Patent EA-005133-B1 (EA)
Title: Polysacchar9des with antithrombotic activity comprising at least a covalent bond with biotin or a biotin derivatives
Inventor: DUCHAUSSOY PHILIPPE
IPC: A61K/
Filed: 2001-09-20
Abstract: 1. Synthetic polysaccharides with antithrombotic activity and their pharmaceutically acceptable salts, characterized in that they exhibit at least one covalent bond with biotin or a biotin derivative. 2. Polysaccharides according to claim 1 of formula: in which: the wavy line denotes a bond situated either below or above the plane of the pyranose ring, Po denotes a polysaccharide, comprising n identical or different monosaccharide units, bonded via its anomeric carbon to Pe, is a diagrammatic representation of a monosaccharide unit with a pyranose structure chosen from hexoses, pentoses and the corresponding deoxy sugars, this unit being bonded via its anomeric carbon to another monosaccharide unit and the hydroxyl groups of this unit being substituted by identical or different R<1> groups, R1 being as defined below, Pe represents a pentasaccharide of structure: h is equal to 1 or 2, n is an integer and can take any value from 0 to 25, R1 represents the -T-Biot linkage, a (C1-C6)alkoxy group or an -OSO3<->group, R2 represents the -T-Biot linkage, a (C1-C6)alkoxy group or an -OSO3<->group, R3 represents the -T-Biot linkage or a (C1-C6)alkoxy group, R4 represents the -T-Biot linkage, a (C1-C6)alkoxy group or an -OSO3-group, or else R4 constitutes an -O-CH2- bridge, the -CH2- group being bonded to the carbon atom carrying the carboxyl functional group on the same ring; it being understood that at least one of the R1, R2, R3 or R4 substituents represents a -T-Biot group, W represents an oxygen atom or a methylene group, T represents one of the linkages chosen from: NH, or in which j and k, which are identical or different, are integers which can take any value from 1 to 10; Biot represents the group: and their pharmaceutically acceptable salts. 3. Polysaccharides according to either of claims 1 and 2 of formula (I.1): denotes a specific family of polysaccharides Po which are bonded via their anomeric carbon to Pe as defined for (I), is as defined for (I), the R1 groups are as defined for (I) and, for a same monosaccharide, can be identical or different, the monosaccharide present in [ ]m is repeated m times, the monosaccharide present in [ ]t is repeated t times and the monosaccharide present in [ ]p is repeated p times, m is an integer varying from 1 to 5, t is an integer varying from 0 to 24 and p is an integer varying from 0 to 24, it being understood that 1 <= =m+t+p <= =25, and their pharmaceutically acceptable salts. 4. Polysaccharides according to claim 3, characterized in that only one of the R1, R2, R3 or R4 substituents represents the -T-Biot linkage with T and Biot being as defined for (I). 5. Hexadecasaccharides according to any one of claims 1 to 4 of formula (I.2): in which: T represents one of the linkages chosen from: NH, or in which j and k, which are identical or different, are integers which can take any value from 1 to 10; Biot represents the group: Pe represents a pentasaccharide of structure: in which: R1 represents a (C1-C6)alkoxy group or an -OSO3<->group, R2 represents a (C1-C6)alkoxy group or an -OSO3<-> group, R3 represents a (C1-C6)alkoxy group, R4 represents the -T-Biot linkage, a (C1-C6)alkoxy group or an -OSO3-group, or else R4 constitutes an -O-CH2- bridge, the -CH2- group being bonded to the carbon atom carrying the carboxyl functional group on the same ring; W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts. 6. Pentasaccharides according to either of claims 1 and 2 of formula (I.3): in which of the R1, R2, R3, R4 and W are as defined for (I), and their pharmaceutically acceptable salts. 7. Pentasaccharides according to claim 6, characterized in that only one of the R1, R2, R3 or R4 substituents represents the -T-Biot linkage with T and Biot being as defined for (I). 8. Pentasaccharides according to either of claims 6 and 7 of formula (I.3) of formula (I.4): in which: T represents one of the linkages chosen from: NH, or in which j and k, which are identical or different, are integers which can take any value from 1 to 10; Biot represents the group: R1 represents a (C1-C6)alkoxy group or an -OSO3<->group, R2 represents a (C1-C6)alkoxy group or an -OSO3<-> group, R3 represents a (C1-C6)alkoxy group, R4 represents the -T-Biot linkage, a (C1-C6)alkoxy group or an -OSO3-group, or else R4 constitutes an -O-CH2- bridge, the -CH2- group being bonded to the carbon atom carrying the carboxyl functional group on the same ring; W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts. 9. Polysaccharides according to either of claims 1 and 2 chosen from: Methyl (2,3,4,6-tetra-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[beta]-D-glucopyranosyl)-(1->4)-(6-biotinamido-6-deoxy-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)-[(2,3,6-tri-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-O-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)]3-(6-O-sulphonato-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranoside, sodium salt, Methyl (2,3,4,6-tetra-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[beta]-D-glucopyranosyl)-(1->4)-(6-[6-(biotinamido)-hexamido]-6-deoxy-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)-[(2,3,6-tri-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-O-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)]3-(6-O-sulphonato-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranoside, sodium salt, Methyl (2,3,4,6-tetra-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-sulphonato-[beta]-D-glucopyranosyl)-(1->4)-(6-[6-(6-biotanamido-hexamido)hexamido]-6-deoxy-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)-[(2,3,6-tri-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-O-(2,3,6-tri-O-methyl-[beta]-D-glucopyranosyl)-(1->4)]3-(6-O-sulphonato-2,3-di-O-methyl-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranoside, sodium salt, Methyl (2-biotinamido-2-deoxy-3,4-di-O-methyl-6-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranoside, sodium salt, Methyl (2-[6-(6-biotinamidohexamido)hexamido]-2-deoxy-3,4-di-O-methyl-6-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-o-sulphonato-[alpha]-D-glucopyranoside, sodium salt, Methyl (2-[6-(6-biotinamidohexamido)hexamido]-2-deoxy-3,4-di-O-methyl-6-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[beta]-D-glucopyranosyluronic acid)-(1->4)-(2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranosyl)-(1->4)-(2,3-di-O-methyl-[alpha]-L-idopyranosyluronic acid)-(1->4)-2,3,6-tri-O-sulphonato-[alpha]-D-glucopyranoside, sodium salt. 10. Pharmaceutical compositions comprising, as active principle, a polysaccharide according to any one of claims 1 to 9, optionally in combination with one or more inert and appropriate excipients. 11. Use of the pharmaceutical compositions according to claim 10 in pathologies resulting from a modification of the homoeostasis of the coagulation system appearing during disorders of the cardiovascular and cerebrovascular system, such as thromboembolic disorders associated with atherosclerosis and diabetes, for example unstable angina, apoplexy, postangioplasty restenosis, endarterectomy or the insertion of endovascular prostheses, or thromboembolic disorders associated with post-thrombolyses rethrombosis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis or with auricular fibrillations, during the use of vascular prostheses for aortocoronary bypasses, in the treatment or prevention of thromboembolic pathologies of venous origin, such as pulmonary embolisms, to prevent or treat the thrombotic complications observed following surgical operations, the growth of tumours or disturbances to coagulation induced by bacterial, viral or enzymatic activators. 12. Use of a polysaccharide according to any one of claims 1 to 9, to cover prostheses. 13. Use of a polysaccharide according to any one of claims 1 to 9 as adjuvants during endarterectomy carried out with porous balloons. 14. Process employing avidin or streptavidin, characterized in that it makes it possible to neutralize the polysaccharides according to any one of claims 1 to 9. 15. Use of avidin or of streptavidin in the preparation of medicaments intended to neutralize the polysaccharides according to any one of claims 1 to 9.