Novel effectors of dipeptidyl peptidase IV

Abstract

Dipeptide compounds and compounds analogous to dipeptide compounds that are formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof used in the treatment of impaired glucose tolerance, glycosuria, hyperlipidaemia, metabolic acidoses, diabetes mellitus, diabetic neuropathy and nephropathy and also of sequelae of diabetes mellitus in mammals.

1 - 18 . (canceled)  
     
     
         19 . A pharmaceutical composition, comprising a pharmaceutically acceptable amount of an effector of dipeptidyl peptidase IV or dipeptidyl peptidase IV analogous enzyme activity in combination with a further anti-diabetic agent, or pharmaceutically acceptable salts thereof.  
     
     
         20 . The pharmaceutical composition according to  claim 19  wherein said effector is selected from the group consisting of substrates, pseudosubstrates, inhibitors, binding proteins and antibodies.  
     
     
         21 . The pharmaceutical composition according to  claim 19  wherein said effector is a dipeptide mimetic inhibitor comprising an amino acid and a pyrrolidine or thiazolidine group.  
     
     
         22 . The pharmaceutical composition according to  claim 21  wherein said dipeptide mimetic inhibitor is selected from the group consisting of L-threo-isoleucyl pyrrolidine, L-threo-isoleucyl thiazolidine, L-allo-isoleucyl thiazolidine, L-allo-isoleucyl pyrrolidine, glutaminyl pyrrolidine, glutaminyl thiazolidine, alanyl thiazolidine, alanyl pyrrolidine, valyl thiazolidine and valyl pyrrolidine.  
     
     
         23 . The pharmaceutical composition according to  claim 22  wherein said further anti-diabetic agent is selected from the group consisting of biguanides, sulphonylureas, saccharides and thiazolidinediones.  
     
     
         24 . The pharmaceutical composition according to  claim 23  wherein said biguanide is metformin.  
     
     
         25 . The pharmaceutical composition according to  claim 23  wherein said sulphonylurea is glibenclamide.  
     
     
         26 . The pharmaceutical composition according to  claim 23  wherein said saccharide is acarbose.  
     
     
         27 . The pharmaceutical composition according to  claim 23  wherein said thiazolidinedione is pioglitazon.  
     
     
         28 . The pharmaceutical composition according to  claim 19  further comprising a pharmaceutically acceptable carrier.  
     
     
         29 . A process for preparing a pharmaceutical composition comprising an effector of dipeptidyl peptidase IV or dipeptidyl peptidase IV analogous enzyme activity, a further anti-diabetic agent or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier therefore, which process comprises admixing the dipeptidyl peptidase IV effector, the further anti-diabetic agent, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.  
     
     
         30 . A method for the treatment of metabolic disorders comprising administering to a mammal a therapeutically effective amount of the pharmaceutical composition of  claim 19 .  
     
     
         31 . The method according to  claim 30  wherein said effector is a dipeptide mimetic inhibitor comprising an amino acid and a pyrrolidine or a thiazolidine group, or pharmaceutically acceptable salts thereof.  
     
     
         32 . The method according to  claim 31  wherein said dipeptide mimetic inhibitor is selected from the group consisting of L-threo-isoleucyl pyrrolidine, L-threo-isoleucyl thiazolidine, L-allo-isoleucyl thiazolidine, L-allo-isoleucyl pyrrolidine, glutaminyl pyrrolidine and glutaminyl thiazolidine, alanyl thiazolidine, alanyl pyrrolidine, valyl thiazolidine and valyl pyrrolidine, and pharmaceutically acceptable salts thereof.  
     
     
         33 . The method according to  claim 32  wherein said further anti-diabetic agent is selected from the group consisting of biguanides, sulphonylureas, saccharides and thiazolidinediones.  
     
     
         34 . The method according to  claim 33  wherein said biguanide is metformin.  
     
     
         35 . The method according to  claim 33  wherein said sulphonylurea is glibenclamide.  
     
     
         36 . The method according to  claim 33  wherein said saccharide is acarbose.  
     
     
         37 . The method according to  claim 33  wherein said thiazolidinedione is pioglitazon.  
     
     
         38 . The method according to  claim 30  wherein said metabolic disorder is selected from the group consisting of impaired glucose tolerance, glucosuria, hyperlipidaemia, metabolic acidosis, diabetic neuropathy, nephropathy, diabetes mellitus and sequelae of diabetes mellitus.  
     
     
         39 . The method according to  claim 30  wherein said administering said pharmaceutical composition results in an increase in stability of at least one of endogenously present or exogenously introduced GIP 1-42 , GLP-1 7-36  and GLP-1 7-37  or analogues thereof.  
     
     
         40 . The method according to  claim 39  wherein said treatment method causes an increase in incretin levels for stimulating incretin receptors on Langerhan's cells.  
     
     
         41 . The method according to  claim 39  wherein said treatment method results in increased effectiveness of the Langerhan's cells.  
     
     
         42 . The method according to  claim 39  wherein said treatment method results in increased stimulation of carbohydrate metabolism of the treated mammal.  
     
     
         43 . The method according to  claim 40  wherein said treatment method results in lowering the blood glucose level in the serum of the mammal being treated below the glucose concentration that is characteristic of hyperglycaemia in said mammal.  
     
     
         44 . The method according to  claim 30 , wherein said pharmaceutical composition is administered orally.