Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders

Abstract

Derivatives of Sydnonimine and its analogues, which bind selectively to dopamine transporter (DAT) proteins are useful for treating and delaying the progression of disorders and illnesses that are alleviated by inhibiting dopamine reuptake.

1 . A method of treating or delaying the progression of disorders alleviated by inhibiting dopamine reuptake in a patient in need of said treatment, the method comprising administering a therapeutically effective amount of at least one compound having the formula: 
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6 , independently of one another, are radicals 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 radical 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 radical 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 R′ and R″ being independently selected from H, C 1 -C 6  alkyl, C 5 -C 14  aryl and C 6 -C 20  aralkyl; 
       R a , R b  and R c , independently of one another, represent radicals selected from H, C 1 -C 4  alkyl, phenyl or phenyl C 1 -C 4  alkyl, said alkyl radical, said phenyl radical and said phenyl C 1 -C 4  alkyl radical 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 R b ≠alkyl when m+n=2; and the pharmaceutically acceptable salts of said compound. 
     
   
   
       2 . The method according to  claim 1 , wherein the compound administered is selected from the group consisting of N-phenylcarbamoyl-3-(p-methyl-benzyl)-syndonimine, N-phenylcarbamoyl-3-(p-carboxylbenzyl)-sydnonimine, N-(3′,4′-dichloro-phenyl)carbamoyl-3-(phenethyl)-sydnonimine, N-(3′4′,-dinitro-phenyl)carbamoyl-3-(p-nitrophenethyl)-sydnonimine, N-phenylcarbamoyl-3-(p-fluoro-benzyl)-sydnonimine, N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine, and N-phenylcarbamoyl-3-(benzyl)-sydnonimine. 
   
   
       3 . The method according to  claim 1 , wherein said at least one compound is administered, optionally in conjunction with at least one other therapeutic agent, for the treatment of cocaine dependence, attention deficit disorder, depression, schizophrenia, narcolepsy, obesity or Parkinson's disease. 
   
   
       4 . The method according to  claim 1 , wherein said compound and said optional other therapeutic agent are administered for the treatment of cocaine addiction. 
   
   
       5 . The method according to  claim 1 , wherein said compound and said optional other therapeutic agent are administered for the treatment of attention deficit disorder. 
   
   
       6 . The method according to  claim 1 , wherein said compound is administered in dosage unit form, said dosage unit containing from about 0.01 to about 200 mg. of said compound per kilogram of patient body weight per day. 
   
   
       7 . The method according to  claim 6 , wherein said dosage unit includes a pharmaceutically acceptable vehicle. 
   
   
       8 . The method according to  claim 1 , wherein said compound is administered orally. 
   
   
       9 . The method according to  claim 1 , wherein said compound is administered parenterally. 
   
   
       10 . The method according to  claim 1 , wherein said at least one compound is administered in conjunction, either simultaneously or sequentially, with at least one additional therapeutic agent selected from the group of L-dopa for the treatment of Parkinson's disease; a selective serotonin reuptake inhibitor for the treatment of depression and/or cocaine abuse and addiction; a dopamine D2 antagonist for the treatment of schizophrenia; and a cholinergic modulator for the treatment of Alzheimer disease or other diseases or conditions in which patients have a cognitive deficit. 
   
   
       11 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6 , independently of one another, are radicals 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 C 1 -C 6  alkyl radical 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 radical 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 R′ and R″ being independently selected from H, C 1 -C 6  alkyl and C 5 -C 14  aryl; 
       R a , R b  and R c , independently of one another, represent radicals selected from H, C 1 -C 4  alkyl, phenyl or phenyl C 1 -C 4  alkyl, said phenyl radical and said phenyl C 1 -C 4  alkyl radical 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 Rb≠alkyl when m+n=2, and the pharmaceutical acceptable salts of said compound, with the proviso that the above formula does not include: 
     
     (i) N-phenylcarbamoyl-3-(benzyl)-sydnonimine; 
     (ii) N-(3′,4′-dichlorophenyl)carbamoyl-3-phenethyl-sydnonimine; 
     (iii) N-(p-chlorophenyl)carbamoyl-3-phenethyl-sydnonimine; and 
     (iv) N-(m-trifluoromethyl)carbamoyl-3-phenethyl-sydnonimine. 
   
   
       12 . A compound selected from the group consisting of N-phenylcarbamoyl-3-(p-methyl-benzyl)-syndonimine, N-phenylcarbamoyl-3-(p-carboxy-benzyl)-sydnonimine, N-(3′4′,-dinitro-phenyl)carbamoyl-3-(p-nitrophenethyl)-sydnonimine, N-phenylcarbamoyl-3-(p-fluoro-benzyl)-sydnonimine, N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine. 
   
   
       13 . A pharmaceutical composition for treating or delaying the progression of disorders alleviated by inhibiting dopamine reuptake, said composition comprising a compound according to  claim 11  and a pharmaceutically acceptable vehicle. 
   
   
       14 . A pharmaceutical composition according to  claim 13 , wherein said compound is selected from the group consisting of N-phenylcarbamoyl-3-(p-methyl-benzyl)-syndonimine, N-phenylcarbamoyl-3-(p-carboxylbenzyl)-sydnonimine, N-(3′4′,-dinitro-phenyl)carbamoyl-3-(p-nitrophenethyl)-sydnonimine, N-phenylcarbamoyl-3-(p-fluoro-benzyl)-sydnonimine, N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine. 
   
   
       15 . A composition according to  claim 13  in solid form, also comprising a pharmaceutically acceptable excipient. 
   
   
       16 . A composition according to  claim 13  in liquid form, also comprising a pharmaceutically acceptable diluent. 
   
   
       17 . A composition according to  claim 13  in unit dosage form. 
   
   
       18 . A composition according to  claim 13 , further comprising at least one selective serotonin reuptake inhibitor. 
   
   
       19 . A pharmaceutical composition according to  claim 17  in unit dosage form. 
   
   
       20 . A method of treating a condition or disease state which is alleviated by modulating dopamine reuptake activity and thereby augmenting dopaminergic functions, said method comprising administering to a patient having said condition or disease state a therapeutically effective amount of at least one compound having the formula: 
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6 , independently of one another, are radicals 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 radical 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 radical 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 R′ and R″ being independently selected from H, C 1 -C 6  alkyl, C 5 -C 14  aryl and C 6 -C 20  aralkyl; 
       R a , R b  and R c , independently of one another, represent radicals selected from H, C 1 -C 4  alkyl, phenyl or phenyl C 1 -C 4  alkyl, said alkyl radical, said phenyl radical and said phenyl C 1 -C 4  alkyl radical 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 R b ≠alkyl when m+n=2; and the pharmaceutically acceptable salts of said compound. 
     
   
   
       21 . The method according to  claim 1 , wherein said condition or disease state is selected from the group consisting of pulmonary conditions; ischemia-reperfusion injury; cardiac conditions; hyperprolactinaemia (BrE) or hyperprolactinemia (AmE) and microprolactinoma; pain; movement disorders; stress, chronic posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorders, postpartum depression; schizophrenia, manic, bipolar, and affective disorder; executive function disorders; cocaine dependency, amphetamine dependency, alcohol dependency, addictive behavior; neuroendocrinal regulatory disorders; inflammatory conditions, autoimmune diseases and rheumatism; neoplastic disorders; visual sensory disorders, color deficiency; and ejaculatory and related sexual dysfunction.