Heterocyclic amides exhibiting and inhibitory activity at the vanilloid receptor 1(vr1)

A compound having the formula I

• wherein:
• ring P is C6-10aryl, C3-7cycloalkyl, C5-6-heteroaryl, which ring P may be fused with phenyl, C5-6-heteroaryl, C3-7cycloalkyl or C3-7heterocycloalkyl;
• R1 is NO2, NH2, halo, N(C1-6alkyl)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkylO, phenylC0-6alkyl, C5-6heteroarylC0-6alkyl, C3-7cycloalkylC0-6alkyl, C3-7heterocycloalkylC0-6alkyl, C1-6alkylOC0-6alkyl, C1-6alkylSC0-6alkyl or C1-6alkylNC0-6alkyl;
• n is 1, 2, 3, 4 or 5;
• X is O, S or N;
• R4 is H, C1-4alkyl, hydroxyC1-6alkyl or C1-6alkylOC1-6alkyl, or is absent when X is N;
• R3 is H, C1-6alkyl, C1-6haloalkyl, R5OC1-6alkyl, R5O(CO), R5CO, NR5R6CO, NR5R6C0-6alkyl, C2-6alkenylOC0-6alkyl or hydroxyC1-6alkyl;
• R5 and R6 are at each occurrence independently selected from H, C1-6alkyl, C6-10aryl, C5-6heteroaryl, C1-4alkylSO2 and C1-3alkylCO;
• R7 and R8 are independently selected from H, C1-6alkyl, halo, cyano, C1-6alkylOC0-6alkyl, OH, NO2 and COR9, N(R9)2;
• and
• R9 is H or C1-6alkyl;
• wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted with one or more A, where A at each occurrence is independently selected from OH, NO2, R9CO, R9O(CO), N(R9)2, R9S, R9SO2, halo or C1-6alkylOC0-6alkyl,
• or a salt, solvate or solvated salt thereof.

A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of compound having the formula I

• wherein:
• ring P is C6-10aryl, C3-7cycloalkyl, C5-6heteroaryl, which ring P may be fused with phenyl, C5-6heteroaryl, C3-7cycloalkyl or C3-7heterocycloalkyl;
• R1 is NO2, NH2, halo, N(C1-6alkyl)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkylO, phenylC0-6alkyl, C5-6heteroarylC0-6alkyl, C3-7cycloalkylC0-6alkyl, C3-7heterocycloalkylC0-6alkyl, C1-6alkylOC0-6alkyl, C1-6alkylSC0-6alkyl or C1-6alkylNC0-6alkyl
• n is 1,2, 3, 4 or 5;
• X is O, S or N;
• R4 is H, C1-4alkyl, hydroxyC1-6alkyl or C1-6alkylOC1-6alkyl, or is absent when X is N;
• R3 is H, C1-6alkyl, C1-6haloalkyl, R5OC1-6alkyl, R5O(CO), R5CO, NR5R6CO, NR5R6C0-6alkyl, C2-6alkenylOC0-6alkyl or hydroxyC1-6alkyl;
• R5 and R6 are at each occurrence independently selected from H, C1-6alkyl, C6-10aryl, C5-6heteroaryl, C1-4alkylSO2 and C1-3alkylCO;
• R7 and R8 are independently selected from H, C1-6alkyl, halo, cyano, C1-6alkylOC0-6alkyl, OH, NO2 and COR9, N(R9)2;
• and
• R9 is H or C1-6alkyl;
• wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted with one or more A, where A at each occurrence is independently selected from OH, NO2, R9CO, R9O(CO), N(R9)2, R9S, R9SO2, halo or C1-6alkylOC0-6alkyl,
• or a salt, solvate or solvated salt thereof,
• in association with one or more pharmaceutically acceptable diluents, excipients or inert carriers.

A method of treatment of VR1 mediated disorders, acute and chronic pain disorders, acute and chronic neuropathic pain, acute or chronic inflammatory pain, or respiratory diseases, comprising administering to a mammal a therapeutically effective amount of compound having the formula I

• wherein:
• ring P is C6-10aryl, C3-7cycloalkyl, C5-6heteroaryl, which ring P may be fused with phenyl, C5-6heteroaryl, C3-7cycloalkyl or C3-7heterocycloalkyl;
• R1 is NO2, NH2, halo, N(C1-6alkyl)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkylO, phenylC0-6alkyl, C5-6heteroarylC0-6alkyl, C3-7cycloalkylC0-6alkyl, C3-7heterocycloalkylC0-6alkyl, C1-6alkylOC0-6alkyl, C1-6alkylSC0-6alkyl or C1-6alkylNC0-6alkyl;
• n is 1,2,3,4 or 5;
• X is O, S or N;
• R4 is H, C1-4alkyl, hydroxyC1-6alkyl or C1-6alkylOC1-6alkyl, or is absent when X is N;
• R3 is H, C1-6alkyl, C1-6haloalkyl, R5OC1-6alkyl, R5O(CO), R5CO, NR5R6CO, NR5R6C0-6alkyl, C2-6alkenylOC0-6alkyl or hydroxyC1-6alkyl;
• R5 and R6 are at each occurrence independently selected from H, C1-6alkyl, C6 10aryl, C5-6heteroaryl, C1-4alkylSO2 and C1-3alkylCO;
• R7 and R8 are independently selected from H, C1-6alkyl, halo, cyano, C1-6alkylOC0-6alkyl, OH, NO2 and COR9, N(R9)2;
• and
• R9 is H or C1-6alkyl;
• wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted with one or more A, where A at each occurrence is independently selected from OH, NO2, R9CO, R9O(CO), N(R9)2, R9S, R9SO2, halo or C1-6alkylOC0-6alkyl,
• or a salt, solvate or solvated salt thereof.

A compound selected from the group consisting of

• Allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate;
• 4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Bromo-2-methyl-benzothiazol-5-ylamine, and
• 4-Chloro-2-methyl-benzothiazole-5-ylamine.

A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the group consisting of:

• 4-tert-Butoxy-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-iodobenzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-morpholin-4-ylbenzamide;
• N-{2-[(Allyloxy)methyl]-1,3-benzothiazol-5-yl}-4-morpholin-4-ylbenzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-propyl-1H-pyrazole-4-carboxamide;
• 1-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-3-methyl-1H-pyrazole-5-carboxamide;
• 4-(Ethoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-1H-pyrazole-5-carboxamide;
• 4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-2-methylbenzamide;
• 4-tert-Butoxy-N-(2-methyl-1,3-benzoxazol-5-yl)benzamide;
• N-(4-Bromo-2-methyl-1,3-benzothiazol-5-yl)-4-tert-butylbenzamide;
• 4-tert-Butyl-N-(4,7-dibromo-2-methyl-1,3-benzothiazol-5-yl)benzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
• 4-Iodo-N-(2-methyl-5-benzothiazolyl)benzamide;
• 4-(tert-Butoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• N-( 1,2-Dimethyl-1H-benzimidazol-5-yl)-4-iodobenzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-isopropoxybenzamide;
• 4-Bromo-2-chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 4-Bromo-2-fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(morpholin-4-ylmethyl)benzamide;
• 3-Fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(trifluoromethyl)benzamide;
• 4-tert-Butoxy-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 4-(tert-Butoxymethyl)-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 3-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;
• 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;
• 2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;
• 4-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;
• 3,4-Dimethyl-N-(2-methyl-benzothiazol-5-yl)-benzamide;
• 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• N-(2-Methyl-1,3-benzothiazol-5-yl)-6-trifluoromethyl-nicotinamide;
• N-(2-Methyl-1,3-benzothiazol-5-yl)-4-propyl-benzamide;
• 3-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 2,5-Dimethyl-furan-3-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 5-tert-Butyl-2-methyl-furan-3-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 4-Bromo-3-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 3,4-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 3-Chloro-2-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• Pyridine-2-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 2-Benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 3-Fluoro-4-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;
• 2-Fluoro-5-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;
• 4-Chloro-N-(2-methyl-benzothiazol-5-yl)-benzamide;
• 1-Phenyl-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 2,3-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;
• 3-Fluoro-4-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Ethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butyl-N-(2-methyl-1,3-benzooxazol-5-yl)-benzamide;
• Biphenyl-4-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 3-Bromo-thiophene-2-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 4-Bromo-2-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 2-Chloro-3,4-dimethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Amino-N-(2-methyl-1,3-benzothiazol-5-yl)-3-nitro-benzamide;
• N-(2-Methyl-1,3-benzothiazol-5-yl)-4-vinyl-benzamide;
• 4-Ethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Ethylsulfanyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Dimethylamino-naphthalene-1-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;
• 2-Fluoro-6-iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-Ethoxymethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• N-(2-Methyl-1,3-benzothiazol-5-yl)-4-trifluoromethoxy-benzamide;
• 4-Chloro-3-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butyl-N-(2-hydroxymethyl-1,3-benzothiazol-5-yl)-benzamide;
• 4-tert-Butyl-N-(2-{[(2-methoxypyridin-3-yl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;
• 4-tert-Butyl-N-[2-( 1-hydroxyethyl)-1,3-benzothiazol-5-yl]benzamide;
• 4-tert-Butyl-N-{2-[(1H-pyrazol-3-ylamino)methyl]-1,3-benzothiazol-5-yl}benzamide;
• 4-(1,1-Dimethylethyl)-N-[2-[[(4-nitrophenyl)amino]methyl]-5-benzothiazolyl]-benzamide;
• N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide;
• 4-tert-Butyl-N-(2-{[(methylsulfonyl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;
• N-{2-[(Acetylamino)methyl]-1,3-benzothiazol-5-yl}-4-tert-butylbenzamide;
• 5-[(4-tert-Butylbenzoyl)amino]-1,3-benzothiazole-2-carboxamide;
• N-1,3-Benzothiazol-5-yl-4-tert-butylbenzamide;
• 4-Chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 1-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-propyl-1H-pyrazole-4carboxamide;
• 1-(4-Chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
• N-(2,4-Dimethyl-1,3-benzothiazol-5-yl)-4-( 1-hydroxy-1-methylethyl)benzamide;
• 4-(Hydroxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;
• 4-tert-Butyl-N-(4-cyano-2-methyl-1,3-benzothiazol-5-yl)benzamide;
• 4-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]benzamide;
• 5-(4-tert-Butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylic acid, and
• 4-tert-Butyl-N-(2-methoxycarbonyl-1,3-benzothiazol-5-yl)-benzamide;
• or a salt, solvate or solvated salt thereof,
• in association with one or more pharmaceutically acceptable diluents, excipients or inert carriers.