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    • 专利摘要:
    In N-({[4- (substituted thiazol-4-yl) phenyl] carbamoyl} methyl) amide derivative, the aryl or heteroaryl group, which is an aromatic ring group, is directly substituted at the N atom of the amide group. It relates to a novel amide derivative. The amide derivatives have good anti-herpes viral activity and are caused by various diseases associated with viral infections with medicines, antiviral agents, especially herpes virus, specifically varicella (bleeding stool) and latent varicella, which accompany infection with varicella zoster virus. It is useful as a prophylactic or therapeutic agent for various herpes virus infections, such as shingles accompanying regression of the herpes virus, labial herpes and herpes encephalitis accompanying HSV-1 infection, and genital herpes accompanying HSV-2 infection.
    公开号:KR20030045180A
    申请号:KR10-2003-7006347
    申请日:2001-11-08
    公开日:2003-06-09
    发明作者:곤타니도루；미야타준지；하마구치와타루；미야자키요지；스즈키히로시；나카이에이이치；가게야마순지
    申请人:야마노우치세이야쿠 가부시키가이샤；가부시키가이샤 소야쿠기쥬쓰겐큐쇼；
    IPC主号:
    专利说明:

    Amide derivatives
    [2] Viruses with the herpes virus cause a variety of infectious diseases in humans and animals. For example, varicella zoster virus causes chickenpox and shingles, and herpes simplex virus type 1 and -2 (HSV-1 and HSV-2) are herpes genital herpes, genitals, respectively. It is known to cause infections such as herpes. In recent years, herpes viruses such as cytomegalovirus (CMV), EB virus (Epstein-Barr virus (EBV), human herpes virus 6,7,8), etc. Infectious diseases have also been identified.
    [3] Currently, as an anti-herpes virus drug of VZV or HSV, nucleic acid-based drugs such as acyclovir (ACV), baracyclovir (VCV) and pampcyclovir (FCV), which are prodrugs thereof, are used. Such nucleic acid-based drugs are monophosphorylated to nucleoside monophosphate by viral thymidine kinase encoded by VZV or HSV, and then converted into triphosphate bodies by enzymes of cells. Finally, triphosphorylated nucleoside moieties are introduced during replication of the viral genome by herpes viral DNA polymerase to inhibit the elongation response of the viral DNA chain. As such, the mechanism of action of the existing anti-herpes virus agents is based on the "competitive inhibitory" effect on deoxynucleoside triphosphate, and therefore high concentrations of drugs are required to exert antiviral effects. Indeed, the clinical dosage of such nucleic acid-based antiherpes agents is administered at high doses of several hundred mg to several g per day. Nucleic acid-based agents are also concerned about their mutagenicity because they can be introduced into the host's genomic DNA by the host's DNA polymerase.
    [4] On the other hand, several drugs have recently been reported to exhibit anti-herpes virus activity as non-nucleic acid drugs. For example, WO 97/24343 discloses an N-valent thiazolyl phenyl carbamoyl methyl of formula G having anti-HSV-1 activity and anti-CMV activity by inhibiting the HSV helicase primase enzyme complex. Amides or sulfonamide derivatives substituted with groups or the like are described. However, the anti-VZV activity of such compounds is not described in detail.
    [5]
    [6] In Formula G above,
    [7] R is hydrogen, lower alkyl, amino, lower alkylamino and the like,
    [8] R 2 is hydrogen or lower alkyl,
    [9] Q is absent or methylene,
    [10] R 3 is hydrogen, lower alkyl and the like,
    [11] R 4 is unsubstituted or substituted phenyl (lower) alkyl, 1-indanyl, 2-indanyl, (lower cycloalkyl)-(lower alkyl), (Het)-(lower alkyl), and the like.
    [12] R 5 is phenylsulfonyl, 1- or 2-naphthylsulfonyl, (Het) -sulfonyl, (unsubstituted or substituted phenyl) -Y- (CH 2 ) n C (O), (Het)-(CH 2 ) n C (O) and the like,
    [13] Y is O or S,
    [14] n is 0, 1 or 2 (for details, refer to this publication).
    [15] WO 00/29399 also describes amide or sulfonamide derivatives having the N atom substituted with thiazolyl phenyl carbamoyl methyl group of the following formula H having anti-HSV-1 activity and anti-CMV activity, but anti-VZV of such compounds No activity is specifically described.
    [16]
    [17] In Formula H above,
    [18] R 1 is NH 2 ,
    [19] R 2 is H,
    [20] R 3 is H,
    [21] R 4 is CH 2 Ph, CH 2- (4-pyridyl), CH 2 -cyclohexyl, and the like,
    [22] R 5 is CO- (substituted phenyl), CO- (unsubstituted or substituted heterocycle) and the like (see the publication for details).
    [23] In addition, recently, inhibitors of various herpes virus proteases (see Waxman Lloyd et al, 2000, Antiviral Chemistry and Chemotherapy, 11, 1-22), and N- (carbonylphenyl) benzamide derivatives which are inhibitors of HSV primases [see also WO 00/58270 has been reported. However, these documents and patent publications also do not describe compounds with good antiVZV activity.
    [24] There is a need for the invention of a non-nucleic acid antiherpes virus agent having sufficient anti-VZV activity and high stability.
    [1] The present invention relates to novel amide derivatives or salts thereof which are useful for the prevention and treatment of diseases involving medicaments, antiviral agents, in particular herpes viruses such as varicella zoster virus (VZV).
    [25] The present inventors earnestly examined the compound having the anti varicella zoster virus (anti-VZV) action, and as a group A to the amide group in which the N atom was substituted with thiazolyl phenyl carbamoyl methyl group as shown in the following formula (I) The novel amide derivatives (including sulfonamide derivatives), characterized in that the aromatic ring group aryl or heteroaryl group is directly substituted without passing through the alkylene chain, have found good anti-VZV activity and completed the present invention. will be.
    [26] That is, the present invention relates to a novel amide derivative of formula (I) or a salt thereof.
    [27]
    [28] In Formula I above,
    [29] R 1 and R 2 are the same or different and are -H, -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, -cycloalkenyl, -NR a R b , -NR c -NR a R b , -NR c- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR c -C (= NH) -NR a Rb,-(nitrogen containing saturated heterocyclic which may be substituted by lower alkyl) Click), -lower alkylene-NR a R b , -lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR a COR b , -NR a CO-OR b , -NR a CO-NR b R c , -NR a CO-lower alkylene-NR b R c , -NR a CO-lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR a SO 2 R b , -NR a SO 2 -NR b R c , -NR a SO 2 -lower alkylene-NR b R c , -NR a SO 2 -lower alkylene- (nitrogen which may be substituted by lower alkyl) Saturated heterocyclic), -CONR a R b , -SO 2 NR a R b , -COOR a , -SO 2 R a , -CONR a -OR b , -OCOR a , -OR a , -halogen,- C OR a , -NO 2 , -CN or -halogeno lower alkyl, wherein R a , R b and R c are the same or different, -H, -lower alkyl, -lower alkenyl, -lower alkynyl,- Cycloalkyl, -cycloalkenyl, -aryl, -5- to 6-membered monocyclic heteroaryl or -lower alkylene-aryl),
    [30] A is aryl which may have a -substituent, heteroaryl which may have a substituent, saturated carbocyclic condensed aryl which may have a -substituent, or saturated heterocyclic condensed aryl which may have a -substituent, provided that it is a saturated carbon ring Condensed aryl and saturated heterocyclic condensed aryl bond to adjacent N atoms via the C atom of the aromatic ring,
    [31] X is C0 or SO 2 ,
    [32] R 3 is -alkyl which may have a substituent, alkenyl which may have a substituent, alkynyl which may have a substituent, cycloalkyl which may have a substituent, cycloalkenyl which may have a substituent, -substituent Aryl which may have, -a heterocyclic ring which may have a substituent or -NR a R b wherein R a and R b are as defined above or adjacent groups -N (A) -X-, wherein A and X is as defined above) or In which Y is O, S, a bond or CH 2 , R 3a is —H, cycloalkyl which may have a -substituent, cycloalkenyl which may have a -substituent, aryl which may have a -substituent, or -Heterocycle which may have a substituent, A 'and B are the same or different, a benzene ring which may have a substituent, and X is as defined above).
    [33] The present invention also relates to pharmaceutical compositions comprising an amide derivative of formula (I) or a salt thereof and a pharmaceutically acceptable carrier, and to anti-herpes virus agents, in particular anti-VZV agents.
    [34] The compounds of formula (I) are further described.
    [35] As used herein, "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Examples of "lower alkyl" are preferably alkyl groups having 1 to 4 carbon atoms, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl group and tert-butyl group. Examples of "lower alkenyl" are preferably alkenyl groups having 2 to 5 carbon atoms, particularly preferably vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3 -Butenyl group. Examples of "lower alkynyl" are preferably alkynyl groups having 2 to 5 carbon atoms, particularly preferably ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl groups. In addition, examples of "lower alkylene" are preferably alkylene groups having 1 to 3 carbon atoms, and particularly preferably methylene, ethylene, trimethylene and dimethylmethylene groups.
    [36] Examples of "alkyl" are preferably linear or branched alkyl groups having 1 to 10 carbon atoms, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2,2-diethylpropyl, n-octyl and n-decyl groups. Examples of "alkenyl" and "alkynyl" are preferably a straight or branched group having 2 to 10 carbon atoms.
    [37] "Aryl" means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, and preferably a phenyl and naphthyl group. Examples of "cycloalkyl" are cycloalkyl groups having 3 to 10 carbon atoms which may have a crosslinking, and are preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups. Examples of "cycloalkenyl" are preferably cycloalkenyl groups having 3 to 10 carbon atoms, and particularly preferably cyclopentenyl and cyclohexenyl groups. Examples of "saturated carbon ring condensed aryl" are condensed ring groups in which a benzene ring or a naphthalene ring and a C 5-6 saturated carbocyclic ring are condensed, and are preferably indanyl and tetrahydronaphthyl.
    [38] A "heterocycle" is a saturated or unsaturated monocyclic or bicyclic to tricyclic 5- to 8-membered heterocycle containing 1 to 4 heteroatoms selected from N, S and O. Preferably, they are "heteroaryl", "5- to 8-membered saturated heterocyclic", and "saturated heterocyclic condensed aryl".
    [39] "5- to 6-membered monocyclic heteroaryl" is a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, S and O, and furyl, thienyl, pyrrolyl, Imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxdiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridinyl and Triazinyl is preferred. "Heteroaryl" is a bicyclic to tricyclic heteroaryl in which the 5- to 6-membered monocyclic heteroaryl and the benzene ring or the heteroaryl ring are condensed. Here, as monocyclic heteroaryl, said thing is preferable, As bicyclic to tricyclic heteroaryl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl , Benzimidazolyl, indolyl, isoindoleyl, indazolyl, quinolyl, isoquinolyl, cinnalinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, imidazopyridyl, indolidinyl, carbazolyl Preference is given to dibenzofuranyl and dibenzothienyl groups.
    [40] "5- to 8-membered monocyclic saturated heterocyclic" is a 5- to 8-membered monocyclic saturated heterocyclic containing 1 to 4 heteroatoms selected from N, S and O, and may have a crosslink. , Preferably tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, thifanyl, thiocanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, azepanyl, diazepa Nil, piperidinyl and morpholinyl groups. More preferably a 5- to 7-membered ring group. In addition, a "nitrogen-containing saturated heterocyclic" is group which has 1 or more ring nitrogen atom among said "5- to 8-membered monocyclic saturated heterocyclic", Preferably it is piperidino and morpholino , 1-piperazinyl and 1-pyrrolidinyl.
    [41] As the "saturated heterocyclic condensed aryl", the 5- to 8-membered monocyclic saturated heterocyclic condensed with a benzene ring or a naphthalene ring is preferably 3,4-dihydro-2H-1,4-benzoxa Genyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxylyl, chromanyl, isochromenyl, 3,4-dihydro-2H-1-benzothiopyranyl, 3,4-dihydro-1H-2-benzothiopyranyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro Quinolyl and 1,2,3,4-tetrahydroisoquinolyl groups.
    [42] When ring A is "saturated carbon ring condensed aryl" or "saturated heterocyclic condensed aryl", ring A is bonded to the N atom of the adjacent amide group via the C atom of the aromatic ring. On the other hand, when R 3 is "saturated carbon ring condensed aryl" or "saturated heterocyclic condensed aryl", R 3 is bonded to an adjacent group X via the C atom of the aromatic ring or the C atom or N atom of the saturated ring.
    [43] Examples of the "halogen" include F, Cl, Br, and I atoms. Roneun "halogeno lower alkyl", wherein the lower alkyl, the halogen is substituted one or more, preferably a -CF 3.
    [44] Substituents in alkyl which may have substituents, alkenyl which may have substituents and alkynyl which may have substituents are preferably 1 to 4 substituents selected from the following C groups.
    [45] C group: -cycloalkyl, -cycloalkenyl, -aryl, -NR a R b , -NR c -NR a R b ,-(-lower alkyl, -lower alkylene-COOR a and -NR a R b Nitrogen-containing saturated heterocyclic which may have selected substituents), -NR c- (nitrogen-containing saturated heterocyclic which may have substituents selected from -lower alkyl, -lower alkylene-COOR a and -NR a R b ) , -O-lower alkylene-NR a R b , -O-lower alkylene-(-lower alkyl, -lower alkylene-COOR a and -NR a R b which may have a substituent selected from nitrogen containing saturated hetero click), -0-lower alkylene -0R a, -O- lower alkyl, -COOR a, -COOR a, - halogen, -COR a, -NO 2, -CN , -OR a, -O- ( halogeno Lower alkyl), -SR a , -SOR a , -SO 2 R a , -CO-NR a R b , -CO-(-lower alkyl, -lower alkylene-COOR a and -NR a R b have the nitrogen-containing cyclic saturated heterocyclic which may), -NR a -COR b, -SO 2 NR a R b , and = O (oxo) (here , R a, R b and R c are as defined above).
    [46] Cycloalkyl which may have substituents, cycloalkenyl which may have substituents, aryl which may have substituents, saturated carbocyclic condensed aryl which may have substituents, saturated heterocyclic condensed aryl which may have substituents, which have substituents The substituent in the heterocyclic 5- to 8-membered and the benzene ring which may have a substituent is preferably 1 to 5 substituents selected from the following D groups.
    [47] D group:-(-OR a , -SR a , -CN, -COOR a , -CONR a , -NR a R b and-(-lower alkyl, -lower alkylene-COOR a and -NR a R b Lower alkyl which may have a substituent selected from nitrogen-containing saturated heterocyclic which may have a selected substituent), -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, 5- or 6-membered monocyclic heteroaryl And the substituents described in the above C group.
    [48] More preferably from 1 to 4 groups selected from the following D1 group.
    [49] D1 group: -lower alkyl, -phenyl, -halogeno lower alkyl, -COOH, -COO-lower alkyl, -halogen, -NO 2 , -CN, -OH, -O-lower alkyl, -0-halogeno lower Alkyl, -0-lower alkylene-0-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-COO-lower alkyl, -O-lower alkylene-NH 2 , -O-lower alkyl Ene-NH-lower alkyl, -O-lower alkylene-N (lower alkyl) 2 , -O-lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NH 2 , -NH -Lower alkyl, -N (lower alkyl) 2 ,-(-lower alkyl and -lower alkylene- nitrogen-containing saturated heterocyclic which may have a substituent selected from COOR a ), -NHCO-lower alkyl, -N (lower) Alkyl) CO-lower alkyl, -CONH 2 , -CONH-lower alkyl, -CON (lower alkyl) 2 , = O (oxo), -SH, -S-lower alkyl, -SO-lower alkyl and -SO 2- Lower alkyl groups.
    [50] In compounds comprising saturated heterocyclics containing S atoms, one or two = 0 (oxo) may be substituted over the S atoms to form an oxide (SO) or dioxide (SO 2 ) compound.
    [51] As a group which R <3> forms with the adjacent group -N (A) -X-, Preferably, the following group is mentioned.
    [52]
    [53] Wherein R 3a is cycloalkyl, cycloalkenyl, aryl, saturated carbocyclic condensed aryl, saturated heterocyclic condensed aryl, heteroaryl, or 5-membered, which may be substituted with 1-4 substituents selected from the group -H or D1 To 8 membered monocyclic saturated heterocyclic, R d and R e are the same or different and are -H, -lower alkyl, -halogen, -OH or -O-lower alkyl.
    [54] Among the compounds of the formula (I) of the present invention, preferred compounds are shown below.
    [55] 1.R 1 and R 2 are the same or different, -H, -lower alkyl, -lower alkenyl, -lower alkynyl, -NR a R b , -NR c -NR a R b ,-(lower alkyl) Saturated heterocyclic which may be substituted), -NR c -C (= NH) -NR a R b , -NR a COR b , -NR a CO-OR b , -NR a CO-NR b R c , -NR a CO-lower alkylene-NR b R c or -NR a CO-lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl),
    [56] Aryl which may have 1 to 5 substituents selected from group D, heteroaryl which may have 1 to 5 substituents selected from group D, saturated carbon ring condensation which may have 1 to 5 substituents selected from group D Saturated heterocyclic condensed aryl which may have 1 to 5 substituents selected from aryl or D group,
    [57] Cycloalkyl which R 3 may have 1 to 5 substituents selected from D group, cycloalkenyl which may have 1 to 5 substituents selected from D group, aryl which may have 1 to 5 substituents selected from D group , Saturated carbocyclic condensed aryl which may have 1 to 5 substituents selected from the D group, saturated heterocyclic condensed aryl which may have 1 to 5 substituents selected from the D group, 1 to 5 substituents selected from the D group A compound which is a 5- to 8-membered monocyclic saturated heterocyclic which may have 1 to 5 substituents selected from heteroaryl or D group which may have.
    [58] 2. A is aryl selected from phenyl and naphthyl; Benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindoleyl, indazolyl, quinolyl, isoquinolyl, cinnalol Heteroaryl selected from the group of the following groups: nil, quinazolinyl, quinoxalinyl, benzodioxolyl, imidazopyridyl and indolidinyl; Saturated carbon ring condensed aryl selected from 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydronaphthalen-1-yl and 5,6,7,8-tetrahydronaphthalen-2-yl; Or 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,3-benzodioxolyl, 2,3-dihydro- 1,4-benzodioxyyl, chromanyl, isochromenyl, 3,4-dihydro-2H-1-benzothiopyranyl, 3,4-dihydro-1H-2-benzothiopyranyl, indolinyl Is saturated heterocyclic condensed aryl selected from isoindolinyl, 1,2,3,4-tetrahydroquinolyl and 1,2,3,4-tetrahydroisoquinolyl groups, wherein the aryl, heteroaryl, saturated Carbocyclic condensed aryl or saturated heterocyclic condensed aryl may each have 1 to 4 substituents selected from the D1 group,
    [59] Cycloalkyl which R 3 may have 1 to 4 substituents selected from the D1 group, cycloalkenyl which may have 1 to 4 substituents selected from the D1 group, aryl which may have 1 to 4 substituents selected from the D1 group , Saturated carbocyclic condensed aryl which may have 1 to 4 substituents selected from the D1 group, saturated heterocyclic condensed aryl which may have 1 to 4 substituents selected from the D1 group, 1 to 4 substituents selected from the D1 group A compound which is a 5- to 8-membered monocyclic saturated heterocyclic which may have 1 to 4 substituents selected from heteroaryl or D1 group which may have.
    [60] 3. A is aryl which may have 1 to 4 substituents selected from the D1 group, heteroaryl which may have 1 to 4 substituents selected from the D1 group or saturated hetero may have 1 to 4 substituents selected from the D1 group Cyclic condensed phenyl,
    [61] Cycloalkyl which R 3 may have 1 to 4 substituents selected from the D1 group, cycloalkenyl which may have 1 to 4 substituents selected from the D1 group, aryl which may have 1 to 4 substituents selected from the D1 group , Saturated heterocyclic condensed phenyl which may have 1 to 4 substituents selected from the D1 group, heteroaryl which may have 1 to 4 substituents selected from the D1 group, or may have 1 to 4 substituents selected from the D1 group 5-7 membered monocyclic saturated heterocyclic compounds.
    [62] 4. Compounds wherein X is CO.
    [63] 5. A compound wherein R 1 is -NH 2 and R 2 is -H.
    [64] 6. Phenyl, benzothier, wherein A can have one or two substituents selected from the group consisting of -lower alkyl, -CF 3 , -halogen, -OH, -SH, -S-lower alkyl and -0-lower alkyl. Group selected from nil, benzothiadiazolyl, benzothiazolyl, indolyl, quinolyl and 5-indanyl; Or 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, which may be substituted by one or two = 0 (oxo) , 3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxyyl and indolinyl group,
    [65] A group selected from cyclohexyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, quinolyl and tetrahydro-2H-pyranyl, wherein R 3 may be substituted with one or two halogens; Or a group selected from tetrahydro-2H-thiopyranyl and 3,4-dihydro-2H-1-benzothiopyranyl, which may be substituted with one or two oxo groups.
    [66] 7. Compounds or salts thereof listed below.
    [67] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (2,3-dihydro-1H-indol-6-yl) benz amides,
    [68] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1,2,3,4-tetrahydroquinolin-6-yl) Benzamide,
    [69] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (2,3-dihydro-1,4-benzodioxin-6-yl) -4 Fluorobenzamide,
    [70] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1,3-benzodioxol-5-yl) -4-fluorobenzamide,
    [71] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-5-yl-4-fluorobenzamide,
    [72] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-6-yl-4-fluorobenzamide,
    [73] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N-indane-5-ylbenzamide,
    [74] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (3-hydroxyindan-5-yl) benzamide,
    [75] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1H-indol-5-yl) benzamide,
    [76] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (3-oxo-3,4-dihydro-2H-1,4 -Benzothiazin-6-yl) benzamide,
    [77] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (3-oxo-3,4-dihydro-2H-1,4 Benzoxadin-6-yl) benzamide,
    [78] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1,2,3-benzothiadiazol-5-yl) -4-fluorobenz amides,
    [79] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide,
    [80] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-5-yl-4-fluorocyclohexa-3-enecarboxamide,
    [81] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-5-yl-4,4-difluorocyclohexanecarboxamide and
    [82] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-indan-5-yltetrahydro-2H-thiopyran-4-carboxamide 1,1- Dioxide.
    [83] Salts of the compounds of formula I of the present invention are pharmaceutically acceptable salts. Specific examples of the acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, And acid addition salts with organic acids such as citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid. In addition, depending on the type of the substituent, a salt with a base may be formed. For example, an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminum, or methylamine, ethylamine, ethanolamine And salts with organic bases such as lysine and ornithine, and ammonium salts.
    [84] Depending on the type of substituent, the compound of the general formula (I) of the present invention may have geometric isomers such as cis-trans or tautomers such as keto-enol, but such isomers are separated from the present invention. Mixtures are included. In addition, the compound of the present invention may have a subtitle carbon atom, and an isomer based on the subtitle carbon atom may exist. The present invention includes mixtures or isolated of such optical isomers. In addition, the compound of this invention may form N-oxide depending on the kind of substituent, and such an N-oxide body is also included in this invention. The present invention also encompasses various hydrates, solvates and polymorphic materials of the compounds of formula (I) of the present invention. In addition, the compounds of the present invention include all compounds, so-called prodrugs, which are metabolized in vivo and converted into the compound of formula (I) or salts thereof. As a group which forms the prodrug of this invention, the group described in literature can be mentioned. Prog. Med. 5: 2157-2161 (1985); Yokogawa Shoten, 1990, "Drug Development, Vol. 7, Molecular Design, 163-198".
    [85] (Manufacturing method)
    [86] Representative methods for the preparation of compounds of formula I of the present invention are described below.
    [87] In addition, in the following manufacturing method, depending on the kind of functional group, it may be effective in manufacturing technique to substitute the said functional group by a suitable protecting group, ie, the group which can be easily converted into the said functional group at the stage of a raw material or an intermediate. Then, the protecting group can be removed as necessary to obtain the target compound. As such a functional group, an amino group, a hydroxyl group, a carboxyl group, etc. are mentioned, for example, As these protecting groups, the protecting group described in the literature is mentioned, for example. Protective Groups in Organic Synthesis Vol. 3, T.W.Green and P.G.M.Wuts, JOHN WILLY & SONS, INC.], It is good to use these properly according to the reaction conditions. The introduction and deprotection of protecting groups may suitably apply the methods described in that reference.
    [88] Manufacturing Method 1
    [89]
    [90] The compound of formula (I) of the present invention can be easily prepared by amidation reaction between carboxylic acid compound (III) and thiazolyl phenyl derivative (II).
    [91] The amidation reaction can be carried out according to a conventional method, and for example, the method described in the literature can be applied (see Japanese Chemical Society, "Experimental Chemistry Lecture", 4th Edition (Maruzen), Vol. 22, p. 137 to 173]. Preferably, the carboxylic acid compound (III) can be converted into a reactive derivative such as an acid halide (acid chloride or the like) or an acid anhydride and then reacted with a thiazolyl phenyl derivative (II). When using a reactive derivative of carboxylic acid, it is preferable to add a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, pyridine). In addition, the amidation of the carboxylic acid is a carboxylic acid of a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-carbonylbis-1H-imidazole (CDI), etc.) It can be carried out in the presence of an activator. At this time, additives such as 1-hydroxybenzotriazole (HOBt) can be added. The reaction temperature can be appropriately selected according to the raw material compound. The solvent is a solvent inert to the reaction, for example, an aromatic hydrocarbon solvent such as benzene or toluene, an ether solvent such as tetrahydrofuran (THF) or 1,4-dioxane, or a halogenated hydrocarbon solvent such as dichloromethane or chloroform. Amide solvents such as solvent, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, basic solvents such as pyridine, and the like. The solvent is appropriately selected depending on the kind of raw material compound, etc., and used alone or by mixing two or more kinds.
    [92] Manufacturing Method 2
    [93]
    [94] Where hal is halogen and the remaining substituents are as defined above.
    [95] This production method is a method for obtaining the compound of formula (I) of the present invention by subjecting the α-halogenated ketone of formula (IV) to a cyclization reaction with compound (V). The cyclization can be carried out according to a conventional method, for example, the method described in the literature can be applied. See Tetrahedron Lett., 9, 24, 1959; The Chemistry of Heterocyclic Compounds "Thiazole and its Derivatives 1,2", J.V. Metzger, John Eiley & Sons Inc.].
    [96] Preferably, it can carry out by making (alpha) -halogenated ketone (IV) which is a raw material compound react with compound (V) under cooling or heating, without using a solvent or a solvent. As a solvent, Preferably, alcohol solvents, such as methanol, ethanol, and isopropanol, carbonyl solvents, such as acetone and methyl ethyl ketone, said ether solvent, a halogenated hydrocarbon solvent, an amide solvent, etc. can be used. These solvents are used individually or in mixture of 2 or more types. The solvent should be appropriately selected depending on the kind of raw material compound and the like. In the reaction, the reaction may proceed smoothly by adding a base (potassium carbonate, sodium carbonate, TEA, etc.).
    [97] Manufacturing Method 3
    [98]
    [99] This production method is a method of amidating or sulfonamide-forming an amine compound of formula (VI) with a carboxylic acid or sulfonic acid compound (i) to obtain a compound of formula (I) of the present invention.
    [100] Amidation can be performed similarly to the manufacturing method 1.
    [101] The sulfonamide reaction can be carried out by reacting the sulfonic acid reactive derivative of formula (X) with the amine compound (VI) according to a conventional method. Examples of the reactive derivatives of sulfonic acid include acid halides (acid chlorides, acid bromide and the like), acid anhydrides (sulphonic anhydrides adjusted with two molecules of sulfonic acid), acid azide and the like. Such reactive derivatives of sulfonic acid can be easily obtained from the corresponding sulfonic acid according to a general method generally practiced. When using an acid halide as a reactive derivative, it is preferable to carry out in the presence of a base (an inorganic base such as sodium hydroxide or sodium hydride or an organic base such as pyridine, TEA, diisopropylethylamine). When reacting with reactive derivatives such as acid anhydride and acid azide, the reaction can be carried out in the absence of a base. If desired, the reaction may be carried out in the presence of an inorganic base such as sodium hydride or an organic base such as TEA, pyridine or 2,6-lutidine. The reaction temperature is appropriately selected depending on the kind of sulfonic acid reactive derivative and the like. As the solvent, a solvent inert to the reaction, for example, a solvent exemplified in the amidation of the above-described production method 1 may be used.
    [102] Moreover, depending on the kind of substituent, the compound of the present invention can be manufactured by carrying out a substituent modification reaction which is well known to those skilled in the art. For example, well-known reactions, such as amidation and sulfonation, and N-alkylation as described in the Japanese Chemical Society "Experimental Chemistry Course" (Maruzen) can be suitably applied. In addition, the reaction sequence may be appropriately changed depending on the target compound and the kind of reaction to be used.
    [103] Process for preparing raw compound
    [104] Said each raw material compound can be manufactured easily using well-known reaction, for example, the reaction described in the Japanese Chemical Society "Experimental Chemistry Lecture" (Maruzen). The typical preparation method thereof is shown below.
    [105] Method for Preparation of Compound (II)
    [106]
    [107] Method of Preparation Compound (III)
    [108]
    [109] Method for Preparation of Compound (IV)
    [110]
    [111] Method for Preparation of Compound (VI)
    [112]
    [113] In the above scheme,
    [114] R is a group capable of forming ester moieties such as lower alkyl and aralkyl,
    [115] P is a protecting group of an amino group such as fluorenylmethoxycarbonyl (Fmoc).
    [116] In the above reaction route diagram, amidation is carried out in the same manner as described in the preparation method 1, cyclization is performed in the same manner as in the preparation method 2, and sulfonamideization is carried out in the same manner as in the preparation method 3. Can be.
    [117] The N-alkylation of compound (X) is carried out using a halogenated alkyl compound (XI), for example, according to a conventional method, for example, in the above-mentioned document ("Experimental Chemistry Lecture" 4th edition (Maruzen) Volume 20 p. 279 to 318 can be carried out according to the method. The reaction temperature can be carried out under cooling to heating, and the solvent may be a solvent which is inert to the reaction, for example, a solvent exemplified in the amidation of the production method 1. The reaction is preferably carried out in the presence of a base such as potassium carbonate, sodium hydroxide or sodium hydride.
    [118] Deprotection for obtaining the carboxylic acid compound (III) can be carried out by appropriately applying a conventional method depending on the type of ester. Preferably, in the case of alkyl esters, such as ethyl ester, it can be performed by treating with bases, such as aqueous sodium hydroxide solution, and in the case of aralkyl esters, such as benzyl ester, to palladium-carbon (Pd-C) under hydrogen atmosphere. have. The reaction can be carried out according to the method described in the above document (Protective Groups in Organic Synthesis 3rd Edition).
    [119] The α-halogenated ketone compound (IV) can be synthesized by halogenating the acyl compound (XV) according to a conventional method. As the halogenating reagent, for example, chlorine, bromine, iodine, copper bromide (II), potassium ureate, benzyltrimethylammonium tribromide, phenyltrimethylammonium tribromide, tetrabutylammonium tribromide, sulfuryl chloride, trimethylsilyl chloride, Trimethylsilyl bromide, 5,5-dibromobarbituric acid, and the like. Examples of the solvent include solvents inert to the reaction, for example, acidic solvents such as acetic acid and hydrobromic acid / acetic acid, alcohol solvents and ethers. And solvents may be mentioned. The reaction temperature can be carried out under cooling to heating.
    [120] Deprotection for obtaining the amine compound (VI) is appropriately carried out using conventional methods depending on the type of protecting group. For example, the methods described in the literature can be applied (Protective Groups in Organic Synthesis, 3rd Edition, p. 503-572).
    [121] Moreover, depending on the kind of substituent, the target raw material compound can be manufactured by performing a substituent modification reaction well known to those skilled in the art.
    [122] The compound of the present invention thus prepared is subjected to a salt treatment according to a free state or a conventional method, and is isolated and purified as a salt thereof. Isolation and purification are carried out by applying conventional chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
    [123] Various isomers can be isolated according to conventional methods using the difference in physicochemical properties between the isomers. For example, the racemic compound can be derived into a stereosterically pure isomer according to a general optical cleavage method (for example, a method of optically dividing a diastereomer salt with a general optically active acid (such as tartaric acid)). . In addition, the mixture of diastereomers can be isolate | separated by fractional crystallization, chromatography, etc., for example. In addition, an optically active compound can be produced by using a suitable optically active material.
    [144] EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail based on an Example. This invention is not limited to what was described in the following example. In addition, the manufacture example of the raw material compound of the compound of this invention is shown to a reference example.
    [145] Reference Example 1
    [146] Potassium carbonate and ethyl bromoacetate are added to the DMF solution of aniline and stirred by heating. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed and dried, and then the solvent was evaporated under reduced pressure to give a crude product. This is dissolved in chloroform, and TEA, 4-fluoro benzoyl chloride and dimethyl amino pyridine (DMAP) are added and stirred. 1M hydrochloric acid is added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by silica gel column chromatography (hereinafter referred to as SCG) to give ethyl [(4-fluorobenzoyl) phenylamino] acetate (colorless oily substance).
    [147] Reference Example 2
    [148] Potassium carbonate and benzyl bromoacetate are added to a DMF solution of ethyl (4-aminophenoxy) acetate and heated and stirred. Water and ethyl acetate are added to the reaction mixture, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. TEA is added to the dichloromethane solution of the obtained crude product, 4-fluoro benzoyl chloride is added dropwise under ice-cooling, and the reaction solution is stirred. 1 M hydrochloric acid is added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give ethyl {4- [benzyloxycarbonylmethyl- (4-fluorobenzoyl) amino] phenoxy} acetate (colorless oily substance).
    [149] Reference Example 3
    [150] The mixture of 6-aminoquinoline, di-tert-butyl dicarbonate and DMAP is heated and stirred. 1,4-dioxane and 1 M aqueous sodium hydroxide solution are added to the reaction mixture, followed by stirring. Ethyl acetate is added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give 6- (tert-butyloxycarbonyl) aminoquinoline. This is dissolved in ethanol, 20% palladium hydroxide carbon is added and stirred under hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain a tetrahydroquinoline compound. This is dissolved in 1,4-dioxane, and 9H-fluorenyl-9-ylmethyl chloroformate and 10% aqueous sodium hydrogen carbonate solution are added and stirred. Ethyl acetate and water are added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The residue is dissolved in chloroform, trifluoroacetic acid is added and stirred. The solvent is distilled off under reduced pressure, ethyl acetate is added to the residue, the residue is washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give 9H-fluorenyl-9-ylmethyl 6-amino-1,2,3,4-tetrahydroquinoline-1-carboxylate. This is dissolved in acetonitrile, potassium carbonate and benzoyl bromo acetate are added, and the mixture is heated and stirred. The reaction mixture is filtered, and the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG. This is dissolved in pyridine, and dichloromethane and 4-fluorobenzoyl chloride are added and stirred. Ethyl acetate and water are added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The obtained crude product was purified by SCG and ethyl {[1- (9H-fluorenyl-9-ylmethyloxycarbonyl) -1,2,3,4-tetrahydroquinolin-6-yl] (4- Fluorobenzoyl) amino} acetate (pale yellow foamy material) is obtained.
    [151] Reference Example 4
    [152] Potassium carbonate and ethyl bromoacetate are added to a DMF solution of 6-amino-1-indanon and heated and stirred. Ethyl acetate was added to the reaction mixture, followed by filtration. The organic layer was washed and dried, and then the solvent was distilled off under reduced pressure to obtain an ester compound. This is dissolved in chloroform, and TEA and 4-fluorobenzoyl chloride are added and stirred. Then, TEA and 4-fluorobenzoyl chloride are added to the reaction solution and stirred. Ethyl acetate was added to the reaction solution, and the resultant was filtered, and then the solvent of the mother liquid was distilled off under reduced pressure. The crude product obtained is purified by SCG. This is dissolved in ethanol, and sodium borohydride is added and stirred. Then, sodium borohydride and methanol are added to the reaction solution and stirred. Water and chloroform were added to the reaction solution, the organic layer was separated, washed and dried, and then the solvent was distilled off under reduced pressure, and the obtained crude product was purified by SCG to obtain ethyl [(4-fluorobenzoyl) (3-hydro Roxyindan-5-yl) amino] acetate (yellow oily substance) is obtained.
    [153] Reference Example 5
    [154] The mixture of 2-chloropyridine and ethylaminoacetate hydrochloride is stirred by heating. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, followed by separation. The organic layer was washed and dried, and then the solvent was evaporated under reduced pressure. The crude product obtained is purified by SCG. This is dissolved in dichloromethane, pyridine, 4-fluorobenzoyl chloride and DMAP are added and stirred. Ethyl acetate and water are added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give ethyl [(4-fluorobenzoyl) (2-pyridyl) amino] acetate (colorless oily substance).
    [155] Reference Example 6
    [156] To a chloroform solution of ethyl [(4-piperidinecarbonyl) (4-methoxyphenyl) amino] acetate, acetic acid, sodium triacetoxy borohydride and 36% aqueous formaldehyde solution are added and stirred. Subsequently, sodium triacetoxy borohydride and 36% aqueous formaldehyde solution are added to the reaction solution, followed by stirring. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution to neutralize the mixture. Chloroform is added to separate the organic layer, followed by washing and drying. The solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give ethyl {[(1-methyl-4-piperidine) carbonyl] (4-methoxyphenyl) amino} acetate (colorless oily substance).
    [157] Reference Example 7
    [158] Thionyl chloride is added to a 1,4-dioxane solution of (1-benzyloxycarbonyl-4-piperidine) carboxylic acid and stirred, and the solvent is distilled off under reduced pressure. The residue is dissolved in chloroform, ethyl [(4-methoxyphenyl) amino] acetate and TEA are added and stirred, and the solvent is distilled off under reduced pressure. The residue is diluted with ethyl acetate, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG. This is dissolved in ethanol, 5% Pd-C is added and then stirred at room temperature under hydrogen atmosphere. After the reaction solution was filtered, the solvent was distilled off under reduced pressure to obtain ethyl [(4-piperidinecarbonyl) (4-methoxyphenyl) amino] acetate. This is dissolved in THF, and di-tert-butyl dicarbonate and TEA are added and stirred. An aqueous 1 M sodium hydroxide solution is added to the reaction solution, followed by stirring, followed by an aqueous 1 M sodium hydroxide solution and ethanol. 1M hydrochloric acid was added to the reaction solution, followed by extraction with chloroform-ethanol (1O / 1), the organic layer was dried, and the solvent was distilled off under reduced pressure to obtain {[(1-tert-butyloxycarbonyl-4- Piperidine) carbonyl] (4-methoxyphenyl) amino} acetic acid (colorless amorphous).
    [159] Reference Example 8
    [160] To a chloroform solution of ethyl [(4-methoxyphenyl)-(tetrahydrothiopyran-4-carbonyl) amino] acetate, 3-chloro perbenzoic acid (> 65%; MCPBA) is added and stirred. After adding an aqueous sodium hydrogen carbonate solution to the reaction mixture, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give ethyl [(4-methoxyphenyl)-(1-oxo-tetrahydrothiopyran-4-carbonyl) amino] acetate (pale brown foamy material).
    [161] Reference Example 9
    [162] NaH was added to the DMF solution of ethyl 4-hydroxycyclohexanecarboxylate and 4-chlorobenzyl bromide and stirred. 10% ammonium chloride and ethyl acetate were added to the reaction solution, the organic layer was separated, washed and dried, and the solvent was evaporated under reduced pressure. The crude product obtained is purified by SCG to give ethyl 4-cis- (4-chlorobenzyloxy) cyclohexanecarboxylate, followed by ethyl 4-trans-4- (chlorobenzyloxy) cyclohexanecarboxylate. 1 M aqueous sodium hydroxide solution is added to the latter ethanol solution and stirred. After adding 1M hydrochloric acid to the reaction solution to make the liquid acidic, chloroform is added, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is washed with diisopropyl ether to give 4-trans- (4-chlorobenzyloxy) cyclohexanecarboxylate. One drop of DMF and oxalyl chloride are added to this dichloromethane solution, followed by stirring. The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, and benzyl [(4-methoxyphenyl) amino] acetate and TEA were added and stirred, followed by addition of phosphorus oxychloride and stirring. Saturated aqueous sodium hydrogen carbonate solution and chloroform are added to the reaction solution, and the organic layer is separated. The crude product obtained is purified by SCG. To this ethyl acetate solution is added 5% Pd-C and stirred under hydrogen atmosphere. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain [(4-trans-hydroxycyclohexanecarbonyl) (4-methoxyphenyl) amino] acetic acid (colorless solid).
    [163] Reference Example 10
    [164] MCPBA was added to the chloroform solution of ethyl [(4-methoxyphenyl)-(tetrahydrothiopyran-4-carbonyl) amino] acetate and stirred. After adding an aqueous sodium hydrogen carbonate solution to the reaction mixture, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG to give ethyl [(4-methoxyphenyl)-(1,1-dioxo-tetrahydrothiopyran-4-carbonyl) amino] acetate (white foamy material). .
    [165] Reference Example 11
    [166] Tert-butyl [4- (4- {2-[(9H-fluorene-9-ylmethoxycarbonyl)-(4-methoxyphenyl) amino] acetylamino} phenyl) thiazol-2-yl] carba Piperidine is added to the chloroform solution of the mate and stirred. Precipitated precipitate is washed after filtration to obtain tert-butyl (4- {4- [2- (4-methoxyphenylaminoacetylamino) phenyl] thiazol-2-yl} carbamate (white solid). .
    [167] Reference Example 12
    [168] To an ethanol solution of ethyl [(4-fluorobenzoyl)-(4-fluorophenyl) amino] acetate, 3M aqueous sodium hydroxide solution was added to reflux heating. The reaction solution is concentrated, 1M hydrochloric acid and chloroform are added to the residue, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. 4-aminoacephenone and WSC.HCl are sequentially added to the dichloromethane solution of the obtained carboxylic acid crude product, followed by stirring. 1 M hydrochloric acid is added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The obtained crude product is purified by SCG to give N-[(4-acetyl-phenylcarbamoyl) methyl] -4-fluoro-N- (4-fluorophenyl) benzamide (white foamy material). .
    [169] Reference Example 13
    [170] An aqueous 1 M sodium hydroxide solution was added to the ethanol solution of methyl N-[(4-acetylphenylcarbamoyl) methyl] -N- (4-fluorophenyl) terephthalamate, followed by heating to reflux. The reaction solution is concentrated, 1M hydrochloric acid and chloroform are added to the residue, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. Thionyl chloride and a small amount of DMF are added to the toluene suspension of the obtained carboxylic acid crude product and heated to reflux. After distilling off the solvent under reduced pressure, the residue was dissolved in dichloromethane and 28% ammonia water was added to the solution under ice-cooling, followed by stirring at the same temperature. The organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The obtained crude product is purified by SCG to give N-[(4-acetylphenylcarbamoyl) methyl] -N- (4-fluorophenyl) terephthalamide (pale yellow solid).
    [171] Reference Examples 14 to 99
    [172] In the same manner as in Reference Example 1 to the compounds of Reference Examples 14 to 38, 40 and 42 to 97 shown in Tables 2 to 6, the compounds of Reference Examples 39 and 41 shown in Table 2 in the same manner as Reference Example 2, In the same manner as in Reference Example 4, the compound of Reference Example 98 shown in Table 6 was also obtained in the same manner as Reference Example 12 to obtain the compounds of Reference Examples 99 and 100 shown in Table 7 below.
    [173] Example 1
    [174] To an ethanol (10 mL) solution of ethyl [(4-fluorobenzoyl) phenylamino] acetate (599 mg) was added 1M aqueous sodium hydroxide solution (2.3 mL), followed by stirring at room temperature for 5 hours. After adding 1M hydrochloric acid to the reaction solution to make the liquid acidic, water and chloroform are added to separate the organic layer. The organic layer is further dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The resulting carboxylic acid crude product was dissolved in DMF (15 mL), then 4- (4-aminophenyl) thiazol-2-yl amine dihydroiodide (831 mg), pyridine (0.23 mL), HOBt (0.3 g) , WSC.HCl (0.42 g) was added sequentially and stirred at room temperature for 22 hours. 1 M aqueous sodium hydroxide solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. The organic layer is further washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the solvent is distilled off under reduced pressure. The resulting crude product was purified by SCG (chloroform / methanol = 97/3) to give 451 mg of a yellow foamy substance. It was dissolved in chloroform-methanol (4 mL-1 mL) and 4M hydrogen chloride-ethyl acetate (0.38 mL) After the addition, the solvent was distilled off under reduced pressure. The obtained crude crystal was recrystallized from ethanol to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N-phenylbenzamide monohydrochloride (pale yellow) 270 mg of crystals) are obtained.
    [175] Example 2
    [176] Ethanol-chloroform of N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (4-methanesulfanylphenyl) benzamide (445 mg) MCPBA (0.35 g) is added to the (20mL-10mL) solution, followed by stirring at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (40 mL) and chloroform (10 mL) were added to the reaction solution, followed by stirring at room temperature for 5 hours. After adding chloroform to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained is purified by SCG (chloroform / methanol = 95/5) to give 217 mg of a yellow oily material. This is dissolved in chloroform-methanol (3 mL-3 mL), 4M hydrogen chloride-ethyl acetate (0.35 mL) is added, and then the solvent is distilled off under reduced pressure. The crude product obtained was washed with ethyl acetate to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (4-methanesulfinylphenyl 80 mg of benzamide monohydrochloride (pale yellow foamy material) is obtained.
    [177] Example 3
    [178] To a solution of ethyl ether (50 mL) of ethyl 4- [ethoxycarbonylmethyl (4-fluorobenzoyl) amino] benzoate (700 mg) was added potassium trimethylsilanolate (0.29 g, 90%), followed by 24 at room temperature. Stir for hours. The precipitate is collected by filtration and dissolved in water, 1M hydrochloric acid is added to make the liquid acidic, and chloroform is added to separate the organic layer. The organic layer is further dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The resulting carboxylic acid crude product was dissolved in DMF (10 mL), then 4- (4-aminophenyl) thiazol-2-ylamine dihydroiodide (358 mg), pyridine (0.09 mL), HOBt (0.16 g) , WSC.HCl (0.23 g) was added sequentially and stirred at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained is purified by SCG (chloroform / methanol = 98/2) to give 130 mg of a colorless foamy material. To a solution of this compound (62 mg) in chloroform-ethanol (2 mL-2 mL) was added 4M hydrogen chloride-ethyl acetate (0.1 mL), and then the solvent was distilled off under reduced pressure. The crude product obtained was washed with ethyl acetate to obtain ethyl 4-[({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl)-(4-fluorobenzoyl) amino] benzoate 1 42 mg of hydrochloride (amorphous solid) are obtained.
    [179] Example 4
    [180] To a ethanol (100 mL) solution of ethyl {4- [benzyloxycarbonylmethyl- (4-fluorobenzoyl) amino] phenoxy} acetate (6.4 g) was added 10% Pd-C (500 mg) and then under hydrogen atmosphere. Stir overnight at room temperature. Pd-C is filtered through Celite and the filtrate is concentrated. The resulting carboxylic acid crude product was dissolved in DMF (80 mL) and then 4- (4-aminophenyl) thiazol-2-ylamine dihydroiodide (5.5 g), pyridine (1.8 mL), HOBt (2.6 g) ), WSC-HCl (3.7 g) was added sequentially and stirred at room temperature for 3 hours. 10% aqueous potassium carbonate solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. In addition, the organic layer was washed twice with 5% brine, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The crude product obtained is purified by SCG (chloroform / methanol = 97/3 → 95/5) to give 2.0 g of a pale yellow foamy material. To a solution of this compound (900 mg) in chloroform-ethanol (20 mL-5 mL) was added 4M hydrogen chloride-ethyl acetate (0.6 mL), and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give ethyl {4- [N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-fluorobenzoyl) 540 mg of amino] phenoxy} acetate monohydrochloride (white crystals) are obtained.
    [181] Example 5
    [182] To an ethanol-THF (50 mL-10 mL) solution of ethyl {[4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl]-(4-fluorobenzoyl) amino} acetate (2.4 g) 1 M aqueous sodium hydroxide solution (9.9 mL) was added, and the mixture was heated and stirred at 60 ° C. for 1 hour. After the reaction solution was concentrated, 1M hydrochloric acid and chloroform were added to the residue, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The resulting carboxylic acid crude product was dissolved in DMF (50 mL), then 4- (4-aminophenyl) thiazol-2-ylamine dihydroiodide (1.5 g), pyridine (0.4 mL), HOBt (580 mg) , WSC · HCl (820 mg) was added sequentially and stirred at room temperature for 3 hours. 10% aqueous potassium carbonate solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. The organic layer was further washed twice with 5% brine, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The resulting crude product was dissolved in chloroform (30 mL), then trifluoroacetate (15 mL) was added and stirred at room temperature for 3 hours. After the reaction solution was concentrated, 10% aqueous potassium carbonate solution and chloroform were added to the residue, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol / 28% aqueous ammonia = 96/4 / 0.4 → 92/8 / 0.8) to give 210 mg of a pale yellow foamy material. This was dissolved in chloroform-ethanol (20 mL-5 mL), 4M hydrogen chloride-ethyl acetate (0.4 mL) was added, the solvent was distilled off under reduced pressure, and the obtained crude crystal was recrystallized from ethanol to obtain N-({[4- 170 mg of (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (4-piperazin-1-ylphenyl) benzamide trihydrochloride (white crystals) are obtained.
    [183] Example 6
    [184] Ethyl {4- [N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-fluorobenzoyl) amino] phenoxy} acetate (1.3 g) 1 M aqueous sodium hydroxide solution (2.4 mL) was added to an ethanol (30 mL) solution, followed by stirring at room temperature overnight. The reaction solution was concentrated, and then the obtained crude product was recrystallized from ethanol to give sodium {4- [N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- ( 680 mg of 4-fluorobenzoyl) amino] phenoxy} acetate (white crystals) are obtained.
    [185] Example 7
    [186] Ethanol (50 mL) solution of ethyl {[1- (tert-butyloxycarbonyl) -2,3-dihydro-1H-indol-6-yl] (4-fluorobenzoyl) amino} acetate (2.57 g) 1M aqueous sodium hydroxide solution (12 mL) was added thereto, and the mixture was stirred at room temperature for 5 hours. 1M hydrochloric acid (12 mL) is added to the reaction solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure after filtration. The obtained carboxylic acid derivative was dissolved in DMF (100 mL), 4- (4-aminophenyl) thiazol-2-ylamine dihydroiodide (2.24 g), pyridine (0.47 mL), HOBt (0.78 g), WSC-HCl (1.1 g) was added sequentially and stirred at room temperature for 18 hours. After adding 1M aqueous sodium hydroxide solution and ethyl acetate to the reaction solution, the organic layer was separated. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol = 98/2) to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N -[1- (tert-butyloxycarbonyl) -2,3-dihydro-1H-indol-6-yl] benzamide is obtained. This is dissolved in chloroform (20 mL), trifluoroacetic acid is added and stirred at room temperature for 20 minutes. The residue was diluted with ethyl acetate, washed with 1M aqueous sodium hydroxide solution, the organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate / hexanes / ethanol (12/4/1) to give 966 mg of a light brown solid. To this solid (398 mg) chloroform-ethanol (1/1) solution was added 4M hydrogen chloride-ethyl acetate (1 mL), and then the solvent was distilled off under reduced pressure. The obtained residue was washed with isopropyl alcohol and washed with N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (2,3-di 283 mg of hydro-1H-indol-6-yl) benzamide dihydrochloride (pale brown amorphous solid) are obtained.
    [187] Example 8
    [188] Ethyl {[1- (9H-fluorenyl-9-ylmethyloxycarbonyl) -1,2,3,4-tetrahydroquinolin-6-yl] (4-fluorobenzoyl) amino} acetate (2.21 g 5% Pd-C (0.22 g) is added to an ethyl acetate (70 mL) solution, and stirred for 3 hours at room temperature under a hydrogen atmosphere. The reaction solution is filtered through Celite and the solvent is distilled off under reduced pressure. The obtained carboxylic acid derivative was dissolved in DMF (50 mL), 4- (4-aminophenyl) thiazol-2-ylamine dihydroiodide (1.34 g), pyridine (0.27 mL), HOBt (0.47 g), WSC-HCl (0.67 g) was added sequentially and stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. The organic layer is dried over anhydrous sodium sulfate and filtered, and then the solvent is distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol = 98.5 / 1.5) to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N -[1- (9H-Fluorenyl-9-ylmethyloxycarbonyl) -1,2,3,4-tetrahydroquinolin-6-yl] benzamide is obtained. It is dissolved in pyrrolidine (12 mL) and stirred at room temperature for 2.5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by SCG (chloroform / methanol = 98/2) and washed with chloroform-ethyl acetate-hexane-ethanol (24/12/12/1) to obtain a colorless solid. do. To this solid (277 mg) solution of chloroform-ethanol (4 mL-4 mL) was added 4M hydrogen chloride-ethyl acetate (0.5 mL), and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from isopropyl alcohol, and N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1,2, 229 mg of 3,4-tetrahydroquinolin-6-yl) benzamide dihydrochloride (pale yellow crystals) are obtained.
    [189] Example 9
    [190] CDI (0.16 g) is added to a DMF (30 mL) solution of isonicotinic acid (0.12 g) and stirred at room temperature for 10 minutes. N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1,2,3,4-tetrahydroisoquinoline- in the reaction solution A solution of DMF (50 mL) of 7-yl) benzamide dihydrochloride (390 mg) was added at 0 ° C. and gently warmed to room temperature for 1 hour with stirring and stirred at room temperature for 1.5 hours. Ethyl acetate is added to the reaction solution, and the mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) -0.16 M aqueous solution of sodium hydroxide (5 mL), followed by saturated brine. The organic layer is dried over anhydrous sodium sulfate and filtered, and then the solvent is distilled off under reduced pressure. The crude product obtained is purified by SCG (chloroform / methanol = 95/5) to give 293 mg of colorless foamy material. This was dissolved in chloroform-methanol (10 mL-10 mL), 4M hydrogen chloride-ethyl acetate (1 mL) was added, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from isopropyl alcohol and N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- [2- (pyridine- 253 mg of 4-carbonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl] benzamide dihydrochloride (pale yellow crystals) are obtained.
    [191] Example 10
    [192] Tribromide phenyltrimethylammonium (1.1 g) was added to a THF (40 mL) solution of N-[(4-acetylphenylcarbamoyl) methyl] -N- (4-fluorophenyl) terephthalamide (1.1 g) at room temperature. Stir for 2 hours. The precipitate precipitated was filtered and the filtrate was concentrated to dissolve the residue in ethanol-THF (20 mL-10 mL), thiourea (200 mg) was added and then heated to reflux for 3 hours. The reaction solution was concentrated, and 5% aqueous potassium carbonate solution and chloroform were added to the residue, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol / 28% aqueous ammonia = 90/10/1 → 85/15 / 1.5) to give 380 mg of a pale yellow amorphous solid. This was subjected to a salt formation reaction with 4M hydrogen chloride-ethyl acetate, and then N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) terephthalamide 220 mg of monohydrochloride (pale yellow amorphous solid) are obtained.
    [193] Example 11
    [194] To a methanol (20 mL) solution of methyl N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) terephthalamate (800 mg) 1M aqueous sodium hydroxide solution (1.5 mL) was added and heated to reflux for 4 hours. To the residue obtained by concentrating the reaction solution, ethanol (20 mL) and diisopropyl ether (10 mL) were added to precipitate crystals. After filtering this crystal, sodium N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) by washing with diisopropyl ether 530 mg of terephthalamate (white crystals) are obtained.
    [195] Example 12
    [196] DMF of N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-methoxymethoxy-N- (4-methoxyphenyl) benzamide (1.1 g) 6M hydrochloric acid (2mL) was added to the (20mL) solution, and the mixture was stirred at room temperature for 3 hours. 10% aqueous potassium carbonate solution and ethyl acetate are added to the reaction solution, and the organic layer is separated. In addition, the organic layer was washed twice with 5% brine, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol = 97/3 → 95/5) to give 630 mg of white crystals. To the chloroform-ethanol (20 mL-5 mL) solution of this crystal is added 4M hydrogen chloride-ethyl acetate (0.5 mL), and then the solvent is distilled off under reduced pressure. The obtained crude crystal was recrystallized from ethanol to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-hydroxy-N- (4-methoxyphenyl) 470 mg of benzamide monohydrochloride (white crystals) are obtained.
    [197] Example 13
    [198] {((1-tert-Butyloxycarbonyl-4-piperidine) carbonyl] (4-methoxyphenyl) amino} 4- (4-aminophenyl) in a DMF (50 mL) solution of acetic acid (1.20 g) ) Thiazol-2-ylamine dihydroiodide (1.03 g), pyridine (0.20 mL), HOBt (0.39 g), and WSC.HCl (0.58 g) were added sequentially and stirred at room temperature for 3 days. Ethyl acetate and 1 M aqueous sodium hydroxide solution were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The crude product obtained is purified by SCG (chloroform / methanol = 98.5 / 1.5). Trifluoroacetic acid (20 mL) was added to a chloroform (20 mL) solution of the obtained amide derivative, stirred at room temperature for 10 minutes, and then the solvent was evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with 1M aqueous sodium hydroxide solution. The precipitate during washing is dissolved in chloroform-methanol (9/1) and washed with water. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The crude product obtained is recrystallized from ethanol-ethyl acetate to give 160 mg of colorless crystals. This crystal is dissolved in chloroform-ethanol (20 mL-20 mL), 4M hydrogen chloride-ethyl acetate (0.3 mL) is added, and the solvent is distilled off under reduced pressure. The foamed material obtained was azeotrope with ethanol and then dried to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl)- 150 mg of 4-piperidinecarboxamide dihydrochloride (pale yellow foamy material) is obtained.
    [199] Example 14
    [200] Tribrominated phenyltrimethylammonium (2.4 g) in THF (40 mL) solution of N-[(4-acetylphenylcarbamoyl) methyl] -4-fluoro-N- (4-fluorophenyl) benzamide (2.0 g) Was added and stirred at room temperature for 2 hours. Precipitated precipitate was filtered, the filtrate was concentrated and the residue obtained was dissolved in ethanol (40 mL), thioacetamide (480 mg) was added, followed by heating under reflux for 1 hour. The reaction solution was concentrated, and 1M sodium hydroxide solution and chloroform were added to the residue, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained crude product was purified by SCG (hexane / ethyl acetate = 2/3), and 4-fluoro-N- (4-fluorophenyl) -N-({[4- (2-methylthiazole-4 1.1 g of -yl) phenyl] carbamoyl} methyl) benzamide (white crystals) are obtained.
    [201] Example 15
    [202] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1,3-benzodioxol-5-yl) -4-fluorobenzamide (480 mg Pyridine (0.32 mL) and acetic anhydride (0.28 mL) were added to a chloroform (20 mL) solution, followed by stirring at room temperature for 14 hours. Further, pyridine (0.32 mL), acetic anhydride (0.28 mL) and DMAP (5 mg) were added to the reaction solution, followed by stirring at room temperature for 2 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate and washed sequentially with 1M hydrochloric acid, water, 1M aqueous sodium hydroxide solution, water, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer is dried over anhydrous sodium sulfate and filtered, and then the solvent is distilled off under reduced pressure. The crude product obtained was washed with chloroform-methanol (1/1) followed by ethanol to give N-({[4- (2-acetylaminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1 190 mg of, 3-benzodioxol-5-yl) -4-fluorobenzamide (colorless solid) is obtained.
    [203] Example 16
    [204] N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1,3-benzodioxol-5-yl) -4-fluorobenzamide (750 mg ) And N- (tert-butoxycarbonyl) glycine (0.35 g) were added sequentially with HOBt (0.27 g) and WSC.HCl (0.38 g) in a DMF (10 mL) solution and stirred at room temperature for 55 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained crude product was purified by SCG (hexane / ethyl acetate = 60/40 → 40/60) to give tert-butyl ({[4- (4- {2-[(1,3-benzodioxol-5) 670 mg of -yl)-(4-fluorobenzoyl) amino] acetylamino} phenyl) thiazol-2-yl] carbamoyl} methyl) carbamate (yellow foamy material) are obtained. This compound (640 mg) is dissolved in trifluoroacetic acid-chloroform (8 mL-8 mL) and stirred at room temperature for 10 minutes. After distilling off the solvent of the reaction solution under reduced pressure, the residue was dissolved in chloroform-methanol (10/1) and washed sequentially with 0.1M aqueous sodium hydroxide solution and water. The organic layer is further dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The crude product obtained was purified by SCG (chloroform / methanol = 98/2) to give 330 mg of a pale yellow foamy material. This is dissolved in chloroform-methanol (8 mL-8 mL), 4M hydrogen chloride-ethyl acetate (0.45 mL) is added, and then the solvent is distilled off under reduced pressure. The obtained crude crystal was recrystallized from methanol to obtain N-[({4- [2- (2-aminoacetylamino) thiazol-4-yl] phenyl} carbamoyl) methyl] -N- (1,3-benzo 196 mg of dioxol-5-yl) -4-fluorobenzamide monohydrochloride (colorless crystals) are obtained.
    [205] Example 17
    [206] N-{[4- (2-aminothiazol-4-yl) phenylcarbamoyl] methyl} -4-fluoro-N- (4-fluorophenyl) benzamide monohydrochloride (200 mg) acetic acid (10 mL) , Dissolved in a mixed solvent of water (5 mL), bromine (20 μl) was added under ice-cooling, and then stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate (30 mL) -saturated sodium hydrogen carbonate water (20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), 4M hydrogen chloride-ethyl acetate solution (0.15 mL) was added, the precipitated solid was collected by filtration and dried, and then recrystallized from methanol-ether to obtain N-{[4- (2-amino 184 mg of -5-bromothiazol-4-yl) phenylcarbamoyl] methyl} -4-fluoro-N- (4-fluorophenyl) benzamide monohydrochloride (colorless powder) is obtained.
    [207] Example 18
    [208] Methanol-chloroform of N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-6-yl-4-oxocyclohexanecarboxyamide (430 mg) Sodium borohydride (0.19 g) was added to the solution (40 mL-20 mL) at 0 ° C, and stirred for 1 hour at room temperature. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained crude product is purified by SCG (chloroform / methanol / 27% aqueous ammonia = 94.8 / 5 / 0.2). This was dissolved in chloroform-methanol (10 mL-10 mL), 4M hydrogen chloride-ethyl acetate (1 mL) was added, and the solvent was distilled off under reduced pressure. The obtained crude crystal was recrystallized from isopropyl alcohol-ethyl acetate (3/1) to give N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothia 259 mg of zol-6-yl-4-hydroxycyclohexanecarboxyamide monohydrochloride (pale yellow crystals) is obtained.
    [209] Examples 19-121
    [210] In the same manner as in Example 1, the compounds of Examples 19 to 46, 49 to 62, 64 to 103, and 105 to 121 shown in Tables 8 to 18 are obtained. In the same manner as in Example 4, the compounds of Examples 47 to 48 were obtained, and the compounds of Example 63 were obtained in the same manner as in Example 7, and the compounds of Example 104 were obtained in the same manner as in Example 16. do.
    [211] Example 121 Synthesis by Permutation Combination Chemistry: General Synthesis
    [212] Various acids in a pyridine (1.0 mL) solution of tert-butyl (4- {4- [2- (4-methoxyphenylaminoacetylamino) phenyl] thiazol-2-yl} carbamate (13.8 mg, 30 μmol) Chloride or sulfonylchloride is added and stirred for 1 to 12 hours at room temperature to 70 [deg.] C. PS-trisamine [see: Scavenger / Resin manufactured by Argonnot, support amount 3.0-5.0 mmol / g] 30 to 50 mg of the solution was stirred at room temperature for 2 to 5 hours to capture excess acid chloride or sulfonyl chloride and chloride ions PS-trisamine was removed by filtration, and pyridine was distilled off from the filtered solution under reduced pressure. N-({[4- (2-tert-butoxycarbonylaminothiazol-4-yl) phenyl] carbamoyl} methyl) free of almost pyridine salts) -N- (4-methoxyphenyl 10-50 mg of amide or sulfonamide derivatives are obtained.
    [213] 0.5 to 2 mL of 4M hydrogen chloride-ethyl acetate or 50% trifluoroacetic acid-methylene chloride is added thereto, and the mixture is stirred for 1 to 4 hours under ice-cooling to room temperature. The solvent was distilled off to remove N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) amide or sulfonamide derivatives. 10-50 mg is obtained as roacetate.
    [214] Purity is confirmed by liquid chromatography, and low purity products are treated by liquid chromatography (methanol / 5 mM trifluoroacetic acid aqueous solution). When eluting from the column, mass spectrometry is performed at the same time to collect only the eluate containing the compound having the desired molecular weight. The solvent is distilled off to obtain the target compound having improved purity.
    [215] <Synthesis example of compound: a-1>
    [216] O-toluoyl in a pyridine (1.0 mL) solution of tert-butyl (4- {4- [2- (4-methoxyphenylaminoacetylamino) phenyl] thiazol-2-yl} carbamate (13.8 mg) Chloride (10 μl) was added and stirred for 1.5 h at 60 ° C. 33 mg of PS-trisamine (support 4.61 mmol / g) was added and stirred at room temperature for 3 hours to give excess o-toluoyl chloride and chloride ions. PS-trisamine is filtered off, and pyridine is distilled off from the filtered solution under reduced pressure N-({[4- (2-tert-butoxycarbonylamino) containing almost no pyridine salt 16.4 mg of thiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) -4-methylbenzamide were added, to which 4M hydrogen chloride-ethyl acetate (1.0 mL) was added, Stir at room temperature for 2.5 hours Solvent distilled off to remove N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) -4 Methylbenzamide hydrochloric acid To afford 17.5mg.
    [217] Likewise, the compounds of a-2 to a-28 shown in Table 19 below and the compounds of b-1 to b-70 shown in Tables 20 and 21 are obtained as hydrochloride or trifluoroacetic acid salts.
    [218] The physicochemical properties of the reference example compounds are shown in Tables 2 to 7, and the structures and physicochemical properties of the example compounds are shown in Tables 8 to 21. Tables 22 to 25 specifically show other compounds included in the present invention. Such compounds can be easily prepared in the same manner as described in the above Examples or Production Methods, or by applying some modifications apparent to those skilled in the art.
    [219] The symbol in the table is Ref: Reference Example; Ex: Example; Co: compound number; Str: structural formula; Sal: salt; Dat: Physical and chemical properties {F: FAB-MS (M + ); F +: FAB-MS [(M + H) + ]; F-: FAB-MS [(MH) - ]; A +: APCI (atmospheric pressure chemical ionization) -MS [(M + H) + ]; E +: ESI (electrospray ionization) -MS [(M + H) + ]; N1: characteristic peak δ ppm of 1 H-NMR (DMSO-d 6 , TMS internal standard); N 2: characteristic peak δ ppm of 1 H-NMR (CDCl 3 , TMS internal standard); Ph: phenyl; Pr: n-propyl; iPr: isopropyl; Ac: acetyl; Bn: benzyl: tBu: tert-butyl; iBu: isobutyl; Bu: n-butyl; cBu: cyclobutyl; Py2: 2-pyridyl; Py3: 3-pyridyl; Py4: 4-pyridyl; Th2: 2-thienyl; Th3: 3-thienyl; Fu: 2-furyl; Pyr: 2-pyrazinyl; Naph1: 1-naphthyl; Naph2: 2-naphthyl; cPen: cyclopentyl; cHex: cyclohexyl; Hep 4: 4-heptyl; Pipe: 4-piperidinyl; Pyrr: 2-pyrrolyl; Pyra: 3-pyrazolyl; Ind 3: 3-indolyl; And Ind5: 5-indolyl, respectively. In addition, the number in front of the substituent indicates a substitution position, for example, 3,4-Cl 2 -F-Ph represents a 3,4-dichloro-5-fluorophenyl group.
    [220]
    [221]
    [222]
    [223]
    [224]
    [225]
    [226]
    [227]
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    [229]
    [230]
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    [243]
    [124] The compound of formula (I) of the present invention has an anti-VZV action and is a medicament, in particular a viral agent such as an anti-herpes virus agent, for the prevention of shingles associated with regression of chickenpox (bleeding) and latent VZV associated with VZV infection or It is useful for treatment.
    [125] In addition, the compound of the present invention, in terms of having the inhibitory activity of the replication of other herpes viruses (HSV-1, HSV-2, etc.), the genitals involved in the infection of the labia herpes, viral encephalitis, HSV-2, accompanied by HSV-1 infection It can be applied also to the prevention or treatment of various herpes virus infections, such as herpes, and is useful as a general purpose anti-herpes virus agent.
    [126] The pharmacological action of the compound of the present invention is confirmed by the following pharmacological test.
    [127] Test Example 1. VZV replication inhibition test
    [128] The experiment is carried out according to the method described in the literature (Shigeta S. The Journal of Infectious Diseases, 147, 3,576-584, (1983)). Specifically, 10,000 HEF cells are seeded in 96-well microtiter plates using a growth medium, and cultured at 37 ° C. under 5% CO 2 for 4 days until monolayer. Cells are washed in maintenance medium and then inoculated with 100 μl / well of VZV (CaQu strain) diluted in maintenance medium to 20-30 pfu / 1000 μl. Plates are centrifuged at 2000 rpm for 20 minutes at room temperature and then warmed for 3 hours at 37 ° C., 5% CO 2 to infect VZV. Wash three times in 100 μl / well of maintenance medium, then add 100 μl of the appropriate concentration of test agent diluted in maintenance medium to each well. Cells are incubated at 37 ° C. under 5% CO 2 for 3-4 days, then 100 μl / well of 10% formalin / PBS is added to fix the cells for 2-3 hours. The fixed solution and the culture supernatant were discarded, and the plate was washed with water, and then, 50 µl / well of staining solution (0.025% crystal violet) was added, stained for 2 to 3 minutes, and washed with water to dry the plate at 37 ° C. Following replication of VZV, infected HEF cells cause cell death, and plaques of dead cells in monolayer HEF cells are formed. The number of plaques is measured under a microscope, and the EC 50 value of the test agent is calculated as a concentration which inhibits the plaques by 50%.
    [129] EC 50 values (μM) of the compounds of the present invention are shown in the table below. The compound of the present invention has a good VZV replication inhibitory effect as compared to acyclovir and known thiazolylphenyl derivatives (comparative compounds a and b).
    [130] Test compound EC 50 Test compound EC 50 Test compound EC 50Example 7 0.046 Example 21 0.062 Example 25 0.067 Example 32 0.094 Example 39 0.042 Example 40 0.038 Example 42 0.087 Example 43 0.031 Example 44 0.030 Example 50 0.059 Example 52 0.042 Example 53 0.065 Example 54 0.034 Example 55 0.055 Example 56 0.041 Example 58 0.049 Example 60 0.081 Example 61 0.046 Example 67 0.081 Example 76 0.095 Example 83 0.043 Example 85 0.090 Example 103 0.12 Example 104 0.52 Example 107 0.025 Example 109 0.049 Example 110 0.026 Example 112 0.040 Example 113 0.070 Example 114 0.028 Example 115 0.033 Example 116 0.065 Example 117 0.059 ACV 4.3 Comparative compound a 3.0 Comparative compound b 1.1
    [131] ACV: Acyclovir
    [132] Comparative Compounds a and b: Compounds Nos. 29 and 34 of Table 1 of WO 97/24343
    [133]
    [134] (Comparative Compound a) (Comparative Compound b)
    [135] Test Example 2 HSV-1 skin infection mouse model (in vivo test)
    [136] The in vivo action of the compounds of the invention is tested using a HSV-1 skin infected mouse model according to the method of H. Machida et al. (Antiviral Res. 1992 17 133-143). HSV-1 by injecting the skin of HR-1 hairless mouse with a needle several times laterally and horizontally into the area where virus fluid (HSV-1 WT-51 strain 1.5 × 10 4 PFU) was added dropwise. Infects. 25 mg / kg is administered orally twice a day for 5 days using a compound of the present invention (the compound of Example 49 or the compound of Example 87) as a methylcellulose suspension. The symptoms of skin lesions caused by HSV-1 infection are scored in seven stages, evaluated for 21 days, and the number of days of survival of the mice is examined.
    [137] As a result, in the placebo group, an increase in the score due to the worsening of the symptoms of the skin lesion is observed after 4 days of infection, and after 7 days, the average lesion score exceeds 6, and the days of survival thereof are 10 days or less. On the other hand, the compound administration group of the present invention almost completely inhibits the appearance of lesions, and the lesion score is 1 or less during the evaluation period. In addition, prolongation of survival days is confirmed, and no deaths during the evaluation period are observed.
    [138] As mentioned above, it is confirmed that the compound of this invention has favorable antiherpes viral action in vivo.
    [139] The pharmaceutical composition of the present invention containing at least one compound of the formula (I) as an active ingredient can be prepared according to a method commonly used using a pharmaceutical carrier, an excipient, and the like, which are commonly used in the art. The administration may be any form of oral administration by tablets, pills, capsules, granules, powders, solutions, or the like, or parenteral administration by injections such as intravenous injections, intramuscular injections, suppositories, eye drops, ointments, inhalants, and the like.
    [140] As solid compositions for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are mixed with one or more inert excipients such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate, and the like. . The composition may contain an inert additive such as a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a dissolution aid according to a conventional method. Tablets or pills can be coated with sugar or gastric or enteric coatings as needed.
    [141] Liquid compositions for oral administration contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water and ethanol. Such compositions may contain, in addition to inert solvents, solubilizers, wetting agents, auxiliaries such as suspending agents, sweetening agents, copulating agents, fragrances, preservatives.
    [142] Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. As an aqueous solvent, distilled water for injection and physiological saline are contained, for example. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, dissolution aids. These are sterilized by, for example, filtration through a bacterial retention filter, blending or irradiation of a bactericide. In addition, they can be used by preparing a sterile solid composition, dissolving and suspending it in sterile water or a sterile solvent for injection before use.
    [143] Typically, for oral administration, a daily dosage of about 0.001 to 50 mg / kg body weight, preferably 0.01 to 30 mg / kg, is suitable, and when administered intravenously, the daily dosage is about O.OOO1 per body weight. To 10 mg / kg is suitable, and it is administered once to several times a day. Dosage is appropriately determined in each case in consideration of symptoms, age, sex, and the like.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] Amide derivatives of formula (I) or salts thereof.

    In Formula I above,
    R 1 and R 2 are the same or different and are -H, -lower alkyl, -lower alkenyl, -lower alkynyl, -cycloalkyl, -cycloalkenyl, -NR a R b , -NR c -NR a R b , -NR c- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR c -C (= NH) -NR a R b ,-(nitrogen containing saturated heterocyclic which may be substituted by lower alkyl Cyclic), -lower alkylene-NR a R b , -lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR a COR b , -NR a CO-OR b ,- NR a CO-NR b R c , -NR a CO-lower alkylene-NR b R c , -NR a CO-lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl), -NR a SO 2 R b , -NR a SO 2 -NR b R c , -NR a SO 2 -lower alkylene-NR b R c , -NR a SO 2 -lower alkylene- (which may be substituted by lower alkyl Saturated heterocyclic nitrogen), -CONR a R b , -SO 2 NR a R b , -COOR a , -SO 2 R a , -CONR a -OR b , -OCOR a , -OR a , -halogen, —COR a , —NO 2 , —CN or —halogeno lower alkyl, wherein R a , R b and R c are the same or different, —H, —lower alkyl, —lower alkenyl, —lower alkynyl, -Cycloalkyl, -cycloalkenyl, -aryl, -5-6 membered monocyclic heteroaryl or -lower alkylene-aryl),
    A is aryl which may have a -substituent, heteroaryl which may have a substituent, saturated carbocyclic condensed aryl which may have a -substituent, or saturated heterocyclic condensed aryl which may have a -substituent, provided that it is a saturated carbon ring Condensed aryl and saturated heterocyclic condensed aryl are bonded to adjacent N atoms via the C atom of the aromatic ring,
    X is C0 or S0 2 ,
    R 3 is -alkyl which may have a substituent, alkenyl which may have a substituent, alkynyl which may have a substituent, cycloalkyl which may have a substituent, cycloalkenyl which may have a substituent, -substituent Aryl which may have, -heterocycle which may have a substituent, or -NR a R b wherein R a and R b are as defined above or an adjacent group -N (-A) -X-, wherein A And X is as defined above) or In which Y is O, S, a bond or CH 2 , R 3a is —H, cycloalkyl which may have a -substituent, cycloalkenyl which may have a -substituent, aryl which may have a -substituent, or -Heterocycle which may have a substituent, A 'and B are the same or different, a benzene ring which may have a substituent, and X is as defined above.
    [2" claim-type="Currently amended] The compound of claim 1, wherein R 1 and R 2 are the same or different, and -H, -lower alkyl, -lower alkenyl, -lower alkynyl, -NR a R b , -NR c -NR a R b ,- (Natural containing saturated heterocyclic which may be substituted by lower alkyl), -NR c -C (= NH) -NR a R b , -NR a COR b , -NR a CO-OR b , -NR a CO -NR b R c , -NR a CO-lower alkylene-NR b R c or -NR a CO-lower alkylene- (nitrogen containing saturated heterocyclic which may be substituted by lower alkyl),
    Aryl which may have 1 to 5 substituents selected from group D, heteroaryl which may have 1 to 5 substituents selected from group D, saturated carbon ring condensation which may have 1 to 5 substituents selected from group D Saturated heterocyclic condensed aryl which may have 1 to 5 substituents selected from aryl or D group,
    Cycloalkyl which R 3 may have 1 to 5 substituents selected from D group, cycloalkenyl which may have 1 to 5 substituents selected from D group, aryl which may have 1 to 5 substituents selected from D group , Saturated carbocyclic condensed aryl which may have 1 to 5 substituents selected from the D group, saturated heterocyclic condensed aryl which may have 1 to 5 substituents selected from the D group, 1 to 5 substituents selected from the D group A 5-8 membered monocyclic saturated heterocyclic which may have 1-5 substituents selected from heteroaryl or D group, which may have
    Wherein the D groups are-(-OR a , -SR a , -CN, -COOR a , -CONR a R b , -NR a R b and-(-lower alkyl, -lower alkylene-COOR a and -NR a lower alkyl which may have one or two substituents selected from nitrogen-containing saturated heterocyclics which may have a substituent selected from a R b ), -lower alkenyl, -lower alkynyl, -halogeno lower alkyl, -5 1-6 membered monocyclic heteroaryl, -cycloalkyl, -cycloalkenyl, -aryl, -NR a R b , -NR c -NR a R b ,-(-lower alkyl, -lower alkylene-COOR a And a nitrogen-containing saturated heterocyclic which may have a substituent selected from -NR a R b ), -NR c -(-lower alkyl, -lower alkylene-COOR a and -NR a R b which may have a substituent selected from Nitrogen-containing saturated heterocyclic), -O-lower alkylene-NR a R b , -O-lower alkylene-(-lower alkyl, -lower alkylene-COOR a and -NR a R b Quality Saturated heterocyclic), -O-lower alkylene-OR a , -O-lower alkyl-COOR a , -COOR a , -halogen, -COR a , -NO 2 , -CN, -OR a ,- O- (halogeno lower alkyl), -SR a , -SOR a , -SO 2 R a , -CO-NR a R b , -CO-(-lower alkyl, -lower alkylene-COOR a and -NR a Nitrogen-containing saturated heterocyclic which may have a substituent selected from R b ), —NR a —COR b , —SO 2 NR a R b and amide derivative that is = 0 (oxo) or a salt thereof.
    [3" claim-type="Currently amended] The amide derivative or salt thereof according to claim 1, wherein X is CO.
    [4" claim-type="Currently amended] The amide derivative or salt thereof according to claim 1, wherein R 1 is -NH 2 and R 2 is -H.
    [5" claim-type="Currently amended] The compound of claim 1, wherein N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (2,3-dihydro-1H-indole -6-yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1,2,3,4- Tetrahydroquinolin-6-yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (2,3-dihydro-1,4 -Benzodioxin-6-yl) -4-fluorobenzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N- (1,3- Benzodioxol-5-yl) -4-fluorobenzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazole-5- Il-4-fluorobenzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-6-yl-4-fluorobenz Amide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N-indan-5-yl benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (3-ha Idroxyindan-5-yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (1H-indole-5 -Yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N- (3-oxo-3,4-dihydro -2H-1,4-benzothiazin-6-yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -4-fluoro-N -(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) benzamide, N-({[4- (2-aminothiazol-4-yl) phenyl] Carbamoyl} methyl) -N- (1,2,3-benzothiadiazol-5-yl) -4-fluorobenzamide, N-({[4- (2-aminothiazol-4-yl) Phenyl] carbamoyl} methyl) -N- (4-methoxyphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide, N-({[4- (2-aminothiazole- 4-yl) phenyl] carbamoyl} methyl) -N-benzothiazol-5-yl-4-fluorocyclohexa-3-enecarboxamide, N-({[4- (2-aminothiazole-4 -Yl) phenyl] carbamoyl} methyl) -N-benzothiazol-5-yl-4,4 -Difluorocyclohexanecarboxamide and N-({[4- (2-aminothiazol-4-yl) phenyl] carbamoyl} methyl) -N-indan-5-yltetrahydro-2H-thiopyran Amide derivatives selected from -4-carboxamide 1,1-dioxide or salts thereof.
    [6" claim-type="Currently amended] A pharmaceutical composition comprising the amide derivative according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.
    [7" claim-type="Currently amended] The pharmaceutical composition according to claim 6, which is an anti-herpes virus agent.
    [8" claim-type="Currently amended] The pharmaceutical composition according to claim 7, which is an anti varicella zoster virus agent.
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    同族专利:
    公开号 | 公开日
    DE60112790T2|2006-05-18|
    CN1473157A|2004-02-04|
    AT302197T|2005-09-15|
    DE60112790D1|2005-09-22|
    US20040034232A1|2004-02-19|
    EP1340750B8|2005-10-19|
    CA2428184A1|2002-05-16|
    JP3913172B2|2007-05-09|
    EP1340750B1|2005-08-17|
    EP1340750A4|2004-01-21|
    JPWO2002038554A1|2004-03-18|
    EP1340750A1|2003-09-03|
    WO2002038554A1|2002-05-16|
    ES2247177T3|2006-03-01|
    CA2428184C|2010-03-30|
    US6949543B2|2005-09-27|
    AU1273402A|2002-05-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-11-10|Priority to JPJP-P-2000-00344354
    2000-11-10|Priority to JP2000344354
    2001-11-08|Application filed by 야마노우치세이야쿠 가부시키가이샤, 가부시키가이샤 소야쿠기쥬쓰겐큐쇼
    2001-11-08|Priority to PCT/JP2001/009790
    2003-06-09|Publication of KR20030045180A
    优先权:
    申请号 | 申请日 | 专利标题
    JPJP-P-2000-00344354|2000-11-10|
    JP2000344354|2000-11-10|
    PCT/JP2001/009790|WO2002038554A1|2000-11-10|2001-11-08|Amide derivatives|
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