Antagonists of the trpv1 receptor and uses thereof

Abstract

The present application is directed to compounds that are TRPV1 antagonictc and have formula (I) wherein variables Ar 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 , Y 2 , and Y 3 , are as defined in the description, which are useful for treating disorders caused by or exacerbated by vanilloid receptor activity.

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein
 L 1  is a bond, alkylene, or cycloalkyl; 
 Y 1  is —N(R b )— or —C(R 8a R 8b )—; 
 Y 2  is ═O, ═S or —N—CN; 
 Y 3  is —N(R c )—; 
 Ar 1  is aryl or heteroaryl when L 1  is cycloalkyl; or Ar 1  is a monocyclic heterocycle fused to an aryl or a monocyclic heterocycle fused to a monocyclic heteroaryl when L 1  is a bond or alkylene; 
 wherein each Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w , two R w  that are attached to the same carbon atom of the monocyclic heterocycle, together with the carbon atom to which they are attached, optionally form a monocyclic cycloalkyl ring wherein said monocyclic cycloalkyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of oxo, alkyl, and haloalkyl; 
 R 1  is hydrogen, hydroxy or alkoxy; 
 R w , R 2 , R 3 , R 4 , and R 5 , are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, nitro, R e OS(O) 2 —, R f R g N—, (R f R g N)alkyl, (R j R k N)carbonyl, (R j R k N)carbonylalkyl or (R j R k N)sulfonyl; 
 R 8a  is hydrogen or alkyl; 
 R 8b  is hydrogen or alkyl; or 
 R 8a  and R 8b  taken together with the carbon atoms to which they are attached, form a 3-6 membered cycloalkyl ring; 
 R b  and R c  are each independently hydrogen or alkyl; 
 R e  is alkyl, haloalkyl, aryl, or arylalkyl; 
 R f  and R g , at each occurrence, are each independently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, arylalkyl, arylcarbonyl, carboxyalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, or heteroarylcarbonyl; or 
 R f  and R g  taken together with the nitrogen atom to which they are attached form a heterocyclic ring; and 
 R j  and R k , at each occurrence, are each independently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, carboxyalkyl, cycloalkylalkyl, haloalkyl, or hydroxyalkyl. 
 
     
     
         2 . The compound according to  claim 1  wherein
 Y 1  is —N(R b )—; 
 Y 2  is O; and 
 Y 3  is —N(R c )—. 
 
     
     
         3 . The compound according to  claim 2 , wherein L 1  is cycloalkyl wherein the cycloalkyl is cyclopentyl or cyclohexyl. 
     
     
         4 . The compound of  claim 3 , wherein Ar 1  is phenyl. 
     
     
         5 . The compound according to  claim 4 , wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         6 . The compound according to  claim 5 , wherein
 R 1  is hydroxy; and   R 2 , R 3 , R 4 , and R 5  are hydrogen.   
     
     
         7 . The compound according to  claim 2 , wherein L 1  is a bond. 
     
     
         8 . The compound according to  claim 7 , wherein Ar 1  is a monocyclic heterocycle fused to a phenyl. 
     
     
         9 . The compound of  claim 8 , wherein
 R 1  is hydroxy;   R 2  is hydrogen, and   Ar 1  is 3,4-dihydro-2H-chromen-3-yl.   
     
     
         10 . The compound according to  claim 9  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         11 . The compound according to  claim 8 , wherein
 R 1  is hydroxy;   R 2  is hydrogen; and   Ar 1  is 3,4-dihydro-2H-chromen-4-yl.   
     
     
         12 . The compound according to  claim 11  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         13 . The compound according to  claim 7 , wherein
 Ar 1  is a monocyclic heterocycle fused to a bicyclic aryl;   R 1  is hydroxy; and   R 2  is hydrogen.   
     
     
         14 . The compound according to  claim 13  wherein Ar 1  is 3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl. 
     
     
         15 . The compound according to  claim 8 , wherein
 R 1  is hydroxy;   R 2  is hydrogen; and   Ar 1  is 1,2,3,4-tetrahydroquinolin-4-yl.   
     
     
         16 . The compound according to  claim 15  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         17 . The compound according to  claim 8 , wherein
 R 1  is hydroxy;   R 2  is hydrogen; and   Ar 1  is 1,2,3,4-tetrahydroquinolin-3-yl.   
     
     
         18 . The compound according to  claim 17  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         19 . The compound according to  claim 2  wherein L 1  is alkylene. 
     
     
         20 . The compound according to  claim 19 , wherein Ar 1  is a monocyclic heterocycle fused to a phenyl. 
     
     
         21 . The compound according to  claim 20 , wherein
 R 1  is hydroxy;   R 2  is hydrogen; and   Ar 1  is 3,4-dihydro-2H-chromen-2-yl, 3,4-dihydro-2H-chromen-3-yl, or 3,4-dihydro-2H-chromen-4-yl.   
     
     
         22 . The compound according to  claim 21  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         23 . The compound according to  claim 20 , wherein
 R 1  is hydroxy;   R 2  is hydrogen; and   Ar 1  is 1,2,3,4-tetrahydro-quinolin-2-yl, 1,2,3,4-tetrahydro-quinolin-3-yl, or 1,2,3,4-tetrahydro-quinolin-4-yl.   
     
     
         24 . The compound according to  claim 23  wherein Ar 1  is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w  and each R w  is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f  and R g  are each independently hydrogen, alkyl, or haloalkyl. 
     
     
         25 . The compound according to  claim 1  selected form the group consisting of:
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea; 
 N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-3,4-dihydro-2H-chromen-3-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(8-tert-butyl-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(7-methoxy-3,4-dihydro-2H-chromen-3-yl)urea; 
 N-(6-chloro-3,4-dihydro-2H-chromen-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-3,4,7,8,9,10-hexahydro-2H-benzo[h]chromen-4-yl-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(6-methyl-3,4-dihydro-2H-chromen-4-yl)urea; 
 N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(3,4-dihydro-2H-chromen-2-ylmethyl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-[(7-ethoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(6-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(8-isopropyl-3,4-dihydro-2H-chromen-2-yl)methyl]urea; 
 N-(8-tert-butyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]urea; 
 N-(1-benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]urea; 
 N-[(1-benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-{[1-benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl]methyl}urea; 
 N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{(3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea; and 
 N-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea. 
 
     
     
         26 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 
     
     
         27 . The pharmaceutical composition according to  claim 26  further including a non-toxic pharmaceutically acceptable carrier and diluent. 
     
     
         28 . A method of treating a disorder, wherein the disorder is ameliorated by inhibiting TRPV1 activity, administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method according to  claim 28 , wherein the disorder is selected from the group of pain, neuropathic pain, migraine, ostheoarthritis pain, chronic lower pain, allodynia, pain associated with inflammation, bladder overactivity, and urinary incontinence.