Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof

Abstract

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. In an embodiment of the invention, the feeding disorder is bulimia, bulimia nervosa or obesity.

1 - 39 . (cancelled)  
     
     
         40 . A compound having the structure:  
       
         
           
           
               
               
           
         
         wherein each R is independently —H; —F; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; —N(R 3 ) 2 ; —NO 2 ; —CN; —CO 2 R 3 ; —OR 3 ; or -CON(R 3 ) 2 ;  
         wherein each R 1  is independently —H; F; Cl; Br; I; —NO 2 ; —N 3 ; —CN; 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, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; —N(R 3 ) 2 ; —OR 3 ; —(CH 2 ) p OR 3 ; —COR 3 ; —CO 2 R 3 ; —CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; —CON(R 3 ) 2 ; CN; —NO 2 ; —N(R 3 ) 2 ; —OR 3 ; —SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7  alkenyl, C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;  
         wherein each R 3  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, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;  
         wherein R 5  is —H; —NO 2 ; —N 3 ; —CN; 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, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; —N(R 3 ) 2 ; —OR 3 ; —(CH 2 ) p OR 3 ; —COR 3 ; —CO 2 R 3 ; —CON (R 3 )  2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; —CON (R 3 ) 2 ; CN; —NO 2 ; —N(R 3 )  2 ; —OR 3 ; —SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7  alkenyl, C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;  
         wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; —CON(R 3 ) 2 ; CN; —NO 2 ; —N(R 3 ) 2 ; —OR 3 ; —SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7  alkenyl, C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;  
         wherein W is 
 (a) C 3 -C 7  cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR 3 ; CO 2 R 3 ; —CON (R 3 ) 2 ; CN; —NO 2 ; —N(R 3 ) 2 ; —OR 3 ; —SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7  alkenyl, C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl; or  
 (b) aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; —CON (R 3 ) 2 ; CN; —NO 2 ; —N(R 3 ) 2 ; —OR 3 ; —SR 3 ; —(CH 2 ) q OR 3 ; —(CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7  alkenyl, C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl;  
 
         wherein each m is independently an integer from 0 to 3 inclusive;  
         wherein n is an integer from 0 to 2 inclusive;  
         wherein p is an integer from 1 to 7 inclusive;  
         wherein q is an integer from 1 to 3 inclusive;  
         wherein t is an integer from 2 to 6 inclusive;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         41 . The (+) enantiomer of the compound of  claim 40 .  
     
     
         42 . The (−) enantiomer of the compound of  claim 40 .  
     
     
         43 . The compound of  claim 40  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of  claim 43  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 44  wherein W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; CO 2 R 3 ; —CON(R 3 ) 2 ; CN; —NO 2 ; —N(R 3 ) 2 ; —OR 3 ; —SR 3 ; —(CH 2 ) q OR 3 ; —(CH 2 ) q SR 3 ; or straight chained or branched C 1 -C 7  alkyl groups.  
     
     
         46 . The compound of  claim 45  having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         47 - 81 . (cancelled)  
     
     
         82 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim , or  40  and a pharmaceutically acceptable carrier.  
     
     
         83 . The pharmaceutical composition of  claim 82 , wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg.  
     
     
         84 . The pharmaceutical composition of  claim 83 , wherein the amount of the compound is an amount from about 0.1 mg to about 60 mg.  
     
     
         85 . The pharmaceutical composition of  claim 84 , wherein the amount of the compound is an amount from about 1 mg to about 20 mg.  
     
     
         86 . The pharmaceutical composition of  claim 82 , wherein the carrier is a liquid and the composition is a solution.  
     
     
         87 . The pharmaceutical composition of  claim 82 , wherein the carrier is a solid and the composition is a tablet.  
     
     
         88 . The pharmaceutical composition of  claim 82 , wherein the carrier is a gel and the composition is a suppository.  
     
     
         89 . A pharmaceutical composition made by combining a therapeutically effective amount of the compound of  claim 40  and a pharmaceutically acceptable carrier.  
     
     
         90 . A process for making a pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 40  and a pharmaceutically acceptable carrier.  
     
     
         91 . A method of treating a subject from suffering from bulimia, obesity or bulimia nervosa which comprises administering to the subject an amount of a compound of  claim 40  and a pharmaceutically acceptable salt.  
     
     
         92 . A method of treating a subject from suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of  claim 40  and a pharmaceutically acceptable salt.