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    • 8. 发明申请
    • AMINO-HETEROCYCLES AS VR-1 ANTAGONISTS FOR TREATING PAIN
    • AMINO-HETEROCYCLES作为VR-1拮抗剂治疗疼痛
    • WO2004046133A1
    • 2004-06-03
    • PCT/GB2003/004969
    • 2003-11-14
    • MERCK SHARP & DOHME LIMITEDBLURTON, PeterBURKAMP, FrankFLETCHER, Stephen, RobertHOLLINGWORTH, Gregory, JohnJONES, A., BrianMCIVER, Edward, GilesMOYES, Christopher, RichardROGERS, Lauren
    • BLURTON, PeterBURKAMP, FrankFLETCHER, Stephen, RobertHOLLINGWORTH, Gregory, JohnJONES, A., BrianMCIVER, Edward, GilesMOYES, Christopher, RichardROGERS, Lauren
    • C07D401/12
    • C07D401/12C07D401/14C07D403/12C07D405/14C07D471/04
    • the present invention provides a compound of formula (I): wherein V represents NR 5 , O, S, SO or S(O) 2 ; W and X each independently represent CH or N; Y represents N, CH or C-Ar 2 , with the proviso that at least one, but no more than two, of W, X and Y are N; Z represents CH or C-Ar 2 , with the proviso that when Y is N or CH then Z is C-Ar 2 , and with the further proviso that when Y is C-Ar 2 then Z is CH; Ar 1 represents a fused 9 or 10 membered heterobicyclic ring system containing one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, wherein at least one of the rings in said ring system is aromatic; Ar 2 represents an aromatic ring selected from phenyl, pyridyl, pyrimidinyl and pyridazinyl which is optionally fused and substituted; R 1 represents halogen, hydroxy, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 3-5 cycloalkylC 1-4 alkyl, cyano, nitro, SR 6 , SOR 6 , SO 2 R 6 , COR 6 , NR 3 COR 6 , CONR 3 R 4 , NR 3 SO 2 R 6 , SO 2 NR 3 R 4 , -(CH 2 ) m carboxy, esterified -(CH 2 ) m carboxy or -(CH 2 ) m NR 3 R 4 ; R 2 represents hydrogen, halogen, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, unsubstituted phenyl or phenyl substituted with one or two groups selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy or haloC 1-6 alkoxy; R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or fluoroC 1-6 alkyl; or R 3 and R 4 and the nitrogen atom to which they are attached together form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C 1-4 alkoxy, which ring may optionally contain as one of the said ring atoms an oxygen or a sulfur atom, S(O), S(O) 2 , or NR 5 ; R 5 represents hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl or C 1-4 alkoxyC 1-4 alkyl; R 6 represents hydrogen, C 1-6 alkyl, fluoroC 1-6 alkyl, C 3-7 cycloalkyl, unsubstituted phenyl, or phenyl substituted with one or two groups selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy or haloC 1-6 alkoxy; m is either zero or an integer from 1 to 4; n is either zero or an integer from 1 to 3; or a pharmaceutically acceptable salt, N-oxide or a prodrug thereof; a pharmaceutical composition comprising it; its use in methods of treatment; use of it for the manufacture of a medicament for treating VR-1 related conditions such as those in which pain and/or inflammation predominate; and methods of treatment using it.
    • 本发明提供式(I)化合物:其中V表示NR 5,O,S,SO或S(O)2; W和X各自独立地表示CH或N; Y表示N,CH或C-Ar2,条件是W,X和Y中至少一个,但不超过两个为N; Z表示CH或C-Ar2,条件是当Y为N或CH时,则Z为C-Ar2,进一步条件是当Y为C-Ar 2时,Z为CH; Ar 1表示含有选自氮,氧和硫的一个,两个,三个或四个杂原子的稠合的9或10元杂双环体系,其中所述环系中的至少一个环是芳族的; Ar2表示任选稠合和取代的选自苯基,吡啶基,嘧啶基和哒嗪基的芳环; R 1表示卤素,羟基,氧代,C 1-6烷基,C 2-6烯基,C 2-6炔基,卤代C 1-6烷基,羟基C 1-6烷基,C 1-6烷氧基,卤代C 1-6烷氧基,羟基C 1-6烷氧基,C 3-7环烷基,C 3-7环烷氧基 ,C 3-8环烷基C 1-4烷基,氰基,硝基,SR 6,SOR 6,SO 2 R 6,COR 6,NR 3 COR 6,CONR 3 R 4,NR SO 2 R 6,SO 2 NR 3 R 4, - (CH 2)m羧基,酯化 - (CH 2)m羧基或 - (CH 2)m NR 3 R 4; R 2表示氢,卤素,羟基,C 1-6烷基,卤代C 1-6烷基,C 3-7环烷基,C 1-6烷氧基,卤代C 1-6烷氧基,未取代的苯基或被一个或两个选自卤素,C 1-6烷基,卤代C C 1-6烷基,C 3-7环烷基,C 1-6烷氧基或卤代C 1-6烷氧基; R 3和R 4各自独立地为氢,C 1-6烷基,C 2-6烯基,C 2-6炔基,C 3-7环烷基或氟C 1-6烷基; 或R 3和R 4并且它们所连接的氮原子一起形成4至7个环原子的杂脂肪族环,任选地被一个或两个选自羟基或C 1-4烷氧基的基团取代,该环可任选地被 含有所述环原子之一为氧或硫原子,S(O),S(O)2或NR 5; R 5表示氢,C 1-4烷基,羟基C 1-4烷基或C 1-4烷氧基C 1-4烷基; R 6表示氢,C 1-6烷基,氟C 1-6烷基,C 3-7环烷基,未取代的苯基或被一个或两个选自卤素,C 1-6烷基,卤代C 1-6烷基,C 3-7环烷基,C 1-6烷氧基或C 1-6烷基的基团取代的苯基 haloC1-6alkoxy; m为零或1至4的整数; n为0或1至3的整数; 或其药学上可接受的盐,N-氧化物或其前药; 包含它的药物组合物; 其用于治疗方法; 使用它来制造用于治疗VR-1相关病症的药物,例如其中疼痛和/或炎症占优势的病症; 和治疗方法