Method of using dopamine reuptake inhibitors and their analogs for treating diabetes symptoms and delaying or preventing diabetes-associated pathologic conditions

Abstract

Method of using dopamine reuptake inhibitors, e.g., sydnonimine derivatives, for the management of diabetic symptoms and associated complications or conditions, such as hyperglycemia and diabetic neuropathy.

What is claimed is: 
     
         1 . A method for treatment of symptoms of Type II diabetes and delay of onset or prevention of occurrence of pathologic conditions associated with Type II diabetes in a patient in need thereof, said method comprising administering an amount of a dopamine reuptake inhibitor that is effective for said treatment and said delay or prevention. 
     
     
         2 . The method of  claim 1 , wherein said dopamine reuptake inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6 , independently of one another, are substituents selected from H, C 1 -C 6  alkyl, OH, halogen, C 5 -C 14  aryl, C 6 -C 20  aralkyl, C 1 -C 6  alkylthio, C 1 -C 6  alkoxy, SH, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, CN, NO 2 , carboxy, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, aminosulfonylalkyl, monoalkylaminosulfonylalkyl, dialkyaminosulfonylalkyl, aminosulfinylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinylalkyl, said alkyl, alkenyl, alkynyl or cycloalkyl substituent being optionally substituted by at least one halogen, OH, SH, NH 2 , C 1 -C 4  alkylmethylamino, C 1 -C 4  dialkylamino, COOH, CN, NO 2 , C 1 -C 4  alkyl or C 1 -C 4  alkoxy group, said aryl and aralkyl substituent being optionally substituted by at least one halogen, OH, SH, NH 2 , C 1 -C 4  alkylmethylamino, C 1 -C 4  dialkylamino, COOH, CN, NO 2 , C 1 -C 4  alkyl or C 1 -C 4  alkoxy group; 
         R a , R b  and R c , independently of one another, represent substituents selected from H, C 1 -C 4  alkyl, phenyl or phenyl C 1 -C 4  alkyl, said alkyl substituent, said phenyl substituent and said phenyl C 1 -C 4  alkyl substituent being optionally substituted by at least one halogen, OH, SH, NH 2 , C 1 -C 4  alkylmethylamino, C 1 -C 4  dialkylamino, COOH, CN, NO 2 , C 1 -C 4  alkyl or C 1 -C 4  alkoxy group; 
         m, n and k are independent integers from 0-4, except that m+n≠0; 
         and the pharmaceutically acceptable salts of said compound. 
       
     
     
         3 . The method of  claim 2 , wherein said dopamine reuptake inhibitor is selected from the group consisting of 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-methylbenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-carboxybenzyl)-sydnonimine-N-phenylcarbamoyl, 3-phenethyl-sydnonimine-N-phenylcarbamoyl, 3-phenethyl-sydnonimine-N-(3′,4′-dichloro-phenyl)-carbamoyl, 3-(p-nitrophenethyl)-sydnonimine-N-(3′,4′-dinitro-phenyl)-carbamoyl, 3-(p-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-benzyl-sydnonimine-N-phenylcarbamoyl, 3-phenethyl-sydnonimine-N-(p-chlorophenyl)-carbamoyl, 3-phenethyl-sydnonimine-N-(m-trifluoromethyl)-phenylcarbamoyl, 3-(3′,5′-difluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(m-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-trifluoromethyl-benzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-tert-butylbenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-methylbenzyl)-sydnonimine-N-(p′-trifluoromethyl-phenyl)carbamoyl, and 3-(p-methylbenzyl)-sydnonimine-N-(p-dimethylamino-phenyl)carbamoyl. 
     
     
         4 . The method of  claim 1 , wherein said dopamine reuptake inhibitor is administered in combination with a therapeutic agent for Type II diabetes selected from the group consisting of glucophage, glyburide, repaglinide, acarbose, pramlintide and sitagliptin. 
     
     
         5 . The method of  claim 4 , wherein the dopamine reuptake inhibitor and the therapeutic agent for Type II diabetes are administered as separate dosage units. 
     
     
         6 . The method of  claim 4 , wherein the dopamine reuptake inhibitor and the therapeutic agent for Type II diabetes are formulated for simultaneous administration to said patient. 
     
     
         7 . The method of  claim 1 , wherein said diabetic symptoms are symptoms of a pre-diabetic condition. 
     
     
         8 . The method of  claim 4 , wherein said diabetic symptoms include at least hyperglycemia. 
     
     
         9 . The method of  claim 1 , wherein said diabetes-associated pathologic conditions comprise at least one selected from the group of diabetic sensory neuropathy, diabetic autonomic neuropathy, diabetic retinopathy, diabetic nephropathy and diabetic angiopathy.