Low molecular weight sulfated polysaccharides and uses thereof

• US 5,646,130 A
• Filed: 06/30/1995
• Issued: 07/08/1997
• Est. Priority Date: 06/30/1995
• Status: Expired due to Fees

• Current Assignee: Qingdao Ocean University
• Original Assignee: Qingdao Ocean University
• Inventors: Shi, Guan Hua
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): Lee, Howard C.
• Application Number:
  US08/498,013
• Time in Patent Office: 739 Days
• Field of Search: 514/54, 514/821, 514/822, 514/824, 514/885, 536/123, 536/123.1, 536/124
• US Class Current: 514/54
• CPC Class Codes: C08B 37/0084 Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates

Abstract

An oligosaccharide containing about 20 monosaccharide units is provided. This oligosaccharide designated (M₉ G)₂ is a copolymer β-D-(1→4) connected mannuronopyranose units and an α-L-(1→4) connected guluronic acid unit at a ratio of 9:1. In addition, 40-60% of the carboxylic functional groups are esterified with propanol, 2-propanol or methanol, and substantially all of the C₂ carbons and about 50% of the C₃ positions of the residues are sulfated, such that the resulting compound contains about 7-13% organic sulfur. The compounds are used for the prevention and therapy of thrombosis-induced ischemic vascular diseases of the heart and the central nervous system, for treating acute thrombosis-induced brain infarction and in coronary ischemia-induced angina, and for treating hyperlipoproteinemia and lowering the relative amount of cholesterol.

Claims

1. A compound represented by formula (I):

##STR3## wherein;

R is --(CH₂)_p CH(OH)(CH₂)_m (CH₃) or CH₂ (CH₂)_s OH in which p, m and s are independently 0 to 6;

R'"'"' is SO₃ Na;

n is about 1 to about 3; and

the resulting compound has a molecular weight less than about 5 kilodaltons.

2. A compound of claim 1, wherein R is selected from among --CH₂ CH(OH)CH₃, --CH₂ CH₂ OH and CH₂ OH.

3. The compound of claim 2, wherein n is 2.

4. A compound of claim 2, wherein R is --CH₂ CH(OH)CH₃.

5. A compound of claim 1, wherein R is --CH₂ CH(OH)CH₃.

6. The compound of claim 3, wherein R is --CH₂ CH(OH)CH₃.

11. A composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12. The composition of claim 1 that is formulated for intravenous administration.

13. The composition of claim 1 that is formulated for local administration.

14. The composition of claim 1 that is formulated for oral administration.

15. The composition of claim 1 that is formulated for topical administration.

16. A composition, comprising an effective amount of a compound of claim 1 for treatment of ischemic or thrombotic vascular diseases of the central nervous system (CNS) and heart, wherein the composition is formulated for single dosage administration.

17. A method for treating ischemic vascular disease of the brain, comprising administering an effective amount of a compound of claim 1.

18. A method for treating pulmonary or deep vein thrombosis, comprising administering an effective amount of a compound of claim 1.

19. A method for treating myocardial infarction, comprising administering an effective amount of a compound of claim 1.

20. A method for treating hyperlipoproteinemia, comprising administering an effective amount of a compound of claim 1.

21. The method of claim 20, wherein the compound is administered intravenously or parenterally.

22. A method for lowering cholesterol, comprising administering an effective amount of a compound of claim 1.

23. The method of claim 22, wherein the compound is administered by mixing it with food.

24. A method for reducing the immunosuppressive side-effects associated with the administration of alkylating agents, comprising administering a immunostimulating amount of a compound of claim 1, simultaneously with, prior to or subsequent to administration of the alkylating agent.

25. A method of preventing atherosclerotic lesions, comprising administering an effective amount of a compound of claim 1 to a patient at risk for developing such lesions.

26. A method of treating coronary ischemia-induced angina, comprising administering an effective amount of a compound of claim 1 to patient experiencing a stroke or myocardial infarction or other acute thrombotic disorder.

27. A composition, comprising the oligosaccharide of claim 1, obtained by a process, comprising:

a) extracting polysaccharides from a marine brown algae by swelling the algae that has been previously dried in water;

b) acid hydrolyzing the mixture of polysaccharides to produce oligosaccharides having molecular weights of 5 kD or less;

c) esterifying the oligosaccharides by reacting the oligosaccharide with an epoxide, methanol, ethanol, or propanol, whereby about 50% of the acid residues on the constituent residues are esterified;

d) sulfating the resulting esterified oligosaccharide, whereby substantially all of the 2-positions on the constituent residues are sulfated, and about 40-50% of the 3-positions on these residues are sulfated, wherein the resulting preparation contains a substantially homogeneous preparation of oligosaccharides.

7. An oligosaccharide produced by a process, comprising:

a) extracting polysaccharides from a marine brown algae by swelling the algae that has been previously dried in water;

b) acid hydrolyzing the mixture of polysaccharides to produce oligosaccharides having molecular weights of 5 kD or less;

c) esterifying the oligosaccharides by reacting the oligosaccharide with an epoxide, methanol, ethanol, or propanol, whereby about 50% of the acid residues on the constituent residues are esterified;

d) sulfating the resulting esterified oligosaccharide, whereby substantially all of the 2-positions on the constituent residues are sulfated, and about 40-50% of the 3-positions on these residues are sulfated, wherein the resulting preparation contains a substantially homogeneous preparation of oligosaccharides.

8. The oligosaccharide of claim 7, wherein steps a) and b) of the process comprise:

i) soaking dried brown algae in water;

ii) acidifying the mixture and refluxing at a temperature of about 100°

C. for about 8-12 hours;

iii) removing the solution and diluting the resulting solid in water to produce a gel and adjusting the pH from about 2.5 to about 3.0; and

iv) centrifuging the resulting mixture, and collecting and desalting the supernatant;

v) repeating steps i)-iv).

9. The oligosaccharide of claim 7, wherein step c) of the process comprises:

reacting the product of step b) with an epoxide containing two or three carbons or with methanol.

10. The oligosaccharide of claim 7, wherein step d) of the process comprises:

reacting the esterified product with chlorosulfonic acid.