Biotinylated hexadecasaccharides, preparation and use thereof

Abstract

The invention concerns novel biotinylated hexadecasaccharides of general formula (I) wherein: Biot is a biotin derivative; R, R 1 and R 2 , represent independently of one another a C 1 -C 6 alkoxy or and —0S0 3 ; R 3 represents a C 1 -C 6 alkoxy or an —OSO 3 , or R 3 constitutes a —O—CH 2 -bridge; Pe represents a saccharide concatenation; as well as their pharmaceutically acceptable salts, and their use as medicines.

1 . A biotinylated hexadecasaccharide of general formula I:  
     
       
         
         
             
             
         
       
     
     in which: 
 T represents a sequence T 1  or T 2  having the following formulae:  
                     
 Biot represents the group:  
                     
 R represents a (C 1 -C 6 )alkoxy radical, or an —OSO 3   −  radical;  
 R 1  represents a (C 1 -C 6 )alkoxy radical, or an —OSO 3   −  radical;  
 R 2  represents a (C 1 -C 6 )alkoxy radical or an —OSO 3   −  radical;  
 R 3  represents a (C 1 -C 6 )alkoxy radical, or an —OSO 3   −  radical, or alternatively R 3  constitutes an —O-CH 2 - bridge, the —CH 2 - group being linked to the carbon atom bearing the carboxylic function on the same ring; and  
 Pe represents a saccharide sequence having the following formula:  
                     
 and a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The biotinylated hexadecasaccharide according to  claim 1  of general formula I, in which 
 R represents a methoxy radical or an —OSO 3   −  radical,    R 1  represents a methoxy radical,    R 2  represents an —OSO 3   −  radical, and    R 3  represents a methoxy radical.    
   
   
       3 . The biotinylated hexadecasaccharide according to  claim 1 , chosen from: 
 methyl (2,3,4,6-tetra-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3, 6-tri-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3,6-tri-O-sulfonato-β-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)-[(2,3, 6-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-O-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)] 3 -(2-[N-(6-biotinamido hexanoyl)]-2-deoxy-3-O-methyl-6-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-α-D-glucopyranosyl-uronic acid)-(1→4)-(2,3,6-tri-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyl-uronic acid)-(1→4)-3-O-methyl-2,6-di-O-sulfonato-α-D-glucopyranoside, sodium salt; and    methyl (2,3,4,6-tetra-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3, 6-tri-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3, 6-tri-O-sulfonato-β-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)-[(2,3,6-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-O-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)] 3 -(2-[N-(6-biotinamido hexanoyl)]-2-deoxy-3-O-methyl-6-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-β-D-glucopyranosyl-uronic acid)-(1→4)-(2,3,6-tri-O-sulfonato-α-D-gluco-pyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyl-uronic acid)-(1→4)-2,3,6-tri-O-sulfonato-α-D-gluco-pyranoside, sodium salt.    
   
   
       4 . The biotinylated hexadecasaccharide according to  claim 3 , wherein the biotinylated hexadecasaccharide is methyl (2,3,4,6-tetra-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-sulfonato-β-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)-[(2,3, 6-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-O-(2,3, 6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)] 3 -(2-[N-(6-biotinamido hexanoyl)]-2-deoxy-3-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2, 3-di-O-methyl-β-D-glucopyranosyluronic acid)-(1→4)-(2,3, 6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyluronic acid)-(1→4)-3-O-methyl-2,6-di-O-sulfonato-α-D-glucopyranoside, sodium salt.  
   
   
       5 . The biotinylated hexadecasaccharide according to  claim 3 , wherein the biotinylated hexadecasaccharide is methyl (2,3,4,6-tetra-O-sulfonato-α-D-glucopyranosyl) -(1→4)-(2,3,6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-sulfonato-β-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)-[(2,3,6-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-O-(2,3,6-tri-O-methyl-β-D-glucopyranosyl)-(1→4)] 3 -(2-[N-(6-biotinamido hexanoyl)]-2-deoxy-3-O-methyl-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-β-D-glucopyranosyluronic acid)-(1→4)-(2,3, 6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyluronic acid)-(1→4)-2,3,6-tri-O-sulfonato-α-D-glucopyranoside, sodium salt.  
   
   
       6 . A pharmaceutical composition containing, as active principle, a biotinylated hexadecasaccharide according to  claim 1 , in combination with at least one inert and suitable excipient.  
   
   
       7 . A method of treating a pathology consecutive to a modification in the homeostasis of the clotting system appearing during disorders of the cardiovascular and cerebrovascular system, comprising: administering to a patient in need thereof an effective amount of a biotinylated hexadecasaccharide according to  claim 1 , wherein the pathology is selected from: unstable angina, apoplexy, post-angioplasty restenosis, and thrombosis associated with endarterectomy or the insertion of endovascular prostheses.  
   
   
       8 . A method of treating a pathology, comprising: administering to a patient in need thereof an effective amount of a biotinylated hexadecasaccharide according to  claim 1 , wherein the pathology is selected from: thromboembolic disorders associated with post-thrombolysis rethrombosis, infarction, dementia of ischaemic origin, peripheral arterial diseases, blood dialysis, auricular fibrillations, thrombosis during the use of vascular prostheses for aorto-coronary bypasses, thromboembolic pathologies of venous origin, pulmonary embolism, thrombotic complications observed following surgical operations, and the development of tumours or the disruption of clotting, induced by bacterial, viral or enzymatic activators.  
   
   
       9 . A method of treating a prosthesis, comprising: covering the prosthesis with a biotinylated hexadecasaccharide according to  claim 1 .  
   
   
       10 . A method of performing an endarterectomy performed with a porous balloon, comprising: using a biotinylated hexadecasaccharide according to  claim 1  as an adjuvant.  
   
   
       11 . A method of neutralizing a biotinylated hexadecasaccharide according to  claim 1 , comprising: contacting said biotinylated hexadecasaccharide with avidin.  
   
   
       12 . A method of neutralizing a biotinylated hexadecasaccharide according to  claim 1 , comprising: contacting said biotinylated hexadecasaccharide with streptavidin.