Imidazo[1, 2-a] pyrazines for the treatment of irritable bowel syndrome

Abstract

Provided herein are methods for treating a subject afflicted with irritable bowel syndrome comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and a compound of the formula wherein: X is CHR 5 , NR 5 , O, S, S(O) n or a single bond, wherein n is equal to 0, 1 or 2; D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted at any available position with from 1-5 of A 1 , A 2 , A 3 , A 4 and A 5 ; and R 2 is C 1-4 alkyl or C 3-8 cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C 1-4 alkoxy, or wherein when X is a bond, R 2 is CN, CF 3 , or C 2 F 5 .

What is claimed is:  
     
         1 . A method of treating a subject afflicted with irritable bowel syndrome comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CHR 5 , NR 5 , O, S, S(O) n  or a single bond, wherein n is equal to 0, 1 or 2;  
 D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted at any available position with from 1-5 of A 1 , A 2 , A 3 , A 4  and A 5 ; A 1 , A 2 , A 3 , A 4  and A 5  are each independently H, C 1-6  alkyl, C 3-6  cycloalkyl, halo, C 1-4  haloalkyl, cyano, nitro, —OR 12 , SH, —S(O) n R 13 , —COR 12 , —CO 2 R 12 , —OC(O)R 13 , —NR 11 COR 12 , —N(COR 12 ) 2 , —NR 11 CONR 12 R 14 , or wherein A 1 , A 2 , A 3 , A 4  and A 5  are each independently phenyl or phenyl substituted with from 1 to 4 of C 1-3  alkyl, C 1-3  alkoxy, halo, cyano, dimethylamino, CF 3 , C 2 F 5 , OCF 3 , SO 2 Me or acetyl;  
 R 1  is C 1-10  alkyl, C 2 -10 alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, C 4-12  cycloalkylalkyl, NR 6 R 7  or —C(R 8 ) (R 9 )—O—R 10 ;  
 R 2  is C 1-4  alkyl or C 3-8  cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C 1-4  alkoxy, or wherein when X is a bond, R 2  is CN, CF 3 , or C 2 F 5 ;  
 R 3  and R 4  are independently H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-5  cycloalkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, halogen, CN, or NR 6 R 7 ;  
 R 5  is H, C 1-4  alkyl or C 3-8  cycloalkyl;  
 R 6  and R 7  are each independently H, C 1-4  alkyl, C 1-4  haloalkyl, C 2-8  alkoxyalkyl, C 3-6  cycloalkyl, C 4-12  cycloalkylalkyl, aryl, aryl(C 1-4  alkyl)-, heteroaryl or heteroaryl(C 1-4  alkyl)-;  
 R 8  and R 9  are each independently H or C 1-4  alkyl, or R 8  and R 9  are taken together as ═CH 2 ;  
 R 10  is H or C1-4 alkyl;  
 R 11  is H, C 1-4  alkyl, C 3-7  cycloalkyl, C 4-12  cycloalkylalkyl, phenyl or benzyl, each phenyl or benzyl optionally substituted on the aryl moiety with 1-3 groups of C 1-4  alkyl, halogen, C 1-4  haloalkyl, nitro, C 1-4  alkoxy, C 1-4  haloalkoxy, or dimethylamino; and,  
 R 12 , R 13  and R 14  are each independently H, C 1-6  alkyl, C 3-10  cycloalkyl, C 4-16  cycloalkylalkyl or C 1-4  haloalkyl.  
 
     
     
         2 . The method of  claim 1 , wherein X is a single bond.  
     
     
         3 . The method of  claim 1 , wherein D is phenyl.  
     
     
         4 . The method of  claim 3 , wherein the phenyl is  
       
         
           
           
               
               
           
         
       
       and wherein each of A 1 , A 2  and A 3  is independently H, C 1-6  alkyl, C 1-6  alkoxy, halogen, C 1-4  haloalkyl or OR 12 .  
     
     
         5 . The method of  claim 4 , wherein A 1  is H, CH 3  or Cl.  
     
     
         6 . The method of  claim 4 , wherein A 2  is Cl, —OCH 3  or —OCHF 2 .  
     
     
         7 . The method of  claim 4 , wherein A 3  is H or CH 3 .  
     
     
         8 . The method of  claim 4 , wherein: A 1  is H, CH 3  or Cl; A 2  is Cl, —OCH 3  or —OCHF 2  and A 3  is H or CH 3 .  
     
     
         9 . The method of  claim 1 , wherein R 1  is —C(R 8 )(R 9 )—O—R 10 .  
     
     
         10 . The method of  claim 9 , wherein each of R 8 , R 9  and R 10  are independently H or C 1-4  alkyl.  
     
     
         11 . The method of  claim 10 , wherein R 8  is H.  
     
     
         12 . The method of  claim 10 , wherein R 9  is C 2 H 5  or C 3 H 7 .  
     
     
         13 . The method of  claim 12 , wherein R 10  is H.  
     
     
         14 . The method of  claim 10 , wherein R 8  is H, R 9  is C 2 H 5  or C 3 H 7  and R 10  is H.  
     
     
         15 . The method of  claim 1 , wherein R 2  is unsubstituted C1-4 alkyl.  
     
     
         16 . The method of  claim 15 , wherein R 1  is C 2 H 5 .  
     
     
         17 . The method of  claim 1 , wherein each of R 3  and R 4  are H 18. The method of  claim 1 , wherein R 1  is —C(R 8 )(R 9 )—O—R 10 , R is unsubstituted C 1-4  alkyl, each of R 3  and R 4  is H, X is a single bond and D is phenyl of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 8  is H, R 9  is C 2 H 5  or C 3 H 7 , R 10  is H, each of Al, is H, A 2  is Cl, —OCH 3  or —OCHF 2  and A 3  is H.