Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings

Abstract

The present invention discloses cysteine prodrugs having the general formula: cystine dimmers of the cysteine prodrugs having the general formula: protected cysteine analogs having the general formula: and dimmers of the protected cysteine analogs having the general formula: The invention further encompasses pharmaceutical compositions containing the disclosed prodrugs, dimmers, analogs, and methods of using such compounds for treatment of schizophrenia and drug addiction.

What is claimed is: 
     
         1 . A cysteine prodrug having the structure: 
       
         
           
           
               
               
           
         
         wherein: R 1  and R 2  are independently selected from OH, ═O, or a branched or straight chain C 1  to C 5  alkoxyl group, with the caveat that when ═O is selected the nitrogen atom adjacent the carbonyl group thusly formed bears a H and a single bond joins the adjacent nitrogen to said carbonyl group; 
         R 3  is H, a branched or straight chain C 1  to C 5  alkyl, a nitrobenzenesulfonyl, a trityl, an aryl thio, an aryl, an alkylthio, an acyl, a benzoyl, a thio acyl, a thio benzoyl, or a benzyl group; and 
         R 4  is selected from the side chain groups of the natural L-amino acids cys, gly, phe, pro, val, ser, arg, asp, asn, glu, gln, ala, his, ile, leu, lys, met, thr, trp, tyr, or D-isomers thereof, with the caveat that when R 4  is the side chain group of the natural L-amino acid gly, R 1  and R 2  are not both selected to be ═O; or 
         a cystine dimer of said prodrug having the structure: 
       
       
         
           
           
               
               
           
         
         wherein: R 1 , R 2 , R 5  and R 6  are independently selected from OH, ═O, or a branched or straight chain C 1  to C 5  alkoxyl group, with the caveat that when ═O is selected the nitrogen atom adjacent the carbonyl group thusly formed bears a H and a single bond joins the adjacent nitrogen to said carbonyl group; and 
         R 4  and R 7  are independently selected from the side chain groups of the natural L-amino acids cys, gly, phe, pro, val, ser, arg, asp, asn, glu, gln, ala, his, ile, leu, lys, met, thr, trp, tyr, or D-isomers thereof, with the caveat that when R 4  and R 7  are both the side chain group of the natural L-amino acid gly, R 1 , R 2 , R 5  and R 6  shall not all be selected to be ═O. 
       
     
     
         2 . The cysteine prodrug according to  claim 1 , wherein said cysteine prodrug has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The cysteine prodrug according to  claim 1 , wherein said cysteine prodrug is in the form of the cystine dimer having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The cysteine prodrug according to  claim 1 , wherein said cysteine prodrug in the form of the cystine dimer includes identical R 4  and R 7  groups. 
     
     
         5 . The cysteine prodrug according to  claim 1 , wherein said cysteine prodrug in the form of the cystine dimer includes non-identical R 4  and R 7  groups. 
     
     
         6 . The cysteine prodrug according to  claim 1 , wherein said cysteine prodrug or cystine dimer thereof includes at least one R 4  and R 7  group that is a cys, said cys further protected by a branched or straight chain C 1  to C 5  alkyl, a nitrobenzenesulfonyl, a trityl, an aryl thio, an aryl, an alkylthio, an acyl, a benzoyl, a thio acyl, a thio benzoyl, or a benzyl group. 
     
     
         7 . A pharmaceutical composition comprising a cysteine prodrug or cystine dimer thereof according to  claim 1  and a pharmaceutically-acceptable carrier. 
     
     
         8 . A method of reducing drug craving in a subject comprising administering to said subject an effective amount of a cysteine prodrug or cystine dimer thereof according to  claim 1 , whereby drug craving is reduced in said subject. 
     
     
         9 . The method according to  claim 8 , wherein the step of administering to said subject is accomplished by oral delivery.