US20070270342A1 - Biotinylated hexadecasaccharides, preparation and use thereof - Google Patents

Biotinylated hexadecasaccharides, preparation and use thereof Download PDF

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Publication number
US20070270342A1
US20070270342A1 US11/684,239 US68423907A US2007270342A1 US 20070270342 A1 US20070270342 A1 US 20070270342A1 US 68423907 A US68423907 A US 68423907A US 2007270342 A1 US2007270342 A1 US 2007270342A1
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Prior art keywords
methyl
glucopyranosyl
tri
sulfonato
biotinylated
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US11/684,239
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Inventor
Philippe Duchaussoy
Jean HERAULT
Jean Herbert
Maurice Petitou
Pierre Savi
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Sanofi Aventis France
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Sanofi Aventis France
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Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Assigned to SANOFI-AVENTIS reassignment SANOFI-AVENTIS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HERAULT, JEAN PASCAL, HERBERT, JEAN MARC, SAVI, PIERRE, DUCHAUSSOY, PHILIPPE, PETITOU, MAURICE
Publication of US20070270342A1 publication Critical patent/US20070270342A1/en
Priority to US12/837,861 priority Critical patent/US8557968B2/en
Priority to US13/611,753 priority patent/US8703738B2/en
Abandoned legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • 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 biotinylated hexadecasaccharides having the anticoagulant and antithrombotic pharmacological activities of heparin.
  • AT III antithrombin III
  • LMWH Low molecular weight heparin
  • Synthetic oligosaccharides corresponding to the Domain-A of heparin are known. They are described, for example, in patents EP 84999 and EP 529 715, the patent application published under the number WO 99/36428 and the publication Bioorg. Med. Chem. (1998), 6, pp. 1509-1516. These synthetic oligosaccharides have the property of selectively inhibiting, via AT III, the clotting factor Xa without having any activity on thrombin. They show antithrombotic activity in venous thrombosis.
  • the present invention relates to novel synthetic biotinylated hexadecasaccharides similar in structure to the compounds described in the patent application published under the number WO 02/24754.
  • the hexadecasaccharides of the invention and also certain compounds described in document WO 02/24754, are covalently bonded to a biotin derivative (hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid) via a “spacer” - sequences of formula (T 1 ) or (T 2 ) as defined in the present patent application—and consequently have the advantage of being able to be rapidly neutralized by a specific antidote, in an emergency situation.
  • This specific antidote is avidin (“The Merck Index”, Twelfth edition, 1996, M.N. 920, pp. 151-152) or streptavidin, two tetrameric proteins with respective masses equal to approximately 66 000 and 60 000 Da, which have very high affinity for biotin.
  • the length of the “spacer” linking the biotin derivative to the hexadecasaccharide chain, and also the position of the biotin on the saccharide unit are factors that influence the efficacy of the neutralization by a specific antidote, and especially, for example, by avidin.
  • the hexadecasaccharide compounds according to the invention have a much higher capacity for neutralization by a specific antidote than those described in the patent application published under the number WO 02/24754, by virtue of a “spacer” of controlled size and the position of the biotin on the saccharide unit.
  • biotinylated hexadecasaccharides of general formula I: in which:
  • the polysaccharide parts consist of uncharged and/or partially charged and/or fully charged alkylated monosaccharide units.
  • the charged or uncharged units may be dispersed along the entire length of the chain or, in contrast, they may be grouped in charged or uncharged saccharide domains.
  • L-iduronic acid may be of 4 C 1 2 S 0 or 4 C 1 conformation.
  • the invention includes hexadecasaccharides in their acid form or in the form of any of their pharmaceutically acceptable salts.
  • the —COO— and —SO 3 ⁇ functions are in —COOH and —SO 3 H form, respectively.
  • pharmaceutically acceptable salt of the polysaccharides of the invention means a polysaccharide in which one or more of the COO ⁇ and/or —SO 3 ⁇ functions are ionically bonded to a pharmaceutically acceptable cation.
  • the salts that are preferred according to the invention are those whose cation is chosen from alkali metal cations and even more preferably those whose cation is Na + or K + .
  • the compounds of formula I above also comprise those in which one or more hydrogen or carbon atoms have been replaced with the radioactive isotope thereof, for example tritium or 14 C.
  • Such labelled compounds are useful in research, metabolism or pharmacokinetic studies, in biochemical tests as ligands.
  • biotin derivatives are commercially available (“Pierce” catalogue 1999-2000, pp. 62 to 81).
  • the present invention relates to the biotinylated hexadecasaccharides of general formula I in which:
  • the invention relates to the following biotinylated hexadecasaccharides:
  • the process for preparing the compounds according to the invention uses di- or oligosaccharide base synthons prepared as reported previously in the literature. Reference will be made especially to the patents or patent applications EP 300 099, EP 529 715, EP 621 282 and EP 649 854 and also to the documents from C. van Boeckel and M. Petitou, Angew. Chem. Int. Ed. Engl., (1993), 32, pp. 1671-1690. These synthons are then coupled to one another so as to give a fully protected equivalent of a polysaccharide according to the invention. This protected equivalent is then converted into a compound according to the invention.
  • One of the base synthons mentioned above contains a particular protected function allowing the subsequent introduction of biotin or of a biotin derivative, 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 an “acceptor” di- or oligosaccharide containing a free hydroxyl.
  • the present invention relates to a process for preparing the compounds of formula I, characterized in that:
  • the pentasaccharide onto which will be grafted the biotin or the biotin derivative is synthesized according to the methods described in particular in the patent applications published under the numbers WO 98/03554 and WO 99/36443 and also in the literature (cited above).
  • the polysaccharide part that is the precursor of Pe is synthesized according to reactions that are well known to those skilled in the art, using the methods for the synthesis of oligosaccharides (G. J. Boons, Tetrahedron, (1996), 52, pp. 1095-1121, WO 98/03554 and WO 99/36443) or an oligosaccharide when an oligosaccharide that is a glycoside bond donor is coupled with an oligosaccharide that is a glycoside bond acceptor to give another oligosaccharide equal in size to the sum of the sizes of the two reactive species. This sequence is repeated until the compound of formula I is obtained.
  • the compounds of the invention are obtained from the fully protected polysaccharide precursors thereof by using the following sequence of reactions:
  • the compounds of the invention may naturally be prepared by using various strategies known to those skilled in the art of oligosaccharide synthesis.
  • the process described above is the preferred process of the invention.
  • the compounds of formula I may be prepared via other well-known methods of sugar chemistry described, for example, in “Monosaccharides, Their chemistry and their roles in natural products”, P. M. Collins and R. J. Ferrier, J. Wiley & Sons, (1995) and in G. J. Boons, Tetrahedron, (1996), 52, pp. 1095-1121.
  • the pentasaccharides Pe may thus be obtained from disaccharide synthons as described in the publication by C. van Boeckel and M. Petitou, Angew. Chem. Int. Ed. Engl., (1993), 32, pp. 1671-1690.
  • the protecting groups used in the process for preparing the compounds of formula I are those commonly used in sugar chemistry, for example in “Protective Groups in Organic Synthesis”, (1981), T. W. Greene, John Wiley & Sons, New York.
  • the protecting groups are advantageously chosen, for example, from acetyl, halomethyl, benzoyl, levulinyl, benzyl, substituted benzyl, optionally substituted trityl, tetrahydropyranyl, allyl, pentenyl, tert-butyldimethylsilyl (tBDMS) and trimethylsilylethyl groups.
  • the activating groups are those conventionally used in sugar chemistry according to, for example, G. J. Boons, Tetrahedron, ( 1996), 52, pp. 1095-1121. These activating groups are chosen, for example, from imidates, thioglycosides, pentenylglycosides, xanthates, phosphites and halides.
  • the chemical literature offers other possibilities that can possibly be used by means of sets of protecting groups that are well known to those skilled in the art.
  • Use will preferably be made of an amine function, or a thiol function, or a carboxylic acid function or alternatively an aldehyde function, which will be reacted with a biotin derivative comprising a reactive group of the activated ester, maleimide, iodoacetyl or primary amine type, the reaction taking place according to the conditions described in the literature (Savage et al., “Avidin-Biotin Chemistry: A Handbook”; (1992), Pierce Chemical Company).
  • the compounds of the invention in acid form may then be neutralized with a base to obtain the desired salt.
  • a base Any mineral or organic base that gives pharmaceutically acceptable salts with the compounds of formula I may be used for the preparation of the salts of the compounds of formula I.
  • Sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide is preferably used as base.
  • the sodium and calcium salts of the compounds of formula I are the preferred salts.
  • the compounds according to the invention underwent biochemical and pharmacological studies.
  • the circulating activity of the compounds according to the invention may be measured by means of their anti-factor IIa activity and the anti-factor Xa activity as described by Herbert et al., Thromb Haemost., (2001), 85(5), pp. 852-60.
  • the compounds according to the invention are administered intravenously (IV) or subcutaneously (SC) to rats.
  • An IV injection of avidin results in a large decrease in the circulating concentration of compound according to the invention (greater than 70%).
  • the circulating concentration of the compound according to Example 1 after IV injection of 100 nmol/kg, is reduced by 88% (reduction measured via the anti-factor Xa activity) and 91% (reduction measured via the anti-factor IIa activity) 2 minutes after the IV administration of avidin (10 mg/kg/625 nmol/kg).
  • the circulating concentration of the compound according to Example 2 after IV injection of 100 nmol/kg, is reduced by 76% (reduction measured via the anti-factor Xa activity) and 89% (reduction measured via the anti-factor IIa activity) 5 minutes after the IV administration of avidin (10 mg/kg/625 nmol/kg).
  • the global antithrombotic activity of the compounds according to the invention and their neutralization was studied in a model of venous thrombosis consisting of an injection of tissue factor followed by stasis of rat vena cava, as described by Herbert et al., Blood, (1998), 91, pp. 4197-4205.
  • the compounds of the present invention are powerful thrombosis inhibitors (IC 50 values of less than 50 nM).
  • Examples 1 and 2 show IC 50 values in this model of 3 and 9.9 nM, respectively, after their IV administration.
  • the bleeding time induced in rats by 30 nmol/kg of the compound according to Example 1 is brought back to the control level by an IV administration of avidin (3 mg/kg; 208 nmol/kg).
  • the bleeding time induced in rats by 100 nmol/kg of the compound according to Example 2 is brought back to the control level by an IV administration of avidin (10 mg/kg; 625 nmol/kg).
  • a subject of the present invention is also a process using avidin or streptavidin, characterized in that it allows the polysaccharides according to the invention to be neutralized.
  • Avidin or streptavidin may be used for the preparation of medicaments for neutralizing the polysaccharides according to the present invention.
  • the oligosaccharides of the present invention constitute highly advantageous medicaments. Their toxicity is entirely compatible with this use. They are also very stable and are thus particularly suitable for constituting the active principle of pharmaceutical specialties.
  • thromboembolic disorders associated with atherosclerosis and diabetes, such as unstable angina, apoplexy, post-angioplasty restenosis, endarterectomy or the insertion of endovascular prostheses; or thromboembolic disorders associated with post-thrombolysis rethrombosis, infarction, dementia of ischaemic origin, peripheral arterial diseases, blood dialysis, auricular fibrillations, or alternatively during the use of vascular prostheses for aorto-coronary bypasses.
  • These products may moreover be used for the treatment or prevention of thromboembolic pathologies of venous origin, such as pulmonary embolisms. They may be used for preventing or treating the thrombotic complications observed, for example, following surgical operations, the growth of tumours or disruption of clotting, induced by bacterial, viral or enzymatic activators.
  • the compounds of the present invention can cover prostheses and thus make them haemocompatible.
  • they can be attached to intravascular prostheses (stents).
  • they can optionally be chemically modified by introduction of a suitable arm at the non-reducing or reducing end, as described according to EP 649 854.
  • the compounds of the present invention may also be used as adjuvants during endarterectomy performed with porous balloons.
  • the compounds according to the invention may be used for the preparation of medicinal products for treating the above diseases.
  • a subject of the present invention is thus a pharmaceutical composition containing, as active principle, a synthetic polysaccharide according to the invention or a pharmaceutically acceptable salt thereof, optionally in combination with one or more inert and suitable excipients.
  • the said excipients are chosen according to the desired pharmaceutical form and the desired mode of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucous, local or rectal.
  • the active principle may also be presented in the form of a complex with a cyclodextrin, for example ⁇ , ⁇ or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ , ⁇ or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • the active principle may also be released by means of a balloon containing it or by means of an endovascular extender introduced into the blood vessels.
  • the pharmacological efficacy of the active principle is thus unaffected.
  • each dosage unit the active principle is present in the amounts suited to the daily doses envisaged in order to obtain the desired prophylactic or therapeutic effect.
  • Each dosage unit can contain from 0.1 to 100 mg and preferably 0.5 to 50 mg of active principle.
  • These doses of anticoagulant compounds may be neutralized with doses of avidin or of streptavidin ranging from 1 to 1000 mg by intravenous injection, bolus or infusion.
  • the compounds according to the invention may also be used in combination with one or more other active principles that are useful for the desired therapy, for instance antithrombotic agents, anticoagulants, platelet aggregation inhibitors, for instance dipyridamole, aspirin, ticlopidine, clopidogrel or glycoprotein IIb/IIIa complex antagonists.
  • active principles for instance antithrombotic agents, anticoagulants, platelet aggregation inhibitors, for instance dipyridamole, aspirin, ticlopidine, clopidogrel or glycoprotein IIb/IIIa complex antagonists.
  • Ph phenyl
  • Biotin Hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid
  • Rf retention time measured on the TLC relative to the migration solvent front.
  • a solution of compound 3 (8.0 g, 26.03 mmol) in 130 ml of an acetonitrile/water mixture [9/1 (v/v)] is added dropwise to a solution of cerium ammonium nitrate (86 g, 156.2 mmol) in 390 ml of an acetonitrile/water mixture [9/1 (v/v)].
  • the mixture is stirred at room temperature for 40 minutes and then diluted with ethyl acetate.
  • the reaction mixture is dried over anhydrous sodium sulfate, filtered and concentrated. Filtration on silica gel allows the cerium ammonium nitrate residues to be partially removed.
  • the imidate compound 30 (170 mg, 56 pmol) obtained in Preparation 27, and compound 34 (114 mg, 112 pmol) obtained in Preparation 30 are dissolved in 2.5 ml of a dichloromethane/diethyl ether mixture [1/2 (v/v)]. After addition of powdered 4 A molecular sieves, the mixture is cooled to ⁇ 20° C. and a 0.1M solution of trimethylsilyl trifluoromethanesulfonate in dichloromethane (84 ⁇ l) is added. After 40 minutes, the mixture is neutralized by addition of solid sodium hydrogen carbonate.
  • aqueous hydrogen peroxide solution (3.9 ml) is added, at ⁇ 5° C., to a solution of compound 36 (111 mg) obtained in Preparation 31 in tetrahydrofuran (4.6 ml). After stirring for 5 minutes, aqueous 0.7M lithium hydroxide solution (1.8 ml) is added dropwise. The reaction mixture is stirred for 1 hour at ⁇ 5° C. and then for 4 hours at 0° C. and finally for 16 hours at room temperature. The reaction mixture is deposited on a column of fine Sephadex G-25 (5 ⁇ 100 cm) eluted with water. The fractions containing the expected compound are combined, concentrated and deposited on a column of Dowex® AG 50 WX4 H + resin (1.9 ml).
  • aqueous hydrogen peroxide solution (2.2 ml) is added, at ⁇ 5° C., to a solution of compound 37 (60 mg) in tetrahydrofuran (5.5 ml). After stirring for 5 minutes, aqueous 0.7M lithium hydroxide solution (1 ml) is added dropwise. The reaction mixture is stirred for 1 hour at ⁇ 5° C., then for 4 hours at 0° C. and finally for 16 hours at room temperature. The mixture is neutralized with 1M hydrochloric acid solution. The solution is deposited on a column of fine Sephadex® G-25 (5 ⁇ 100 cm) eluted with water.
  • compound 38 obtained in Preparation 33 is co-distilled with N,N-dimethylformamide (3 ⁇ 2 ml).
  • N,N-dimethylformamide 2 ml
  • sulfur trioxide-triethylamine complex 351 mg
  • the mixture is stirred for 16 hours at 55° C. in the absence of light.
  • the mixture cooled to 0° C., is added dropwise to a solution of sodium hydrogen carbonate in water.
  • the resulting mixture is stirred for 16 hours at room temperature and concentrated to dryness.
  • the residue, dissolved in water, is deposited on a column of fine Sephadex® G-25 eluted with 0.2M sodium chloride.

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US11/684,239 2004-09-09 2007-03-09 Biotinylated hexadecasaccharides, preparation and use thereof Abandoned US20070270342A1 (en)

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US12/837,861 US8557968B2 (en) 2004-09-09 2010-07-16 Biotinylated hexadecasaccharides, preparation and use thereof
US13/611,753 US8703738B2 (en) 2004-09-09 2012-09-12 Biotinylated hexadecasaccharides, preparation and use thereof

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FR0409557A FR2874924B1 (fr) 2004-09-09 2004-09-09 Hexadecasaccharides biotinyles, leur preparation et leur utilisation therapeutique
FR0409557 2004-09-09
PCT/FR2005/002218 WO2006030104A1 (fr) 2004-09-09 2005-09-07 Hexadecasaccharides biotinyles, leur preparation et leur utilisation

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FR2912408A1 (fr) * 2007-02-14 2008-08-15 Sanofi Aventis Sa Heparine comprenant au moins une liaison covalente avec la biotine ou un derive de la biotine,leur procede de preparation,leur utilisation
TW201006479A (en) * 2008-07-18 2010-02-16 Sanofi Aventis Use of idrabiotaparinux for decreasing the incidence of bleedings during an antithrombotic treatment
EP2145624A1 (en) * 2008-07-18 2010-01-20 Sanofi-Aventis Use of idrabiotaparinux for decreasing the incidence of bleedings during an antithrombotic treatment
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FR2935387B1 (fr) * 2008-08-26 2010-09-10 Sanofi Aventis Hexadecasaccharides a activite antithrombotique comprenant une liaison covalente avec une chaine amine
FR2952935B1 (fr) 2009-11-20 2011-12-02 Sanofi Aventis Procede de preparation du n-biotinyl-6-aminocaproate de n succinimidyle

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ZA200702255B (en) 2008-09-25
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US8557968B2 (en) 2013-10-15
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