EP1853253A1 - Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques - Google Patents

Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques

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Publication number
EP1853253A1
EP1853253A1 EP06725989A EP06725989A EP1853253A1 EP 1853253 A1 EP1853253 A1 EP 1853253A1 EP 06725989 A EP06725989 A EP 06725989A EP 06725989 A EP06725989 A EP 06725989A EP 1853253 A1 EP1853253 A1 EP 1853253A1
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EP
European Patent Office
Prior art keywords
radical
thrombotic
hydrogen atom
allyl
prevention
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.)
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Application number
EP06725989A
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German (de)
English (en)
French (fr)
Inventor
Tony Verbeuren
Alain Rupin
Patricia Sansilvestri-Morel
Marie-Odile Vallez
Marie-Françoise Boussard
Michel Wierzbicki
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP1853253A1 publication Critical patent/EP1853253A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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

Definitions

  • the subject of the present invention is the use of derivatives of diosmetin for the production of pharmaceutical compositions intended for the prevention and / or treatment of thrombotic pathologies as well as pathologies with thrombotic risk.
  • the invention particularly relates to the use of the diosmetin derivative 6,8-diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one for obtaining pharmaceutical compositions for the prevention and / or treatment of thrombotic pathologies.
  • the physiological process of hemostasis is triggered by the alteration of the endothelial cells of the blood vessels, either for accidental reasons or for more complex pathological reasons. It aims at filling and sealing the blood leakage by two distinct but intricate steps that are dependent on each other: primary haemostasis and plasma coagulation.
  • Primary haemostasis is the emergency mechanism involving circulating platelets that adhere to the endothelium to form the white thrombus or platelet nail.
  • the platelet thrombus is consolidated by the constitution of a fibrin network which encloses aggregated platelets in its mesh.
  • Insoluble fibrin is generated from a soluble plasma protein, fibrinogen, by the action of thrombin, the final product of the enzymatic activation cascade of the coagulation system.
  • fibrin-platelet thrombus is resorbed by the phenomenon of fibrinolysis. Indeed, thanks to its ability to reduce the amount of fibrin in the vascular circulation, fibrinolysis allows the body to fight against the occurrence of thrombosis and to destroy the thrombus that initially stopped bleeding.
  • Fibrinolysis mainly implements plasmin, a proteolytic enzyme, which degrades the long chains of fibrin polymerized into D-dimer.
  • This enzyme is present in plasma as a zymogen, plasminogen, which is activated in plasmin by different serine proteases present on the surface of the fibrin-platelet clot.
  • serine proteases are, in particular, tissue-type plasminogen activators (t-PA), essentially released by activated endothelial cells, and of urokinase type (u-PA), the release of which in the form of pro-urokinases is much more ubiquitous. .
  • Fibrinolysis is itself negatively regulated by a three component system comprising plasmin inhibitors (ot 2 -antiplasmin and ⁇ 2 -macroglobulin), plasminogen activating inhibitors (PAI-1 or Plasminogen Activator Inhibitor). 1, PAI-2) and the thrombin activatable fibrinolysis inhibitor (TAFI).
  • plasmin inhibitors ot 2 -antiplasmin and ⁇ 2 -macroglobulin
  • PAI-1 or Plasminogen Activator Inhibitor Plasminogen Activator Inhibitor
  • PAI-2 Plasminogen Activator Inhibitor
  • TAFI thrombin activatable fibrinolysis inhibitor
  • PAI-1 The main inhibitor of plasminogen activators is PAI-1.
  • the PAI-1 protein belonging to the serpin superfamily (Serin Protease Inhibitor), is a 379 amino acid glycoprotein (47KDa) devoid of cysteine but very rich in methionine residues.
  • PAI-1 protein produced by many cell types such as endothelial cells, monocytes, hepatocytes, fibroblasts, adipocytes and megakaryocytes, is present in plasma and platelets.
  • the active site of PAI-1 located at the C-terminus of the protein in position (Arg 346 -Met 347 ), behaves like a pseudo substrate for tissue type plasminogen activators.
  • the main target proteins of PAI-1 are therefore t-PA and u-PA.
  • the plasma level of PAI-1 is high in 30% of patients with venous thromboembolism (Tabernero et al Incidence of increased plasminogen activator inhibitor in patients with deep venous thrombosis and / or pulmonary embolism, 1989, Thromb Res, 56 , 565-570).
  • the consequence is a general dysfunction of the fibrinolytic system and in particular a fall of t-PA.
  • the same observations have been made in patients with pulmonary hypertension following embolism (Huber et al., Fibrinogen, PA-PAI-I and plasma levels in patients with primary pulmonary hypertension, 1994, Am J Crit Care Med, 150, 929-933).
  • the elevation of PAI-1 is due to the endothelial cells located in the thrombosis zone which show an increase in the release of PAI-1 linked to an induction by either thrombin or by a mediator released by platelets.
  • PAI-1 Since a high level of PAI-1 is deleterious in the context of cardiovascular syndromes, it has been imagined to restore normal fibrinolytic activity to prevent the occurrence of thrombotic events in patients at risk.
  • the parenteral anticoagulants are in particular unfractionated heparin (UFH), fractionated heparins (LMWH) and acenocoumarol (Sintrom®).
  • UHF unfractionated heparin
  • LMWH fractionated heparins
  • Sintrom® acenocoumarol
  • fibrinolytic or thrombolytic action More recent treatments with fibrinolytic or thrombolytic action have been developed, they accelerate the dissolution of intra-vascular clots by promoting the conversion of inactive plasminogen into active plasmin (Marder VJ., Thrombolytic therapy: foundations and clinical results in "Haemostasis and Thrombosis” , Fourth Edition 2001, Editors Colman RW et al.).
  • These fibrinolytics or thrombolytics are exclusively administered parenterally, either by general intravenous infusion or bolus, or locally, for example intra-coronary or intra-arterial.
  • these pharmaceutical compositions must be administered as soon as possible after constitution of the thrombus in an attempt to dissolve it and thus lift the obstruction of the vessel.
  • thrombolytics therefore consist of plasminogen or t-PA tissue activator analogs such as for example: genetically engineered alteplase is identical to t-PA, reteplase is a simplified analogue of human t-PA or Tenecteplase is a recombinant protein that is close to endogenous t-PA and has a greater affinity for thrombus fibrin.
  • reteplase is a simplified analogue of human t-PA
  • Tenecteplase is a recombinant protein that is close to endogenous t-PA and has a greater affinity for thrombus fibrin.
  • MAI 12 is a murine antibody specific for human PAI-1 interfering neither with PAI-2 nor with t-PA or r ⁇ 2-antiplasmin.
  • this monoclonal antibody increases fibrinolysis in vitro and in vivo (Levi et al., Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis, 1992, Circulation, 85, 305-312).
  • the monoclonal antibody CLB-2C binds between positions 128 and 145 of the amino acid sequence of vitronectin and thus prevents the binding of PAI-1 protein thereto by accelerating its inactivation.
  • these monoclonal antibodies binds between positions 128 and 145 of the amino acid sequence of vitronectin and thus prevents the binding of PAI-1 protein thereto by accelerating its inactivation.
  • these specific inhibitors of PAI-1 are unusable from a medical point of view given the difficulties related to lack of humanization of antibodies, immunogenicity risks and development costs.
  • the object of the present invention is therefore to propose an alternative strategy to the fibrinolytic modulation mechanisms already available for preventive and curative purposes of thrombotic pathologies, with a view to at least partially overcoming the disadvantages of known treatments for thromboembolic events.
  • This alternative strategy is based on inhibition of PAI-1 gene expression.
  • the invention proposes, as such, the use of diosmetin derivatives for obtaining pharmaceutical compositions intended for the prevention and / or treatment of thrombotic pathologies.
  • the diosmetin derivatives according to the invention are the compounds of general formula (I):
  • R 1 represents a hydrogen atom or a propyl or allyl radical
  • R 2 represents a hydrogen atom or a propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl or 3-acetyloxy-2-hydroxypropyl radical;
  • R 3 represents a hydrogen atom or a propyl or allyl radical
  • R 4 represents a hydrogen atom or a methyl, propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl radical or a radical of formula -COR 4; in which R 4 represents a linear or branched (C 1 -C 5 ) alkyl radical or a phenyl radical;
  • R 5 represents a hydrogen atom or a propyl or allyl radical
  • - Re represents a hydrogen atom or a methyl, propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl radical, a radical of formula -COR ' 6 (wherein R' ⁇ represents a linear or branched (C 1 -C 5 ) alkyl radical or a phenyl radical) or a radical of formula (I '):
  • R 1 , R 2 and R 3 each simultaneously represent an atom of hydrogen, then R 4 also represents a hydrogen atom, their diastereoisomers and enantiomers, and their addition salts with a pharmaceutically acceptable acid or base.
  • diosmetin derivatives used according to the invention are the following derivatives, described in patent EP 0 709 383, of formulas (II) to (XVII):
  • the preferred compound of formula (I) according to the invention is 6 ) 8-diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran. -4-one of formula (XVII):
  • the present invention thus relates to the use of derivatives of diosmetin of formula (I):
  • R 1 represents a hydrogen atom or a propyl or allyl radical
  • R 2 represents a hydrogen atom or a propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl or 3-acetyloxy-2-hydroxypropyl radical;
  • R 3 represents a hydrogen atom or a propyl or allyl radical
  • R 4 represents a hydrogen atom or a methyl, propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl or a radical d ⁇ formula -COR 4 in which R 4 represents a linear or branched (C 1 -C 5 ) alkyl radical or a phenyl radical;
  • R 5 represents a hydrogen atom or a propyl or allyl radical
  • R ⁇ represents a hydrogen atom or a methyl, propyl, allyl, 2,3-dihydroxypropyl, (2,2-dimethyl-1,3-dioxol-4-yl) methyl radical, a radical of formula -COR ' 6 (wherein R ' 6 represents a linear or branched (C 1 -C 5 ) alkyl radical or a phenyl radical) or a radical of formula (I 1 ):
  • At least one of the groups R 1, R 2, R 3 , R 4, R 5 and Re is different from a hydrogen atom
  • R 4 also represents a hydrogen atom, their diastereoisomers and enantiomers, and also their addition salts with an acid or a pharmaceutically acceptable base acceptable, for obtaining pharmaceutical compositions for the prevention and / or treatment of thrombotic pathologies.
  • thrombotic pathologies is defined by any pathology caused by the formation of thrombosis in the cardiovascular system (veins, arteries, heart, microcirculation). ).
  • Local obstruction of the vessel by a clot or obstruction by clot embolization is responsible for the clinical signs of thrombotic disease.
  • Deep vein thromboses appear mainly in the legs; if they become embolized in the lungs, they will cause pulmonary embolism.
  • Arterial thromboses most often occur in association with vascular disease, the most common being atherosclerosis.
  • micro-circulatory thrombosis is usually a complication of disseminated intravascular coagulation in which micro-thrombi produce ischemic necrosis.
  • preventive corresponds to a preventive treatment intended to reduce the risk of developing thrombosis in pre-disposing contexts such as in atherosclerotic diseases, diabetes or metabolic syndrome.
  • preventive may be understood as secondary prevention that is intended to decrease prevalence by reducing the course and duration of the disease. Secondary prevention is essential following cardiovascular events and strokes to reduce the risk of recurrence.
  • treatment means a curative treatment prescribed for the purpose of treating thrombosis complicated or not by embolism.
  • the invention relates preferably to the use of 6,8-diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4- one of formula (XVII):
  • compositions for the prevention and / or treatment of thrombotic pathologies.
  • the present invention further relates to the use of derivatives of diosmetin for obtaining pharmaceutical compositions for the prevention and / or treatment of thrombotic risk pathologies.
  • Thrombotic risk diseases means any pathology during which thrombotic events occur.
  • Pathologies aggravating atherosclerosis such as hypercholesterolemia, diabetes, hypertension, obesity, smoking and atrial fibrillation are the main pathologies at arterial thrombotic risk.
  • Genetic abnormalities or acquired coagulation proteins, orthopedic surgery are the main pathologies at risk of venous thrombosis, but we can also mention obesity, certain hormonal treatments, certain cancers and their treatments, pregnancy, causes of immobilization extended.
  • septic shock is the main pathology at risk for micro-circulatory thromboses.
  • a high level of triglycerides such as in hypercholesterolemia is a particularly aggravating marker of cardiovascular risk in general and thrombosis in particular.
  • the invention also extends to the use of diosmetin derivatives, as active principle, in combination with one or more pharmaceutically acceptable excipients for obtaining pharmaceutical compositions intended for the prevention and / or treatment of thrombotic pathologies or at thrombotic risk.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a diosmetin derivative according to the invention in combination with one or more pharmaceutically acceptable excipients intended for the prevention and / or treatment of thrombotic or thrombotic risk disorders.
  • active principle is meant any substance responsible for the pharmacodynamic or therapeutic properties of the pharmaceutical composition.
  • excipients is understood to mean any substance into which the active principle of a medicament is incorporated in order to facilitate the preparation and administration thereof and to condition the consistency thereof, the form and than the volume.
  • compositions intended for the prevention and / or treatment of thrombotic or thrombotic risk conditions are in a form suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
  • the diosmetin derivatives according to the invention are used for obtaining pharmaceutical compositions for oral administration intended for the prevention and / or treatment of thrombotic or thrombotic risk disorders.
  • the oral administration of pharmaceutical compositions for thrombotic or thrombotic risk is particularly suitable for preventive treatment because of their ease of use by patients.
  • the dosage varies according to the sex, the age and the weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.1 mg and 1 g per 24 hours in one or more takes.
  • the present invention is illustrated without being limited by the following examples.
  • the study is carried out on a HepG2 human hepatocyte line (ATCC, No.
  • the cells are cultured in a MEM (minimum essential medium) medium with glutamax-1 (Gibco TM) at 10% FCS (calf serum fetal), 1% non-essential amino acids, 1% sodium pyruvate, and supplemented with penicillin and streptomycin.
  • MEM minimum essential medium
  • FCS calf serum fetal
  • non-essential amino acids 1% sodium pyruvate
  • the set of primers used (Chen et al., Differential mechanisms of PAI-1 gene activation by transforming growth factor beta and tumor necrosis factor alpha in endothelial cells, 2001, Thrmb Haemost, 86, 1563-72) is as follows: -TTACGCGTGGGTTTGGGGCTGGACTTG-S '(SEQ ID NO.1) and ⁇ '-CGAGATCTCAGAGGTGCCTTGCGATTGG-S' (SEQ ID NO.2).
  • the Perkin Elmer 2400 PCR program has high temperature initiation at 94 ° C for 2 min followed by 35 cycle amplification.
  • the PCR product is then precipitated for 1 hour at -80 ° C. in the presence of 7.5 M ammonium acetate and ethanol. After centrifugation at 14,000 rpm at 40 ° C., the pellet is resuspended in 70% ethanol and again centrifuged at 14,000 rpm at 4 ° C. The pellet obtained is then dried and then taken up in water.
  • the amplified sequence is then digested in two stages by the restriction enzymes BgI II and MIu I.
  • the amplified sequence is digested for 1h30 at 37 ° C. in the presence of 1 unit / ⁇ l of enzyme and 100 ⁇ g / ml of BSA (Serum Bovine). Albumin). After each digestion, the product obtained is systematically purified on Micro Bio-Spin columns ® Chromatography (Bio-Rad) to remove the buffer salts.
  • the plasmid pGL3 Basic (Promega), containing the firefly luciferase luciferase gene, is digested with the restriction enzymes BglII and MIuI according to the same protocol as for the insert and then purified on a 1% Low Melting agarose gel.
  • the plasmid PGL3 / PAI-1 is transfected into HepG2 cells.
  • the transfection takes place in plates having cells at 50% confluency, depositing in each of the wells of Lipofectin® (1 mg / ml) and 1.5 ⁇ g of PGL3 / PAI-1 plasmid.
  • Lipofectin® is activated for 30 min in an OPTI-MEM medium (GIBCO TM) and then placed in contact for 15 minutes with the previously diluted plasmids in the medium.
  • the cells are incubated 6 hours at 37 ° C in an atmosphere at 5% CO 2 and 95% O 2 .
  • the transfection medium is removed and replaced overnight with enriched culture medium to stabilize the cells.
  • Induction of the expression of the reporter genes is carried out for 24 hours in a MEM serum-free medium.
  • the cells are scraped and lysed in lysis buffer (Dual-Luciferase® kit, Promega) and then stored at -2O 0 C.
  • the induction phase is 24h for HepG2 cells, in the presence of TGF ⁇ 1 (1 ng / ml ).
  • an inhibitor of PAI-1 expression may be added 4 hours before the TGF ⁇ 1 and kept in contact with the cells until the end of the 24h of inductive phase.
  • the activity of the PAI-1 promoter is determined by a quantification of the luciferase activity produced (Dual-Luciferase® kit, Promega). In each well is added a solution of luciferin, the substrate of firefly luciferase. This results in light emission. The plate is incubated for 10 min in the dark since the luciferase activity is sensitive to light, then starts a reading with the luminometer to quantify the emitted photons (Wallac, Perkin Elmer), the result obtained being the average of cpm (shots per second). minute) over a period of 5s.
  • PAI-1 under basal conditions and under TGF ⁇ L-induced conditions 6,8-Diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4- one (69%) is as potent as T686 (67%) in basal conditions and is significantly more potent in induced conditions (78% inhibition versus
  • the rats are treated with the test compound, for example 6,8-diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one.
  • the model of arterial thrombosis induced by iron chloride on the abdominal aorta in rats makes it possible to verify the effectiveness of the diosmetin derivatives according to the invention as antithrombotic agents and in particular the diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one (compound A).
  • the activity of 6,8-diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one is evaluated as a function of weight of the clot removed from the aorta, this activity will be all the more important as the weight of the clot will be low.
  • 6,8-Diallyl-5,7-dihydroxy-2- (2-allyl-3-hydroxy-4-methoxyphenyl) -4H-1-benzopyran-4-one significantly and significantly reduces clot weight relative to control; this reduction of the clot is of the order of 30%.

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EP06725989A 2005-03-01 2006-02-28 Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques Withdrawn EP1853253A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0502044A FR2882654B1 (fr) 2005-03-01 2005-03-01 Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques
PCT/FR2006/000441 WO2006092490A1 (fr) 2005-03-01 2006-02-28 Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques

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JP (1) JP2008531660A (es)
KR (2) KR100971589B1 (es)
CN (1) CN101132788A (es)
AR (1) AR053149A1 (es)
AU (1) AU2006219853B2 (es)
BR (1) BRPI0607562A2 (es)
CA (1) CA2599658A1 (es)
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FR (1) FR2882654B1 (es)
MA (1) MA29316B1 (es)
MX (1) MX2007010364A (es)
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NZ (1) NZ560749A (es)
UA (1) UA91848C2 (es)
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AR053149A1 (es) 2007-04-25
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CA2599658A1 (fr) 2006-09-08
WO2006092490A1 (fr) 2006-09-08
UA91848C2 (ru) 2010-09-10
JP2008531660A (ja) 2008-08-14
KR20090128581A (ko) 2009-12-15
US20080176934A1 (en) 2008-07-24
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AU2006219853A1 (en) 2006-09-08
FR2882654A1 (fr) 2006-09-08

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