TRPV1 Vanilloid Receptor Antagonists With A Bicyclic Portion

Abstract

The invention discloses compounds of formula I wherein Y is a group of formula A, B, C, D, or E: and W, Q, n, R1, R2, R3, U1-U5, J and K have the meanings given in the description. The compounds of formula I are TRPV1 antagonists and are useful as active ingredients of pharmaceutical compositions for the treatment of pain and other conditions ameliorated by the inhibition of the vanilloid receptor TRPV1.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         Y is a group of formula A or B: 
       
       
         
           
           
               
               
           
         
         wherein: 
         J and K are independently NH or O; and 
         wherein: 
         W is NH, O, a bond or CH 2 ; 
         Q is NH, O, a bond or CH 2 ; 
         n is 0 or 1; 
         U 1 , U 2 , U 3 , U 4  and U 5  form an aromatic ring and are independently CH, N, O, S, or one of them may be absent; 
         R 1  and R 2  are independently selected from hydrogen, halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, which can be optionally substituted by OH, phenyl, heterocycle, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino, or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino; 
         R 3  is hydrogen or with n=1 is CH 2  and forms a cycle with R 1 ═CH 2  or ═CH 2 —CH 2 , 
         With the proviso that when n is 0, Q is NH and W is a bond, then Y is not A, and with the exclusion of the compounds 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acid benzyl ester and benzyl (7-oxo)-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate. 
       
     
     
         2 . The compound according to  claim 1  wherein Y is A and W and Q are NH, said compound having formula (IA) 
       
         
           
           
               
               
           
         
         wherein: 
         J and K are independently NH or 0; 
         n is 0 or 1; 
         U 1 , U 2 , U 3 , U 4  and U 5  form an aromatic ring and are independently CH, N, O, S, or one of them may be absent; 
         R 1  is hydrogen, halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, heterocycle, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino; 
         R 2  is halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino; 
         R 3  is hydrogen or when n=1 is CH 2  and forms a cycle with R 1 ═CH 2 . 
       
     
     
         3 . The compound according to  claim 2  wherein R 1  and R 2  are independently pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or 2-(dimethylamino)ethoxy. 
     
     
         4 . A compound selected from:
 1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(trifluoromethyl)-2-morpholinobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-fluorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-chloro-2-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2-(dimethylamino)-4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)-3-((pyridin-4-yl)methyl)urea   1-((6-chloropyridin-3-yl)methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(5-(trifluoromethyl-furan-2-yl)-methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea   1-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea   1-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[[2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[(4-tert-butylphenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methyl]urea   1-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[(4-tert-butyl-2-chloro-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-[(4-tert-butyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea   1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-fluoro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-chloro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-(trifluoromethyl)-2-morpholinobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea   1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea   1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea   1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea   
     
     
         5 . The compound according to  claim 1  wherein Y is A or B, W is NH, Q is a bond and R 3  is hydrogen, said compounds having formula (ID) or (IE), 
       
         
           
           
               
               
           
         
         wherein: 
         J and K are independently NH or O; 
         n is 0 or 1; 
         R 1  is hydrogen, halogen, trifluoromethyl, (C 1 -C 4 )alkyl, 
       
       (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino;
 R 2  is halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino. 
 
     
     
         6 . The compound according to  claim 5  wherein R 1  and R 2  are independently pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or 2-(dimethylamino)ethoxy. 
     
     
         7 . The compound according to  claim 1 ,  5  or  6  selected from:
 2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)acetamide; 
 2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)acetamide; and 
 2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)acetamide. 
 
     
     
         8 . The compound according to  claim 1  wherein Y is A Q is NH and R 3  is hydrogen, said compounds having formula (IG) 
       
         
           
           
               
               
           
         
         wherein: 
         J and K are independently NH or 
         W is O or a bond; 
         n is 0 or 1; 
         R 1  is hydrogen, halogen, trifluoromethyl, (C 1 -C 4 )alkyl, 
       
       (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino;
 R 2  is halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino; 
 with the proviso that when n is 0, Q is NH and W is a bond, then Y is not A. 
 
     
     
         9 . The compound according to  claim 8  wherein R 1  and R 2  are independently pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, or 2-(dimethylamino)ethoxy. 
     
     
         10 . A compound according to  claim 1 , selected from:
 N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide; and   N-(4-(trifluoromethyl)-2-morpholinobenzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide.   
     
     
         11 - 13 . (canceled) 
     
     
         14 . A method of treating a disease or condition ameliorated by inhibition of the vanilloid receptor TRPV1 selected from: pain associated with burns, post-operative pain, osteoarthritis, rheumatoid arthritis, headaches, dental pain, pelvic pain, migraine, mastalgia, visceral pain, neuropathy, irritable bowel syndrome, gastro-esophageal reflux disease, Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, urinary incontinence, urinary bladder hypersensitiveness, psoriasis, dermatitis, myocardial ischemia, hirsutism, alopecia, rhinitis, pancreatitis, vulvodynia, dry eye, anxiety or obesity, the method comprising administering an effective amount of a compound of  claim 1 , to a subject in need thereof. 
     
     
         15 . A method of treating Dry Eye comprising administering an effective amount of a compound of  claim 1 , to a subject in need thereof. 
     
     
         16 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         Y is a group of formula C, D, or E: 
       
       
         
           
           
               
               
           
         
         wherein: 
         J and K are O; and 
         wherein: 
         W is NH, O, a bond or CH 2 ; 
         Q is NH, O, a bond or CH 2 ; 
         n is 0 or 1; 
         U 1 , U 2 , U 3 , U 4  and U 5  form an aromatic ring and are independently CH, N, O, S, or one of them may be absent; 
         R 1  and R 2  are independently selected from hydrogen, halogen, trifluoromethyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis-(C 1 -C 4 )alkylamino, monocyclic ring system containing 0-4 heteroatoms independently selected from N and O, which can be optionally substituted by OH, phenyl, heterocycle, and wherein the alkyl chains of said (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, mono- or bis (C 1 -C 4 )alkylamino can be optionally substituted with an amino, mono- or bis-(C 1 -C 4 )alkylamino, morpholino, piperidino, pyrrolidino, or piperazino group, provided that there are at least two carbon atoms between the nitrogen atom of said group and the oxygen atom of the (C 1 -C 4 )alkoxy or the nitrogen atom of said mono- or bis-(C 1 -C 4 )alkylamino; 
         R 3  is hydrogen or with n=1 is CH 2  and forms a cycle with R 1 ═CH 2  or ═CH 2 —CH 2 ; with the proviso that when n is 0, Q is NH and W is a bond, then Y is not E, and with the exclusion of benzyl (7-oxo)-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate. 
       
     
     
         17 . A method of treating a disease or condition ameliorated by inhibition of the vanilloid receptor TRPV1 selected from: pain associated with burns, post-operative pain, osteoarthritis, rheumatoid arthritis, headaches, dental pain, pelvic pain, migraine, mastalgia, visceral pain, neuropathy, irritable bowel syndrome, gastro-esophageal reflux disease, Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, urinary incontinence, urinary bladder hypersensitiveness, psoriasis, dermatitis, myocardial ischemia, hirsutism, alopecia, rhinitis, pancreatitis, vulvodynia, dry eye, anxiety or obesity, the method comprising administering an effective amount of a compound of  claim 4 , to a subject in need thereof. 
     
     
         18 . A method of treating dry eye comprising administering an effective amount of a compound of  claim 4 , to a subject in need thereof. 
     
     
         19 . A method of treating a disease or condition ameliorated by inhibition of the vanilloid receptor TRPV1 selected from: pain associated with burns, post-operative pain, osteoarthritis, rheumatoid arthritis, headaches, dental pain, pelvic pain, migraine, mastalgia, visceral pain, neuropathy, irritable bowel syndrome, gastro-esophageal reflux disease, Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, urinary incontinence, urinary bladder hypersensitiveness, psoriasis, dermatitis, myocardial ischemia, hirsutism, alopecia, rhinitis, pancreatitis, vulvodynia, dry eye, anxiety or obesity, the method comprising administering an effective amount of a compound of  claim 16 , to a subject in need thereof. 
     
     
         20 . A method of treating dry eye comprising administering an effective amount of a compound of  claim 16 , to a subject in need thereof. 
     
     
         21 . A composition comprising the compound of  claim 1 ; and a pharmaceutically acceptable carrier. 
     
     
         22 . A composition comprising the compound of  claim 4 ; and a pharmaceutically acceptable carrier. 
     
     
         23 . A composition comprising the compound of  claim 16 ; and a pharmaceutically acceptable carrier.