Amino-heterocycles as vr-1 antagonists for treating pain

摘要

the present invention provides a compound of formula (I): wherein V represents NR⁵, O, S, SO or S(O)₂; W and X each independently represent CH or N; Y represents N, CH or C-Ar₂, with the proviso that at least one, but no more than two, of W, X and Y are N; Z represents CH or C-Ar₂, with the proviso that when Y is N or CH then Z is C-Ar₂, and with the further proviso that when Y is C-Ar₂ then Z is CH; Ar₁ 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; Ar₂ represents an aromatic ring selected from phenyl, pyridyl, pyrimidinyl and pyridazinyl which is optionally fused and substituted; R¹ represents halogen, hydroxy, oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, haloC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkoxy, haloC_1-6alkoxy, hydroxyC_1-6alkoxy, C_3-7cycloalkyl, C_3-7cycloalkoxy, C_3-5cycloalkylC_1-4alkyl, cyano, nitro, SR⁶, SOR⁶, SO₂R⁶, COR⁶, NR³COR⁶, CONR³R⁴, NR³SO₂R⁶, SO₂NR³R⁴, -(CH₂)_mcarboxy, esterified -(CH₂)_mcarboxy or -(CH₂)_mNR³R⁴; R² represents hydrogen, halogen, hydroxy, C_1-6alkyl, haloC_1-6alkyl, C_3-7cycloalkyl, C_1-6alkoxy, haloC_1-6alkoxy, unsubstituted phenyl or phenyl substituted with one or two groups selected from halogen, C_1-6alkyl, haloC_1-6alkyl, C_3-7cycloalkyl, C_1-6alkoxy or haloC_1-6alkoxy; R³ and R⁴ are each independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl or fluoroC_1-6alkyl; or R³ and R⁴ 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_1-4alkoxy, which ring may optionally contain as one of the said ring atoms an oxygen or a sulfur atom, S(O), S(O)₂, or NR⁵; R⁵ represents hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; R⁶ represents hydrogen, C_1-6alkyl, fluoroC_1-6alkyl, C_3-7cycloalkyl, unsubstituted phenyl, or phenyl substituted with one or two groups selected from halogen, C_1-6alkyl, haloC_1-6alkyl, C_3-7cycloalkyl, C_1-6alkoxy or haloC_1-6alkoxy; 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.