Trpv1 antagonists including dihydroxy substituent and uses thereof

Abstract

The disclosure relates to Compounds of Formula (I) and pharmaceutically acceptable derivatives thereof, where R 1 , R 4 , R 8 , R 9 , and m are as defined herein, compositions comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS, comprising administering to an animal in need thereof an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  is -halo or —CF 3 ; 
 R 4  is —H or —CH 3 ; 
 each R 8  and R 9  is independently —H, -halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OR 10 ; 
 R 10  is —(C 1 -C 4 )alkyl; 
 each halo is independently —F, —Cl, —Br, or —I; and 
 m is the integer 0 or 1; 
 (1) provided that if R 4  is —H then m is 1; and 
 (2) provided that if R 4  is —H and the carbon atom at the a position of the a-b bond is in the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group; 
 (3) if R 4  is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8  is —H, and R 9  is -halo, then the methyl group bonded to the piperazine ring is a (R)-3-methyl group; 
 (4) if R 4  is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8  is —F, and R 9  is —F, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methyl group; and 
 (5) if R 4  is —CH 3  the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration, R 8  is —H, R 9  is -halo, and m is 1, then the methyl group bonded to the piperazine ring is a (S)-3-methyl group or a (R)-3-methyl group. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable derivative thereof, wherein R 1  is —F, —Cl, or —CF 3 . 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable derivative thereof, wherein R 1  is —F. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable derivative thereof, wherein R 9  is —H, —F, —Cl, —Br, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OCH 2 CH 3 . 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable derivative thereof, wherein R 8  is —H, —F, or —CH 3 . 
     
     
         9 - 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, radiolabeled form, a co-crystal, or a combination thereof. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein the pharmaceutically acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal. 
     
     
         19 - 22 . (canceled) 
     
     
         23 . The compound of  claim 1  or a pharmaceutically acceptable derivative thereof, which is 
       
         
           
           
               
               
           
         
       
     
     
         24 - 28 . (canceled) 
     
     
         29 . A composition comprising the compound of  claim 1  or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient. 
     
     
         30 - 35 . (canceled) 
     
     
         36 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein:
 R 4  is —H or —CH 3 ; 
 R 8  is —H, —F, or —CH 3 ; 
 R 9  is —H, -halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , or —C(O)OCH 2 CH 3 ; and 
 each halo is independently —F, —Cl, —Br, or —I; 
 (1) provided that if R 4  is —H and the carbon atom at the a position of the a-b bond is in the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group; 
 (2) if R 4  is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8  is —H, and R 9  is -halo, then the methyl group bonded to the piperazine ring is a (R)-3-methyl group; 
 (3) if R 4  is —H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R 8  is —F, and R 9  is —F, then the methyl group bonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methyl group; and 
 (4) if R 4  is —CH 3  the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration, R 8  is —H, and R 9  is -halo, then the methyl group bonded to the piperazine ring is a (S)-3-methyl group or a (R)-3-methyl group. 
 
     
     
         37 . (canceled) 
     
     
         38 . The compound of  claim 36  or a pharmaceutically acceptable derivative thereof, wherein R 4  is —CH 3  and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration. 
     
     
         39 . The compound of  claim 36  or a pharmaceutically acceptable derivative thereof, wherein R 4  is —CH 3  and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (R) configuration. 
     
     
         40 - 44 . (canceled) 
     
     
         45 . The compound of  claim 36 , wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, or a fumarate co-crystal. 
     
     
         46 . The compound of  claim 36 , wherein the pharmaceutically acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal. 
     
     
         47 - 59 . (canceled) 
     
     
         60 . The compound of  claim 36  or a pharmaceutically acceptable derivative thereof, which is 
       
         
           
           
               
               
           
         
       
     
     
         61 - 69 . (canceled) 
     
     
         70 . A composition comprising the compound of  claim 36  or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient. 
     
     
         71 - 76 . (canceled) 
     
     
         77 . A compound which is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof. 
     
     
         78 . A composition comprising the compound of  claim 77  or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient. 
     
     
         79 - 84 . (canceled)