Polysaccharides comprising two antithrombin iii-binding sites, preparation thereof and use thereof as antithrombotic medicaments

Abstract

The invention relates to sulphated polysaccharides which have the general structure of the constituent polysaccharides of heparin and which have a molecular weight of less than 8000 Daltons, comprising two antithrombin III-binding hexasaccharide sequences corresponding to formula (I): in which: R1 represents an OH group when the hexasaccharide of formula (I) is located at the reducing end of the polysaccharide, or else R1 represents a bond with another saccharide unit of said polysaccharide, R2 represents a hydrogen atom when the hexasaccharide of formula (I) is located at the non-reducing end of the polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a double bond, or else R2 represents a bond with another saccharide unit of said polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit is a single bond. Preparation thereof, use thereof as antithrombotic medicaments, and also use thereof in a method for analysing a sample of a heparin derivative.

1 . A sulfonated polysaccharide having a polysaccharide of heparin which has a molecular weight of less than 8000 Daltons, said sulfonated polysaccharide comprising two antithrombin III-affinity sites, wherein said sulfonated polysaccharide is in mixture with other polysaccharides. 
     
     
         2 . The sulfonated polysaccharide according to  claim 1 , comprising two antithrombin III-binding hexasaccharide sequences. 
     
     
         3 . The sulfonated polysaccharide according to  claim 2 , wherein said sulfonated polysaccharide twice comprises the antithrombin III-binding hexasaccharide sequence corresponding to formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         the bond represented as a dashed line between carbon atoms 4 and 5 of the first saccharide unit is either a single bond or a double bond, 
         the wavy line denotes a bond located either below or above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R1 represents an OH group when the hexasaccharide of formula (I) is located at the reducing end of the polysaccharide, or else R1 represents a bond with another saccharide unit of said polysaccharide, in which case the bond is located above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R2 represents a hydrogen atom when the hexasaccharide of formula (I) is located at the non-reducing end of the polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a double bond, or else R2 represents a bond with another saccharide unit of said polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a single bond, 
         said polysaccharide being in acid form or in salified form. 
       
     
     
         4 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide comprises between 12 and 22 saccharide units. 
     
     
         5 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide corresponds to formula (II):
   (A) d -(Formula(I))-(B) f -(Formula(I))-(C) 9    (II)
   in which:   the A, B and C units, which may be identical to or different from one another, represent disaccharide sequences,   the units of formula (I) represent a hexasaccharide sequence corresponding to Formula (I):   
       
         
           
           
               
               
           
         
         in which: 
         the bond represented as a dashed line between carbon atoms 4 and 5 of the first saccharide unit is either a single bond or a double bond, 
         the wavy line denotes a bond located either below or above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R1 represents an OH group when the hexasaccharide of formula (I) is located at the reducing end of the polysaccharide, or else R1 represents a bond with another saccharide unit of said polysaccharide, in which case the bond is located above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R2 represents a hydrogen atom when the hexasaccharide of formula (I) is located at the non-reducing end of the polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a double bond, or else R2 represents a bond with another saccharide unit of said polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a single bond, 
         said polysaccharide (I) being in acid form or in salified form; 
         the subscripts d, f and g each represent an integer equal to 0 or comprised between 1 and 5, on the condition that the sum of the integers d, f and g is comprised between 0 and 5. 
       
     
     
         6 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide corresponds to formula (II):
   (A) n -(Formula(I))-(B) m -(Formula(I))-(C) k    (II)
   in which:   the A, B and C units, which may be identical to or different from one another, represent disaccharide sequences,   the units of formula (I) represent a hexasaccharide sequence corresponding to formula (I):   
       
         
           
           
               
               
           
         
         in which: 
         the bond represented as a dashed line between carbon atoms 4 and 5 of the first saccharide unit is either a single bond or a double bond, 
         the wavy line denotes a bond located either below or above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R1 represents an OH group when the hexasaccharide of formula (I) is located at the reducing end of the polysaccharide, or else R1 represents a bond with another saccharide unit of said polysaccharide, in which case the bond is located above the plane of the pyranose ring of the glucosamine unit to which R1 is attached, 
         R2 represents a hydrogen atom when the hexasaccharide of formula (I) is located at the non-reducing end of the polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a double bond, or else R2 represents a bond with another saccharide unit of said polysaccharide, in which case the bond between carbon atoms 4 and 5 of the first saccharide unit of said hexasaccharide is a single bond, 
         said polysaccharide (II) being in acid form or in salified form; 
         the subscripts n, m and k each represent an integer equal to 0 or to 1, on the condition that, when one of the subscripts n, m or k is equal to 1, then the other two subscripts are equal to 0. 
       
     
     
         7 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide comprises 12 saccharide units and corresponds to formula (III): 
       
         
           
           
               
               
           
         
         said polysaccharide (III) being in acid form or in salified form. 
       
     
     
         8 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide comprises 14 saccharide units. 
     
     
         9 . The sulfonated polysaccharide according to  claim 8 , wherein said sulfonated polysaccharide corresponds to formulae (IV), (V) or (VI): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which the wavy line denotes a bond located either below or above the plane of the pyranose ring of the glucosamine unit, said polysaccharide (IV), (V) or (VI) being in acid form or in salified form. 
       
     
     
         10 . The sulfonated polysaccharide according to  claim 1 , wherein said sulfonated polysaccharide is in the form of a sodium salt. 
     
     
         11 . A low-molecular-weight or ultra-low-molecular-weight heparin, comprising one or more sulfonated polysaccharides according to  claim 1 , in mixture with other polysaccharides. 
     
     
         12 . The low-molecular-weight or ultra-low-molecular-weight heparin according to  claim 11 , comprising the sulfonated polysaccharide of formula (III), in mixture with other polysaccharides: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition, comprising the sulfonated polysaccharide according to  claim 1 , or a pharmaceutically acceptable salt thereof, in mixture with other polysaccharides, and at least one pharmaceutically acceptable excipient. 
     
     
         14 . A method for treating and preventing thrombosis, comprising administering to a patient in need thereof a therapeutically effective amount of the sulfonated polysaccharide of  claim 1 , in a mixture with other polysaccharides, or a pharmaceutically acceptable salt thereof.