Selective NPY (Y5) antagonists

Abstract

This invention is directed to triazine derivatives, bicyclic compounds and tricyclic compounds which are selective antagonists for a NPY (Y5) 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 provides a pharmaceutical composition made by combining a therapeutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. This invention 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. The invention further provides the use of a compound of the invention for the preparation of a pharmaceutical composition for treating an abnormality, wherein the abnormality is alleviated by decreasing the activity of a human Y5 receptor.

1 - 55 . (canceled)  
   
   
       56 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is F; Cl; Br; I; NR 3 R 4 ; or phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or a C 3 -C 7  cycloalkyl or cycloalkenyl; 
 wherein R 2  is NR 3 R 4 ;  
 wherein R 3  is independently H; —(CH 2 ) u YR 5 ; —(CH 2 ) t C(Y)NR 5 R 6 ; —(CH 2 ) n NR 5 C(Y)R 5 ; —(CH 2 ) t C(Y)R 7 ; —(CH 2 ) t CO 2 R 5 ; —(CH 2 ) n NR 5 R 6 ; —(CH 2 ) u CN; —C(Y)R 5 ; —C(Y)NR 5 R 6 ; —CO 2 R 5 ; straight chained or branched C 1 -C 7  alkyl; C 2 -C 7  alkenyl, or C 2 -C 7  alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl, C 1 -C 6  phenylalkyl, or C 1 -C 6  heteroarylalkyl; wherein the phenyl, C 1 -C 6  phenylalkyl, or C 1 -C 6  heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or a C 3 -C 7  cycloalkyl or cycloalkenyl;  
 wherein R 4  is independently H; —(CH 2 ) u YR 5 ; —(CH 2 ) t C(Y)NR 5 R 6 ; —(CH 2 ) u NR 5 C(Y)R 5 ; —(CH 2 ) t C(Y)R 7 ; —(CH 2 ) t CO 2 R 5 ; —(CH 2 ) u NR 5 R 6 ; —(CH 2 ) u CN; straight chained or branched C 1 -C 7  alkyl; straight chained or branched C 2 -C 7  alkenyl, or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl or C 1 -C 6  phenylalkyl; wherein the phenyl or C 1 -C 6  phenylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or a C 3 -C 7  cycloalkyl or cycloalkenyl;  
 or R 3  and R 4  taken together with the nitrogen atom to which they are attached are 1-azetidinyl, 1- pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl, wherein the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl is substituted with one or more of F, —CN, —(CH 2 ) n NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, a C 3 -C 7  cycloalkyl or cycloalkenyl, or phenyl or heteroaryl; wherein if —(CH 2 ) n NR 5 R 6 , —(CH 2 ) n YR 5 , or —(CH 2 ) n NR 5 C(Y)R 5  are in the 2-position, then n is not 0; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or a C 3 -C 7  cycloalkyl or cycloalkenyl;  
 or R 3  and R 4  taken together with the nitrogen atom to which they are attached are morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl, wherein the morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl is substituted with one or more straight chained or branched C 1 -C 7  alkyl or C 1 -C 7  phenylalkyl; and wherein the nitrogen atom of the piperazinyl or [1,4]diazepanyl ring is substituted with —(CH 2 ) u YR 5 ; —(CH 2 ) t C(Y)NR 5 R 6 ; —(CH 2 ) u NR 5 C(Y)R 5 ; —(CH 2 ) t C(Y)R 7 ; —(CH 2 ) t CO 2 R 5 ; —(CH 2 ) n NR 5 R 6 ; —(CH 2 ) u CN; —C(Y)R 5 ; —C(Y)NR 5 R 6 ; —CO 2 R 5 ; straight chained or branched C 1 -C 7  alkyl; C 2 -C 7  alkenyl, or C 2 -C 7  alkynyl; or C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl; C 1 -C 6  phenylalkyl; or C 1 -C 6  heteroarylalkyl; wherein the phenyl, C 1 -C 6  phenylalkyl, or C 1 -C 6  heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or C 3 -C 7  cycloalkyl or cycloalkenyl;  
 wherein each of R 5 , R 6  and R 7  is independently H; or straight chained or branched C 1 -C 7  alkyl;  
 wherein each n independently is an integer from 0 to 6 inclusive;  
 wherein each t independently is an integer from 1 to 4 inclusive;  
 wherein each u independently is an integer from 2 to 4 inclusive;  
 wherein Y is O or S;  
 wherein R 8  is  
                     
 provided that if R 8  contains a piperidinyl group and m is O, then the compound is not an alpha aminal containing compound;  
 wherein each of R 9  and R 10  is independently H; straight chained or branched C 1 -C 4  alkyl;  
 wherein R 11  is H or  
                     
 wherein R 12  is H;  
 wherein R 13  is independently H; —(CH 2 ) u YR 5 ; —(CH 2 ) t C(Y)NR 5 R 6 ; —(CH 2 ) u NR 5 C(Y)R 5 ; —(CH 2 ) t C(Y)R 7 ; —(CH 2 ) t CO 2 R 5 ; —(CH 2 ) u NR 5 R 6 ; —(CH 2 ) u CN; —C(Y)R 5 ; —C(Y)NR 5 R 6 ; —CO 2 R 5 ; straight chained or branched C 1 -C 7  alkyl; C 1 -C 7  alkyl substituted with one or more F or Cl; C 3 -C 7  cycloalkyl-C 1 -C 7  alkyl; straight chained or branched C 2 -C 7  alkenyl, or alkynyl; or C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl or C 1 -C 6  phenylalkyl; wherein the phenyl or C 1 -C 6  phenylalkyl may be substituted with one or more of F, Cl, —CN, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , a straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or C 3 -C 7  cycloalkyl or cycloalkenyl;  
 or R 12  and R 13  together with the amide linkage to which they are attached are pyrrolidinonyl or piperidonyl;  
 wherein R 14  is H; straight chained or branched C 1 -C 7  alkyl; F; or —(CH 2 ) n OR 5 ;  
 wherein R 15  is H, straight chained or branched C 1 -C 7  alkyl, or F;  
 wherein R 16  is phenyl, 1-naphthyl, quinolinyl, or 2,1,3-benzothiadiazolyl; wherein the phenyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO 2 , —NR 5 R 6 , —(CH 2 ) n NR 5 C(Y)R 5 , —SO 2 R 5 , —(CH 2 ) n C(Y)R 7 , —(CH 2 ) n YR 5 , —(CH 2 ) n C(Y)NR 5 R 6 , —(CH 2 ) n CO 2 R 5 , —(CH 2 ) n SO 2 NR 5 R 6 , ethylenedioxy, methylenedioxy, straight chained or branched C 1 -C 7  alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C 2 -C 7  alkenyl or alkynyl, or C 3 -C 7  cycloalkyl or cycloalkenyl;  
 wherein each m independently is an integer from 0 to 3 inclusive;  
 wherein each s independently is an integer from 1 to 6 inclusive;  
 wherein each p independently is an integer from 0 to 2 inclusive;  
 wherein each q independently is an integer from 1 to 2 inclusive;  
 wherein each r independently is an integer from 1 to 2 inclusive; and  
 wherein X is N or C;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       57 . A compound having the structure:  
     
       
         
         
             
             
         
       
       wherein each R 1  is independently H, F, Cl, Br, —CN, —OH, —NO 2 , —NR 5 R 6 , —SO 2 R 5 , —(CH 2 ) n OR 5 , —(CH 2 ) n CONR 5 R 6 , —(CH 2 ) n NR 5 COR 5 , perfluoroalkyl, polyfluoroalkyl, aminoalkyl, or straight chained or branched C 1 -C 7  alkyl;  
       wherein R 5  is independently H; or straight chained or branched C 1 -C 7  alkyl;  
       wherein R 6  is independently H; or straight chained or branched C 1 -C 7  alkyl;  
       wherein R 12  is H, straight chained or branched C 1 -C 7  alkyl, —(CH 2 ) u OR 17 , or —O(CH 2 ) u OR 17 ;  
       wherein R 13  is straight chained or branched C 1 -C 7  alkyl; C 1 -C 7  alkyl in which the C 2 -C 7  atoms may be optionally substituted with one or more F or Cl; C 3 -C 7  cycloalkyl-C 1 -C 7  alkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; or C 3 -C 7  cycloalkyl;  
       or R 12  and R 13  together with the amide linkage to which they are attached are pyrrolidinonyl, piperidonyl or oxazolidinonyl;  
       wherein R 17  is H, straight chained or branched C 1 -C 4  alkyl, perfluoroalkyl, or polyfluoroalkyl;  
       wherein each n independently is an integer from 0 to 6 inclusive;  
       wherein each r independently is an integer from 0 to 3 inclusive; and  
       wherein each u independently is an integer from 2 to 4 inclusive;  
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       58 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 56  and a pharmaceutically acceptable carrier.  
   
   
       59 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 57  and a pharmaceutically acceptable carrier.  
   
   
       60 . A method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of a human Y5 receptor comprising administering to the subject a therapeutically effective amount of a compound of  claim 56  to treat the subject's abnormality.  
   
   
       61 . The method of  claim 60 , wherein the abnormality is selected from the group consisting of an eating disorder, obesity and bulimia nervosa.  
   
   
       62 . The method of  claim 60 , wherein the abnormality is selected from the group consisting of a sexual disorder, a reproductive disorder, depression, an epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure and a sleep disturbance.  
   
   
       63 . A method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of a human Y5 receptor comprising administering to the subject a therapeutically effective amount of a compound of  claim 57  to treat the subject's abnormality.  
   
   
       64 . The method of  claim 63 , wherein the abnormality is selected from the group consisting of an eating disorder, obesity and bulimia nervosa.  
   
   
       65 . The method of  claim 63 , wherein the abnormality is selected from the group consisting of a sexual disorder, a reproductive disorder, depression, an epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure and a sleep disturbance.