US4500519A
Expired / Lapsed
US
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Mucopolysaccharides having biological properties, preparation and method of use
Assignee: Choay SA
•
Filing: 1981-11-20
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Granted: 1985-02-19
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Expires: 2001-11-20
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 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.
Inventors
- 👤 Jean-Claude Lormeau
- 👤 Maurice Petitou
- 👤 Jean Choay
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 20:18
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/70; A61K31/715; 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: 47
Claim 1
Independent Claim
210 words
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 1 is selected from the group consisting of aldehyde, alcohol or carboxylic acid and R 2 is selected from the group consisting of hydrogen or --SO 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° 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.
Claim 2
Dependent Claim
210 words
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 1 is selected from the group consisting of aldehyde, alcohol or carboxylic acid and R 2 is selected from the group consisting of hydrogen or --SO 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° 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.
Claim 3
Dependent Claim
22 words
The process of claim 1 wherein the depolymerization is carried out at a pH in the range of about 2 to 3.
Claim 4
Dependent Claim
21 words
The process of claim 1 wherein the depolymerization is stopped by adjusting the pH to a pH outside the depolymerization range.
Claim 5
Dependent Claim
18 words
The process of claim 3 wherein the depolymerization is stopped by adjusting the pH to an alkaline pH.
Claim 6
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 or an ether salt.
Claim 7
Dependent Claim
13 words
The process of claim 5 wherein the salt is an alkaline earth salt.
Claim 8
Dependent Claim
12 words
The process of claim 6 wherein the alkaline salt is sodium nitrite.
Claim 9
Dependent Claim
23 words
The process of claim 5 wherein the nitrous acid is generated by the addition of an acid which has a physiologically acceptable anion.
Claim 10
Dependent Claim
11 words
The process of claim 8 wherein the acid is hydrochloric acid.
Claim 11
Dependent Claim
37 words
The process of claim 5 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 12
Dependent Claim
29 words
The process of claim 10 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 13
Dependent Claim
23 words
The process of claim 5 wherein the reaction is carried out at a temperature of from about 0° C. to about 10° C.
Claim 14
Dependent Claim
13 words
The process of claim 3 wherein the pH is increased to about 7.5.
Claim 15
Dependent Claim
22 words
The process of claim 4 wherein the pH is adjusted to an alkaline pH with an alkaline agent which is sodium hydroxide.
Claim 16
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 17
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 18
Dependent Claim
12 words
The process of claim 16 wherein the reducing agent is potassium borohydride.
Claim 19
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 20
Dependent Claim
12 words
The process of claim 18 wherein the oxidizing agent is potassium permanganate.
Claim 21
Dependent Claim
100 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 and a carboxylic acid and R 2 is selected from the group consisting of hydrogen or --SO 3 , which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts thereof.
Claim 22
Dependent Claim
100 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 and a carboxylic acid and R 2 is selected from the group consisting of hydrogen or --SO 3 , which fractions have a molecular weight in the range of about 2,000 to 8,000 daltons and the physiologically acceptable salts thereof.
Claim 23
Dependent Claim
25 words
The mucopolysaccharide heparinic fractions of claim 20 wherein fractions have R 2 which is --SO 3 and R 1 is selected from the specified groups.
Claim 24
Dependent Claim
23 words
The mucopolysaccharide haparinic fractions of claim 21 wherein fractions have R 2 which is --SO 3 and R 1 is an aldehyde radical.
Claim 25
Dependent Claim
23 words
The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have R 2 which is --SO 3 and R 1 is --CH 2 OH.
Claim 26
Dependent Claim
21 words
The mucopolysaccharide heparinic fractions of claim 21 wherein R 1 is --CH 2 OH and R 2 is --SO 3 .
Claim 27
Dependent Claim
22 words
The mucopolysaccharide heparinic fractions of claim 20 wherein the molecular weight is in the range of about 3,000 to about 5,000 daltons.
Claim 28
Dependent Claim
20 words
The mucopolysaccharide heparinic fractions of claim 20 which is soluble in a water-ethanol medium having a titer of 55°-61° GL.
Claim 29
Dependent Claim
34 words
The mucopolysaccharide heparinic fractions of claim 20 which have a Yin-Wessler titer higher than that of heparin and of at least 200 IU/mg and a Yin-Wessler to USP titer ratio of at least 10.
Claim 30
Dependent Claim
27 words
The mucopolysaccharide heparinic fractions of claim 20 wherein the Yin-Wessler titer is at least 250 IU/mg and the ratio of YW to USP titer is about 22.
Claim 31
Dependent Claim
20 words
The mucopolysaccharide heparinic fractions of claim 21 which is soluble in a water-ethanol medium having a titer of 55°-61° GL.
Claim 32
Dependent Claim
14 words
The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannose.
Claim 33
Dependent Claim
14 words
The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannitol.
Claim 34
Dependent Claim
15 words
The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have the terminal structure, 2,5-anhydro-D-mannonic acid.
Claim 35
Dependent Claim
21 words
The mucopolysaccharide heparinic fractions of claim 21 wherein fractions have a Yin-Wessler activity from about 200 IU/mg to about 270 IU/mg.
Claim 36
Dependent Claim
36 words
Partially 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 37
Dependent Claim
36 words
Partially 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 38
Dependent Claim
22 words
The partially depolymerized heparin products of claim 34 which have a YW/USP ratio in the range of about 10 to about 22.
Claim 39
Dependent Claim
36 words
Partially 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 40
Dependent Claim
36 words
Partially 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 41
Dependent Claim
37 words
Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannoic 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 42
Dependent Claim
37 words
Partially depolymerized heparin products having fragments which have a 2,5-anhydro-D-mannoic 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 43
Dependent Claim
23 words
The mucopolysaccharide heparinic fractions of claims 34, 36, or 37 which is soluble in a water-ethanol medium having a titer of 55°-61° GL.
Claim 44
Dependent Claim
69 words
A biological composition which has antithrombotic activity higher than that of heparin (as measured by the Yin-Wessler test) which has increased selective inhibition of the Xa factor in vitro and in vivo, which composition comprises a therapeutically acceptable carrier and in a therapeutically effective amount, a mucopolysaccharide of claims 20, 21, 22, 23, 24, 25, 26, 27, 28 29, 30, 31, 32, 33, 34, 35, 36, 37 or 41.
Claim 45
Dependent Claim
29 words
A therapeutic method for controlling thrombosis in a patient which comprises administering to said patient a biological composition of claim 39 and controlling thrombosis by inhibiting coagulation factor Xa.
Claim 46
Dependent Claim
20 words
The mucopolysaccharide heparinic fractions of claim 20 which have a ratio of anti-Xa to USP titers of at least 6.
Claim 47
Dependent Claim
29 words
The mucopolysaccharide fractions of claim 20 which have an anti-Xa titer of over about 22 units/mg and a ratio of titers of anti-Xa to USP of at least 3.
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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) | 1988-02-19 | 1988-08-20 | 1989-02-19 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-02-19 | 1992-08-20 | 1993-02-19 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-02-19 | 1996-08-20 | 1997-02-19 | $7700.00 | Window Closed / Lapsed |