Use of GAL3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods

Abstract

This invention is directed to pyrimidine and indolone derivatives which are selective antagonists for the GAL3 receptor. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and/or anxiety. This invention also provides a method of treating depression and/or anxiety in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist.

1 - 272 . (canceled) 
   
   
       273 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure: 
     
       
         
         
             
             
         
       
       wherein each of Y 1 , Y 2 , Y 3 , and Y 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl, or C 5 -C 7  cycloalkenyl; —F, —Cl, —Br, or —I; —NO 2 ; —N 3 ; —CN; —OR 4 , —SR 4 —OCOR 4 , —COR 4 , —NCOR 4 , —N(R 4 ) 2 , —CON(R 4 ) 2 , or —COOR 4 ; aryl or heteroaryl; or any two of Y 1 , Y 2 , Y 3  and Y 4  present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each R 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl, aryl or aryl(C 1 -C 6 )alkyl; 
       wherein A is A′, straight chained or branched C 1 -C 7  alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl; 
       wherein A′ is 
     
     
       
         
         
             
             
         
       
       wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ; 
       wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine 
       wherein Q 6  is 
     
     
       
         
         
             
             
         
       
       wherein n is an integer from 1 to 4 inclusive; 
       wherein each R 22  is independently H, F, Cl, or straight chained or branched C 1 -C 4  alkyl; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       274 . The pharmaceutical composition of  claim 273 , wherein the compound is an enantiomerically and diastereomerically pure compound. 
   
   
       275 . The pharmaceutical composition of  claim 273 , wherein the compound is a pure E imine isomer or a pure E alkene isomer. 
   
   
       276 . The pharmaceutical composition of  claim 273 , wherein the compound is a pure Z imine isomer or a pure Z alkene isomer. 
   
   
       277 . The pharmaceutical composition of  claim 273 , wherein the composition can be administered orally. 
   
   
       278 . The pharmaceutical composition of  claim 273 , wherein B is Q 6 . 
   
   
       279 . The pharmaceutical composition of  claim 278 , wherein A is aryl. 
   
   
       280 . The pharmaceutical composition of  claim 279 , wherein the compound has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       281 . The pharmaceutical composition of  claim 280 , wherein the compound is: 
     
       
         
         
             
             
         
       
     
   
   
       282 . A compound having the structure: 
     
       
         
         
             
             
         
       
       wherein each of Y 1 , Y 2 , Y 3 , and Y 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl, or C 5 -C 7  cycloalkenyl; —F, —Cl, —Br, or —I; —NO 2 ; —N 3 ; —CN; —OR 4 , —SR 4 —OCOR 4 , —COR 4 , —NCOR 4 , —N(R 4 ) 2 , —CON(R 4 ) 2 , or —COOR 4 ; aryl or heteroaryl; or any two of Y 1 , Y 2 , Y 3  and Y 4  present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each R 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl, aryl or aryl(C 1 -C 6 )alkyl; 
       wherein A is A′, straight chained or branched C 1 -C 7  alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl; 
       wherein A′ is 
     
     
       
         
         
             
             
         
       
       wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ; 
       wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine 
       wherein Q 6  is 
     
     
       
         
         
             
             
         
       
       wherein n is an integer from 1 to 4 inclusive; 
       wherein each R 22  is independently H, F, Cl, or straight chained or branched C 1 -C 4  alkyl; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       283 . An enantiomerically and diastereomerically pure compound of  claim 282 . 
   
   
       284 . A pure E imine isomer or a pure E alkene isomer of the compound of  claim 282 . 
   
   
       285 . A pure Z imine isomer or a pure Z alkene isomer of the compound of  claim 282 . 
   
   
       286 . The compound of  claim 282 , wherein B is Q 6 . 
   
   
       287 . The compound of  claim 286 , wherein A is aryl. 
   
   
       288 . The compound of  claim 287 , wherein the compound has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       289 . The compound of  claim 288 , wherein the compound is: