Oligosaccharides having anti-Xa activity and pharmaceutical compositions containing them

Abstract

Oligosaccharides obtainable from heparin including heparinic constituents of molecular weights ranging from 2000 to 50,000. Said fractions have a Yin-Wessler titer and a USP titer in a ratio of at least 30. They consist of chains constituted by no more than 8 saccharidic moities. They possess a strong antithrombotic activity and are then useful as antithrombotic drugs.

Claims

1. An oligosaccharide fraction of the heparin chain which oligosaccharide has improved antithrombotic activity in vivo higher than that of heparin (as measured by the Yin-Wessler test), which oligosaccharide fraction (1) comprises not more than 8 saccharide units, (2) of which one is an N-sulfate-3-O-sulfate-D-glucosamine unit (3) has anti-Xa activity at least 10 times that of heparin, (4) specific affinity for AT III, (5) a ratio of Yin-Wessler titer to USP titer of at least 30 and (6) virtually no anticoagulant activity (as determined by the USP test) and, the biologically acceptable salts of said oligosaccharide.

2. The oligosaccharide of claim 1 which oligosaccharide contains a saccharide sequence of units selected from the group consisting of ABCDEFGH, ABGHCDEF, ABCDEF, CDEFGH and DEFGH, wherein A, B, C, D, E, F, G and H are defined as follows

A=unsaturated or saturated uronic acid

B=N-sulfate-D-Glucosamine or N-sulfate-6-O-sulfate-D-glucosamine

C=L-iduronic acid or, where present at a chain end, unsaturated uronic acid

D=N-acetyl-D-glucosamine or N-acetyl-6-O-sulfate-D-glucosamine

E=D-glucuronic acid

F=N-sulfate-3-O-sulfate-D-glucosamine or N-sulfate-3-O-sulfate-6-O-sulfate-D-glucosamine

G=2-O-sulfate-L-iduronic acid, and

H=N-sulfate-D-glucosamine or N-sulfate-6-O-sulfate-D-glucosamine.

3. The oligosaccharide of claim 1 wherein the N-sulfate-D-glucosamine is N-sulfate-3-O-sulfate-6-O-sulfate-D-glucosamine.

4. The oligosaccharide of claim 1 which includes a unit selected from the group consisting of N-acetyl-D-glucosamine, D-glucuronic acid, 2-O-sulfate-L-iduronic acid or N-sulfate-D-glucosamine.

5. The oligosaccharide of claim 1 which includes a unit selected from the group consisting of 2-O-sulfate-4,5 unsaturated uronic acid, N-sulfate-D-glucosamine or L-iduronic acid.

6. The oligosaccharide of claim 1 which includes a unit selected from the group consisting of N-sulfate-6-O-sulfate-D-glucosamine, L-iduronic acid, 2-O-sulfate-L-iduronic acid or N-sulfate-D-glucosamine.

7. The oligosaccharide of claim 2 wherein the saccharide sequence is selected from the group consisting of CDEFGH or ABCDEF.

8. The oligosaccharide of claim 2 wherein the saccharide sequence is selected from the group consisting of DEFGH.

9. The oligosaccharide of claim 1 which is the sodium, calcium or magnesium salt.

10. The oligosaccharide of claim 1 wherein the N-sulfate-D-glucosamine unit is at the reducing end of the oligosaccharide chain.

11. The oligosaccharide of claim 1 which comprises one N-acetyl-glucosamine saccharide moiety for every two or three N-sulfate-glucosamine saccharide moieties.

12. A therapeutic antithrombotic composition which has antithrombotic activity higher than that of heparin (as measured by the Yin-Wessler test) which composition comprises a therapeutically acceptable carrier and in a therapeutically effective amount, an oligosaccharide of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

13. The therapeutic composition of claim 12 in which the ratio of Yin-Wessler titer to USP titer is at least about 100.

14. The therapeutic composition of claim 12 in which the oligosaccharide has a Yin-Wessler titer of 100 to about 2,000 U/mg.

15. A therapeutic method for controlling thrombosis in a patient which comprises administering to said patient the therapeutic antithrombotic composition of claim 12 and controlling thrombosis.

16. The therapeutic method of claim 15 in which the administration of the composition is at periodic intervals.