Glycosidase inhibitors and methods of synthesizing same

Abstract

A method for synthesizing Salacinol, its stereoisomers, and non-naturally occurring selenium and nitrogen analogues thereof having the general formula (I): The compounds are potentially useful as glycosidase inhibitors. The synthetic schemes comprise reacting a cyclic sulfate with a 5-membered ring sugar containing a heteroatom (X). The heteroatom preferably comprises sulfur, selenium, or nitrogen. The cyclic sulfate and ring sugar reagents may be readily prepared from carbohydrate precursors, such as D-glucose, L-glucose, D-xylose and L-xylose. The target compounds are prepared by opening of the cyclic sulfates by nucleophilic attack of the heteroatoms on the 5-membered ring sugars. The resulting heterocyclic compounds have a stable, inner salt structure comprising a heteroatom cation and a sulfate anion. The synthetic schemes yield various stereoisomers of the target compounds in moderate to good yields with limited side-reactions. In an alternative embodiment of the invention, the cyclic sulfate may be similarly reacted with a 6-membered ring sugar containing a heteroatom (X) to yield a compound having the general formula (XII):

What is claimed is:  
     
         1 . A non-naturally occurring compound selected from the group consisting of compounds represented by the general formula (I) and stereoisomers and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       where X is selected from the group consisting of S, Se and NH; R 1 , R 2 , R 3 , R 4  and R 5  are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides; and R 6  is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals.  
     
     
         2 . The compound as defined in  claim 1 , wherein R 1 , R 2 , R 3 , R 4  and R 6  are OH and R 5  is H.  
     
     
         3 . The compound as defined in  claim 1 , wherein R 1 , R 2 , R 3 , R 4  and R 5  are OH and R 6  is C 3 H 7 O 3 .  
     
     
         4 . A process for the production of the compound of  claim 1 , comprising reacting a cyclic sulfate having the general formula (II) with a 5-membered ring sugar having the general formula (III)  
       
         
           
           
               
               
           
         
       
       where X is selected from the group consisting of S, Se, and NH; R 1  and R 2  are selected from the group consisting of H and a protecting group; R 3  is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals and their protected derivatives; and R 4 , R 5  and R 6  are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and their protected derivatives  
     
     
         5 . The process as defined in  claim 4 , wherein said cyclic sulfate is a 2,4-di-O-protected-D-or L-erythritol-1,3-cyclic sulfate.  
     
     
         6 . The process as defined in  claim 5 , wherein said cyclic sulfate is 2,4-O-Benzylidene-D-or L-erythritol-1,3-cyclic sulfate.  
     
     
         7 . The process as defined in  claim 4 , wherein R 3  is a protected polyhydroxylated alkyl chain.  
     
     
         8 . The process as defined in  claim 4 , wherein R 4 , R 5 , and R 6  are selected from the group consisting of OH and OCH 2 C 6 H 5 .  
     
     
         9 . The process as defined in  claim 4 , comprising the step of opening the cyclic sulfate (II) by nucleophilic attack of the heteroatom X on the sugar (III).  
     
     
         10 . The process as defined in  claim 4 , wherein the coupling reaction is carried out in a solvent selected from the group consisting of acetone and methanol.  
     
     
         11 . The process as defined in  claim 10 , further comprising the step of adding a base to said solvent.  
     
     
         12 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  together with a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating a carbohydrate metabolic disorder in an affected patient comprising the step of administering to said patient a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         14 . The method of  claim 13 , wherein said carbohydrate metabolic disorder is non-insulin dependent diabetes.  
     
     
         15 . A method of treating tumor cell proliferation and metastasis in an affected patient comprising administering to said patient a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         16 . A process for the production of a compound having the formula (VI) comprising reacting a cyclic sulfate selected from the group consisting of compounds having the formulas (VII) and (VIII) with a sugar compound having the formula (IX) where R═H, COR, CH 2 C 6 H 5 , CH 2 C 6 H 4 —OMe p .  
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound selected from the group consisting of compounds represented by the general formula (XII) and stereoisomers and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       where X is selected from the group consisting of S, Se and NH; R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are the same or different and are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides; and R 7  is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals.  
     
     
         18 . A process for the production of the compound of  claim 17 , comprising reacting a cyclic sulfate having the general formula (II) with a 6-membered ring sugar having the general formula (XI)  
       
         
           
           
               
               
           
         
       
       where X is selected from the group consisting of S, Se, and NH; R 1  and R 2  are selected from the group consisting of H and a protecting group; R 3  is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals and their protected derivatives; and R 4 , R 5 , R 6  and R 7  are selected from the group consisting of H, OH, SH, NH 2 , halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and their protected derivatives.  
     
     
         19 . The process of  claim 18 , wherein R 3  is a protected polyhydroxylated alkyl chain or its protected derivative.