US4804652A
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US
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Mucopolysaccharides having biological properties, preparation and application thereof as drugs
Assignee: Choay SA
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Filing: 1985-02-19
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Granted: 1989-02-14
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Expires: 2005-02-19
Abstract
Abstract Mucopolysaccharides biologically active and more specific than heparin, particularly with respect to the blood factor Xa. These mucopolysaccharides may be obtained by partial depolymerization, 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.
Inventors
- 👤 Jean-Claude Lormeau
- 👤 Maurice Petitou
- 👤 Jean Choay
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 22:57
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/70; A61K31/715; A61P; A61P7/00; A61P7/02; C; C08; C08B; C08B37/00; C08B37/006; C08B37/0063; C08B37/0075; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/86; G01N2333/00; G01N2333/81; G01N2333/8107; G01N2333/811; G01N2333/8121; G01N2333/8128; G01N2400/00; G01N2400/10; G01N2400/38; G01N2400/40
Claims Analysis
Total Claims: 36
Claim 1
Independent Claim
240 words
A process for making mucopolysacharide 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 components of herparin, which mucopolysaccharide 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 1 , is selected from the group consisting of aldehyde, alcohol and carboxylic acid and R 2 is selected from the group consisting of hydrogen and --SO 3 , said mucopolysaccharides having a high and improved antithrombotic activity as measured by anti-X a activity determined by the Yin Wessler test (YW) as compared to heparin, and a YW/USP ratio of at least 2, which comprises the step of partially depolymerizing heparinic chains having a molecular weight in the range of about 2,000 to about 50,000 daltons by contacting said herparinic chains with nitrous acid in an aqueous medium at a temperature in the range from about 0° C. to about ambient temperature, and at a pH in the range of about 2 to 3, discontinuing the polymerization when the mucopolysaccharides have reached a molecular weight in the range of about 2,000 to about 8,000 daltons by adjusting the pH to a pH outside the depolymerization range of about 2 to 3 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.
Claim 2
Dependent Claim
240 words
A process for making mucopolysacharide 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 components of herparin, which mucopolysaccharide 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 1 , is selected from the group consisting of aldehyde, alcohol and carboxylic acid and R 2 is selected from the group consisting of hydrogen and --SO 3 , said mucopolysaccharides having a high and improved antithrombotic activity as measured by anti-X a activity determined by the Yin Wessler test (YW) as compared to heparin, and a YW/USP ratio of at least 2, which comprises the step of partially depolymerizing heparinic chains having a molecular weight in the range of about 2,000 to about 50,000 daltons by contacting said herparinic chains with nitrous acid in an aqueous medium at a temperature in the range from about 0° C. to about ambient temperature, and at a pH in the range of about 2 to 3, discontinuing the polymerization when the mucopolysaccharides have reached a molecular weight in the range of about 2,000 to about 8,000 daltons by adjusting the pH to a pH outside the depolymerization range of about 2 to 3 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.
Claim 3
Dependent Claim
18 words
The process of claim 1 wherein the depolymerization is stopped by adjusting the pH to an alkaline pH.
Claim 4
Dependent Claim
22 words
The process of claim 2 wherein the pH is adjusted to an alkaline pH with an alkaline agent which is sodium hydroxide.
Claim 5
Dependent Claim
28 words
The process of claim 1 wherein the nitrous acid is generated in situ from a derivative selected from the group consisting of a salt and an ether salt.
Claim 6
Dependent Claim
23 words
The process of claim 4 wherein the nitrous acid is generated by the addition of an acid which has a physiologically acceptable anion.
Claim 7
Dependent Claim
11 words
The process of claim 5 wherein the acid is hydrochloric acid.
Claim 8
Dependent Claim
37 words
The process of claim 4 wherein the final concentration of heparin is from about 1 to about 10 g per 100 ml of reaction medium and the concentration of sodium nitrite is from about 0.02M to 0.1M.
Claim 9
Dependent Claim
29 words
The process of claim 7 wherein the concentration of heparin is about 2 g per 100 ml of reaction medium and the concentration of sodium nitrite is about 0.05M.
Claim 10
Dependent Claim
23 words
The process of claim 4 wherein the reaction is carried out at a temperature of from about 0° C. to about 10° C.
Claim 11
Dependent Claim
13 words
The process of claim 4 wherein the salt is an alkaline earth salt.
Claim 12
Dependent Claim
12 words
The process of claim 10 wherein the alkaline salt is sodium nitrite.
Claim 13
Dependent Claim
13 words
The process of claim 1 wherein the pH is increased to about 7.5.
Claim 14
Dependent Claim
32 words
The process of claim 1 wherein alcohol is added in a proportion of about at least 5 volumes with respect to the volume of the reaction medium to separate the mucopolysaccharide fractions.
Claim 15
Dependent Claim
24 words
A process according to claim 1 which further comprises reducing the recovered polysaccharide fragments recovering polysaccharide fragments having terminal structures which are 2,5-anhydro-D-mannitol groups.
Claim 16
Dependent Claim
12 words
The process of claim 14 wherein the reducing agent is potassium borohydride.
Claim 17
Dependent Claim
30 words
A process according to claim 1 which further comprises oxidizing the recovered polysaccharide fragments recovering polysaccharide fragments having terminal structures which are 2,5-anhydro-D-mannonic acid groups and their pharmaceutically acceptable salts.
Claim 18
Dependent Claim
12 words
The process of claim 16 wherein the oxidizing agent is potassium permanganate.
Claim 19
Dependent Claim
102 words
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 1 is selected from the groups consisting of an alcohol, an aldehyde and a carboxylic acid and R 2 is selected from the group consisting of hydrogen and --SO 3 , which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts therof.
Claim 20
Dependent Claim
102 words
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 1 is selected from the groups consisting of an alcohol, an aldehyde and a carboxylic acid and R 2 is selected from the group consisting of hydrogen and --SO 3 , which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts therof.
Claim 21
Dependent Claim
24 words
The mucopolysaccharide heparinic fractions of claim 18 wherein fractions have R 2 which is hydrogen and R 1 is selected from the specified groups.
Claim 22
Dependent Claim
22 words
The mucopolysaccharide haparinic fractions of claim 19 wherein fractions have R 2 which is hydrogen and R 1 is an aldehyde radical.
Claim 23
Dependent Claim
24 words
The mucopolysaccharide heparinic fractions of claim 19 wherien fractions have R 2 which is hydrogen and R 1 is --CH 2 OH or aldehyde.
Claim 24
Dependent Claim
19 words
The mucopolysaccharide heparinic fractions of claim 19 wherein R 1 is COOH and R 2 is --SO 3 .
Claim 25
Dependent Claim
20 words
The mucopolysaccharide heparinic fractions of claim 22 which have a ratio of anti-Xa to USP titers of at least 6.
Claim 26
Dependent Claim
29 words
The mucopolysaccharide fractions of claim 22 which have an anti-Xa titer of over about 200 units/mg and a ratio of titers of anti-Xa to USP of at least 3.
Claim 27
Dependent Claim
38 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannose terminal structure and a --SO 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.
Claim 28
Dependent Claim
38 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannose terminal structure and a --SO 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.
Claim 29
Dependent Claim
21 words
The partially nitrous acid depolymerized heparin products of claim 25 which have a YW/USP ratio of about 10 to about 22.
Claim 30
Dependent Claim
38 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannitol terminal structure and a --SO 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.
Claim 31
Dependent Claim
38 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannitol terminal structure and a --SO 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.
Claim 32
Dependent Claim
39 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannonic acid terminal structure and a --SO 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.
Claim 33
Dependent Claim
39 words
Partially nitrous acid depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannonic acid terminal structure and a --SO 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.
Claim 34
Dependent Claim
22 words
The mucopolysaccharide heparinic fractions of claims 27 or 28 which is soluble in a water-ethanol medium having a titer of 55-61° GL.
Claim 35
Dependent Claim
54 words
A biological composition which has anti-thrombotic activity higher then that of heparin which has increased selective inhibition of the X a factor in vitro and in vivo, which composition comprises a therapeutically acceptable carrier and in a therapeutically effective amount, a mucopolysaccharide of claims 18, 19, 20, 21, 22, 25, 26, 27 or 28.
Claim 36
Dependent Claim
29 words
A therapeutic method for controlling thrombosis in a patient which comprises administering to said patient a biological composition of claim 30 and controlling thrombosis by inhibiting coagulation factor Xa.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1992-02-14 | 1992-08-15 | 1993-02-14 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1996-02-14 | 1996-08-15 | 1997-02-14 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2000-02-14 | 2000-08-15 | 2001-02-14 | $7700.00 | Window Closed / Lapsed |