Use of GALR3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods

Abstract

This invention is directed to indolone derivatives which are antagonists for the GALR3 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.

1 . 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 , —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 R 1  and R 2  are each independently H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , or —CN;  
 wherein R 3  is H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , —CN, —OR 6 , aryl or heteroaryl;  
 wherein R 5  is straight chained or branched C 1 -C 7  alkyl, —N(R 4 ) 2 , —OR 4  or aryl;  
 wherein R 6  is straight chained or branched C 1 -C 7  alkyl or aryl;  
 wherein B is C 3 -C 7  cycloalkyl, C 5 -C 7  cycloalkenyl, adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, indazolyl, benzimidazolyl, benzo[b]thiazolyl, purinyl, imidazo(2,1-b)thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3-benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, or phthalimidyl; provided however, if B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, indazolyl, benzimidazolyl, benzo[b]thiazolyl, purinyl, imidazo[2,1-b]thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3-benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1,8-napthyridinyl, pteridinyl, or phthalimidyl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following —F, —Cl, —Br, —I, —CN, methyl, ethyl or methoxy;  
 wherein n is an integer from 1 to 4 inclusive.  
 
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein A is aryl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl or —(CH 2 ) n —CC—R 4 ; wherein the aryl is substituted with —OH;  
   
   
       3 . The pharmaceutical composition  claim 1 , wherein A is aryl, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl; and 
 wherein aryl is substituted with —F, —Cl, —Br, —I, —NO 2 , —CN, straight chained or branched C 1 -C 7  alkyl, straight chained or branched C 1 -C 7  monofluoroalkyl, straight chained or branched C 1 -C 7  polyfluoroalkyl, straight chained or branched C 2 -C 7  alkenyl, straight chained or branched C 2 -C 7  alkynyl, C 3 -C 7  cycloalkyl, C 3 -C 7  monofluorocycloalkyl, C 3 -C 7  polyfluorocycloalkyl, C 5 -C 7  cycloalkenyl, —N(R 4 ) 2 , —OR 4 , —SR 4 , —OCOR 4 , —COR 4 , —NCOR 4 , —CO 2 R 4 , —CON(R 4 ) 2  or —(CH 2 ) n O(CH 2 ) m CH 3 .    
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein each of Y 1 , Y 2 , Y 3 , and Y 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, —CF 3 , —F, —Cl, —Br, —I, —OR 4 , —N(R 4 ) 2 , or —CON(R 4 ) 2 ; 
 wherein each R 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, —CF 3 , or phenyl;    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; and    wherein A′ is                          
   
   
       5 . The pharmaceutical composition of  claim 4 , wherein B is C 3 -C 7  cycloalkyl or adamantyl.  
   
   
       6 . The pharmaceutical composition of  claim 4 , wherein B is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, indazolyl, benzimidazolyl, benzo[b]thiazolyl, purinyl, imidazo[2,1-b]thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3-benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1,8-napthyridinyl, pteridinyl, or phthalimidyl.  
   
   
       7 . The pharmaceutical composition of  claim 4 , wherein B is aryl.  
   
   
       8 . The pharmaceutical composition of  claim 7 , wherein B is phenyl and the phenyl is optionally substituted with one or more of the following: —F, —Cl, —Br, —CF 3 , straight chained or branched C 1 -C 7  alkyl, —N(R 4 ) 2 , —OR 4 , —COR 4 , —NCOR 4 , —CO 2 R 4 , or —CON(R 4 ) 2 .  
   
   
       9 . The pharmaceutical composition of  claim 8 , wherein A is aryl.  
   
   
       10 . The pharmaceutical composition of  claim 9 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       11 . The pharmaceutical composition of  claim 7 , wherein A is A′ and A′ is  
     
       
         
         
             
             
         
       
     
   
   
       12 . The pharmaceutical composition of  claim 11 , wherein the compound is:  
     
       
         
         
             
             
         
       
     
   
   
       13 . 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 R 1  and R 2  are each independently H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , or —CN;  
 wherein R 3  is H, straight chained or branched C 1 -C 7  alkyl, —F, —Cl, —Br, —I, —NO 2 , —CN, —OR 6 , aryl or heteroaryl;  
 wherein R 5  is straight chained or branched C 1 -C 7  alkyl, —N(R 4 ) 2 , —OR 4  or aryl;  
 wherein R 6  is straight chained or branched C 1 -C 7  alkyl or aryl;  
 wherein B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, indazolyl, benzimidazolyl, benzo[b]thiazolyl, purinyl, imidazo[2,1-b]thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3-benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1,8-napthyridinyl, pteridinyl, or phthalimidyl; provided however, that the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following —F, —Cl, —Br, —I, —CN, methyl, ethyl or methoxy;  
 wherein n is an integer from 1 to 4 inclusive;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       14 . The compound of  claim 1 , wherein A is aryl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl or —(CH 2 ) n —CC—R 4 ; wherein the aryl is substituted with —OH;  
   
   
       15 . The compound of  claim 1 , wherein A is aryl, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl; and 
 wherein aryl is substituted with —F, —Cl, —Br, —I, —NO 2 , —CN, straight chained or branched C 1 -C 7  alkyl, straight chained or branched C 1 -C 7  monofluoroalkyl, straight chained or branched C 1 -C 7  polyfluoroalkyl, straight chained or branched C 2 -C 7  alkenyl, straight chained or branched C 2 -C 7  alkynyl, C 3  -C7 cycloalkyl, C 3 -C 7  monofluorocycloalkyl, C 3 -C 7  polyfluorocycloalkyl, C 5 -C 7  cycloalkenyl, —N(R 4 ) 2 , —OR 4 , —SR 4 , —OCOR 4 , —COR 4 , —NCOR 4 , —CO 2 R 4 , —CON(R 4 ) 2  or —(CH 2 ) n O(CH 2 ) m CH 3 .    
   
   
       16 . An enantiomerically and diastereomerically pure compound of  claim 15 .  
   
   
       17 . An enantiomerically or diastereomerically pure compound of  claim 15 .  
   
   
       18 . A pure Z imine isomer or a pure Z alkene isomer of the compound of  claim 15 .  
   
   
       19 . A pure E imine isomer or a pure E alkene isomer of the compound of  claim 15 .  
   
   
       20 . The compound of  claim 15 , 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; and 
 A′ is                          
   
   
       21 . The compound of  claim 20 , wherein each of Y 1 , Y 2 , Y 3 , and Y 4  is independently —H; straight chained or branched C 1 -C 7  alkyl, —CF 3 , —F, —Cl, —Br, —I, —OR 4 , —N(R 4 ) 2 , or —CON(R 4 ) 2 .  
   
   
       22 . The compound of  claim 21 , wherein A is aryl or aryl(C 1 -C 6 )alkyl.  
   
   
       23 . The compound of  claim 22 , wherein the compound is selected from the group consisting of: