EP2328936A1 - Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amine - Google Patents
Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amineInfo
- Publication number
- EP2328936A1 EP2328936A1 EP09737026A EP09737026A EP2328936A1 EP 2328936 A1 EP2328936 A1 EP 2328936A1 EP 09737026 A EP09737026 A EP 09737026A EP 09737026 A EP09737026 A EP 09737026A EP 2328936 A1 EP2328936 A1 EP 2328936A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- glucopyranosyl
- methyl
- tri
- sulfonato
- radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to novel synthetic hexadecasaccharides having at least one covalent linkage with an amino chain and having the anticoagulant and antithrombotic pharmacological activities of heparin.
- Patent application WO 2006/030104 discloses synthetic hexadecasaccharides which have a covalent bond with biotin (hexahydro-2-oxo- ⁇ -thieno [3,4-d] imidazole-4-pentanoic acid) or with a derivative of biotin.
- biotin hexahydro-2-oxo- ⁇ -thieno [3,4-d] imidazole-4-pentanoic acid
- Such hexadecasaccharides have antithrombotic activity which makes them usable as anticoagulants and have, in addition, the advantage of being rapidly neutralized by a specific antidote, in an emergency situation.
- This specific antidote is avidin (The Merck Index, Twelfth edition, 1996, MN 920, pages 151-152) or streptavidin, two tetrameric proteins of respective masses equal to about 66,000 and 60,000 Da, which possess a very strong affinity for biotin.
- the invention therefore relates to synthetic hexadecasaccharides with antithrombotic activity having at least one covalent bond with an amino chain of formula -NH-CO- (CH 2 ) S -NH 2 .
- the present invention relates to hexadecasaccharides of formula (I):
- T represents a group -NH-CO- (CH 2 ) S -NH 2 ,
- R represents a radical (C r C 6 ) alkoxy, especially a methoxy radical or a radical -OSO 3 " ,
- R 1 represents a (C 1 -C 6) alkyl radical, in particular a methoxy radical or a radical -OSO 3 " ,
- R 2 represents a radical (C 1 -C 6 JaClOXy or a radical -OSO 3 " ,
- R 3 represents a radical (C r C 6 ) alkoxy, in particular a methoxy radical or a radical -OSO 3 " , or R 3 constitutes a bridge -O-CH 2 -, the group -CH 2 - being linked to the a carbon atom bearing the carboxylic function on the same ring,
- Pe represents a saccharide sequence of following formula:
- the polysaccharide moieties consist of uncharged and / or partially charged and / or fully charged alkylated monosaccharide units.
- the charged or uncharged units may be dispersed throughout the chain or they may instead be grouped into charged or uncharged saccharide domains.
- L-iduronic acid may be of 4 C 1 2 S 0 or 4 C 1 conformation.
- the invention encompasses hexadecasaccharides in their acid form or in the form of any of their pharmaceutically acceptable salts.
- the -COO " and -SO 3 " functions are respectively in the form -COOH and -SO 3 H.
- pharmaceutically acceptable salt means polysaccharides of the invention, a polysaccharide in which one or more of the functions -COO ' and / or -SO 3 ' are ionically bonded to a pharmaceutically acceptable cation.
- the preferred salts according to the invention are those whose cation is chosen from alkali metal cations and more preferably still those whose cation is Na + or K + .
- the compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium or C 14 carbon.
- radioactive isotope for example tritium or C 14 carbon.
- (C 1 -C 6) alkyl radical is a -O-alkyl radical, the alkyl group being a linear or branched, saturated aliphatic radical having a chain of 1 to 6 carbon atoms.
- alkyl radicals mention may be made of methyl, ethyl, propyl, isopropylbutyl, isobutyl and tertbutyl radicals.
- Examples of (C 1 -C 6 ) alkoxy radicals that may be mentioned are methoxy and ethoxy radicals,
- the present invention relates to biotinylated hexadecasaccharides of general formula (I) in which:
- R represents a methoxy radical or a radical - OSO 3 " ,
- R 1 represents a methoxy radical
- - R 2 represents a radical -OSO 3 "
- - R 3 represents a methoxy radical
- the invention relates to the following hexadecasaccharides: • Methyl (2,3,4,6-tetra-O-sulphonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3, 6-tri-O-sulphonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3,6-tri-O-sulphonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2, 3-di-O-methyl-6-O-sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3,6-tri-O-methyl- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - [(2,3,6-tri-O-methyl- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) -O- (2,3,6-tri-O-O-O-(
- the process for preparing the compounds according to the invention uses di- or oligosaccharide base synthons prepared as previously reported in the literature.
- These synthons are then coupled to each other so as to provide a fully protected equivalent of a hexadecasaccharide according to the invention. This protected equivalent is then converted into a compound according to the invention.
- One of the basic synthons mentioned above contains a particular protected function allowing the subsequent introduction of the group -CO- (CH 2 ) S -NH 2 (so as to form the chain -NH-CO- (CH 2 ) S -NH 2 on hexadecasaccharide), for example a latent amine function in the form of an azido group or protected in the form of N-phthalimido.
- a "donor" di- or oligosaccharide activated on its anomeric carbon, reacts with a "acceptor” di- or oligosaccharide having a free hydroxyl.
- the present invention relates to a process for the preparation of compounds of formula (I) characterized in that:
- This pentasaccharide precursor protected is itself extended by a precursor protected from the polysaccharide domain Pe;
- the negatively charged groups are introduced and / or unmasked; in a third step, the amine function is deprotected on the hexadecasaccharide and then the protected -CO- (CH 2 ) S-NH 2 group is introduced;
- the synthesis of the pentasaccharide on which the -CO- (CH 2 ) 5 -NH 2 group will be grafted may be carried out according to the methods described in particular in the patent applications published under the numbers WO 98/03554 and WO 99/36443, as well as than in the polysaccharide literature.
- the synthesis of the polysaccharide precursor part of Pe is carried out according to reactions well known to those skilled in the art, using the methods of oligosaccharide synthesis (GJ Boons, Tetrahedron, (1996), 52, pp. 1095-1121, WO 98/03554 and WO 99/36443).
- a glycosidic link donor oligosaccharide is coupled with a glycosidic link acceptor oligosaccharide to yield another oligosaccharide the size of which is equal to the sum of the sizes of the two reactive species. This sequence is repeated until the desired compound of formula (I) is obtained.
- the nature and the charge profile of the desired final compound determine the nature of the chemical entities used in the various steps of the synthesis, according to the rules well known to those skilled in the art.
- the compounds of the invention are obtained from their completely protected polysaccharide precursors by using the following sequence of reactions: the alcohol functions to be converted into an O-sulfo group and the carboxylic acids are deprotected by the elimination of the groups protectors used during the development of the skeleton,
- the compounds of the invention can naturally be prepared using various strategies known to those skilled in the art of oligosaccharide synthesis.
- the process described above is the preferred method of the invention.
- the compounds of formula (I) can be prepared by other well known methods of sugar chemistry described for example in "Monosaccharides, Their chemistry and their roles in natural products", P.M. Collins and RJ. Ferrier, J. Wiley & Sons, (1995) and in GJ. Boons, Tetrahedron, (1996), 52, pp.1095-1121.
- the pentasaccharides Pe can thus be obtained from disaccharide synthons in the manner described in the publication by C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl. (1993), 32, 1671-1690.
- the protecting groups used in the process for the preparation of the compounds of formula I are those commonly used in the chemistry of sugars, as described, for example, in "Protective Groups in Organic Synthesis", (1981), TW Greene , John Wiley & sounds, New York.
- the protective groups may for example be chosen from acetyl, halomethyl, benzoyl, levulinyl, benzyl, substituted benzyl, optionally substituted trityl, tetrahydropyranyl, allyl, pentenyl, tert-butyldimethylsilyl (tBDMS) or trimethylsilylethyl groups.
- Activator groups are those conventionally used in sugar chemistry according to GJ for example.
- the introduction of the -CO- (CH 2 ) 5 -NH 2 group on the free amine function of the hexadecasaccharide can be carried out using an Act type reagent.
- -CO- (CH 2 ) 5 -NH-Pg wherein "Act” represents an activating group of an acid function (such as an imide, for example a succinimide derivative, or a mixed anhydride, or any other known activating agent in peptide chemistry for amino / acid coupling reactions) and "Pg” represents an amine protecting group (such as a benzyloxycarbonyl group).
- Act represents an activating group of an acid function (such as an imide, for example a succinimide derivative, or a mixed anhydride, or any other known activating agent in peptide chemistry for amino / acid coupling reactions)
- Pg represents an amine protecting group (such as a benzyloxycarbonyl group).
- the compounds of the invention in the form of salts are contacted with a cation exchange resin in acid form.
- the compounds of the invention in the form of acids can then be neutralized with a base to obtain the desired salt.
- any inorganic or organic base can be used, giving with the compounds of formula (I), pharmaceutically acceptable salts.
- Sodium, potassium, calcium or magnesium hydroxide is preferably used as the base.
- the sodium and calcium salts of the compounds of formula (I) are the preferred salts.
- the phases are separated and the aqueous phase is extracted with ethyl acetate.
- the organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness before purification on a column of silica gel with a mixture of ethyl acetate / pentane (75/25 v / v) as eluent.
- the fractions, once evaporated, give 1.13 g of succinimidyl 6- (benzyloxycarbonylamino) hexanoate in the form of an oil.
- the product 1 obtained after the previous step (190 mg) is solubilized in deuterated water (6 ml), 30% palladium-on-charcoal (19 mg) is added and the mixture is allowed to stir. the solution at room temperature for 36 hours under a hydrogen atmosphere After filtration, the solution is added dropwise to 30 ml of tert-butyl methyl ether and the suspension is stirred for 1 h and filtered to give 140 mg of compound 1.
- Proton NMR at 600 MHz in deuterated water the structure of the expected product is confirmed, because the spectrum obtained is identical to that performed on a product synthesized according to Example 1 of the patent application WO 2006/030104 , without the signals due to the atoms of the biotin part.
- the compounds according to the invention have been the subject of biochemical and pharmacological studies.
- the oligosaccharides of the present invention constitute very interesting drugs. Their toxicity is perfectly compatible with this use. They are also very stable and are therefore particularly suitable for constituting the active principle of pharmaceutical specialties.
- thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy, placement of endovascular prostheses; or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation, or the use of aortic bypass graft vascular prostheses. -coronariens.
- These products can also be used for the treatment or prevention of venous thromboembolic pathologies such as pulmonary embolism and deep vein thrombosis. They can be used or to prevent or treat thrombotic complications observed for example as a result of surgical operations, tumor development or disruption of coagulation, induced by bacterial, viral or enzymatic activators.
- the compounds of the present invention can cover prostheses and thus make them hemocompatible.
- they can be attached to intravascular prostheses (stents).
- they may optionally be chemically modified by introduction to the non-reducing or reducing end of a suitable arm, as described in EP 649854.
- the compounds of the The present invention can also be used as adjuvants during endarterectomy performed with porous balloons.
- the compounds of the invention can be used for the preparation of medicaments for treating the above diseases.
- the subject of the present invention is therefore a pharmaceutical composition containing, as active ingredient, a synthetic polysaccharide according to the invention or a pharmaceutically acceptable salt thereof, optionally in combination with one or more inert excipients. and appropriate.
- Said excipients are chosen according to the desired pharmaceutical form and mode of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, local or rectal.
- the active ingredient may also be presented as a complex with a cyclodextrin, for example ⁇ , ⁇ or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
- the active ingredient can also be released by a balloon containing it or by an endovascular stent introduced into the blood vessels. The pharmacological effectiveness of the active ingredient is thus not affected.
- each dosage unit the active ingredient is present in the appropriate amounts in order to obtain the desired prophylactic or therapeutic effect.
- Each dosage unit may contain from 0.1 to 100 mg of active ingredient, preferably 0.5 to 50 mg.
- the compounds according to the invention may also be used in combination with one or more other active ingredients that are useful for the desired therapy, such as, for example, antithrombotics, anticoagulants, antiplatelet agents such as, for example, dipyridamole, aspirin or ticlopidine. , clopidogrel or antagonists of the ⁇ b / ⁇ ia glycoprotein complex.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0804705A FR2935387B1 (fr) | 2008-08-26 | 2008-08-26 | Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amine |
PCT/FR2009/001024 WO2010023375A1 (fr) | 2008-08-26 | 2009-08-24 | Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amine |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2328936A1 true EP2328936A1 (fr) | 2011-06-08 |
Family
ID=40513857
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09737026A Withdrawn EP2328936A1 (fr) | 2008-08-26 | 2009-08-24 | Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amine |
Country Status (5)
Country | Link |
---|---|
US (1) | US20110212907A1 (fr) |
EP (1) | EP2328936A1 (fr) |
JP (1) | JP2012500885A (fr) |
FR (1) | FR2935387B1 (fr) |
WO (1) | WO2010023375A1 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2970969B1 (fr) * | 2011-01-27 | 2013-10-18 | Sanofi Aventis | Oligosaccharides 3-o-alkyles activateurs des recepteurs des fgfs, leur preparation et leur application en therapeutique |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2874924B1 (fr) * | 2004-09-09 | 2006-12-01 | Sanofi Aventis Sa | Hexadecasaccharides biotinyles, leur preparation et leur utilisation therapeutique |
-
2008
- 2008-08-26 FR FR0804705A patent/FR2935387B1/fr not_active Expired - Fee Related
-
2009
- 2009-08-24 EP EP09737026A patent/EP2328936A1/fr not_active Withdrawn
- 2009-08-24 WO PCT/FR2009/001024 patent/WO2010023375A1/fr active Application Filing
- 2009-08-24 JP JP2011524424A patent/JP2012500885A/ja not_active Withdrawn
- 2009-08-24 US US13/060,745 patent/US20110212907A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO2010023375A1 * |
Also Published As
Publication number | Publication date |
---|---|
FR2935387B1 (fr) | 2010-09-10 |
WO2010023375A1 (fr) | 2010-03-04 |
US20110212907A1 (en) | 2011-09-01 |
JP2012500885A (ja) | 2012-01-12 |
FR2935387A1 (fr) | 2010-03-05 |
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