Method of using dopamine reuptake inhibitors and their analogs for treating autoimmune conditions and delaying or preventing autoimmune related pathologic progressions

Abstract

Dopamine reuptake inhibitors, and their analogs, are disclosed for treating and delaying the progression of autoimmune diseases.

We claim: 
     
         1 . A method of providing relief from or alleviating symptoms of or delaying the progression of autoimmune disease in a patient in need of said provision of relief or alleviation of symptoms or delay of progression, 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 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  monoalkylamino, 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  monoalkylamino, 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. 
       
     
     
         2 . The method according to  claim 1 , wherein said at least one compound administered is selected from the group consisting of 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl, 3-(3′,5′-difluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(m-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-trifluoromethyl-benzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-fluorobenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-tert-butylbenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(p-methylbenzyl)-sydnonimine-N-(p′-trifluoromethyl-phenyl)carbamoyl, 3-(p-methylbenzyl)-sydnonimine-N-phenylcarbamoyl, 3-(phenylethyl)-sydnonimine-N-phenylcarbamoyl, (3-(phenylethyl)-sydnonimine-N-phenylcarbamoyl and 3-(p-methylbenzyp-sydnonimine-N-(p′-dimethylamino-phenyl)carbamoyl. 
     
     
         3 . The method according to  claim 1 , wherein said at least one compound administered is 3-(phenylpropyl)-sydnonimine-N-phenylcarbamoyl. 
     
     
         4 . The method according to  claim 1 , wherein said at least one compound is administered in conjunction with at least one other therapeutic agent selected from the group consisting of a dopamine receptor agonist, corticosteroid, and chemotherapeutic agent. 
     
     
         5 . The method according to  claim 4 , wherein said compound is administered in conjunction with a dopamine receptor agonist selected from the group consisting of cabergoline, pergolide, pramipexole, ropinirole, apomorphine, rotigotine, fenoldopam, dopamine, and levodopa. 
     
     
         6 . The method according to  claim 4 , wherein said compound is administered in conjunction with a corticosteroid selected from the group consisting of betamethasone, dexamethasone, hydrocortisone, methyl prednisone acetate, and prednisone. 
     
     
         7 . The method according to  claim 4 , wherein said compound is administered in conjunction with a chemotherapeutic agent selected from the group consisting of cyclophosphamide, chlorambucil, azathioprine, methotrexate, 6-mercaptopurine, leflunomide, cyclosporine, tacrolimus, sirilimus, and mycophenolate. 
     
     
         8 . The method according to  claim 1 , wherein said autoimmune disease is selected from the group consisting of Type I diabetes mellitus, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, Graves' disease, Guillain-Barré syndrome, psoriasis, and Sjögren's syndrome. 
     
     
         9 . The method according to  claim 1 , wherein said autoimmune disease is rheumatoid arthritis. 
     
     
         10 . The method according to  claim 1 , wherein said at least one compound is administered in solid form, also comprising a pharmaceutically acceptable excipient. 
     
     
         11 . The method according to  claim 1 , wherein said at least one compound is administered in liquid form, also comprising a pharmaceutically acceptable diluents. 
     
     
         12 . The method according to  claim 1 , wherein said at least one compound is administered in dosage unit form. 
     
     
         13 . The method according to  claim 12 , wherein said compound is administered in dosage unit form containing from about 0.01 to about 200 mg of said compound per kilogram of patient body weight per day. 
     
     
         14 . The method according to  claim 13 , wherein said dosage unit includes a pharmaceutically acceptable vehicle. 
     
     
         15 . The method according to  claim 13 , wherein said dosage unit includes a pharmaceutically suitable vehicle for extended release. 
     
     
         16 . The method according to  claim 1 , wherein said compound is administered via a route selected from the group of orally, parenterally, by intraperitoneal injection, by intrathecal injection, by subcutaneous injection, or transdermally. 
     
     
         17 . The method according to  claim 1 , wherein said at least one compound is administered as a prodrug.