Process for the preparation of highly o-sulfated epimerized derivatives of k5 polysaccharide and intermediates therein

Abstract

A new method is described for the oversulfation of epiK5-N-sulfate to obtain an epiK5-amine-O-oversulfate with very high sulfation degree which, by subsequent N-sulfation, provides new epiK5-N,O-oversulfate-derivatives with a sulfation degree of at least 4, basically free of activity on the coagulation parameters and useful in the cosmetic or pharmaceutical field. Also described are new low molecular weight epiK5-N-sulfates useful as intermediates in the preparation of the corresponding LMW-epiK5-N,O-oversulfate-derivatives.

1 . A process for the preparation of epiK5-amine-O-oversulfate-derivatives having a glucosamine 3-O-sulfate content of at least 40%, which comprises
 (a) treating an epiK5-N-sulfate-derivative, in acidic form, with a tertiary or quaternary organic base, letting the reaction mixture to stand for a time period of 30-60 minutes at a pH of approximately 7 and isolating the corresponding organic base salt of said epiK5-N-sulfate; and   (b) treating said tertiary amine or quaternary ammonium salt of said epiK5-N-sulfate-derivative with an O-sulfation agent in the conditions of O-oversulfation and isolating the epiK5-amine-O-oversulfate-derivative.   
     
     
         2 . The process of  claim 1 , wherein said epiK5-amine-O-oversulfate-derivative is isolated in form of sodium salt and optionally converted into another chemically or pharmaceutically acceptable salt. 
     
     
         3 . The process of  claim 1 , wherein said other chemically or pharmaceutically acceptable salt is a member selected from the group consisting of alkaline-earth metals, ammonium, tetra(C 1 -C 4 )alkylammonium, aluminum and zinc salts. 
     
     
         4 . The process of  claim 1 , wherein an epiK5-N-sulfate-derivative having a mean molecular weight from approximately 1,000 to approximately 25,000 is used as starting material. 
     
     
         5 . The process of  claim 4 , wherein said starting epiK5-N-sulfate-derivative has a mean molecular weight from approximately 1,000 to approximately 12,000. 
     
     
         6 . The process of  claim 4 , wherein said starting epiK5-N-sulfate-derivative has a mean molecular weight from approximately 1,500 to approximately 25,000. 
     
     
         7 . The process of  claim 6 , wherein said epiK5-N-sulfate-derivative has a mean molecular weight from approximately 10,000 to approximately 25,000. 
     
     
         8 . The process of  claim 1 , wherein said epiK5-N-sulfate-derivative is a LMW-epiK5-N-sulfate having a content in iduronic acid of from 40% to 60% and a mean molecular weight from approximately 1,500 to approximately 12,000. 
     
     
         9 . The process of  claim 8 , wherein said LMW-epiK5-N-sulfate has a mean molecular weight of from approximately 1,500 to approximately 10,000. 
     
     
         10 . The process of  claim 9 , wherein said LMW-epiK5-N-sulfate has a mean molecular weight of from approximately 1,500 to approximately 7,500. 
     
     
         11 . The process of  claim 1 , wherein an epiK5-N-sulfate-derivative consisting of a mixture of chains in which at least 90% of said chains have the formula I 
       
         
           
           
               
               
           
         
       
       in which 20-60% of the uronic units are those of iduronic acid, n is an integer from 2 to 100 and the corresponding cation is chemically or pharmaceutically acceptable, is used as starting material. 
     
     
         12 . The process of  claim 11  wherein said starting material consists of a mixture of chains in which at least 90% of said chains have the formula I, in which 40-60% of the uronic units are those of iduronic acid. 
     
     
         13 . The process of  claim 12  wherein, in formula I, n is an integer from 3 to 100. 
     
     
         14 . A LMW-epiK5-N-sulfate free of NH 2  and acetyl groups having a content in iduronic acid of from 20% to 60% and a mean molecular weight of from approximately 1,000 to approximately 12,000. 
     
     
         15 . The LMW-epiK5-N-sulfate of  claim 14  having a content in iduronic acid of from 40% to 60% and a molecular weight of from approximately 1,500 to approximately 10,000. 
     
     
         16 . The LMW-epiK5-N-sulfate of  claim 15  having a mean molecular weight of from approximately 1,500 to approximately 7,500.