Methods for alleviating deleterious effects of 3-deoxyglucosone

Abstract

Disclosed is a class of compounds which inhibit the enzymatic conversion of fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction in a newly discovered metabolic pathway. According to the normal functioning on this pathway, fructose-lysine-3-phosphate (FL3P) is broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins). Also disclosed are therapeutic methods of using such inhibitors to alleviate deleterious effects of 3DG.

1 - 3 . (canceled)  
   
   
       4 . A method of treating glycogen storage diseases in a patient in need thereof by administering a therapeutically effective amount of a compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein X is a divalent moiety selected from the group consisting of —NR′—, —S(O)—, —S(O) 2 —, or —O—, R′ being selected from the group consisting of H, and linear or branched chain alkyl group (C 1 -C 4 ) an unsubstituted or substituted aryl group (C 6 -C 10 ) and an aralkyl group (C 7 -C 10 ); R is a substituent selected from the group consisting of H, an amino acid residue said amino acid including said NR′ moiety, a polyaminoacid residue said polyamino acid including said NR′ moiety, a peptide chain, a linear or branched chain aliphatic group (C 3 -C 8 ), which is unsubstituted or substituted with at least one nitrogen or oxygen-containing substituent, a linear or branched chain aliphatic group (C 1 -C 8 ), which is unsubstituted or substituted with at least one nitrogen- or oxygen-containing substituent and interrupted by at least one —O—, —NH—, or —NR″— moiety, R″ being linear or branched chain alkyl (C 1 -C 6 ) and an unsubstituted or substituted aryl group (C 6 -C 10 ) or aralkyl group, (C 7 -C 10 ), with the proviso that when X represents —NR′—, R and R′, together with the nitrogen atom to which they are attached, may also represent a substituted or unsubstituted heterocyclic ring having from 5 to 7 ring atoms, with at least one of nitrogen and oxygen being the only heteroatoms in said ring, said aryl group (C 6 -C 10 ) or aralkyl group (C 7 -C 10 ), and said heterocyclic ring substituents being selected from the group consisting of H, alkyl (C 1 -C 6 ), halogen, CF 3 , CN and -0-alkyl (C 1 -C 6 ); R 1  is a polyol moiety having 1 to 4 linear carbon atoms, Y is a hydroxymethylene moiety —CHOH—; Z is selected from the group consisting of —H, O-alkyl (C 1 -C 6 ), -halogen, —CF 3 , —CN, —COOH and —SO 3 H 2 , and Z may optionally be —OH; or its pharmaceutically acceptable salt or its stereoisomer, except that X—R in the above formula does not represent hydroxyl or thiol.  
   
   
       5 . The method according to  claim 4 , wherein said glycogen storage disease is Franconi's syndrome.  
   
   
       6 . The method according to  claim 4 , wherein 3-O-methyl-sorbitol lysine is administered for the treatment of said glycogen storage disease.  
   
   
       7 . The method according to  claim 4 , wherein meglumine is administered for the treatment of said glycogen storage disease.  
   
   
       8 . The method according to  claim 4 , wherein sorbitol lysine is administered for the treatment of said glycogen storage disease.  
   
   
       9 . The method according to  claim 4 , wherein mannitol lysine is administered for the treatment of said glycogen storage disease.  
   
   
       10 . A method of treating a pathological condition resulting from the formation of 3-deoxyglucosone in a patient in need of said treatment by administering a therapeutically effective amount of a compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein X is a divalent moiety selected from the group consisting of —NR′—, —S(O)—, —S(O) 2 —, or —O—, R′ being selected from the group consisting of H, and linear or branched chain alkyl group (C 1 -C 4 ) an unsubstituted or substituted aryl group (C 6 -C 10 ) and an aralkyl group (C 7 -C 10 ); R is a substituent selected from the group consisting of H, an amino acid residue said amino acid including said NR′ moiety, a polyaminoacid residue said polyamino acid including said NR′ moiety, a peptide chain, a linear or branched chain aliphatic group (C 3 -C 8 ), which is unsubstituted or substituted with at least one nitrogen or oxygen-containing substituent, a linear or branched chain aliphatic group (C 1 -C 8 ), which is unsubstituted or substituted with at least one nitrogen- or oxygen-containing substituent and interrupted by at least one —O—, —NH—, or —NR″— moiety, R″ being linear or branched chain alkyl (C 1 -C 6 ) and an unsubstituted or substituted aryl group (C 6 -C 10 ) or aralkyl group, (C 7 -C 10 ), with the proviso that when X represents —NR′—, R and R′, together with the nitrogen atom to which they are attached, may also represent a substituted or unsubstituted heterocyclic ring having from 5 to 7 ring atoms, with at least one of nitrogen and oxygen being the only heteroatoms in said ring, said aryl group (C 6 -C 10 ) or aralkyl group (C 7 -C 10 ), and said heterocyclic ring substituents being selected from the group consisting of H, alkyl (C 1 -C 6 ), halogen, CF 3 , CN and -0-alkyl (C 1 -C 6 ); R 1  is a polyol moiety having 1 to 4 linear carbon atoms, Y is a hydroxymethylene moiety —CHOH—; Z is selected from the group consisting of —H, —O-alkyl (C 1 -C 6 ), -halogen, —CF 3 , —CN, —COOH and —SO 3 H 2 , and Z may optionally be —OH; or its pharmaceutically acceptable salt or its stereoisomer, except that X—R in the above formula does not represent hydroxyl or thiol.  
   
   
       11 . A method according to  claim 10 , wherein said condition is at least one of hypertension, stroke, neurodegenerative disorder, circulatory disease, atherosclerosis, osteoarthritis, cataracts and debilitating effects of aging.  
   
   
       12 . The method according to  claim 10 , wherein 3-O-methyl-sorbitol lysine is administered for the treatment of said condition.  
   
   
       13 . The method according to  claim 10 , wherein meglumine is administered for the treatment of said condition.  
   
   
       14 . The method according to  claim 10 , wherein sorbitol lysine is administered for the treatment of said condition.  
   
   
       15 . The method according to  claim 10 , wherein mannitol lysine is administered for the treatment of said condition.