Selective NPY (Y5) antagonists (triazines)

Abstract

This invention is directed to triazine derivatives which are selective antagonists for a NPY (Y5) receptor. 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.

What is claimed is:  
     
         1 . 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 1  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 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 C 2 -C 7  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, C1, 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 substitute, 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 7 , —(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 ) 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 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, a C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or a 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 is independently an integer from 0 to 6 inclusive;  
         wherein each t is independently an integer from 1 to 4 inclusive;  
         wherein each u is independently an integer from 2 to 4 inclusive;  
         wherein Y is O or S;  
         wherein R 8  is  
         
           
             
             
                 
                 
             
           
         
         provided teat if R 8  contains a piperidinyl group and m is O, then the compound is not an α-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 a 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 NR 3 R 4 , unsubstituted straight chained or branched C 2 -C 7  alkyl, substituted straight chained or branched C 1 -C 7  alkyl, wherein the C 1 -C 7  alkyl may be substituted with one or more of F, Cl, —CN, —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 )—OCF 3 , monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C 2 -C 7  alkenyl or C 2 -C 7  alkynyl, or C 3 -C 7  cycloalkyl or cycloalkenyl, phenyl, heteroaryl, or C 1 -C 7  phenylalkyl, wherein the phenyl, heteroaryl, or C 1 -C 7  phenylalkyl 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; quinolinyl, 1-naphthyl, 2-naphthyl, or 2,1,3-benzothiadiazolyl; with the provisos that when R 1  is F, Cl, Br, or I, then R 16  is 1-naphthyl; and when R 1  and R 2  are morpholinyl, then R 16  is not NR 3 R 4 ;  
         wherein each m is independently an integer from 0 to 3 inclusive;  
         wherein each s is independently an integer from 1 to 6 inclusive;  
         wherein each p is independently an integer from 0 to 2 inclusive;  
         wherein each q is independently an integer from 1 to 2 inclusive;  
         wherein each r is independently an integer from 1 to 2 inclusive;  
         wherein X is N or C;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein the compound comprises the (+) enantiomer.  
     
     
         3 . The compound of  claim 1 , wherein the compound comprises the (−) enantiomer.  
     
     
         4 . The compound of  claim 1 , wherein R 8  is  
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein R 1  is F, Cl, Br, I, or NR 3 R 4 .  
     
     
         6 . The compound of  claim 1 , wherein R 1  and R 2  are both NR 3 R 4  where R 3  and R 4  are independently H; 
 straight chained or branched C 1 -C 7  alkyl;    straight chained or branched C 2 -C 7  alkenyl or alkynyl; or R 3  and R 4  taken together with the nitrogen atom to which on they are attached are morpholinyl, piperazinyl, or 1-pyrrolidinyl, wherein the morpholinyl, piperazinyl, or 1-pyrrolidinyl 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 ring is substituted with 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; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl; C 1 -C 6  phenylalkyl; or C 1 -C 6  heteroarylalkyl.    
     
     
         7 . The compound of  claim 1 , 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.  
     
     
         8 . The compound of  claim 1 , wherein R 9  is H, R 10  is H, p is 1, and m is 1.  
     
     
         9 . The compound of  claim 4 , wherein R 1  is F, Cl, Br, I, or NR 3 R 4 .  
     
     
         10 . The compound of  claim 9 , wherein R 1  and R 2  are both NR 3 R 4 , where R 3  and R 4  are independently H; straight haired or branched C 1 -C 7  alkyl; straight chained or branched C 2 -C 7  alkenyl or alkynyl; or R 3  and R 4  taken together with the nitrogen atom to which they are attached are morpholinyl, piperazinyl, or 1-pyrrolidinyl, wherein the morpholinyl, piperazinyl, or 1-pyrrolidinyl 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 ring is substituted with 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; straight chained or branched C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl; C 1 -C 6  phenylalkyl; or C 1 -C 6  heteroarylalkyl.  
     
     
         11 . The compound of  claim 10 , 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.  
     
     
         12 . The compound of  claim 11 , wherein R 9  is H, R 10  is H, p is 1, and m is 1.  
     
     
         13 . The compound of  claim 1 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         17 . A pharmaceutical composition of  claim 16 , wherein the amount of he compound is an amount from about 0.01 mg to about 800 mg.  
     
     
         18 . A pharmaceutical composition of  claim 17 , wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg.  
     
     
         19 . A pharmaceutical composition of  claim 18 , wherein the amount of the compound is an amount from about 0.01 mg to about 250 mg.  
     
     
         20 . A pharmaceutical composition of  claim 19 , wherein the amount of the compound is an amount from about 0.1 mg to about 60 mg.  
     
     
         21 . A pharmaceutical composition of  claim 20 , wherein the amount of the compound is an amount from about 1 mg to about 20 mg.  
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein them carrier is a liquid and the composition is a solution.  
     
     
         23 . The pharmaceutical composition of  claim 16 , wherein the carrier is a solid and the composition is a tablet.  
     
     
         24 . The pharmaceutical composition of  claim 16 , wherein the carrier is a gel and the composition is a suppository.  
     
     
         25 . A pharmaceutical composition made by combining a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         26 . A process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.