(Oxime)carbamoyl fatty acid amide hydrolase inhibitors

Abstract

The present invention relates to novel oxime carbamyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase. These pharmaceutical compositions are useful for the treatment of conditions which can be effected by inhibiting fatty acid amide hydrolase including, but not limited to, neuropathic pain, emesis, anxiety, altering feeding behaviors, movement disorders, glaucoma, brain injury, and cardiovascular disease.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof,  
       wherein 
 A is represented by Formula II:  
                     
 wherein  
 a is 1 or 2;  
 R is C 1-16  alkoxy optionally substituted with phenyl, pyridyl or morpholinyl; phenyl optionally substituted with C 1-4  alkyl; phenoxy; phenyl-C 1-4  alkyloxy-; pyridyloxy; pyridyl-C 1-4  alkyloxy-; —N(H)—C(O)—C 1-16  alkyl; or —C(O)—N(H)—C 1-16  alkyl;  
 R 1  is a bond or a C 1-3  branched or linear aliphatic hydrocarbon; and  
 B is C 1-4 alkyl, indolyl, benzofuranyl, benzothienyl, dibenzofuranyl; dibenzothienyl, fluorenyl, carbazolyl, naphthyl, quinolinyl or isoquinolinyl, wherein each is optionally substituted with one or more of the same or different substituent selected from the group consisting of C 1-4  branched or linear aliphatic hydrocarbon, C 1-4  alkoxy, halo, haloalkyl, nitro and (C 1-3  alkyl) 0-2 amino-; or Formula IV:  
                     
 wherein  
 X is CH or nitrogen;  
 R 4  is C 1-4  branched or linear aliphatic hydrocarbon, C 1-4  alkoxy, halo, haloalkyl, nitro or amino; and  
 b is 0 to 3.  
 
     
     
         2 . (canceled)  
     
     
         3 . (canceled)  
     
     
         4 . (canceled)  
     
     
         5 . (canceled)  
     
     
         6 . The compound of  claim 1  wherein B is represented by Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is CH;  
 R 4  is halo; and  
 b is 1.  
 
     
     
         7 . The compound of  claim 1  wherein B is represented by Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is nitrogen; and  
 b is 0.  
 
     
     
         8 . The compound of  claim 1  wherein B is represented by Formula V:  
       
         
           
           
               
               
           
         
       
       wherein X is nitrogen.  
     
     
         9 . The compound of  claim 1  wherein B is represented by Formula IV or Formula V:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is CH or nitrogen,  
 R 4  is C 1-4  branched or linear aliphatic hydrocarbon, C 1-4  alkoxy, halo, haloalkyl or amino, and  
 b is 0 to 3.  
 
     
     
         10 . (canceled)  
     
     
         11 . (canceled)  
     
     
         12 . (canceled)  
     
     
         13 . (canceled)  
     
     
         14 . A compound of Formula VII:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof,  
       wherein 
 a is 1;  
 R is C 1-12  alkoxy;  
 R 4  is halo;  
 X is CH or nitrogen; and  
 b is 0 to 2,  
 with the proviso that when X is nitrogen then b is 0.  
 
     
     
         15 . The compound of  claim 14  wherein X is CH selected from the group consisting of: 
 (4-undecyloxy-phenyl)-carbamic acid phenyl ester;    (4-decyloxy-phenyl)-carbamic acid phenyl ester;    (4-dodecyloxy-phenyl)-carbamic acid phenyl ester;    (4-octyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester;    (4-octyloxy-phenyl)-carbamic acid phenyl ester;    (4-heptyloxy-phenyl)-carbamic acid phenyl ester; and    (4-decyloxy-phenyl)-carbamic acid 2-fluoro-phenyl ester.    
     
     
         16 . A compound of Formula VIII  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof,  
       wherein 
 a is 1;  
 R is C 1-12  alkoxy;  
 R 1  is a C 1-3  branched or linear aliphatic hydrocarbon;  
 R 4  is phenyl, C 1-3  alkoxy or halo;  
 X is CH or nitrogen; and  
 b is 2.  
 
     
     
         17 . The compound of  claim 16  wherein X is CH selected from the group consisting of: 
 (4-butoxy-benzyl)-carbamic acid 4-fluoro-phenyl ester;    pyridine-3-carbaldehyde, O-[[(4-butoxy-benzyl)am ino]carbonyl]oxime;    (4-butoxy-benzyl)-carbamic acid phenyl ester;    [1-(4-butoxy-phenyl)-propyl]-carbamic acid 2-fluoro-phenyl ester;    (4-butoxy-benzyl)-carbamic acid 2,4-difluoro-phenyl ester;    (4-butoxy-benzyl)-carbamic acid 4-methoxy-phenyl ester;    [1-(4-butoxy-phenyl)-propyl]-carbamic acid 4-fluoro-phenyl ester;    (4-butoxy-benzyl)-carbamic acid 2-fluoro-phenyl ester; and    (4-butoxy-benzyl)-carbamic acid 3-chloro-phenyl ester.    
     
     
         18 . A compound of Formula IX:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof,  
       wherein 
 a is 1;  
 R is C 1-12  alkoxy;  
 R 1  is a C 1-3  branched or linear aliphatic hydrocarbon; and  
 X is CH or nitrogen.  
 
     
     
         19 . The compound of  claim 18  selected from the group consisting of: 
 (4-butoxy-benzyl)-carbamic acid quinolin-6-yl ester;    (4-butoxy-benzyl)-carbamic acid naphthalen-2-yl ester;    [1-(4-butoxy-phenyl)-propyl]-carbamic acid quinolin-6-yl ester; and    (4-butoxy-benzyl)-carbamic acid naphthalen-1-yl ester.    
     
     
         20 . (canceled)  
     
     
         21 . A method of treating neuropathic pain, acute pain, chronic pain, emesis, anxiety, feeding behavior, movement disorders, glaucoma, brain injury, or cardiovascular disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined in  claim 1 .  
     
     
         22 . (canceled)  
     
     
         23 . (canceled)  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . (canceled)  
     
     
         27 . (canceled)  
     
     
         28 . (canceled)  
     
     
         29 . (canceled)  
     
     
         30 . (canceled)  
     
     
         31 . (canceled)  
     
     
         32 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in  claim 1  and a pharmaceutically acceptable carrier, adjuvant or diluent.