethyl, (1-6C) alkyl, 1- or 2-adamantyl (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (6 -10C) aryl, (3-9C) heteroaryl, (3-6C) cycloalkyl, (2-6C) heterocycloalkyl, (1-4C) alkylthio (1-4C) alkyl, (6-10C) aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1-4C) alkyl, R ⁸ , R ⁹ -aminocarbonyl (1-4C) alkyl, R ⁸ , R ⁹ -amino (1-4C) alkyl, R ⁸ -oxycarbonyl (1-4C) alkyl, R ⁸ -oxy (1- 4C) alkyl, R ⁸ -carbonyl (1-4C) alkyl;
[16] Note that when R ⁶ is H, XY may not be a bond.
[17] When R ⁶ is phenyl, phenyl is (6-10C) aryl, (6-10C) aryloxy, (6-10C) aryl (1) in addition to the substituents for the (6-10C) aryl group as mentioned herein -4C) alkoxy, (3-9C) heteroaryl, (3-9C) heteroaryloxy, (3-9C) heteroaryl (1-4C) alkoxy, (1-4C) alkylcarbonylamino, (1-4C ) Alkylcarbonyloxy, (3-6C) cycloalkylcarbonyloxy, (1-4C) alkoxycarbonyl (1-4C) alkylcarbonyloxy, (1-4C) alkoxy (1-4C) alkylcarbonyloxy , (6-10C) arylcarbonyloxy, (3-9C) heteroarylcarbonyloxy, (1-4C) alkylsulfonyloxy, (6-10C) arylsulfonyloxy, (3-9C) heteroarylsul Phenyloxy, (1-4C) (di) alkylcarbamoyl, (6-10C) (di) arylcarbamoyl, (2-6C) heterocycloalkylcarbamoyl, (6-10C) (di) aryl Optionally substituted with amino, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl, (2-6C) heterocycloalkyl (1-4C) alkyl Can be.
[18] R ⁷ is H, (1-4C) alkyl, (1-4C) alkoxy, halogen, trifluoromethyl, cyano, nitro, hydroxyl;
[19] R ⁸ and / or R ⁹ is H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (6-10C) aryl, (3-9C) heteroaryl, (6 -10C) aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1- 4C) alkyl, (1-4C) (di) alkylamino (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylthio (1-4C) alkyl, (1 -4C) alkylcarbonylamino (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) alkoxycarbonylamino (1-4C) alkyl, (3-6C) Or cycloalkyl, (2-6C) heterocycloalkyl, or R ⁸ and R ⁹ may be bonded in the (2-6C) heterocycloalkyl ring.
[20] The compounds according to the present invention modulate FSH receptor action, and when they act like agonists, can be used for the same clinical uses as native FSH, which exhibits modified stability and has the advantage of being able to be administered in various ways. When blocking the receptor, it can be used, for example, as a contraceptive.
[21] Thus, the FSH-receptor modulators of the present invention can be used for the treatment of infertility, contraception and for the treatment of hormone-dependent diseases such as breast cancer, prostate cancer and endometriosis. Compounds of the invention are preferably used to inactivate FSH-receptors.
[22] As used herein, the term (1-4C) alkyl refers to a branched or unbranched alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t -Butyl and the like.
[23] As used herein, the term (1-6C) alkyl refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t Butyl and hexyl; (1-5C) alkyl groups are preferred, and (1-4C) alkyl is most preferred.
[24] The term 1- or 2-adamantyl (1-4C) alkyl means an adamantyl group bonded at position 1 or 2 relative to an alkyl group having 1 to 4 carbon atoms having the same meaning as defined above.
[25] The term (2-4C) alkenyl refers to a branched or unbranched alkenyl group having 2 to 4 carbon atoms, such as ethenyl and 2-butenyl and the like.
[26] The term (2-6C) alkenyl refers to a branched or unbranched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 2-butenyl and n-pentenyl.
[27] The term (2-4C) alkynyl refers to a branched or unbranched alkynyl group having 2 to 4 carbon atoms, such as ethynyl and propynyl and the like.
[28] The term (2-6C) alkynyl refers to a branched or unbranched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl and n-pentynyl and the like.
[29] The term (3-6C) cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
[30] The term (2-6C) heterocycloalkyl has 2 to 6 carbon atoms, preferably 3 to 5 carbon atoms and includes one or more heteroatoms selected from N, O and / or S, heteroatoms, if possible Or a heterocycloalkyl group which may be bonded via a carbon atom. N or O is preferable as a hetero atom. Most preferred are piperidine, morpholine and pyrrolidine.
[31] The term (1-4C) alkoxy refers to an alkoxy group having 1 to 4 carbon atoms, with the alkyl moiety having the same meaning as defined above. The (1-2C) alkoxy group is preferable.
[32] The term (6-10C) aryl means an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl, and the like, which is hydroxy, amino, halogen, nitro, tri 1 selected from fluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino Optionally substituted with the above substituents, the alkyl moiety having the same meaning as defined above. The aromatic hydrocarbon group is preferably phenyl.
[33] The term (3-9C) heteroaryl refers to a substituted or unsubstituted aromatic group having 3 to 9 carbon atoms and containing one or more heteroatoms selected from N, O and / or S, examples of which are imidazolyl, thia Diazolyl, pyridyl, (benz) thienyl, (benzo) furyl, quinolyl, tetrahydroquinolyl, quinoxalyl or indolyl and the like. Substituents on the heteroaryl group may be selected from the group of substituents given for the aryl group. Heteroaryl groups may be bonded via carbon atoms or heteroatoms where possible. Heteroaryl groups are preferably thienyl, furyl and pyridyl.
[34] The term (6-10C) aryloxy means an aryl group containing 6 to 10 carbon atoms as described above, bonded to an oxygen atom. The (3-9C) heteroaryloxy group is an analog of a (6-10C) aryloxy group containing one or more heteroatoms selected from N, O or S.
[35] The term (1-4C) alkoxycarbonyl (1-4C) alkyl refers to an alkoxycarbonylalkyl group, wherein the alkoxy group comprises 1 to 4 carbon atoms having the same meaning as defined above, wherein the alkyl group is defined above It includes 1 to 4 carbon atoms having the same meaning as.
[36] The term (1-4C) alkoxy (1-4C) alkyl refers to an alkoxyalkyl group, wherein the alkoxy group comprises 1 to 4 carbon atoms having the same meaning as defined above and the alkyl group means the same meaning as defined above It contains 1-4 carbon atoms which have.
[37] The term (3-6C) cycloalkyl (1-4C) alkyl means a cycloalkyl group having 3 to 6 carbon atoms bonded to an alkyl group having 1 to 4 carbon atoms, wherein the cycloalkyl group is as defined above ( 3-6C) cycloalkyl group, and the alkyl group is a (1-4C) alkyl group as defined above.
[38] The term (2-6C) heterocycloalkyl (1-4C) alkyl refers to a heterocycloalkyl group having 2 to 6 carbon atoms bonded to an alkyl group having 1 to 4 carbon atoms, wherein the heterocycloalkyl group is defined above A (2-6C) heterocycloalkyl group as described above, and the alkyl group is a (1-4C) alkyl group as defined above.
[39] The term (1-4C) (di) alkylamino refers to a (di) alkylamino group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above.
[40] The term (6-10C) (di) arylamino refers to a (di) arylamino group, whose aryl group contains 6 to 10 carbon atoms as defined above.
[41] The term (1-4C) (di) alkylamino (1-4C) alkyl refers to a (di) alkylaminoalkyl group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above.
[42] The term (1-4C) alkylthio (1-4C) alkyl refers to an alkylthioalkyl group whose alkyl group contains from 1 to 4 carbon atoms and is as defined above.
[43] In the definition of R ⁸ , R ⁹ -aminocarbonyl (1-4C) alkyl, the term aminocarbonyl (1-4C) alkyl refers to an aminocarbonylalkyl group, the alkyl group of which comprises 1 to 4 carbon atoms, It has the same meaning as defined above. As the aminocarbonylalkyl group, an aminocarbonylmethyl group is preferable.
[44] In the definition of R ⁸ , R ⁹ -amino (1-4C) alkyl, the term amino (1-4C) alkyl refers to an aminoalkyl group, the alkyl group of which contains 1 to 4 carbon atoms, the same meaning as defined above Has
[45] The term oxycarbonyl (1-4C) alkyl in the definition of R ⁸ -oxycarbonyl (1-4C) alkyl refers to an oxycarbonylalkyl group whose alkyl group comprises from 1 to 4 carbon atoms, as defined above Has the same meaning as As the oxycarbonylalkyl group, an oxycarbonylmethyl group is preferable.
[46] The term oxy (1-4C) alkyl in the definition of R ⁸ -oxy (1-4C) alkyl refers to an oxyalkyl group whose alkyl group contains from 1 to 4 carbon atoms and is as defined above.
[47] The term carbonyl (1-4C) alkyl in the definition of R ⁸ -carbonyl (1-4C) alkyl refers to a carbonylalkyl group whose alkyl group contains from 1 to 4 carbon atoms and is as defined above.
[48] The term (6-10C) aryl (1-4C) alkyl means an arylalkyl group having 7 to 14 carbon atoms, where the alkyl group is a (1-4C) alkyl group and the aryl group is as defined above (6-10C) Aryl. As the arylalkyl group, a phenyl (1-4C) alkyl group such as benzyl is preferable. (3-9C) heteroaryl (1-4C) alkyl groups are analogs of (6-10C) aryl (1-4C) alkyl groups containing one or more heteroatoms selected from N, O and / or S, the heteroaryl groups of which are And may be bonded via a carbon atom or heteroatom.
[49] In the definition of NR ⁸ R ⁹ , in which R ⁸ and R ⁹ form a ring together with the nitrogen atom to which they are attached, the term bonded within the (2-6C) heterocycloalkyl ring includes a nitrogen atom and includes up to 2 to 6 carbon atoms By a ring that further comprises an atom and may comprise one or more additional heteroatoms selected from N, O and / or S. Examples of such rings include azetidine, pyrrolidine, piperidine, piperazine and (thio) morpholine.
[50] The term halogen means fluorine, chlorine, bromine or iodine.
[51] The term (1-6C) alkylcarbonyl refers to an alkylcarbonyl group whose alkyl group contains 1 to 6 carbon atoms and has the same meaning as defined above. (1-4C) alkylcarbonyl group is preferable.
[52] The term (1-4C) alkylcarbonylamino (1-4C) alkyl refers to an alkylcarbonylaminoalkyl group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above.
[53] The term (6-10C) aryl (1-4C) alkoxy means an aryl group containing 6 to 10 carbon atoms as defined above bonded to a (1-4C) alkoxy group as defined above. (3-9C) heteroaryl (1-4C) alkoxy groups are analogs of (6-10C) aryl (1-4C) alkoxy groups containing one or more heteroatoms selected from N, O or S, the heteroaryl groups of which are It may be bonded by a carbon atom or a hetero atom.
[54] The term (1-4C) alkylcarbonyloxy refers to an alkylcarbonyloxy group whose alkyl group contains 1 to 4 carbon atoms. The term (3-6C) cycloalkylcarbonyloxy refers to a cycloalkylcarbonyloxy group, whose cycloalkyl group contains 3 to 6 carbon atoms, whose cycloalkyl moiety has the meaning as defined above.
[55] The term (1-4C) alkoxycarbonyl (1-4C) alkylcarbonyloxy means a (1-4C) alkoxycarbonyl group bonded to an alkylcarbonyloxy group, the alkyl moiety of which contains 1 to 4 carbon atoms and , And its alkoxy group has the meaning as defined above.
[56] The term (1-4C) alkoxy (1-4C) alkylcarbonyloxy means an alkoxy group having 1-4 carbon atoms bonded to an alkylcarbonyloxy group having 1-4 carbon atoms, wherein the alkoxy and alkyl groups are It has the same meaning as defined.
[57] The term (1-4C) alkylcarbonylamino refers to an alkylcarbonylamino group whose alkyl group contains from 1 to 4 carbon atoms.
[58] The term (1-4C) alkoxycarbonylamino (1-4C) alkyl means an alkoxycarbonyl group having 1 to 4 carbon atoms having the same meaning as defined above bound to an aminoalkyl group, the alkyl group of which is 1-4 Carbon atoms and the same meanings as defined above.
[59] The term (6-10C) arylcarbonyloxy refers to an arylcarbonyloxy group whose aryl group contains 6 to 10 carbon atoms. As an arylcarbonyloxy group, a phenylcarbonyloxy group is preferable. The (3-9C) heteroarylcarbonyloxy group contains one or more heteroatoms selected from N, O or S and, where possible, analogs of the (6-10C) arylcarbonyloxy group which may be bonded via a carbon atom or heteroatom to be.
[60] The term (1-4C) alkylsulfonyl refers to an alkylsulfonyl group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above.
[61] The term (1-6C) alkylsulfonyl refers to an alkylsulfonyl group whose alkyl group contains 1 to 6 carbon atoms and has the same meaning as defined above. (1-3C) alkylsulfonyl group is preferable.
[62] The term (1-4C) alkylsulfonyloxy refers to an alkylsulfonyloxy group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above. (1-3C) alkylsulfonyloxy group is preferable.
[63] The term (6-10C) arylsulfonyloxy refers to an arylsulfonyloxy group, whose aryl group contains 6 to 10 carbon atoms and has the same meaning as defined above. Phenylsulfonyloxy group is preferable. The (3-9C) heteroarylsulfonyloxy group is an analog of the (6-10C) arylsulfonyloxy group containing at least one heteroatom selected from N, O or S which may be bonded via a carbon atom or heteroatom if possible.
[64] The term (1-4C) (di) alkylcarbamoyl refers to a (di) alkylcarbamoyl group whose alkyl group contains 1 to 4 carbon atoms and has the same meaning as defined above.
[65] The term (6-10C) (di) arylcarbamoyl refers to a (di) arylcarbamoyl group, whose aryl moiety contains 6 to 10 carbon atoms and has the meaning as defined above.
[66] The term (2-6C) heterocycloalkylcarbamoyl refers to a heterocycloalkylcarbamoyl group whose heterocycloalkyl group contains 2 to 6 carbon atoms and has the meaning as defined above.
[67] Preferred compounds of the present invention are compounds of formula I, wherein Y-X is C (O) -NH, OC (O) -NH or C (O) -O. More preferably, Y-X is C (O) -NH.
[68] More preferred are compounds wherein R ¹ is (1-4C) alkylcarbonyl, preferably acetyl and / or R ² and / or R ³ and R ⁵ are independently (1-4C) alkyl, more preferably methyl Do. R ⁶ is preferably a bulky group. R ⁶ is preferably (6-10C) aryl, (3-9C) heteroaryl, (6-10C) aryl (1-4C) alkyl or (3-9C) heteroaryl (1-4C) alkyl. Most preferred are compounds wherein R ⁶ is (6-10C) aryl, more preferably phenyl. R ⁷ group is preferably H, (1-4C) alkyl or (1-4C) alkoxy. H or (1-4C) alkyl is preferred, with H or methyl being more preferred. Most preferred are compounds wherein R ⁷ is H.
[69] In the most preferred compounds according to the invention, R ¹ is (1-4C) alkylcarbonyl, R ² , R ³ , R ⁵ are independently (1-4C) alkyl, R ⁴ is phenyl and YX is C Most preferred are compounds wherein (O) -NH and R ⁷ is H. More preferred are compounds wherein R ¹ is acetyl, R ² , R ³ , R ⁵ are independently methyl, R ⁴ is phenyl, YX is C (O) —NH, and R ⁷ is H.
[70] In the above preferred compounds, the substitutions follow those indicated in the definition of the group. Phenyl in R ⁶ may be further substituted as indicated in the definition of R ^6.
[71] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-ethylcarbonyl-6-amino-4-phenyl-1,2, 3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-6-benzoylamino-4- (4-methylphenyl) -1,2,3,4-tetrahydro-2,2,4- Trimethylquinoline, 1-acetyl-6-amino-4- (4-aminophenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-4-phenyl-1, 2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline, 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6,8- The compounds of pentamethylquinoline and 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline are excluded from the present invention.
[72] This notation is described in Teor. Prakt. Sorbtsionnykh Protsessov , 17:39, 1985; Teor. Prakt. Sorbtsionnykh Protsessov , 16: 117, 1983; Ref. Zh., Khim. Abstr . 1 Zh 311, 1972; Khim. Geterosikl. Soedin . 7: 795, 1971].
[73] Suitable methods for preparing the compounds of the present invention are as follows.
[74]
[75] R ² and R ³ is methyl in the compounds of the invention R ⁷ is as defined above that are the same as those of the formula II-ae of the (protected) with the aniline as a starting material by a known Skraup reaction in Reference 1 of the formula III-ae It can be produced by calculating a, 2-dihydro-2,2,4-trimethylquinoline derivative.
[76] Related Skraup cyclization reactions are described in A. Knoevenagel, Chem. Ber . 54: 1726, 1921; RL Atkins and DE Bliss, J. Org. Chem . 43: 1975, 1978; JV Johnson, BS Rauckman, DP Baccanari and B. Roth, J. Med. Chem . 32: 1942, 1989; WC Lin, S.-T. Huang and S.-T. Lin, J. Chin. Chem. Soc . 43: 497, 1996; JP Edwards, SJ West, KB Marschke, DE Mais, MM Gottardis and TK Jones, J. Med. Chem . 41: 303, 1998.
[77] The above reactions are usually carried out at high temperatures in the presence of iodine or amphoterics such as hydrochloric acid, p-toluenesulfonic acid or aqueous hydrogen iodide in acetone, mesityl oxide or ethylacetoacetate. Alternatively, 1,2-dihydro-2,2,4-trimethylquinoline of Formula III-ae is reacted with acetone of the corresponding aniline of Formula II-ae in the presence of MgSO ₄ , 4-t-butylcatechol and iodine. Can be generated. See, LG Hamann, RI Higuchi, L. Zhi, JP Edwards and X.-N. Wang, J. Med. Chem , 41: 623, 1998]. Starting materials can be obtained directly from commercial sources, or are described, for example, in H. Cerfontain, Y. Zou and BH Bakker, Recl. Trav. Chim. Pays-Bas , 113: 403, 1994; A. Coppock, J. Org. Chem . 22: 325, 1957; M. Schlosser, JH Choi and S. Takagishi, Tetrahedron , 46: 5633, 1990, which can be produced by known aromatic ring substitution reactions.
[78] In addition, R ² and R ³ are (2-4C) alkyl, and R ⁷ is a compound of formula VI-ae as described above, generally using a suitable ketone of formula V to undergo cyclization of the aniline of formula IV-ae. It can synthesize | combine by.
[79]
[80] The above-mentioned reactions are usually carried out at high temperature in an inert solvent such as toluene using, but not limited to, protic acid or Lewis acids such as p-toluenesulfonic acid or boron trifluoride to promote the cyclization reaction. do. See H. Walter, H. Sauter and T. Winkler, Helv. Chim. Acta , 75: 1274, 1992; H. Walter, Helv. Chim. Acta , 77; 608, 1994; H. Walter and J. Schneider, Heterocycles , 41: 1251, 1995; JP Edwards, JD Ringgenberg and TK Jones, Tetrahedron Lett. 39: 5139, 1998].
[81] Essential building blocks of formula IV-a-e may be produced by the Wittig reaction of ketones of formula VII-a-e. The introduction of substituent A on the aromatic ring can be carried out using known aromatic ring substitutions in the aniline step or in the 1,2-dihydro-2,2,4-trimethylquinoline step as described above for the compound of formula II. have.
[82]
[83] Alternatively, compounds of formula VI-ae wherein R ² = R ³ = H can be produced from aniline of formula II-ae by reaction with 1-methylstyrene and formaldehyde in acetonitrile at room temperature or high temperature. Can be. Related cyclization reactions are described in JM Mellor and GD Merriman, Tetrahedron , 51: 6115, 1995.
[84] Thereafter, the 1-N-acylation or 1-N-sulfonylation reaction of the compound of Formula VI, wherein R ² , R ³ , R ⁷ and A are as defined above, can be carried out using standard conditions well known to those skilled in the art. Can be. In a typical embodiment, the compound of formula VI is selected from a base such as N, N-diisopropylethylamine, triethylamine, piperidine or sodium hydride in a solvent such as dichloromethane, tetrahydrofuran, toluene or pyridine. But not limited thereto) to react with acyl halides or acid anhydrides or sulfonylchlorides in the presence of N-acylated or N-sulfonylated 1,2-dihydro- of formulas VIII-a and VIII-b, respectively. To produce a 4-methylquinoline derivative.
[85]
[86] Related N-acylation reactions of dihydroquinoline scaffolds are described by Zh. V. Shmyreva, Kh. S. Shikhaliev and EB Shpanig, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol . 31:45, 1988; Zh. V. Shmyreva, Kh. S. Shikhaliev, LP Zalukaev, YA Ivanov, YS Ryabokobylko and IE Pokrovskaya, Zh. Obshch. Khim . 59: 1391, 1989.
[87] The 1-N-formylation reaction reacts the dihydroquinoline of formula VI with formic acid at high temperature in the presence of trifluoroacetic acid or P. Bouyssou, C. Le Goff and J. Chenault, J. Heterocycl. Chem. 29: 895, 1992 or in N. Atanes, S. Perez, E. Guitan, L. Castedo and JM Saa, Tetrahedron , 50: 11257, 1994, can be readily performed by reacting with formic acid ethyl ester in the presence of sodium acetate.
[88] The introduction of the essential phenyl group at the 4 position of the dihydroquinoline scaffold is characterized by the alkylation of Friedel-Crafts of (substituted) benzene derivatives in which R ¹ , R ² , R ³ , R ⁷ and A are as defined above. By reaction.
[89]
[90] The latter reaction is usually carried out at high temperature in a neat (substituted) benzene or in a suitable inert solvent such as heptane or hexane using (substituted) benzene as a preparation for Lewis acid (e.g. AlCl ₃ , AlBr ₃ , FeCl ₃ or SnCl). ₄ ) by the catalytic reaction. Friedel-Crafts alkylation using 1,2-dihydro-2,2,4-trimethylquinoline is described by BA Lugovik, LG Yudin and AN Kost, Dokl. Akad. Nauk SSSR , 170: 340, 1966; BA Lugovik, LG Yudin, SM Vinogradova and AN Kost, Khim. Geterosikl. Soedin , 7: 795, 1971.
[91] R ⁵ is not Me, and the compounds of the present invention of the general formula (XII) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ and A are as defined above may be prepared by using tetrahydroquinoline ketone of the general formula (X) as starting material. Can be synthesized. Thus, the Wittig reaction of ketones of formula X with the appropriate Wittig formulation yields unsaturated derivatives of formula XI, which are Friedel-Crafts of benzene (substituted) by the same method as described above for the preparation of compounds of formula IX. It is the starting material for the alkylation reaction.
[92]
[93] The Wittig reaction described above is well known to those skilled in the art.
[94] The essential ketone of formula (X) is reacted with 3-chloro-3-methyl-1-butyne (XIII) of aniline of formula (II) in diethyl ether / water in the presence of copper powder and triethylamine to yield an alkyne of formula (XIV) Can be generated. The hydrogen-halogen exchange is carried out by the addition of p-toluenesulfonylchloride at a temperature of 50 ° C. or lower to a deprotonation reaction in which an compound of formula (XIV) is reacted with n-butyllithium in an inert solvent such as tetrahydrofuran. Chloride can be calculated. Finally, an acid (eg sulfuric acid) catalyzed cyclization reaction is carried out in a solvent such as polyethylene glycol at high temperature to yield a compound of formula XVI, which is acylated or sulfonylated as defined above for derivatives of formula VI. Can be processed.
[95]
[96] The above reaction sequence is described in [P. Barmettler and H.-J. Hansen, Helv. Chim. Acta , 73: 1515, 1990 (and incorporated herein by reference).
[97] Functionalization of position 6 in tetrahydroquinoline of Formula XII can be accomplished by known deprotection-coupling methods.
[98] Compounds of formula (Ia) wherein X = O and Y = C (O), S (O) ₂ , NHC (O), NHC (S), OC (O), or a bond) are 6-methods of formula XII-a It may be produced from oxy containing tetrahydroquinoline. Demethylation reactions are well known to those skilled in the art.
[99]
[100] In a typical experiment, the demethylation reaction is carried out by reacting a compound of formula (XII-a) with BBr ₃ at low temperature in an inert solvent such as dichloromethane or tetrahydrofuran (but not limited to) to remove the deprotected compound of formula (XVII). Calculate and perform Alternatively, the demethylation reaction is carried out by reacting the compound of formula XII-a with the BF ₃ · Me ₂ S complex at room temperature in an inert solvent as described for the demethylation reaction with BBr ₃ .
[101]
[102] In addition, subsequent functionalization of the free OH groups in derivatives of formula XVII is well known to those skilled in the art, which can be easily carried out using the formulations of formula XVIII-a-g.
[103] In the case of halide containing formulations of formula XVIII, the above-mentioned reaction is carried out in a suitable solvent such as an aprotic solvent such as N, N-dimethylformamide, dichloromethane or tetrahydrofuran, such as N, N-diisopropylethyl Typically performed at room temperature in the presence of, but not limited to, amines or sodium hydride. Additives such as N, N-dimethylaminopyridine or tetrabutylammonium iodide may promote the latter reaction. In addition, the use of isocyanates or isothiocyanates of formulas XVIII-d and XVIII-e yields compounds of formula I-a wherein Y = NHC (O) or NHC (S), respectively, at room or high temperature in an inert solvent.
[104] In addition, compounds wherein Y = C (O) may be used as a coupling agent in a solvent such as N, N-dimethylformamide or dichloromethane such as O- (benzotriazol-1-yl) -N, N, N ', N '-Tetramethyluronium tetrafluoroborate (TBTU), O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) Or by using a carboxylic acid of formula XVIII-b at room or high temperature using bromotripyrrolodinophosphonium hexafluorophosphate (PyBrOP) and a tertiary base such as N, N-diisopropylethylamine have.
[105] Compounds of formula (Ibc), each of W = R ⁸ , R ⁹ N or R ⁸ O, can be synthesized by reacting a compound of formula (XVII) with an acid chloride of formula (XIX) using standard conditions.
[106]
[107] Alternatively, compounds of formula (Ibc) are prepared from derivatives of formula (XVII) and acid chlorides of formula (XIX, wherein W = OEt), followed by base mediated (eg, NaOH) saponification reactions, and then coupling agents such as TBTU, HATU described above. Or a condensation reaction of the free carboxylic acid with an amine of the formula R ⁸ , R ⁹ NH or an alcohol of the formula R ⁸ OH in the presence of PyBrOP and a tertiary base such as N, N-diisopropylethylamine.
[108] Compounds of formula Ide, wherein V is R ⁸ , R ⁹ N or R ⁸ O, respectively, are halogens, such as amines of formula R ⁸ , R ⁹ NH or alcohols of formula R ⁸ OH, in the compounds of formula XXI, such as Obtained by the nucleophilic substitution reaction of Br. In addition, the essential tetrahydroquinolines of formula XXI can be synthesized from the compounds of formula XVII and bromoacylchloride of formula XX using known synthetic procedures.
[109]
[110] Compounds of the formula Ifg, wherein U is (substituted) heteroaromatic or (substituted) phenyl, respectively, may be prepared by reacting the (substituted) iodobenzoyl derivative of formula XXII by suzuki coupling with boronic acid of formula XXIII-ab. Can be generated.
[111]
[112] In a typical experiment, a compound of formula XXII was added under a nitrogen atmosphere at high temperature using a cesium fluoride and a palladium catalyst such as palladium tetrakistriphenylphosphine or tris (dibenzylideneacetone) dipalladium in a solvent mixture such as dimethoxyethane / ethanol. Iodide is reacted with boronic acid of formula XXIII-ab. Triphenylphosphine can be added to promote the reaction and improve yield. The above reactions are described in the literature. References [A. Suzuki, Acc. Chem. Res . 15: 178, 1982; N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh and A. Suzuki, J. Am. Chem. Soc . 111: 314, 1989.
[113] Likewise, compounds of formula (I-h), wherein X is NH and Y is as defined above, can be synthesized in the same manner as described for compounds of formula (Ia-g) wherein X is O.
[114] Ih
[115] Compounds of formula Iij, wherein X is C (O) or S (O) ₂ and Y is NH or O, are corresponding acyl or sulfides of formula XXV in the same manner as defined above for the preparation of compounds of formula Ia. Phenyl chloride can be obtained by reaction with an amine of formula R ⁶ NH ₂ or an alcohol of formula R ⁶ OH.
[116]
[117] Essential acyl or sulfonyl chlorides of formula XXV are treated with, for example, POCl ₃ , PCl ₅ , oxalylchloride, phosgene or SOCl _{2 in} a solvent such as toluene, acetonitrile or N, N-dimethylformamide as described in the literature. Can be produced from the corresponding compounds of formula (XXIV). M. Bonnat, M. Bradley and JD Kilburn, Tetrahedron Lett . 37: 5409, 1996; JG Montana, GM Buckley, N. Cooper, HJ Dyke and L. Gowers, Bioorg. Med. Chem. Lett , 8: 2635, 1998; J. Hayler, PD Kane, D. LeGrand, F. Lugrin, K. Menear, R. Price, M. Allen, X. Cockcroft, J. Ambler, K. Butler and K. Durren, Bioorg. Med. Chem. Lett . 10: 1567, 2000].
[118] Alternatively, compounds of formula XXIV, wherein X is C (O), can be used directly as starting materials for the preparation of derivatives of formula I-i-j using coupling agents as defined above.
[119] For compounds of the formula Ikp, wherein X is C (O) or S (O) ₂ , Y is NH or O and n is 1 to 4, a known synthesis technique can be used as follows.
[120]
[121] Thus, the preparation of tetrahydroquinoline of formula (I-k-l) can be carried out by condensing the corresponding amine or alcohol of formula (XXVI), wherein Y is NH or O, respectively, with chloride of formula (XXV) using standard methods. In a similar manner, amines or alcohols of formula XXVII can be used to produce compounds of formula I-m-n. Finally, the compound of formula (I-o-p) is prepared by the Suzuki coupling reaction described above using boronic acid of formula (XXIII).
[122] Compounds of the invention wherein X-Y of formula I-q are a bond may also be prepared directly from the aniline of formula XXVIII, which is commercially available or easy to prepare by the Skraup reaction sequence, acylation and Friedel-Crafts alkylation.
[123]
[124] In another method, the compound of formula Ir wherein XY is a bond and U is a (substituted) heteroaromatic or (substituted) phenyl may be substituted with the corresponding 6-iodo tetrahydroquinoline derivative of Formula XXIX as defined above. It can be produced by condensation reaction of Suzuki with boronic acid.
[125]
[126] Essential iodides of formula (XXIX) can be obtained from the corresponding amines by known Sandmeijer reactions.
[127] Certain compounds of the present invention may exist in the form of a free base, which may be separated from the reaction mixture in the form of a pharmaceutically acceptable salt. In addition, pharmaceutically acceptable salts may be formulated with a free base of formula (I) as an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid. It can be obtained by treating with tartaric acid, citric acid, benzoic acid and ascorbic acid.
[128] The compounds of the present invention comprise at least one chiral carbon atom and can thus be obtained as pure enantiomers or as a mixture of enantiomers or as mixtures of diastereomers. Methods for obtaining pure enantiomers are well known in the art, for example, crystallization of salts from optically active acids and racemic mixtures, or chromatography using chiral columns. In the case of diastereomers, linear or reversed phase columns can be used.
[129] The compounds of the present invention may form hydrates or solvates. Those skilled in the art are aware that charged compounds upon lyophilization with water can form hydrated species or can be solvated species when concentrated in solution using a suitable organic solvent. Compounds of the present invention may include hydrates or solvates of the compounds presented.
[130] For the selection of active compounds, tests at 10 ^-5 M yield at least 20% of the maximum activity when FSH is used as reference. Another criterion is that the EC ₅₀ value should be <10 ⁻⁵ M, preferably <10 ⁻⁷ M.
[131] Those skilled in the art will appreciate that the preferred EC ₅₀ value depends on the compound tested. For example, compounds having an EC ₅₀ of less than 10 ⁻⁵ M are generally considered as candidates for drug selection. This value is preferably less than 10 ⁻⁷ M. However, compounds with high EC ₅₀ values but selectivity for particular receptors may be better candidates.
[132] In vitro and in vivo experimental assays for determining the biological activity of gonadotropin, as well as methods for measuring receptor binding capacity, are well known. In general, the expressed receptor is contacted with the compound to be tested and the binding or stimulation or inhibition of the functional response is measured.
[133] To measure the functional response, isolated DNA encoding the FSH receptor gene, preferably the human receptor, is expressed in an appropriate host cell. Such cells can be Chinese hamster ovary cells, but other cells are also suitable. The cell is preferably of mammalian origin. Jia et al, Mol. Endocrin. , 5: 759-776, 1991].
[134] Methods for constructing recombinant FSH expressing cell lines are well known in Sambrook et al., Molecular Cloning: a Laboratory Manual , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, final. Expression of the receptor is obtained by the expression of DNA encoding a given protein. Site-directed mutations, ligation of additional sequences, PCR and construction of appropriate expression systems are all well known in the art. Some or all of the DNA encoding a given protein can be constructed synthetically using standard solid phase techniques to include restriction sites, preferably to facilitate ligation. Control components suitable for transcription and translation of the included coding sequence can be provided to the DNA coding sequence. As is well known, expression systems can be used that are compatible with a wide variety of hosts including prokaryotic hosts such as bacteria and eukaryotic cells such as yeast, plant cells, insect cells, mammalian cells, algal cells and the like.
[135] Cells expressing the receptor are contacted with the test compound to observe binding or stimulation or inhibition of the functional response.
[136] Alternatively, isolated cell membranes containing expressed receptors can be used to measure binding of the compounds.
[137] To measure the binding force, radiolabeled or fluorescently labeled compounds can be used. As a reference compound, human recombinant FSH can be used. In addition, competitive binding force analysis can be performed.
[138] Another assay involves screening for FSH receptor agonist compounds by measuring stimulation of receptor mediated cAMP accumulation. Thus, such methods include expression of receptors on the cell surface of host cells and exposure of cells to test compounds. Thereafter, the content of cAMP is measured. The level of cAMP is reduced or increased depending on the inhibitory or stimulatory effect of the test compound upon binding to the receptor.
[139] In addition to measuring measurements such as cAMP levels in exposed cells, besides transfection with receptor encoding DNA, cell lines transfected with a second DNA encoding the reporter gene can be used, the expression of which responds to the level of cAMP. . Such reporter genes may be cAMP inducible or may be constructed in a manner that binds to novel cAMP reactive components. In general, reporter gene expression can be controlled by any response component that responds to varying cAMP levels. Examples of suitable reporter genes include LacZ, alkaline phosphatase, firefly luciferase and green fluorescent proteins. The principle of such transactivation assays is well known in the art and described in Stratowa, Ch., Himmler, A. and Czernilofsky, AP, (1995) Curr. Opin. Biotechnol . 6: 574.
[140] The present invention relates to a pharmaceutical composition comprising a tetrahydroquinoline derivative of formula (I) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant and optionally with other therapeutic agents. Such adjuvants must be "acceptable" in that they must be compatible with the other ingredients in the composition and not deleterious to their receptors. In addition, the pharmaceutical composition is tetrahydroquinoline derivatives 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-ethylcarbonyl-6 -Amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-6-benzoylamino-4- (4-methylphenyl) -1,2,3, 4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-6-amino-4- (4-aminophenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline , 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline, 1-acetyl-4-phenyl-1,2,3,4-tetrahydro -2,2,4,6,8-pentamethylquinoline and 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline and the like can do.
[141] The compositions include, for example, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, topical or rectal administration, all in the form of unit dosage forms for administration.
[142] For oral administration, the active ingredient may be presented as discrete units such as tablets, capsules, powders, granules, solutions, suspensions and the like.
[143] For parenteral administration, the pharmaceutical compositions of the present invention may be presented as a predetermined amount of injection solution in unit dose or multiple dose containers such as, for example, sealed vials and ampoules, and may also be used as a sterile carrier such as water prior to use. It may be stored in a lyophilized state requiring only addition.
[144] The pharmaceutically acceptable adjuvant as described, for example, in the standard literature by Gennaro, AR et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, Part 5: Pharmaceutical Manufacturing). Active agents in admixture with may be compressed into solid dosage units such as pills, tablets or processed into capsules or suppositories. By pharmaceutically acceptable solution, the active agent may be administered as a fluid composition, such as injectable preparations, in the form of solutions, suspensions, emulsions, or as a spray, such as a nasal spray.
[145] In the case of solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like can be considered. In general, any pharmaceutically acceptable additive may be used that does not interfere with the function of the active compound. Examples of suitable carriers to which the active agents of the present invention can be administered as solid compositions include lactose, starch, cellulose derivatives, and the like, or mixtures thereof, used in appropriate amounts. For parenteral administration, pharmaceutically acceptable dispersants and / or wetting agents can be used, for example, aqueous suspensions including propylene glycol or butylene glycol, isotonic saline solutions, sterile injectable solutions.
[146] In addition, the present invention includes pharmaceutical compositions as described above in combination with suitable packaging materials for such compositions, which packaging instructions include instructions for the use of the composition for use as described above.
[147] In addition, the tetrahydroquinoline derivatives of the present invention may be administered in the form of implantable pharmaceutical devices consisting of a core of active substance packaged in a release rate controlling membrane. Such implants are applied subcutaneously or topically, which will release the active material at a relatively constant rate over a relatively long period of time, for example weeks or years. Methods for the preparation of such implantable pharmaceutical devices are known in the art and are described, for example, in EP 0,303,306 (Akzo Nobel V.).
[148] The exact dosage of the administration of the active ingredient or pharmaceutical composition thereof and the regimen depends on the therapeutic effect to be achieved (fertility treatment; contraception), which depends on the particular compound, route of administration, and age of the individual subject to which the drug is to be administered. And state.
[149] In general, parenteral administration requires smaller dosages than other methods of administration, which are more dependent on absorption. However, in the case of human, it is preferable that the dosage contains 0.0001-25 mg per kg of body weight. A given dose may be presented as a single dose or as a plurality of subdoses to be administered at appropriate intervals per day, or for female subjects, to be administered at appropriate intervals of one day throughout the menstrual cycle. It may be presented in a dosage. Dosage and administration regimen may vary depending on female and male receptors.
[150] Therefore, the compounds according to the invention can be used for treatment.
[151] A further embodiment of the present invention is a tetramer of formula I for the preparation of a medicament for It relates to the use of hydroquinoline derivative compounds. The compounds according to the invention can also be used for the treatment of hormone dependent diseases such as breast cancer, prostate cancer and endometriosis.
[152] The invention is illustrated by the following examples.
[153] Example
[154] Example 1
[155] 1-acetyl-6- (t-butoxycarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[156] (a). 6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2,4-trimethylquinoline
[157] A mixture of N-Boc-1,4-phenylenediamine (5.0 g) and iodine (1.3 g) in mesityl oxide (25 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed with heptane / dichloromethane = 8/2 as eluent on Al ₂ O ₃ (Alumina B, act. III).
[158] Yield: 2.9 g. MS-ESI: [M + H] ⁺ = 289.2
[159] (b). 1-acetyl-6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2,4-trimethylquinoline
[160] Acetyl chloride (11.1 mL) and acetic anhydride (11.1 mL) were added to 6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2, in pyridine (22 mL) and dichloromethane (212 mL). To the solution of 4-trimethylquinoline (8.5 g) was added dropwise. After stirring for 18 hours, the reaction mixture was washed with 2M HCl and water. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 8/2 (v / v) as eluent.
[161] Yield: 6.7 g. MS-ESI: [M + H] ⁺ = 331.2
[162] (c). 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[163] A mixture of 1-acetyl-6- (t-butoxycarbonyl) amino-2,2,4-trimethyl-1,2-dihydroquinoline (2.4 g) and AlCl ₃ (9.5 g) in benzene (150 mL) Was stirred at 70 ° C. for 1 h. The reaction mixture was cooled (0 ° C.), the reaction was terminated with water and further 2 M NaOH solution was added. The organic phase was separated, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 8/2 (v / v) as eluent.
[164] Yield: 1.6 g. MS-ESI: [M + H] ⁺ = 309.2
[165] (d). 1-acetyl-6- (t-butoxycarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[166] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) in tetrahydrofuran (4 mL), (Boc) ₂ O ( 30 mg) and N, N-diisopropylethylamine (20 μl) were stirred at 60 ° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using dichloromethane / methanol = 1/0 → 95/5 (v / v) as eluent.
[167] Yield: 8 mg. MS-ESI: [M + H] ⁺ = 409.2
[168] Example 2
[169] 6-amino-1-butyryl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[170] (a). 6- (t-butoxycarbonyl) amino-1-butyryl-1,2-dihydro-2,2,4-trimethylquinoline
[171] Butyryl chloride (185 μl) was added 6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2,4-trimethylquinoline (50 mg) in pyridine (4 mL) and a catalytic amount of N, To the solution of N-dimethylaminopyridine was added dropwise. After stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 7/3 (v / v) as eluent.
[172] Yield: 47 mg. MS-ESI: [M + H] ⁺ = 359.4
[173] (b). 6-amino-1-butyryl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[174] Of 1-butyryl-6- (t-butoxycarbonyl) amino-2,2,4-trimethyl-1,2-dihydroquinoline (47 mg) and AlCl ₃ (52 mg) in benzene (2 mL) The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was cooled (0 ° C.), the reaction was terminated with water and further a solution of 2 M NaOH was added. The organic phase was separated, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC.
[175] Yield: 10 mg. MS-ESI: [M + H] ⁺ = 337.2; HPLC: Rt = 6.97 min. (Method 1)
[176] Example 3
[177] 1-acetyl-6-amino-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[178] Of 1-acetyl-6- (t-butoxycarbonyl) amino-2,2,4-trimethyl-1,2-dihydroquinoline (25 mg) and AlCl ₃ (35 mg) in chlorobenzene (2 mL) The mixture was stirred for 1 hour. Water was used to terminate the reaction of the reaction mixture and additionally a solution of 2 M NaOH and ethyl acetate was added. The organic phase was separated, dried over MgSO ₄ and concentrated in vacuo.
[179] Yield: 20 mg. MS-ESI: [M + H] ⁺ = 343.4; HPLC: Rt = 6.16 min. (Method 1)
[180] Example 4
[181] 1-acetyl-6-amino-4- (4-fluorophenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[182] In the presence of AlCl ₃ (35 mg) fluorobenzene (2 mL) was added 1-acetyl-6- (t-butoxycarbonyl) amino-2,2,4-trimethyl-1,2-dihydroquinoline (25 Mg), and the Friedel-Crafts alkylation reaction was carried out by the method described in Example 3.
[183] Yield: 15 mg. MS-ESI: [M + H] ⁺ = 327.4; HPLC: Rt = 5.63 min. (Method 1)
[184] Example 5
[185] 1-acetyl-6-amino-1,2,3,4-tetrahydro-4- (4-tolyl) -2,2,4-trimethylquinoline
[186] Toluene (2 mL) was added 1-acetyl-6- (t-butoxycarbonyl) amino-2,2,4-trimethyl-1,2-dihydroquinoline (25 mg) in the presence of AlCl ₃ (35 mg). Friedel-Crafts alkylation was carried out by the method described in Example 3.
[187] Yield: 22 mg. MS-ESI: [M + H] ⁺ = 323.2
[188] Example 6
[189] 1-acetyl-6- (4-chlorobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[190] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) in tetrahydrofuran (1 mL), 4-chlorobenzoyl chloride ( 11 mg) and N, N-diisopropylethylamine (22 μl) were stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 0.5 HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[191] Yield: 9.5 mg. MS-ESI: [M + H] ⁺ = 447.4; HPLC: Rt = 10.87 min. (Method 1)
[192] Example 7
[193] 1-acetyl-6-benzoylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[194] 1-acetyl-6-amino-4-phenyl-1,2,3,4- with benzoyl chloride (9.1 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[195] Yield: 1.2 mg. MS-ESI: [M + H] ⁺ = 413.4; HPLC: Rt = 10.01 min. (Method 1)
[196] Example 8
[197] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-6- (4- [trifluoromethyl] benzoyl) amino-2,2,4-trimethylquinoline
[198] 1-acetyl-6-amino-4-phenyl-1, using 4-trifluoromethylbenzoyl chloride (14 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL), The acylation reaction of 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[199] Yield: 8.9 mg. MS-ESI: [M + H] ⁺ = 481.4; HPLC: Rt = 10.76 min. (Method 1)
[200] Example 9
[201] 1-acetyl-6- (4-nitrobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[202] 1-acetyl-6-amino-4-phenyl-1,2,3 using 4-nitrobenzoyl chloride (12 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[203] Yield: 8.2 mg. MS-ESI: [M + H] ⁺ = 458.4; HPLC: Rt = 10.02 min. (Method 1)
[204] Example 10
[205] 1-acetyl-4-phenyl-6- (4-n-propylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[206] 1-acetyl-6-amino-4-phenyl-1,2 using 4-n-propylbenzoyl chloride (12 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[207] Yield: 6.7 mg. MS-ESI: [M + H] ⁺ = 455.4; HPLC: Rt = 11.19 min. (Method 1)
[208] Example 11
[209] 1-acetyl-6- (3-bromo-2,6-dimethoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[210] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 3-bromo-2, in dichloromethane (4 mL), 6-dimethoxybenzoic acid (23 mg), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (68 mg) And a mixture of N, N-diisopropylethylamine (32 μl) was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, which was washed with 0.5 M HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[211] Yield: 28 mg. MS-ESI: [M + H] ⁺ = 551.4; HPLC: Rt = 3.75 min. (Method 2)
[212] Example 12
[213] 1-acetyl-4-phenyl-6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[214] 1-acetyl-6-amino-4-phenyl-1,2 using 4-biphenylcarbonyl chloride (16 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 3,4-tetrahydro-2,2,4-trimethylquinoline (11 mg) was carried out by the method described in Example 6.
[215] Yield: 1.0 mg. MS-ESI: [M + H] ⁺ = 489.4; HPLC: Rt = 11.62 min. (Method 1)
[216] Example 13
[217] 1-acetyl-6- (4- [4-chlorophenyl] benzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[218] (a). 1-acetyl-6- (4-iodobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[219] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (300 mg) in 4-pyridine (4 mL), 4-iodobenzoyl chloride (520 Mg) and a mixture of catalytic amounts of N, N-dimethylaminopyridine were stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo.
[220] Yield: 460 mg. MS-ESI: [M + H] ⁺ = 539.4; HPLC: Rt = 10.98 min. (Method 1)
[221] (b). 1-acetyl-6- (4- [4-chlorophenyl] benzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[222] 1-acetyl-6- (4-iodobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethyl in dimethoxyethane / ethanol 4: 1 (5 mL) Of quinoline (25 mg), 4-chlorobenzeneboronic acid (22 mg), cesium fluoride (14 mg), triphenylphosphine (5.0 mg) and tris (dibenzylideneacetone) dipalladium (0) (4.3 mg) The mixture was stirred for 15 minutes while bubbling nitrogen into the solution. After 3 h at 80 ° C., the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[223] Yield: 16 mg. MS-ESI: [M + H] ⁺ = 523.4; HPLC: Rt = 4.40 min. (Method 2)
[224] Example 14
[225] 1-acetyl-4-phenyl-6- (4- [3-pyridyl] benzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[226] 1-acetyl-6- (4-iodobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2 in dimethoxyethane / ethanol 4: 1 (v / v) (5 mL), 2,4-trimethylquinoline (25 mg), pyridine-3-boronic acid-1,3-propanediol cyclic ester (23 mg), cesium fluoride (14 mg), triphenylphosphine (5.0 mg) and tris ( Suzuki cross coupling reaction of dibenzylideneacetone) dipalladium (0) (4.3 mg) was carried out by the method described in Example 13.
[227] Yield: 17 mg. MS-ESI: [M + H] ⁺ = 490.4; HPLC: Rt = 7.11 min. (Method 1)
[228] Example 15
[229] 1-acetyl-4-phenyl-6- (2-phenyl-5-methoxybenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[230] (a). 1-acetyl-6- (2-bromo-5-methoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[231] 1-acetyl-6 with 2-bromo-5-methoxybenzoic acid (21 mg) in the presence of HATU (68 mg) and N, N-diisopropylethylamine (32 μl) in dichloromethane (4 mL) The condensation reaction of -amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) was carried out by the method described in Example 11.
[232] Yield: 31 mg. MS-ESI: [M + H] ⁺ = 521.4; HPLC: Rt = 3.74 min. (Method 2)
[233] (b). 1-acetyl-4-phenyl-6- (2-phenyl-5-methoxybenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[234] 1-acetyl-4-phenyl-6- (2-bromo-5-methoxybenzoyl) amino-1,2,3,4- in dimethoxyethane / ethanol 4: 1 (v / v) (5 mL) Tetrahydro-2,2,4-trimethylquinoline (30 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg), triphenylphosphine (7.0 mg) and tris (dibenzylideneacetone) dipalladium ( 0) (6.0 mg) of Suzuki cross coupling reaction was carried out by the method described in Example 13.
[235] Yield: 23 mg. MS-ESI: [M + H] ⁺ = 519.4; HPLC: Rt = 10.87 min. (Method 1)
[236] Example 16
[237] 1-acetyl-4-phenyl-6- (2-phenyl-3-methylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[238] (a). 1-acetyl-4-phenyl-6- (2-bromo-3-methylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[239] 1-acetyl-6- with 2-bromo-3-methylbenzoic acid (19 mg) in the presence of HATU (68 mg) and N, N-diisopropylethylamine (32 μl) in dichloromethane (4 mL). Condensation reaction of amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) was carried out by the method described in Example 11.
[240] Yield: 16.3 mg. MS ESI: [M + H] ⁺ = 505.2; HPLC: Rt = 3.80 min. (Method 2)
[241] (b). 1-acetyl-4-phenyl-6- (2-phenyl-3-methylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[242] 1-acetyl-4-phenyl-6- (2-bromo-3-methylbenzoyl) amino-1,2,3,4-tetra in dimethoxyethane / ethanol 4: 1 (v / v) (5 mL) Hydro-2,2,4-trimethylquinoline (16 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg), triphenylphosphine (7.0 mg) and tris (dibenzylideneacetone) dipalladium (0 ) (6.0 mg) of Suzuki cross coupling reaction was carried out by the method described in Example 13.
[243] Yield: 4.9 mg. MS-ESI: [M + H] ⁺ = 503.3; HPLC: Rt = 4.61 min (Method 2)
[244] Example 17
[245] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-6- (α-toluenesulfonyl) amino-2,2,4-trimethylquinoline
[246] 1-acetyl-6-amino-4-phenyl-1,2 using α-toluenesulfonyl chloride (12 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (25 mL) The sulfonylation reaction of, 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the acylation method described in Example 6.
[247] Yield: 9.8 mg. MS-ESI: [M + H] ⁺ = 463.4; HPLC: Rt = 9.49 min. (Method 1)
[248] Example 18
[249] 1-acetyl-4-phenyl-6- (phenylaminocarbonyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[250] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), phenyl isocyanate (8.0 mg) in tetrahydrofuran (1 mL) And a mixture of N, N-diisopropylethylamine (22 μl) for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[251] Yield: 3.8 mg. MS-ESI: [M + H] ⁺ = 428.4; HPLC: Rt = 10.39 min. (Method 1)
[252] Example 19
[253] 1-acetyl-6- (t-butylaminothiocarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[254] 1-acetyl-6-amino-4-phenyl-1,2 using t-butyl isothiocyanate (7.5 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) Thiourea formation of, 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was performed by the method described in Example 18.
[255] Yield: 0.50 mg. MS-ESI: [M + H] ⁺ = 424.4; HPLC: Rt = 5.90 min. (Method 1)
[256] Example 20
[257] 1-acetyl-6- (4-t-butylbenzyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinolinetrifluoroacetic acid
[258] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4- (t-butyl in tetrahydrofuran (1 mL) A mixture of benzylchloride (6.5 mg) and N, N-diisopropylethylamine (10 μl) was stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 0.5 HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[259] Yield: 3.1 mg. MS-ESI: [M + H] ⁺ = 455.4; HPLC: Rt = 10.00 min. (Method 1)
[260] Example 21
[261] 1-acetyl-4-phenyl-6- (3-phenylpropionyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[262] 1-acetyl-6-amino-4-phenyl-1,2, using 3-phenylpropionyl chloride (11 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL), An acylation reaction of 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[263] Yield: 1.2 mg. MS-ESI: [M + H] ⁺ = 441.4; HPLC: Rt = 10.25 min. (Method 1)
[264] Example 22
[265] 1-acetyl-6- (2-furoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[266] 1-acetyl-6-amino-4-phenyl-1,2,3 using 2-furoyl chloride (8.5 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[267] Yield: 7.7 mg. MS-ESI: [M + H] ⁺ = 403.4; HPLC: Rt = 8.91 min. (Method 1)
[268] Example 23
[269] 1-acetyl-6- (isovaleryl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[270] 1-acetyl-6-amino-4-phenyl-1,2,3, using isovaleryl chloride (7.8 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) The acylation reaction of 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[271] Yield: 5.3 mg. MS-ESI: [M + H] ⁺ = 393.4; HPLC: Rt = 9.35 min. (Method 1)
[272] Example 24
[273] 1-acetyl-6- (3- [adamantan-1-yl] propionyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[274] 1-acetyl with 3- (adamantan-1-yl) propionic acid (10 mg) in the presence of HATU (25 mg) and N, N-diisopropylethylamine (22 μl) in dichloromethane (1 mL) The condensation reaction of -6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[275] Yield: 6.7 mg. MS-ESI: [M + H] ⁺ = 499.4; HPLC: Rt = 12.43 min. (Method 1)
[276] Example 25
[277] 1-acetyl-6- (ethylmalonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[278] 1-acetyl-6-amino-4-phenyl-1,2,3, using ethylmalonyl chloride (147 mg) and N, N-diisopropylethylamine (314 μl) in tetrahydrofuran (8 mL), The acylation reaction of 4-tetrahydro-2,2,4-trimethylquinoline (150 mg) was carried out by the method described in Example 6.
[279] Yield: 163 mg. MS-ESI: [M + H] ⁺ = 423.2; HPLC: Rt = 8.48 min. (Method 1)
[280] Example 26
[281] 1-acetyl-6-([4-methoxybenzylamino] carbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[282] (a). 1-acetyl-6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[283] 1-acetyl-6- (ethylmalonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4 in dioxane / water 4: 1 (v / v) (12 mL) To a stirred solution of trimethylquinoline (161 mg) was added dropwise 2 M NaOH solution until the pH was 14. After stirring for 3.5 hours, the reaction mixture was poured into water, which was extracted at pH 2 with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo.
[284] Yield: 163 mg. MS-ESI: [M + H] ⁺ = 395.2; HPLC: Rt = 7.43 min. (Method 1)
[285] (b). 1-acetyl-6-([4-methoxybenzylamino] carbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[286] 1-acetyl-6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl in the presence of HATU (19 mg) and N, N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 mL) Condensation reaction of 4-methoxybenzylamine (5.2 mg) using -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11. .
[287] Yield: 7.3 mg. MS-ESI: [M + H] ⁺ = 514.4; HPLC: Rt = 8.80 min. (Method 1)
[288] Example 27
[289] 1-acetyl-6-([ethoxycarbonylmethylamino] carbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[290] 1-acetyl-6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl in the presence of HATU (19 mg) and N, N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 mL) The condensation reaction of glycine ethyl ester.HCl (5.3 mg) using -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[291] Yield: 4.6 mg. MS-ESI: [M + H] ⁺ = 480.6; HPLC: Rt = 7.94 min. (Method 1)
[292] Example 28
[293] 1-acetyl-6-([N-ethyl-N-benzylamino] carbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[294] 1-acetyl-6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl in the presence of HATU (19 mg) and N, N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 mL) Condensation reaction of N-ethylbenzylamine (5.2 mg) with -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[295] Yield: 7.3 mg. MS-ESI: [M + H] ⁺ = 512.6; HPLC: Rt = 9.36 min. (Method 1)
[296] Example 29
[297] 1-acetyl-6-([2,4-difluorobenzylamino] methylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[298] (a). 1-acetyl-6- (bromoacetyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[299] 1-acetyl-6-amino-4-phenyl-1,2,3,4 using bromoacetyl chloride (69 μl) and N, N-diisopropylethylamine (121 μl) in dichloromethane (10 mL) Acylation of tetrahydro-2,2,4-trimethylquinoline (130 mg) was carried out by the method described in Example 6.
[300] Yield: 151 mg. MS-ESI: [M + H] ⁺ = 431.2
[301] (b). 1-acetyl-6-([2,4-difluorobenzylamino] methylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[302] 1-acetyl-6- (bromoacetyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) in dioxane (2 mL), 2, A mixture of 4-difluorobenzylamine (6.0 mg) and N, N-diisopropylethylamine (10 μl) was stirred at 40 ° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel using dichloromethane / methanol = 1/0 → 95/5 (v / v) as eluent.
[303] Yield: 5.5 mg. MS-ESI: [M + H] ⁺ = 492.4; HPLC: Rt = 6.74 min. (Method 1)
[304] Example 30
[305] 1-acetyl-6-([4- {1-phenyl} piperazinyl] methylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[306] 1-acetyl-6- (bromoacetyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) in dioxane (2 mL) and N, N-alkylation reaction of 1-phenylpiperazine (7.0 μl) with N-diisopropylethylamine (10 μl) was carried out by the method described in Example 29.
[307] Yield: 8.4 mg. MS-ESI: [M + H] ⁺ = 511.4; HPLC: Rt = 7.01 min. (Method 1)
[308] Example 31
[309] 1-acetyl-6-([N-morpholino] methylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[310] 1-acetyl-6- (bromoacetyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) and N in dichloromethane (2 mL), N-alkylation of morpholine (4.0 μl) with N-diisopropylethylamine (9.0 μl) was carried out as described in Example 29.
[311] Yield: 10 mg. MS-ESI: [M + H] ⁺ = 436.4; HPLC: Rt = 5.64 min. (Method 1)
[312] Example 32
[313] 1-acetyl-6- (2-thiophenmethylamino) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[314] (a). 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester
[315] Skraup reaction of methyl 4-aminobenzoate (5.0 g) and iodine (1.7 g) in mesityl oxide (25 mL) was carried out by the method described in Example 1.
[316] Yield: 2.3 g. MS-ESI: [M + H] ⁺ = 232.2
[317] (b). 1-acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester
[318] A mixture of 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (2.3 g) and a catalytic amount of N, N-dimethylaminopyridine in acetic anhydride (60 mL) at 100 ° C Stir for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/1 → 1/9 (v / v) as eluent.
[319] Yield: 2.3 g.
[320] (c). 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester
[321] Friedel- of benzene (60 mL) using 1-acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (2.3 g) in the presence of AlCl ₃ (4.4 g) Crafts alkylation reaction was carried out by the method described in Example 3.
[322] Yield: 1.2 g. MS-ESI: [M + H] ⁺ = 352.4; HPLC: Rt = 9.72 min. (Method 1)
[323] (d). 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid
[324] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid in dioxane / water 4: 1 (v / v) (50 mL) To a stirred solution of methyl ester (1.2 g) was added dropwise 2 M NaOH solution until the pH reached 12. After stirring for 18 hours, the reaction mixture was poured into water and extracted at pH 2 with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo.
[325] Yield: 891 mg. MS-ESI: [M + H] ⁺ = 338.2
[326] (e). 1-acetyl-6- (2-thiophenmethylamino) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[327] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2, in the presence of HATU (23 mg) and N, N-diisopropylethylamine (19 μl) in dichloromethane (2 mL), Condensation reaction of 2-thiophenmethylamine (5.0 mg) using 2,4-trimethylquinoline-6-carboxylic acid (10 mg) was carried out by the method described in Example 11.
[328] Yield: 3.0 mg. MS-ESI: [M + H] ⁺ = 433.4; HPLC: Rt = 9.28 min. (Method 1)
[329] Example 33
[330] 1-acetyl-6- (2- [4-methoxyphenyl] ethylamino) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[331] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2, in the presence of HATU (23 mg) and N, N-diisopropylethylamine (19 μl) in dichloromethane (2 mL), Condensation reaction of 2- (4-methoxyphenyl) ethylamine (6.1 mg) with 2,4-trimethylquinoline-6-carboxylic acid (10 mg) was carried out by the method described in Example 11.
[332] Yield: 9.9 mg. MS-ESI: [M + H] ⁺ = 457.4; HPLC: Rt = 9.34 min. (Method 1)
[333] Example 34
[334] 1-acetyl-6- (3-isopropoxypropylamino) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[335] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2, in the presence of HATU (23 mg) and N, N-diisopropylethylamine (19 μl) in dichloromethane (2 mL), Condensation reaction of 3-isopropoxypropylamine (5.2 mg) using 2,4-trimethylquinoline-6-carboxylic acid (10 mg) was carried out by the method described in Example 11.
[336] Yield: 8.8 mg. MS-ESI: [M + H] ⁺ = 437.4; HPLC: Rt = 8.80 min. (Method 1)
[337] Example 35
[338] 1-acetyl-6- (2- [methylthio] ethylamino) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[339] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2, in the presence of HATU (23 mg) and N, N-diisopropylethylamine (19 μl) in dichloromethane (2 mL), Condensation reaction of 2- (methylthio) ethylamine (4.1 mg) with 2,4-trimethylquinoline-6-carboxylic acid (10 mg) was carried out by the method described in Example 11.
[340] Yield: 10 mg. MS-ESI: [M + H] ⁺ = 411.4; HPLC: Rt = 3.33 min. (Method 2)
[341] Example 36
[342] 1-acetyl-6- (4-methoxybenzyloxy) carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[343] 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2, in the presence of HATU (23 mg) and N, N-diisopropylethylamine (19 μl) in dichloromethane (2 mL), Condensation reaction of 4-methoxybenzyl alcohol (6.2 mg) using 2,4-trimethylquinoline-6-carboxylic acid (10 mg) was carried out by the method described in Example 11.
[344] Yield: 7.2 mg. MS-ESI: [M + H] ⁺ = 458.4; HPLC: Rt = 3.90 min. (Method 2)
[345] Example 37
[346] 1-acetyl-6- (4-phenylbenzoyl) oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[347] (a). 1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline
[348] Skraup reaction of 4-anisidine (5.0 g) and iodine (1.7 g) in mesityl oxide (25 mL) was carried out by the method described in Example 1.
[349] Yield: 2.3 g. MS-ESI: [M + H] ⁺ = 204.2
[350] (b). 1-acetyl-1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline
[351] Chloride in a cooled (0 ° C.) solution of 1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.7 g) and a catalytic amount of N, N-dimethylaminopyridine in pyridine (60 mL) Acetyl (8 mL) was added dropwise. After stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1 M HCl, water, 5% aqueous NaHCO ₃ , water and brine. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel with dichloromethane as eluent.
[352] Yield: 1.8 g. MS-ESI: [M + H] ⁺ = 246.2
[353] (c). 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[354] Fiedel-Crafts alkylation of benzene (25 mL) with 1-acetyl-1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.8 g) in the presence of AlCl ₃ (3.0 g) Was carried out by the method described in Example 3.
[355] Yield: 1.9 g. HPLC: Rt = 9.62 min. (Method 1)
[356] (d). 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[357] Cooled (0 ° C.) of 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.9 g) in dichloromethane (75 mL) Boron trifluoride (1.30 mL) was added dropwise to the solution. After stirring for 18 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, 5% aqueous NaHCO ₃ and water, dried (MgSO ₄ ) and concentrated in vacuo.
[358] Yield: 950 mg. MS-ESI: [M + H] ⁺ = 310.2; HPLC: Rt = 8.41 min. (Method 1)
[359] (e). 1-acetyl-4-phenyl-6- (4-phenylbenzoyl) oxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[360] 1-acetyl-6-hydroxy-4-phenyl-1, using 4-biphenylcarbonyl chloride (14 mg) and N, N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 mL), The acylation reaction of 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[361] Yield: 8.2 mg. MS-ESI: [M + H] ⁺ = 490.4; HPLC: Rt = 12.81 min. (Method 1)
[362] Example 38
[363] 1-acetyl-6- (t-butylacetyl) oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[364] 1-acetyl-6-hydroxy-4-phenyl-1,2, using t-butylacetyl chloride (9.0 μl) and N, N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 mL), An acylation reaction of 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[365] Yield: 3.9 mg. MS-ESI: [M + H] ⁺ = 408.4; HPLC: Rt = 11.28 min. (Method 1)
[366] Example 39
[367] 1-acetyl-6- (cyclopropylmethyl) oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[368] 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg), cesium carbonate (63 mg) in acetonitrile (1 mL) , A mixture of tetrabutylammonium bromide (29 mg) and chloromethylcyclopropane (8.4 μl) was stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 6/4 (v / v) as eluent.
[369] Yield: 10 mg. MS-ESI: [M + H] ⁺ = 364.2; HPLC: Rt = 10.73 min. (Method 1)
[370] Example 40
[371] 1-acetyl-6- (3-pyridylmethyl) oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[372] 1-acetyl-6-hydroxy-4-phenyl-1 using 3-picolylchloride.HCl (12 mg), cesium carbonate (63 mg) and tetrabutylammonium bromide (30 mg) in acetonitrile (1 mL) The alkylation reaction of, 2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) was carried out by the method described in Example 39.
[373] Yield: 10 mg. MS-ESI: [M + H] ⁺ = 401.2; HPLC: Rt = 8.40 min. (Method 1)
[374] Example 41
[375] 1-acetyl-6-ethyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[376] (a). 1,2-dihydro-6-ethyl-2,2,4-trimethylquinoline
[377] Skraup reaction of p-ethylaniline (1.0 g) and iodine (0.34 g) in mesityl oxide (5 mL) was carried out by the method described in Example 1.
[378] Yield: 800 mg. MS-ESI: [M + H] ⁺ = 202.2
[379] (b). 1-acetyl-6-ethyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[380] Acylation of 1,2-dihydro-6-ethyl-2,2,4-trimethylquinoline (800 mg) with acetyl chloride (3.5 mL) and pyridine in pyridine (25 mL) and catalytic amount of N, N-dimethylaminopyridine The reaction was carried out by the method described in Example 37.
[381] Yield: 410 mg. MS-ESI: [M + H] ⁺ = 244.2
[382] (c). 1-acetyl-6-ethyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[383] Friedel- of benzene (10 mL) with 1-acetyl-6-ethyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (410 mg) in the presence of AlCl ₃ (710 mg). Crafts alkylation reaction was carried out by the method described in Example 3.
[384] Yield: 407 mg. MS-ESI: [M + H] ⁺ = 322.4
[385] Example 42
[386] 1-acetyl-6- (1,1'-biphenyl) -4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[387] (a). 1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[388] Sodium nitrate solution (31 mg) was diluted with 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (128 mg) in water (2 mL) and To the cooled (0 ° C.) solution of sulfuric acid (82 mg) was added dropwise. After stirring for 15 min at 0 ° C., potassium iodide solution (105 mg) was added. After stirring for 18 hours, the reaction mixture was poured into dichloromethane. The organic phase was separated, washed with 5% aqueous sodium thiosulfate and water, dried (MgSO ₄ ) and concentrated in vacuo.
[389] Yield: 160 mg. MS-ESI: [M + H] ⁺ = 420.0
[390] (b). 1-acetyl-6- (1,1'-biphenyl-yl) -4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[391] 1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline in dimethoxyethane / ethanol 4: 1 (v / v) (5 mL) (20 mg), (1,1'-biphenyl-4-yl) boronic acid (28 mg), cesium fluoride (15 mg), triphenylphosphine (5 mg) and tris (dibenzylideneacetone) dipalladium (0) Suzuki cross coupling reaction of (4.5 mg) was carried out by the method described in Example 13.
[392] Yield: 16 mg. MS-ESI: [M + H] ⁺ = 446.4; HPLC: Rt = 6.84 min. (Method 2)
[393] Example 43
[394] 1-acetyl-6- (4-chlorophenyl) -4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[395] 1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline in dimethoxyethane / ethanol 4: 1 (v / v) (5 mL) Suzuki of (20 mg), 4-chlorophenylboronic acid (22 mg), cesium fluoride (15 mg), triphenylphosphine (5 mg) and tris (dibenzylideneacetone) dipalladium (0) (4.5 mg) Cross coupling reactions were carried out by the method described in Example 13.
[396] Yield: 8.6 mg. MS-ESI: [M + H] ⁺ = 404.4; HPLC: Rt = 5.94 min. (Method 2)
[397] Example 44
[398] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline
[399] (a). 1-acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline
[400] N-Boc-2-methyl-1,4-phenylenediamine (2.3 g), magnesium sulfate (6.3 g), 4-t-butylcatechol (100 mg) and iodine (300 mg) in acetone (15 mL) The mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and it was filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on SiO ₂ using heptane / ethyl acetate = 1/0 → 3/1 (v / v) as eluent. The product 6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2,4,7-tetramethylquinoline was converted to acetyl chloride in a mixture of pyridine (1.0 mL) and toluene (10 mL). (1.0 mL) was used to acylate. After stirring for 1 hour, the reaction mixture was washed with 3% aqueous citric acid and water. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 3/1 (v / v) as eluent.
[401] Yield: 350 mg. MS-ESI: [M + H] ⁺ = 345.4
[402] (b). 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline
[403] AlCl ₃ (266 mg) in a heated (70 ° C.) solution of 1-acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline (100 mg) in benzene (10 mL) ) Was added. After 3 hours, the mixture was cooled down and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 3/1 (v / v) as eluent.
[404] Yield: 75 mg. MS-ESI: [M + H] ⁺ = 323.4
[405] Example 45
[406] 1-acetyl-6- (4-phenylbenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline
[407] 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro- using 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 μl) in tetrahydrofuran (5 mL) The acylation reaction of 2,2,4,7-tetramethylquinoline (20 mg) was carried out by the method described in Example 6.
[408] Yield: 24 mg. MS-ESI: [M + H] ⁺ = 503.4
[409] Example 46
[410] 1-acetyl-6- (4-phenylbenzoyl) amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[411] (a). 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[412] N-Boc-3-methoxy-1,4-phenylenediamine (450 mg), magnesium sulfate (1.0 g), 4-t-butylcatechol (10 mg) and iodine (20 mg) in acetone (10 mL) Skraup reaction), acylation of the product with acetyl chloride (250 μL) and pyridine (250 μL) in toluene (10 mL), and Friedel-Crafts alkylation reaction with AlCl ₃ (266 mg) in Example 44. It was carried out by the method described.
[413] Yield: 71 mg. MS-ESI: [M + H] ⁺ = 339.4
[414] (b). 1-acetyl-6- (4-phenylbenzoyl) amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[415] 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3, using 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 μl) in tetrahydrofuran (5 mL), The acylation reaction of 4-tetrahydro-2,2,4-trimethylquinoline (20 mg) was carried out by the method described in Example 6.
[416] Yield: 25 mg. MS-ESI: [M + H] ⁺ = 519.4
[417] Example 47
[418] 1-acetyl-6- (2-furoyl) amino-1,2,3,4-tetrahydro-4-tolyl-2,2,4-trimethylquinoline
[419] 1-acetyl-6-amino-4-tolyl-1,2,3 using 2-furoyl chloride (8.1 mg) and N, N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[420] Yield: 12 mg. MS-ESI: [M + H] ⁺ = 417.4; HPLC: Rt = 4.90 min. (Method 2)
[421] Example 48
[422] 1-acetyl-6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-4-tolyl-2,2,4-trimethylquinoline
[423] 1-acetyl-6-amino-4-tolyl-1,2 using 4-biphenylcarbonyl chloride (14 mg) and N, N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 mL) The acylation reaction of, 3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[424] Yield: 9.3 mg. MS-ESI: [M + H] ⁺ = 503.4; HPLC: Rt = 6.08 min. (Method 2)
[425] Example 49
[426] 1-acetyl-6- (ethylmalonyl) amino-1,2,3,4-tetrahydro-4-tolyl-2,2,4-trimethylquinoline
[427] 1-acetyl-6-amino-4-tolyl-1,2,3, using ethylmalonyl chloride (9.4 mg) and N, N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 mL) The acylation reaction of 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[428] Yield: 12 mg. MS-ESI: [M + H] ⁺ = 437.4; HPLC: Rt = 4.71 min. (Method 2)
[429] Example 50
[430] 1-acetyl-6- (3,5-dibromobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[431] 1-acetyl-6-amino-4-phenyl-1, using 3,5-dibromobenzoic acid (10 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL), HATU condensation reaction of 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[432] Yield: 15.9 mg. MS-ESI: [M + H] ⁺ = 470.9; HPLC: Rt = 10.11 min. (Method 1)
[433] Example 51
[434] 1-acetyl-6- (5-bromo-2-methylaminobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[435] 1-acetyl-6-amino-4-phenyl- with 5-bromo-2-methylaminobenzoic acid (8.4 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of 1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[436] Yield: 13.2 mg. MS-ESI: [M + H] ⁺ = 522.1; HPLC: Rt = 8.95 min. (Method 1)
[437] Example 52
[438] 1-acetyl-6- (3,4,5-trimethoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[439] 1-acetyl-6-amino-4-phenyl using 3,4,5-trimethoxybenzoyl chloride (12 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) An acylation reaction of -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 6.
[440] Yield: 14.5 mg. MS-ESI: [M + H] ⁺ = 503.2; HPLC: Rt = 11.26 min. (Method 1)
[441] Example 53
[442] 1-acetyl-6- (3,5-dichloro-2,6-dimethoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[443] 1-acetyl-6-amino-4 using 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of -phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[444] Yield: 15.1 mg. MS-ESI: [M + H] ⁺ = 541.1; HPLC: Rt = 10.92 min. (Method 1)
[445] Example 54
[446] 1-acetyl-6- (2-acetyloxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[447] 1-acetyl-6-amino-4-phenyl-1,2,3 using 2-acetyloxybenzoic acid (6.0 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[448] Yield: 1.1 mg. MS-ESI: [M + H] ⁺ = 471.2; HPLC: R t = 14.35 min. (Method 1)
[449] Example 55
[450] 1-acetyl-6- (2-acetamido-5-bromobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[451] 1-acetyl-6-amino-4-phenyl using 2-acetamido-5-bromobenzoic acid (6.0 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[452] Yield: 2.3 mg. MS-ESI: [M + H] ⁺ = 530.2; HPLC: Rt = 12.01 min. (Method 1)
[453] Example 56
[454] 1-acetyl-6- (5-bromo-2-N, N-dimethylcarbamoylbenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[455] 1-acetyl-6-amino-4-phenyl-1,2,3 using 5-bromosalicylic acid (8.0 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[456] Yield: 3.0 mg. MS-ESI: [M + H] ⁺ = 580.2; HPLC: Rt = 12.53 min. (Method 1)
[457] Example 57
[458] 1-acetyl-6- (2- [4-tolyloxy] benzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[459] 1-acetyl-6-amino-4-phenyl-1 using 2- [4-tolyloxy] benzoic acid (8.0 mg) and N, N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of, 2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) was carried out by the method described in Example 11.
[460] Yield: 8.0 mg. MS-ESI: [M + H] ⁺ = 519.4; HPLC: R t = 13.11 min. (Method 1)
[461] Example 58
[462] 1-acetyl-6- (2-methylsulfonyloxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[463] (a). 1-acetyl-6- (2-methoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[464] 1-acetyl-6-amino-4-phenyl-1,2, using 2-methoxybenzoyl chloride (1.0 g) and N, N-diisopropylethylamine (1.7 mL) in tetrahydrofuran (60 mL), The acylation reaction of 3,4-tetrahydro-2,2,4-trimethylquinoline (0.60 g) was carried out by the method described in Example 6.
[465] Yield: 0.65 g. MS-ESI: [M + H] ⁺ = 443.4
[466] (b). 1-acetyl-6- (2-hydroxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[467] A solution of 1-acetyl-6- (2-methoxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.64 g) in dichloromethane (40 mL) To BBr ₃ (0.69 mL) was added dropwise. After stirring for 4 hours, TLC showed the reaction was complete. Water was added to the reaction mixture, which was kept stirring for 15 minutes. The mixture was washed with 5% aqueous NaHCO ₃ and water. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo. The product was used without further purification.
[468] Yield: 0.62 g. MS-ESI: [M + H] ⁺ = 429.4
[469] (c). 1-acetyl-6- (2-methylsulfonyloxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[470] 1-acetyl-6- (2-hydroxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline using methylsulfonyl chloride (6.5 μl) (12 Mg) sulfonylation reaction was carried out in pyridine (1 mL). TLC analysis after stirring for 16 hours showed that the product was converted to a highly fluid product. The mixture was concentrated and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by silica gel column chromatography. Eluent: heptane / ethyl acetate = 8/2 (v / v).
[471] Yield: 8.0 mg. MS-ESI: [M + H] ⁺ = 507.4; HPLC: Rt = 5.03 min. (Method 2)
[472] Example 59
[473] 1-acetyl-6- (2- [3,5-dimethylisoxazole-4-sulfonyl] oxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4- Trimethylquinoline
[474] 1-acetyl-6- (2-hydroxybenzoyl) amino-4-phenyl-1,2,3 using 3,5-dimethylisoxazole-4-sulfonyl chloride (27 mg) in pyridine (2 mL) The sulfonylation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (20 mg) was carried out by the method described in Example 58.
[475] Yield: 14 mg. MS-ESI: [M + H] ⁺ = 588.4; HPLC: Rt = 14.46 min. (Method 1)
[476] Example 60
[477] 1-acetyl-6- (2-methoxycarbonylethylcarbonyloxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[478] 1-acetyl-6- (2-hydroxybenzoyl) amino using 3-carbomethoxypropionyl chloride (14 mg) and N, N-diisopropylethylamine (40 μl) in tetrahydrofuran (2 mL) The acylation reaction of -4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) was carried out by the method described in Example 6.
[479] Yield: 21.4 mg. MS-ESI: [M + H] ⁺ = 543.6; HPLC: Rt = 6.98 min. (Method 1)
[480] Example 61
[481] 1-acetyl-6- (2- [5-methylisoxazole-3-carbonyl] oxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[482] 1-acetyl-6- (2-hydride) with 5-methylisoxazole-3-carbonyl chloride (10 mg) and N, N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 mL) The acylation reaction of oxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) was carried out by the method described in Example 6.
[483] Yield: 4.0 mg. MS-ESI: [M + H] ⁺ = 538.4; HPLC: Rt = 9.84 min. (Method 1)
[484] Example 62
[485] 1-acetyl-6- (2- [2-oxazolidinone-5-methyl] oxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[486] 1-acetyl-6- (2-hydroxy) with 5-chloromethyl-2-oxazolidinone (7 mg), cesium carbonate (63 mg) and tetrabutylammonium bromide (30 mg) in acetonitrile (1 mL) The alkylation reaction of benzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) was carried out by the method described in Example 39.
[487] Yield: 25 mg. MS-ESI: [M + H] ⁺ = 542.4; HPLC: Rt = 8.21 min. (Method 1)
[488] Example 63
[489] 1-acetyl-6- (2- [morpholino-4-carbonyl] oxybenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[490] 1-acetyl-6- (2-hydroxybenzoyl) using morpholino-4-carbonyl chloride (12 μl) and N, N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 mL) An acylation reaction of amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) was carried out by the method described in Example 6.
[491] Yield: 5.4 mg. MS-ESI: [M + H] ⁺ = 542.4; HPLC: Rt = 10.02 min. (Method 1)
[492] Example 64
[493] 1-acetyl-6- (2-phenylaminobenzoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[494] 1-acetyl-6-amino-4-phenyl-1,2,3 using N-phenylanthranilic acid (21 mg) and N, N-diisopropylethylamine (33 μl) in tetrahydrofuran (1 mL) HATU condensation reaction of, 4-tetrahydro-2,2,4-trimethylquinoline (15 mg) was carried out by the method described in Example 11.
[495] Yield: 5.8 mg. MS-ESI: [M + H] ⁺ = 504.4; HPLC: R t = 13.42 min. (Method 1)
[496] Example 65
[497] 1-acetyl-6- (2-pyrrolidone-N-ethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[498] (a). 1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[499] 1-acetyl-6-amino-4-phenyl-1,2,3, using acryloyl chloride (39 μl) and N, N-diisopropylethylamine (0.21 mL) in tetrahydrofuran (10 mL) The acylation reaction of 4-tetrahydro-2,2,4-trimethylquinoline (0.12 g) was carried out by the method described in Example 6.
[500] Yield: 0.13 g. MS-ESI: [M + H] ⁺ = 363.2
[501] (b). 1-acetyl-6- (2-pyrrolidone-N-ethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[502] To a mixture of 2-pyrrolidone (19 mg) and NaH (18 mg, 60% in oil) in THF (1 mL), 1-acetyl-6-acryloylamino-4-phenyl-1 in THF (1 mL) , 2,3,4-tetrahydro-2,2,4-trimethylquinoline (8 mg) was added. After stirring for 18 hours, TLC analysis showed a high flowability product. The mixture was diluted with ethyl acetate and washed with water, 0.5 N HCl and water. The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification was carried out by silica gel column chromatography using heptane / ethyl acetate = 8/2 → 1/1 (v / v) as eluent.
[503] Yield: 4.6 mg. MS-ESI: [M + H] ⁺ = 448.4; HPLC: Rt = 4.51 min. (Method 2)
[504] Example 66
[505] 1-acetyl-6- (ethoxyethoxyethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[506] 2-ethoxyethanol (19 mg) and 1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline in THF (1 mL) (8 mg) Michael addition reaction was carried out by the method described in Example 65.
[507] Yield: 1.0 mg. MS-ESI: [M + H] ⁺ = 453.4; HPLC: Rt = 5.03 min. (Method 2)
[508] Example 67
[509] 1-acetyl-6- (2-pyrrolidone-N-methoxycarbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[510] N-hydroxymethyl-2-pyrrolidone (22 mg) and 1-acetyl- in the presence of HATU (29 mg) and N, N-diisopropylethylamine (33 μl) in tetrahydrofuran (2 mL). Condensation reaction of 6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) in the method described in Example 11 Was performed by.
[511] Yield: 4.6 mg. MS-ESI: [M + H] ⁺ = 478.4; HPLC: Rt = 5.53 min. (Method 2)
[512] Example 68
[513] 1-acetyl-6- (t-butylcarbamoyl-N- [2-ethoxy] carbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4 -Trimethylquinoline
[514] T-butyl-N- (2-hydroxyethyl) carbamate (29 μl) in the presence of HATU (29 mg) and N, N-diisopropylethylamine (33 μl) in tetrahydrofuran (2 mL). And condensation reaction of 1-acetyl-6- (hydroxycarbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg). It carried out by the method described in Example 11.
[515] Yield: 11 mg. MS-ESI: [M + H] ⁺ = 538.4; HPLC: Rt = 5.32 min. (Method 2)
[516] Example 69
[517] 1-acetyl-6- (2-furylmethoxycarbonylmethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[518] Purfuryl alcohol (17 μl) and 1-acetyl-6- (hydroxycarbonylmethyl in the presence of HATU (29 mg) and N, N-diisopropylethylamine (33 μl) in tetrahydrofuran (2 mL) Condensation reaction of carbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) was carried out by the method described in Example 11.
[519] Yield: 7.1 mg. MS-ESI: [M + H] ⁺ = 475.4; HPLC: Rt = 5.30 min. (Method 2)
[520] Example 70
[521] 1-acetyl-6-([cyclopropylmethylaminomethylcarbonyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[522] 1-acetyl-6- (bromoacetyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) in dichloromethane (1 mL) and N, Alkylation of cyclopropylmethylamine (4 μl) with N-diisopropylethylamine (13 μl) was carried out as described in Example 29.
[523] Yield: 6.8 mg. MS-ESI: [M + H] ⁺ = 535.6; HPLC: Rt = 6.29 min. (Method 2)
[524] Example 71
[525] 1-acetyl-4- (2-methoxyphenyl) -6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[526] (a). 1-acetyl-6- (4-phenylbenzoyl) amino-1,2-dihydro-2,2,4-trimethylquinoline
[527] 1-acetyl-6- (t-butoxycarbonyl) amino-1,2-dihydro-2,2,4-trimethylquinoline (1.0 g) was converted to trifluoroacetic acid / CH ₂ Cl ₂ (1/1, v / v, 25 mL) and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with 5% aqueous NaHCO ₃ . The organic layer was separated, dried (MgSO ₄ ) and concentrated. The residue was dissolved in CH ₂ Cl ₂ (25 mL), N, N-diisopropylethylamine (5.2 mL) and 4-phenylbenzoyl chloride (2.0 g) were added and the mixture was stirred for 16 h. The mixture was concentrated and chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[528] Yield: 0.63 g. MS-ESI: [M + H] ⁺ = 411.2
[529] (b). 1-acetyl-4- (2-methoxyphenyl) -6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline and 1-acetyl-4- (4-methoxyphenyl) -6- (phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[530] Anisole (25 mL) using 1-acetyl-6- (4-phenylbenzoyl) amino-1,2-dihydro-2,2,4-trimethylquinoline (0.50 g) in the presence of AlCl ₃ (0.50 g) , Friedel-Crafts acylation reaction of the molecular sieve 3 Å) was carried out by the method described in Example 3. Purification of silica gel chromatography (eluent: heptane / ethyl acetate = 1/0 → 0/1, v, v) to 2-methoxyphenyl-substituted derivatives as small amounts of product and 4-methoxy as large amounts of product Phenyl-substituted derivatives were obtained.
[531] Yield: 46 mg. MS-ESI: [M + H] ⁺ = 518.0 (2-methoxyphenyl)
[532] Yield: 0.20 g. MS-ESI: [M + H] ⁺ = 518.1 (4-methoxyphenyl)
[533] Example 72
[534] 1-acetyl-4- (4-hydroxyphenyl) -6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[535] 1-acetyl-4- (4-methoxyphenyl) -6- (4-phenylbenzoyl) amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.46 in CH ₂ C1 ₂ To the cooled (0 ° C.) solution of g) was added BBr ₃ under a nitrogen atmosphere. The conversion reaction was complete after stirring at room temperature for 3 hours. The mixture was cooled and 1 M NaOH was added until a basic pH was obtained, then ethyl acetate was added and the mixture was made acidic with 1 M HCl. The organic layer was separated, dried (MgSO ₄ ) and concentrated. The residue was chromatographed on silica gel using heptane / ethyl acetate = 1/0 → 0/1 (v / v) as eluent.
[536] Yield: 0.13 g. MS-ESI: [M + H] ⁺ = 504.0
[537] Example 73
[538] 1-acetyl-6- (5-methylnicotinoyl) amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline
[539] 1-acetyl-6-amino-4-phenyl with 5-methyl nicotinic acid (0.13 g) in the presence of HATU (0.18 g) and N, N-diisopropylethylamine (0.28 mL) in dichloromethane (2 mL) The condensation reaction of -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.10 g) was carried out by the method described in Example 11.
[540] Yield: 0.12 g. MS-ESI: [M + H] ⁺ = 427.0
[541] Example 74
[542] CHO-FSH in vitro viability
[543] The FSH activity of the compounds was tested with Chinese hamster ovary (CHO) cells stably transfected with the human FSH receptor and cross-transfected with cAMP reactive component (CRE) / promoter to direct expression of the firefly luciferase reporter gene. Binding of the ligand to the Gs-coupled FSH receptor results in an increase in cAMP, which in turn results in increased transactivation of the luciferase reporter construct. Lucifera signal was quantified using a luminescence counter. For test compounds, the EC ₅₀ value [concentration of the test compound causing stimulation of half the maximum (50%)] was calculated. For this purpose, the software program GraphPad PRISM, version 3.0 (GraphPad Software Inc., San Diego, USA) was used.
[544] The compounds of all examples had an activity (EC ₅₀ ) of less than 10 ⁻⁵ M. Examples 1, 6-13, 15, 16, 21-24, 30, 36, 37, 45, 46, 48, 50-53, 55, 57, 58, 61, 63 and 64 have EC ₅₀ values. It was found to be less than 10 ⁻⁷ M.

权利要求:
Claims (9)
[1" claim-type="Currently amended] Tetrahydroquinoline derivative compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
Formula I

In the above formula,
R ¹ is formyl, (1-6C) alkylcarbonyl or (1-6C) alkylsulfonyl;
R ² and R ³ are H or (1-4C) alkyl;
R ⁴ is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, Phenyl which may be optionally substituted with one or more substituents selected from the group of (1-4C) (di) alkylamino;
R ⁵ is (1-4C) alkyl;
YX is C (O) -O, S (O) ₂ -O, NHC (O) -O, NHC (S) -O, OC (O) -O, Bond-O, C (O) -NH, S (O) ₂ -NH, NHC (O) -NH, NHC (S) -NH, OC (O) -NH, bond-NH, NH-C (O), OC (O), NH-S (O) ₂ or OS (O) ₂ or XY is a bond;
R ⁶ is H (unless YX is a bond), trifluoromethyl, (1-6C) alkyl, 1- or 2-adamantyl (1-4C) alkyl, (2-6C) alkenyl, (2 -6C) alkynyl, (3-9C) heteroaryl, (3-6C) cycloalkyl, (2-6C) heterocycloalkyl, (1-4C) alkylthio (1-4C) alkyl, (6-10C) Aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1-4C) alkyl , R ⁸ , R ⁹ -aminocarbonyl (1-4C) alkyl, R ⁸ , R ⁹ -amino (1-4C) alkyl, R ⁸ -oxycarbonyl (1-4C) alkyl, R ⁸ -oxy (1 -4C) alkyl, R ⁸ -carbonyl (1-4C) alkyl or (6-10C) aryl and (6-10C) aryl is phenyl, phenyl is hydroxy, amino, halogen, nitro, trifluoro Methyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino, (6-10C ) Aryl, (6-10C) aryloxy, (6-10C) aryl (1-4C) alkoxy, (3-9C) heteroaryl, (3-9C) heteroaryloxy, (3-9C) heteroaryl (1 -4C) alkoxy, (1-4C) alkylcar Carbonylamino, (1-4C) alkylcarbonyloxy, (3-6C) cycloalkylcarbonyloxy, (1-4C) alkoxycarbonyl (1-4C) alkylcarbonyloxy, (1-4C) alkoxy (1 -4C) alkylcarbonyloxy, (6-10C) arylcarbonyloxy, (3-9C) heteroarylcarbonyloxy, (1-4C) alkylsulfonyloxy, (6-10C) arylsulfonyloxy, ( 3-9C) heteroarylsulfonyloxy, (1-4C) (di) alkylcarbamoyl, (6-10C) (di) arylcarbamoyl, (2-6C) heterocycloalkylcarbamoyl, (6 -10C) (di) arylamino, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl or (2-6C) heterocycloalkyl (1 May be substituted with alkyl, and all aryl and heteroaryl groups at R ⁶ are hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) al May be substituted with one or more substituents selected from kenyl, (2-4C) alkynyl, (1-4C) alkoxy or (1-4C) (di) alkylamino;
R ⁷ is H, (1-4C) alkyl, (1-4C) alkoxy, halogen, trifluoromethyl, cyano, nitro, hydroxyl;
R ⁸ and / or R ⁹ is H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (6-10C) aryl, (3-9C) heteroaryl, (6 -10C) aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1- 4C) alkyl, (1-4C) (di) alkylamino (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylthio (1-4C) alkyl, (1 -4C) alkylcarbonylamino (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) alkoxycarbonylamino (1-4C) alkyl, (3-6C) Or cycloalkyl, (2-6C) heterocycloalkyl, or R ⁸ and R ⁹ may be bonded in the (2-6C) heterocycloalkyl ring.
[2" claim-type="Currently amended] 1-acetyl-6-benzoylamino-4- (4-methylphenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-4-phenyl-1,2,3 , 4-tetrahydro-2,2,4,6-tetramethylquinoline, 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6,8-pentamethylquinoline , 1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-6-trifluoroacetylamino-4- (4 -Methylphenyl) -1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, 1-acetyl-6-trifluoroacetylamino-4-phenyl-1,2,3,4-tetrahydro -2,2,4-trimethylquinoline, 1-acetyl-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2,2,4,6--tetramethylquinoline and 1-acetyl Tetrahydroquinoline derivative compounds of formula (I) or pharmaceutically acceptable salts thereof except for 4- (4-bromophenyl) -1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline .
Formula I

In the above formula,
R ¹ is formyl, (1-6C) alkylcarbonyl or (1-6C) alkylsulfonyl;
R ² and R ³ are H or (1-4C) alkyl;
R ⁴ is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, Phenyl which may be optionally substituted with one or more substituents selected from the group of (1-4C) (di) alkylamino;
R ⁵ is (1-4C) alkyl;
YX is C (O) -O, S (O) ₂ -O, NHC (O) -O, NHC (S) -O, OC (O) -O, Bond-O, C (O) -NH, S (O) ₂ -NH, NHC (O) -NH, NHC (S) -NH, OC (O) -NH, bond-NH, NH-C (O), OC (O), NH-S (O) ₂ or OS (O) ₂ or XY is a bond;
R ⁶ is H (unless YX is a bond), trifluoromethyl, (1-6C) alkyl, 1- or 2-adamantyl (1-4C) alkyl, (2-6C) alkenyl, (2 -6C) alkynyl, (3-9C) heteroaryl, (3-6C) cycloalkyl, (2-6C) heterocycloalkyl, (1-4C) alkylthio (1-4C) alkyl, (6-10C) Aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1-4C) alkyl , R ⁸ , R ⁹ -aminocarbonyl (1-4C) alkyl, R ⁸ , R ⁹ -amino (1-4C) alkyl, R ⁸ -oxycarbonyl (1-4C) alkyl, R ⁸ -oxy (1 -4C) alkyl, R ⁸ -carbonyl (1-4C) alkyl or (6-10C) aryl and (6-10C) aryl is phenyl, phenyl is hydroxy, amino, halogen, nitro, trifluoro Methyl, cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino, (6-10C ) Aryl, (6-10C) aryloxy, (6-10C) aryl (1-4C) alkoxy, (3-9C) heteroaryl, (3-9C) heteroaryloxy, (3-9C) heteroaryl (1 -4C) alkoxy, (1-4C) alkylcar Nylamino, (1-4C) alkylcarbonyloxy, (3-6C) cycloalkylcarbonyloxy, (1-4C) alkoxycarbonyl (1-4C) alkylcarbonyloxy, (1-4C) alkoxy (1 -4C) alkylcarbonyloxy, (6-10C) arylcarbonyloxy, (3-9C) heteroarylcarbonyloxy, (1-4C) alkylsulfonyloxy, (6-10C) arylsulfonyloxy, ( 3-9C) heteroarylsulfonyloxy, (1-4C) (di) alkylcarbamoyl, (6-10C) (di) arylcarbamoyl, (2-6C) heterocycloalkylcarbamoyl, (6 -10C) (di) arylamino, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl or (2-6C) heterocycloalkyl (1 May be substituted with alkyl, and all aryl and heteroaryl groups at R ⁶ are hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2-4C) al May be substituted with one or more substituents selected from kenyl, (2-4C) alkynyl, (1-4C) alkoxy or (1-4C) (di) alkylamino;
R ⁷ is H, (1-4C) alkyl, (1-4C) alkoxy, halogen, trifluoromethyl, cyano, nitro, hydroxyl;
R ⁸ and / or R ⁹ is H, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (6-10C) aryl, (3-9C) heteroaryl, (6 -10C) aryl (1-4C) alkyl, (3-9C) heteroaryl (1-4C) alkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2-6C) heterocycloalkyl (1- 4C) alkyl, (1-4C) (di) alkylamino (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, (1-4C) alkylthio (1-4C) alkyl, (1 -4C) alkylcarbonylamino (1-4C) alkyl, (1-4C) alkoxycarbonyl (1-4C) alkyl, (1-4C) alkoxycarbonylamino (1-4C) alkyl, (3-6C) Or cycloalkyl, (2-6C) heterocycloalkyl, or R ⁸ and R ⁹ may be bonded in the (2-6C) heterocycloalkyl ring.
[3" claim-type="Currently amended] The tetrahydroquinoline derivative compound or pharmaceutically acceptable salt thereof according to claim 2, wherein Y-X is C (O) -NH, OC (O) -NH or C (O) -O.
[4" claim-type="Currently amended] The tetrahydroquinoline derivative compound according to claim 2 or 3, wherein Y-X is C (O) -NH, or a pharmaceutically acceptable salt thereof.
[5" claim-type="Currently amended] The tetrahydroquinoline derivative compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein R ¹ is (1-4C) alkylcarbonyl.
[6" claim-type="Currently amended] The tetrahydroquinoline derivative compound according to any one of claims ^{2 to 5} , or a pharmaceutically acceptable salt thereof, wherein R ² , R ³ and R ⁵ are independently (1-4C) alkyl.
[7" claim-type="Currently amended] 7. The compound of claim 2, wherein R ⁶ is (6-10C) aryl, (3-9C) heteroaryl, (6-10C) aryl (1-4C) alkyl or (3-9C) ) Heteroaryl (1-4C) alkyl and (6-10C) aryl is phenyl, phenyl is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C) alkyl, (2 -4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) (di) alkylamino, (6-10C) aryl, (6-10C) aryloxy, (6- 10C) Aryl (1-4C) alkoxy, (3-9C) heteroaryl, (3-9C) heteroaryloxy, (3-9C) heteroaryl (1-4C) alkoxy, (1-4C) alkylcarbonylamino , (1-4C) alkylcarbonyloxy, (3-6C) cycloalkylcarbonyloxy, (1-4C) alkoxycarbonyl (1-4C) alkylcarbonyloxy, (1-4C) alkoxy (1-4C ) Alkylcarbonyloxy, (6-10C) arylcarbonyloxy, (3-9C) heteroarylcarbonyloxy, (1-4C) alkylsulfonyloxy, (6-10C) arylsulfonyloxy, (3- 9C) heteroarylsulfonyloxy, (1-4C) (di) alkylcarbamoyl, (6-10C) (di) arylcar Lebamoyl, (2-6C) heterocycloalkylcarbamoyl, (6-10C) (di) arylamino, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C) alkyl, (2 -6C) heterocycloalkyl or (2-6C) heterocycloalkyl (1-4C) alkyl, and all of the aryl and heteroaryl groups in R ⁶ are hydroxy, amino, halogen, nitro, trifluoromethyl At least one substituent selected from cyano, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy or (1-4C) (di) alkylamino Tetrahydroquinoline derivative compounds or pharmaceutically acceptable salts thereof, which may be substituted.
[8" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 2 to 7 and a pharmaceutically suitable adjuvant.
[9" claim-type="Currently amended] Use of a compound according to any one of claims 2 to 8 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for modulating fertilization.

类似技术:

---

公开号 | 公开日 | 专利标题

---

TWI648273B|2019-01-21|Heterocyclyl as kinase inhibitors of Amides |

---

US20180007043A1|2018-01-04|Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders

---

JP6745856B2|2020-08-26|Fused bicyclic pyridyl derivatives as FGFR4 inhibitors

---

KR101884493B1|2018-08-01|Cyclopropylamines as lsd1 inhibitors

---

AU2011297889B2|2015-12-24|Pharmaceutically active compounds as Axl inhibitors

---

JP4395823B2|2010-01-13|Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas

---

ES2369652T3|2011-12-02|C-met modulators and methods of use.

---

AU2007252506C1|2012-07-19|Antitumor agent for thyroid cancer

---

CA3008345C|2019-10-22|Crystalline forms of an androgen receptor modulator

---

RU2248979C2|2005-03-27|Bicyclic heteroaromatic compounds as lh agonists and pharmaceutical composition

---

JP3664492B2|2005-06-29|Tachikinin NK ▲ Lower 3 ▼ Quinoline derivatives as receptor antagonists

---

KR101238430B1|2013-02-28|Imidazo[4,5-d]pyrimidines, their uses and methods of preparation

---

US8063055B2|2011-11-22|Substituted pyridone compounds and methods of use

---

US7365068B2|2008-04-29|Substituted aryl acylthioureas and related compounds; inhibitors of viral replication

---

RU2296764C2|2007-04-10|Derivatives of naphthyridine, method for their preparing and using

---

KR100926399B1|2009-11-12|Diarylamine-containing compounds and compositions, and their use as modulators of steroid hormone nuclear receptors

---

JP2693233B2|1997-12-24|Aminoalkaliindole, its manufacturing method and therapeutic agent for estrogen-dependent diseases and tumors

---

KR20160098380A|2016-08-18|Prodrugs of pyridone amides useful as modulators of sodium channels

---

US6514988B1|2003-02-04|Condensed-ring thiophene derivatives, their production and use

---

AU2016349080A1|2018-05-31|7-| pyrrolopyrimidine compound as TLR7 agonist

---

KR101954322B1|2019-03-05|Methods of using c-met modulators

---

US5817674A|1998-10-06|Quinoline compounds

---

KR100748294B1|2007-08-09|Propane-1,3-Dione Derivatives

---

CA2549606C|2015-10-06|Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment

---

EP0874827B1|2003-05-21|Quinoline derivatives as nk3 antagonists

同族专利:

---

公开号 | 公开日

---

US20040236109A1|2004-11-25|

---

AT319451T|2006-03-15|

---

WO2003004028A1|2003-01-16|

---

HK1061810A1|2006-06-16|

---

MXPA03011908A|2004-06-03|

---

RU2347570C2|2009-02-27|

---

PE20030273A1|2003-03-21|

---

AR034669A1|2004-03-03|

---

NO20035763L|2003-12-29|

---

HU0400390A2|2004-09-28|

---

ECSP034932A|2004-02-26|

---

NZ530198A|2005-11-25|

---

KR100908468B1|2009-07-21|

---

US8258293B2|2012-09-04|

---

US8058441B2|2011-11-15|

---

PL367638A1|2005-03-07|

---

NO325516B1|2008-06-02|

---

AU2002317848B2|2006-08-31|

---

ES2260458T3|2006-11-01|

---

SA1759B1|2007-03-25|

---

IL159288D0|2004-06-01|

---

CZ20042A3|2004-04-14|

---

HRP20031080A2|2004-04-30|

---

PT1406628E|2006-06-30|

---

CA2452606A1|2003-01-16|

---

RU2004102693A|2005-06-27|

---

CN1529601A|2004-09-15|

---

DK1406628T3|2006-07-03|

---

DE60209734T2|2006-08-31|

---

IS2418B|2008-10-15|

---

CN1261099C|2006-06-28|

---

CA2452606C|2011-09-13|

---

ZA200309921B|2005-03-22|

---

BR0210645A|2004-10-05|

---

JP2004535456A|2004-11-25|

---

EP1406628A1|2004-04-14|

---

SK16342003A3|2004-07-07|

---

EP1406628B1|2006-03-08|

---

JP4523273B2|2010-08-11|

---

DE60209734D1|2006-05-04|

---

US20120202996A1|2012-08-09|

---

IS7071A|2003-12-11|

---

SK286759B6|2009-05-07|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
2001-07-02|Priority to EP01202531.8

---

2001-07-02|Priority to EP01202531

---

2002-06-25|Application filed by 악조 노벨 엔.브이.

---

2002-06-25|Priority to PCT/EP2002/007053

---

2004-04-09|Publication of KR20040030714A

---

2009-07-21|Application granted

---

2009-07-21|Publication of KR100908468B1

优先权:

---

申请号 | 申请日 | 专利标题

---

EP01202531.8|2001-07-02|

---

EP01202531|2001-07-02|

---

PCT/EP2002/007053|WO2003004028A1|2001-07-02|2002-06-25|Tetrahydroquinoline derivatives|