Pharmaceutical compositions containing an N-(substituted glycyl)-2- cyanopyrrolidine and at least one other antidiabetic agent and their use in inhibiting dipeptidyl peptidase-IV

Abstract

The present invention relates to certain N-(substituted glycyl)-2-cyanopyrrolidines of formula I wherein Y is as defined herein, in free form or in acid addition salt form. Compounds of formula I inhibit DPP-IV (dipeptidyl-peptidase-IV) activity. They are therefore indicated for use as pharmaceuticals in inhibiting DPP-IV and in the treatment of conditions mediated by DPP-IV, such as non-insulin-dependent diabetes mellitus, arthritis, obesity, osteoporosis and further conditions of impaired glucose tolerance.

What is claimed is:  
     
         1 . A compound of formula i:  
       
         
           
           
               
               
           
         
       
       where Y is: 
 a) a group of the formula  
                     
 where R is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C 1-6 alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is mono- or di-substituted on the phenyl ring by halo or C 1-6 alkyl;  
 b) a group of the formula  
                     
 where R 1  is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C 1-6 alkyl; C 1-6 alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C 1-6 alkyl;  
 c) a group of the formula  
                     
 , where R 2  is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo or C 1-6 alkyl;  
 d) a group of the formula  
                     
 , where R 3  is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-6 -alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; C 3-8  cycloalkylcarbonyl;  
 unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C 1-6 alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is mono- or di-substituted on the phenyl ring by halo or C 1-6 alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is mono- or di-substituted by halo or C 1-6 alkoxy;  
 e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or a group of the formula  
                     
 , where R 4  is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl;  
 and wherein the bond containing the wavy line signifies the point of attachment of the “Y” group to the glycyl-2-cyanopyrrolidine moiety;  
 or an acid addition salt thereof.  
 
     
     
         2 . A compound according to  claim 1  of formula Ia:  
       
         
           
           
               
               
           
         
       
       where Y′ is: 
 a) a group of the formula  
                     
 , where R′ is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl or cyano; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C 1-6  alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C 1-6 alkyl;  
 b) a group of the formula  
                     
 , where R 1  is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C 1-6  alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-6 -alkyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C 1-6 alkyl; C 1-6 alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C 1-6 alkyl;  
 c) a group of the formula  
                     
 , where R 2 ′ is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo or C 1-6 alkyl;  
 d) a group of the formula  
                     
 , where R 3 ′ is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; C 3-8 cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C 1-6 alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by halo or C 1-6 alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by halo or C 1-6 alkoxy;  
 e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or  
 f) a group of the formula  
                     
 , where R 4 ′ is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C 1-6 alkyl;  
 or an acid addition salt thereof.  
 
     
     
         3 . A compound according to  claim 2  of formula Ib:  
       
         
           
           
               
               
           
         
       
       where Y″ is: 
 a) a group of the formula  
                     
 , where R″ is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono-substituted by halo, trifluoromethyl or cyano or di-substituted by halo; unsubstituted benzoyl; a benzoyl group which is mono-substituted by halo or C 14 -alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C 1-4 alkyl;  
 b) a group of the formula  
                     
 , where R 1 ″ is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C 1-4 -alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-4 -alkyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C 1-4 alkyl; C 1-4 alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C 1-4 alkyl;  
 c) a group of the formula  
                     
 , where R 2 ″ is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo or C 1-4 alkyl;  
 d) a group of the formula  
                     
 , where R 3 ″ is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C 1-4 -alkyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; C 3-8 cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C 1-4 alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by halo or C 1-4 alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by halo or C 1-4 alkoxy;  
 e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or  
 f) a group of the formula  
                     
 , where R 4  is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C 1-4 alkyl;  
 or an acid addition salt thereof.  
 
     
     
         4 . A compound according to  claim 3  of formula Ic:  
       
         
           
           
               
               
           
         
       
       where Y′″ is: 
 a) a group of the formula  
                     
 , where R′″ is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is monosubstituted by chloro, trifluoromethyl or cyano or disubstituted by chloro; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro, methyl or ethyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by chloro;  
 b) a group of the formula  
                     
 , where R 1 ′″ is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by chloro, trifluoromethyl or cyano; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by chloro or trifluoromethyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro; C 1-6 alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by chloro;  
 c) a group of the formula  
                     
 , where R 2 ′″ is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by fluoro;  
 d) a group of the formula  
                     
 , where R 3 ′″ is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by chloro or trifluoromethyl; C 1-6 alkylcarbonyl; di-C 1-6 alkylaminocarbonyl; C 3-8 cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by chloro; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by chloro or methoxy;  
 e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or  
 f) a group of the formula  
                     
 , where R 4 ′″ is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by chloro or trifluoromethyl;  
 or an acid addition salt thereof.  
 
     
     
         5 . The compound according to  claim 1  which is selected from the group consisting of 1-[[[4-(benzoylamino)cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, 1-[[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, and 1-[[[4-[(4-fluorobenzoyl)amino]cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, or, in each case, an acid addition salt thereof.  
     
     
         6 . A compound according to  claim 5  in free base form.  
     
     
         7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 3 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 4 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         11 . A pharmaceutical composition according to  claim 7  wherein the compound is selected from the group consisting of 1-[[[4-(benzoylamino)cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, 1-[[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, and 1-[[[4-[(4-fluorobenzoyl)amino]cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, or, in each case, an acid addition salt thereof.  
     
     
         12 . A pharmaceutical composition according to  claim 11  wherein the compound is in free base form.  
     
     
         13 . A method of inhibiting dipeptidyl peptidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         14 . A method of inhibiting dipeptidyl pepidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         15 . A method of inhibiting dipeptidyl pepidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 3 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         16 . A method of inhibiting dipeptidyl pepidase-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 4 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         17 . A method according to  claim 13  wherein the compound administered is selected from the group consisting of 1-[[[4-(benzoylamino)cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, 1-[[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, and 1-[[[4-[(4-fluorobenzoyl)amino]cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, or, in each case, an acid addition salt thereof.  
     
     
         18 . A method according to  claim 17  wherein the compound administered is in free base form.  
     
     
         19 . A method of treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effectve amount of a compound according to  claim 1 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         20 . A method of treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 2 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         21 . A method of treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 3 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         22 . A method of treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 4 , or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         23 . A method according to  claim 19  wherein the compound administered is selected from the group consisting of 1-[[[4-(benzoylamino)cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, 1-[[[1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, and 1-[[[4-[(4-fluorobenzoyl)amino]cyclohexyl]amino]acetyl]-2-cyano-(S)-pyrrolidine, or, in each case, an acid addition salt thereof.  
     
     
         24 . A method according to  claim 23  wherein the compound administered is in free base form.  
     
     
         25 . A method according to  claim 19  wherein the condition treated is non-insulin-dependent diabetes mellitus.  
     
     
         26 . A method according to  claim 20  wherein the condition treated is non-insulin-dependent diabetes mellitus.  
     
     
         27 . A method according to  claim 21  wherein the condition treated is non-insulin-dependent diabetes mellitus.  
     
     
         28 . A method according to  claim 22  wherein the condition treated is non-insulin-dependent diabetes mellitus.  
     
     
         29 . A method according to  claim 23  wherein the condition treated is non-insulin-dependent diabetes mellitus.  
     
     
         30 . A method according to  claim 24  wherein the condition treated is non-insulin dependent diabetes mellitus.  
     
     
         31 . A compound according to  claim 1  selected from formulae  
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a combination comprising a compound according to  claim 1  or a pharmaceutically acceptable acid addition salt thereof and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.  
     
     
         33 . A method of inhibiting dipetidyl peptidace-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a combination comprising a compound according to  claim 1  or a pharmaceutically acceptable acid addition salt thereof and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.  
     
     
         34 . A method of treating conditions mediated by dipeptidyl peptidase-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a combination comprising a compound according to  claim 1  or a pharmaceutically acceptable acid addition salt thereof and at least one other antidiabetic agent or a pharmaceutically acceptable salt thereof.  
     
     
         35 . A method according to  claim 34  wherein the condition treated is non-insulin-dependent diabetes mellitus.