Alginate oligosaccharides and the derivatives thereof as well as the manufacture and the use of the same

Abstract

The invention provides an alginate oligosaccharide and its derivatives with the degree of polymerization ranging from 2 to 22. The alginate oligosaccharide is composed of β-D-mannuronic acid linked by 1,4 glycosidic bonds. The derivatives with the reduced terminal in position 1 of carboxyl radical can be prepared by oxidative degradation. The invention also provides a process for preparing the alginate oligosaccharide and its derivatives, which includes the procedure that an alginate solution is reacted for 2 to 6 h in an autoclave at pH 2˜6 and the temperature of 100˜120° C., and adjusted pH to 7 after the reaction is stopped, after which the resultant oligosaccharide is oxidized in the presence of an oxidant to obtain an oxidative product. The alginate oligosaccharide and its derivatives of the invention can be used in the manufacture of a medicament for the prophylaxis and treatment of AD and diabetes.

1 . An alginate oligosaccharide or its derivatives represented by formula (I) or pharmaceutically-acceptable salts thereof, said oligosaccharide is composed of β-D-mannuronic acid linked by 1,4 glycosidic bonds, as shown by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein, n represents a integer of 0 or 1 to 19. 
     
     
         2 . The alginate oligosaccharide or its derivatives or pharmaceutically-acceptable salts thereof according to  claim 1 , characterized in that the reduced terminal in position 1 of said alginate oligosaccharide derivative is carboxyl radical, as shown by the following formula (II): 
       
         
           
           
               
               
           
         
       
       wherein, n represents a integer of 0 or 1 to 19. 
     
     
         3 . The alginate oligosaccharide or its derivatives or pharmaceutically-acceptable salts thereof according to  claim 1 , characterized in that n is 2˜12, preferably n is 4 to 8. 
     
     
         4 . A process for preparing the alginate oligosaccharide or its derivatives or pharmaceutically-acceptable salts thereof according to  claim 1 , which comprises the following steps: an alginate solution is reacted for about 2 to 6 h in an autoclave at pH 2˜6 and the temperature of about 100˜120° C., and adjusted pH to about 7 after the reaction is stopped. 
     
     
         5 . The process according to  claim 4 , characterized in that said alginate is sodium alginate and reacted for 4 h at the condition of pH 4 and 110° C. 
     
     
         6 . The process according to  claim 4 , characterized in that after adjusting pH to about 7, alcohol is added to precipitate; the alcohol precipitate is filtered off with suction, dehydrated, dried and desalted. 
     
     
         7 . The process according to  claim 4 , characterized in that after the alginate solution reacting for about 2 to 6 h in an autoclave at pH 2˜6 and the temperature of about 100˜120° C., an oxidant is added and reacted for 15 min to 2 h at the temperature of 100˜120° C. 
     
     
         8 . The process according to  claim 7 , characterized in that said oxidant is copper hydroxide and reacted for 30 min at the temperature of 100° C. 
     
     
         9 . A pharmaceutical composition containing an effective amount of the alginate oligosaccharide or its derivatives according to  claim 1 , and pharmaceutically-acceptable carriers. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , characterized in that the composition is any one of a medicament for the prophylaxis and treatment of AD, an amyloid-β protein fibrils forming inhibitor, a medicament for the prophylaxis and treatment of diabetes, an islet amyloid protein fibrils forming inhibitor and a fibrils disaggregating promoter.