Mucopolysaccharides having biological properties, preparation and method of use
AssigneeChoay S.A.
InventorsJean-Claude Lormeau, Maurice Petitou, Jean Choay
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Abstract
Mucopolysaccharides biologically active and more specific than heparin, particularly with respect to the blood factor Xa. These mucopolysaccharides may be obtained by partial depolymerisation, under controlled conditions, of heparin, by the action of a chemical agent such as nitrous acid. The conditions implemented allow the preparation of mucopolysaccharides having a USP titer lower than that of the starting heparin and a Yin-Wessler titer at least equal to that of said heparin. These products may be used particularly as antithrombotic drugs.
Claims42
A process for making mucopolysaccharide heparinic fractions which have the L-iduronosyl-2-O-sulfate-(1-alpha-4)-N-sulfo-D-glucosamine-6-O-sulfate disaccharide structural units of heparin with the O-sulfated iduronic component of heparin, which mucopolysaccharide heparinic fractions do not differ from heparin with respect to the unsulfated iduronic acid component and are further defined by having a terminal structure as follows ##STR6## wherein R.sub.1 is selected from the group consisting of aldehyde, alcohol or carboxylic acid and R.sub.2 is selected from the group consisting of hydrogen or --SO.sub.3, said mucopolysaccharides having a high and improved antithrombotic activity (as measured by anti-Xa activity determined by the Yin-Wessler test (YW)) as compared to heparin, and a YW/USP ratio of at least 2, which comprises the steps of partially depolymerizing heparinic chains having a molecular weight in the range of about 2,000 to about 50,000 daltons by contacting said heparinic chains with nitrous acid in an aqueous medium at a temperature in the range from about 0.degree. C. to about ambient temperature, discontinuing the depolymerization when the mucopolysaccharides has reached a molecular weight in the range of about 2,000 to about 8,000 daltons and separating the mucopolysaccharides having said terminal structure and which do not differ from heparin with respect to the amount of the unsulfated iduronic acid component.
Mucopolysaccharide heparinic fractions which have the L-iduronosyl-2-O-sulfate-(1-alpha-4)-N-sulfo-D-glucosamine-6-O-sulfate disaccharide structural units of heparin with the O-sulfated iduronic component of heparin, which mucopolysaccharide heparinic fractions do not differ from heparin with respect to the unsulfated iduronic acid component and are further defined by having a terminal structure as follows ##STR7## wherein R.sub.1 is selected from the groups consisting of an alcohol and a carboxylic acid and R.sub.2 is selected from the group consisting of hydrogen or --SO.sub.3, which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts thereof.
Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannose terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.
Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannitol terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.
Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannoic acid terminal structure and a --SO.sub.3 primary alcohol function in the 6-position, which products have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.
Dependencies are inferred from the claim text.