Novel post-amadori inhibitors of advanced glycation reactions

Abstract

The present invention provides novel compounds, pharmaceutical compositions, methods, and kits for inhibiting the conversion of Amadori compounds to post Amadori advanced glycation endproducts, and for treating and preventing chronic tissue damage and diabetic complication

We claim:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein R1, R1′, R5, and R5′ are independently selected from the group consisting of (CH 2 ) n X wherein n is between 0 and 6 and X is H, OH, SH, COOH or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl; with the proviso that at least one R1, R1′, R5, and R5′ is selected from the group consisting of OH, SH, and NH 2 ;  
         wherein R2, R2′, R4 and R4′ are independently selected from the group consisting of (CH 2 ) n Z, wherein n has the meaning given above and Z is H, OH, SH, COOH, or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl;  
         wherein R3 and R3′ are independently selected from the group consisting of H and mono-, di-, or tri-halogenated C1-6 alkyl;  
         wherein R6 and R6′ are (CH 2 )x, wherein x is between 1 and 6;  
         wherein R7 is selected from NH and HOP═O;  
         or wherein R6, R6′, and R7 combine to form an aryl group, heteroaryl group, or  
         
           
             
             
                 
                 
             
           
         
         or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof;  
         wherein the compound is not dipyridoxylamine.  
       
     
     
         2 . The compound of  claim 1  selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition comprising an amount effective to inhibit the conversion of Amadori compounds to post Amadori advanced glycation endproducts of a compound of the general formula  
       
         
           
           
               
               
           
         
         wherein R1, R1′, R5, and R5′ are independently selected from the group consisting of (CH 2 ) n X wherein n is between 0 and 6 and X is H, OH, SH, COOH or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl; with the proviso that at least one R1, R1′, R5, and R5′ is selected from the group consisting of OH, SH, and NH 2 ;  
         wherein R2, R2′, R4 and R4′ are independently selected from the group consisting of (CH2) n Z, wherein n has the meaning given above and Z is H, OH, SH, COOH, or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl;  
         wherein R3 and R3′ are independently selected from the group consisting of H and mono-, di-, or tri-halogenated C1-6 alkyl;  
         wherein R6 and R6′ are (CH 2 )x, wherein x is between 1 and 6;  
         wherein R7 is selected from NH and HOP═O;  
         or wherein R6, R6′, and R7 combine to form an aryl group, heteroaryl group, or  
         
           
             
             
                 
                 
             
           
         
         or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof;  
         and a pharmaceutically acceptable carrier.  
       
     
     
         4 . A pharmaceutical composition comprising an amount effective for treating or preventing an AGE related pathology in a mammal of a compound of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R1, R1′, R5, and R5′ are independently selected from the group consisting of (CH 2 ) n X wherein n is between 0 and 6 and X is H, OH, SH, COOH or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl; with the proviso that at least one R1, R1′, R5, and R5′ is selected from the group consisting of OH, SH, and NH 2 ; 
 wherein R2, R2′, R4 and R4′ are independently selected from the group consisting of (CH2) n Z, wherein n has the meaning given above and Z is H, OH, SH, COOH, or NH 2 ; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl;  
 wherein R3 and R3′ are independently selected from the group consisting of H and mono-, di-, or tri-halogenated C1-6 alkyl;  
 wherein R6 and R6′ are (CH 2 )x, wherein x is between 1 and 6;  
 wherein R7 is selected from NH and HOP═O;  
 or wherein R6, R6′, and R7 combine to form an aryl group, heteroaryl group, or  
                     
 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof;  
 and a pharmaceutically acceptable carrier.  
 
     
     
         5 . The pharmaceutical composition of  claim 3  wherein the compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The pharmaceutical composition of  claim 4  wherein the compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A method for inhibiting the conversion of Amadori compounds to post Amadori advanced glycation endproducts in a mammal comprising administering to a mammal an amount effective to. inhibit the conversion of Amadori compounds to post Amadori advanced glycation endproducts of a compound or pharmaceutical composition of any one of claims  1 - 6 .  
     
     
         8 . A method for treating or preventing an AGE related pathology in a mammal comprising administering to a mammal an amount effective to treat or prevent the AGE-related pathology of a compound or pharmaceutical composition of any one of claims  1 - 6 .  
     
     
         9 . The method of  claim 8  wherein the AGE related pathology is selected from the group consisting of dialysis-related pathologies, proteinuria, impaired glomerular clearance, diabetic nephropathy, and protein cross-linking.  
     
     
         10 . The method of  claim 8  wherein the mammal has an elevated blood sugar level.  
     
     
         11 . An improved dialysis solution, wherein the improvement comprises the addition of an amount effective to inhibit post-Amadori AGE formation of the compound or pharmaceutical composition of any one of claims  1 - 6 .