WO2012158003A1 - Nouvel inhibiteur du facteur xii - Google Patents

Nouvel inhibiteur du facteur xii Download PDF

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Publication number
WO2012158003A1
WO2012158003A1 PCT/LV2012/000008 LV2012000008W WO2012158003A1 WO 2012158003 A1 WO2012158003 A1 WO 2012158003A1 LV 2012000008 W LV2012000008 W LV 2012000008W WO 2012158003 A1 WO2012158003 A1 WO 2012158003A1
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WO
WIPO (PCT)
Prior art keywords
thrombosis
meldonium
arterial
acid addition
addition salt
Prior art date
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PCT/LV2012/000008
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English (en)
Inventor
Ivars Kalvins
Anatolijs Birmans
Maris Veveris
Original Assignee
Tetra, Sia
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Filing date
Publication date
Application filed by Tetra, Sia filed Critical Tetra, Sia
Publication of WO2012158003A1 publication Critical patent/WO2012158003A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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 present invention relates generally to novel intrinsic pathway blood coagulation inhibitor and its combination with warfarin and use thereof as anticoagulant agents.
  • Thromboembolic diseases are among the leading causes of death despite the availability of anticoagulants such as warfarin, and antiplatelet agents such as acetylsalicylic acid and clopidogrel.
  • the extrinsic pathway is initiated by the complex of factor VII with the membrane protein tissue factor (TF).
  • TF membrane protein tissue factor
  • the intrinsic or contact activation pathway is initiated when factor XII comes into contact to negatively charged surfaces.
  • the targets of new inhibitors are the same as those of warfarin, they may compromise hemostasis, causing bleeding while preventing thrombosis.
  • the ideal drug for prophylaxis and treatment of thrombotic disease remains an agent that will inhibit thrombosis but not hemostasis.
  • Factor X as the common element, joining the extrinsic and intrinsic branch of the coagulation cascade was a logical target for selective inhibitors, not influencing the upstream levels of the cascade.
  • Apixaban an oral direct F Xa inhibitor, was shown to inhibit human clot- bound F Xa activity in vitro. (Jiang X et al. J Thromb Haemost 2009;101(4):780-2). Apixaban was also effective in rat thrombosis models at doses producing modest increases in multiple bleeding time models. (Schumacher WA et al. J Cardiovasc Pharmacol 2010;55(6):609-16). In one clinical study, in patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage (Connolly SJ et al.
  • a new and promising approach to developing new anticoagulants is by selecting agents that predominantly act on different coagulation factors than warfarin upstream of the common factor X on the intrinsic pathway.
  • factor XI and XII deficient mice indicate that these factors are not associated with abnormal hemostasis, but impair formation of thrombi in arterial injury models. If the same mechanism operates in humans, factor XI of XII could be ideal targets for drugs to treat or prevent thromboembolic disease without impairing hemostasis (Gailani D, Renne T. Arterioscler Thromb Vase Biol 2007;27:2507-13. J Thromb Haemost 2007;5(6): 1 106-12).
  • factor XII One of the first factors activated in the blood is factor XII.
  • Activated factor Xlla then activates factor XI that further activates factor IX.
  • Factor IXa combines with factor Villa to activate factor X.
  • the intrinsic pathway factors XII and XI play a functional role in thrombus formation and stabilization during stroke, because their deficiency protects from cerebral ischemia without significantly affecting hemostasis. Based on the accumulated evidence that thrombus formation and hemostasis are not indissoluble linked, new approach to treatment of ischemic stroke has emerged (Stoll G, Nieswandt B. Blood 2008;112(9):3555-62).
  • mice lacking factor XI are resistant to experimental thrombosis but have normal hemostasis, targeted inhibition of factor XIa may be useful antithrombotic strategy with mild bleeding risk (Cheng Q, Tucker EI, Pine MS. et al Blood 2010;116(19):3981-89).
  • F XII was identified as novel (ideal) target for antithrombotic therapy, especially arterial thrombosis with minimal or no risk of bleeding (Renne T et al. J Exp Med 2005;202(2)271-81. Blood Cells Mol Dis 2006;36(2): 148-51. Expert Rev Cardiovasc Ther 2007;5(4):733-41).
  • warfarin-aspirin or warfarin-clopidogrel therapy is widely used for the long-term primary and secondary prevention of atherothrombotic and
  • the present invention provides meldonium acetylsalicylate as novel factor XII inhibitor and use thereof as anticoagulant agent.
  • the present invention also provides for synergistic therapeutic combination comprising meldonium acetylsalicylate and warfarin for use as anticoagulant agent.
  • the present invention also provides a method for treating and/or preventing blood clotting disorders comprising administering to a person in need of such treatment a therapeutically effective amount of meldonium acetylsalicylate and optionally a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention also provides a method for treating and/or preventing blood clotting disorders comprising administering to a person in need of such treatment a therapeutically effective amount of meldonium acetylsalicylate, optionally together with pharmaceutically acceptable carrier, excipient, or diluent, and a therapeutically effective amount of warfarin, optionally together with pharmaceutically acceptable carrier, excipient, or diluent, as a single dosage form or separate dosage forms thereof.
  • the present invention provides meldonium acetylsalicylate as novel oral anticoagulant with reduced risk of bleeding and synergistic effect in combination with warfarin.
  • mice Male Wistar rats (280-360 g) were used in experiments. Animals were kept in climatized room at 22 ⁇ 1 °C, relative humidity 60 ⁇ 5% and 12/12 hour light/darkness cycle with free access to food and water. All experiments were carried out in accordance with the European Community Council's Directive of 24 November 1986 (86/609/EEC) relative to experimental animal care.
  • Rats were randomly divided into various experimental groups, each consisting of ten animals.
  • the solvent or test compounds MAS A (5 or 10 mg/kg), WF (0.5 mg/kg) were introduced p.o. once daily for 7 days.
  • the rats were anaesthetized with pentobarbital sodium (50 mg/kg i.p.) and were placed on a temperature controlled operation table to maintain a body temperature of 37 °C.
  • the collected blood was hemolysed by the addition of Triton X-100, and the optical density was measured photometrically at 546 nm.
  • a standard curve was constructed with pooled blood collected from three intact rats. The amount of blood lost was deducted from the standard curve.
  • Table 2 shows effects of WF or MASA on coagulation factors VII, X, XI, and XII after repeated (7 days) application.
  • WF 0.5 mg/kg/d
  • MASA completely depressed factors VII and X, but did not significantly influence levels of factors XI and XII.
  • MASA contrary to WF did not influence factor VII, but significantly lowered levels of factors XI and XII (Table 2).
  • MASA also (more significant in dose 10 mg/kg) lowered factor X, but significantly less than WF.
  • the action of MASA on factors XI and X may be direct and/or indirect via factor XII.
  • Rats Male Wistar rats (330-410 g) were used in the published method (Kurz K et al. Thromb Res 1990;60:269-80; Wang X, Xu L. Thromb Res 2005;1 15:95-100). Rats were randomly divided into various experimental groups, each consisting of not less than seven animals.
  • the solvent or test compound MAS A (10 mg/kg), ASA (5 mg/kg), WF (0.25 mg/kg), combination MASA+WF (10+0.25 mg/kg) or ASA+WF (5+0.25 mg/kg) were administered by oral route (throw cateter into stomach).
  • WF dose of 0.25 mg/kg was based on our data, indicating that a 0.5 mg/kg dose of WF causes a considerable increase of TBT and bleeding volume. Also the published data on WF toxicity indicate that administration of WF in 0.5 mg/kg dose to rats (Smith G et al. Thromb Res 1988;50:163-74) after 9-1 1 days displays high efficiency (protection against experimental thrombosis and significant change of PT and aPTT), but also a noticeably toxicity; in dose of 0.25 mg/kg/d it is not toxic, but still active, while the repeated doses of 0.0625 mg/kg do not display any noticeable biological activity.
  • Rats were anaesthetized with pentobarbital sodium (50 mg/kg i.p. and 10 mg/kg/h) and were placed on a heat controlled operating table throughout the experiment to maintain a body temperature of 37 °C.
  • pentobarbital sodium 50 mg/kg i.p. and 10 mg/kg/h
  • One of the carotid arteries was exposed by cervical incision, separated from the adherent tissue, vagus nerve, and a flow probe (electromagnetic blood flow meter MFV 1200, Nicon Kohden, Japan) was placed on the exposed segment of common carotid artery to record the blood flow. After a stabilization period of 15 min, thrombosis was induced by topically applying (in contact with the adventitial surface of vessel) two pieces (2x1 mm) of Whatman paper, soaked in 15% solution of FeCl 3 .
  • Thrombosis time of carotid artery was recorded as time taken for the complete cessation of the blood flow and was reported as time till occlusion (TTO). If the blood flow did not cease within 90 min. in the drug treated groups TTO was reported as >90 min.
  • FeCl 3 in the control group animals caused vascular thrombosis and stoppage of blood flow in the carotid after about 23.6 min (Table 3).
  • a single preventive dose of MAS A caused highly significant prolongation of TTO (PO.005 vs Control).
  • ASA caused a less pronounced, compared to MAS A (146 to 173%), but also significant prolongation of TTO, although the bleeding volume was twice as high and the bleeding time also significantly longer.
  • a single 0.25 mg/kg dose of WF introduced 2h before the experiment did not cause significant changes of TTO, bleeding time and bleeding volume due to slow onset of action, generally 24 h after application (USP 20080221204 Al).
  • MAS A in combination with WF displayed a substantially better protection against thrombosis than the combination of ASA+WF (Table 3).
  • the bleeding volume in MASA+WF group was significantly smaller than in ASA+WF.
  • MASA in combination with WF caused a substantial increase of TTO compared to MASA and WF (223 to 193 to 94; see Table 5), but did not increase the TBT and bleeding volume, that indicates a potential for safe use of MASA or
  • WF in dose 0.25 mg/kg/d substantially changed PT, prolonged aPTT time and substantially lowered F VII levels.
  • ASA did not cause significant changes in PT, aPTT and coagulation factors.
  • MASA+WF contrary to ASA+WF significantly more influenced aPTT time increase and decrease of factor XII activity (see Table 6). It should be noticed that in therapeutic doses addition of WF to MASA further decreased factor XII levels while the decrease of factor VII levels were similar to that of WF alone.
  • MASA and MASA+WF (10+0.06 mg/kg/d) caused substantially larger significant changes in aPTT and F XII than those caused by WF in sub-therapeutic dose 0.06 mg/kg/d.
  • MASA+WF 10+0.06 mg/kg/d
  • the combined administration of MASA+WF (10+0.06 mg/kg/d) caused significant decrease in F VII levels compared to MASA and control group, and substantially larger than those caused by WF. It allows predicting beneficial effects of combination of MASA with sub-therapeutic dose of WF in prevention of thrombotic complications and wider area of application compared to MASA.
  • mice Male ICR mice (26-30 g) were used for experiments. The efficiency of repeated (for 7 days once daily) administration of MASA and WF was compared. The mice were injected with 30 mg/kg thromboplastin (dissolved in saline) into the tail vein. Survival of the mice for 15 min after thromboplastin injection was recorded and used as the index for the antithrombotic effects of the agents.
  • MASA significantly lowers the levels of intrinsic pathway factor XII while showing practically no effect of extrinsic factor VII levels.
  • WF the change of dose from- 0.5 to 0.25 and further down to 0.06 mg/kg/d substantially diminished the influence on coagulation factors (see Tables 2, 6 and 7) and drastically changed the bleeding risk (see TBT and blood loss changes for WF in Tables 1, 3 and 4).
  • MASA is designed for use as oral anticoagulant therefore it can be administered as usual peroral pharmaceutical formulations - tablets or capsules. Since MASA displays beneficial activity in a range of doses, it is possible to select the dosage of MASA or pharmaceutical composition thereof according to clinical need. Combination of MASA with warfarin has beneficial effects when warfarin is administrated in doses that are generally regarded as devoid of anticoagulant activity. Therefore it is possible to use minimal warfarin dose in synergistic combination with MASA to achieve beneficial effect. Clinical experience will demonstrate the most advantageous component ratio and quantity in a combination pharmaceutical product that can be manufactured as single pharmaceutical formulation.
  • MASA is readily soluble in water
  • solution of MASA might find application for intravenous administration in emergency situations.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Diabetes (AREA)
  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne un acétylsalicylate de meldonium en tant que nouvel inhibiteur du facteur XII et son utilisation en tant qu'anticoagulant. Cette invention concerne en outre une association thérapeutique synergique comprenant ledit acétylsalicylate de meldonium et une warfarine sodique pour une utilisation en tant qu'anticoagulant.
PCT/LV2012/000008 2011-05-17 2012-05-16 Nouvel inhibiteur du facteur xii WO2012158003A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LVP-11-69A LV14606B (lv) 2011-05-17 2011-05-17 Jauns XII faktora inhibitors
LVP-11-69 2011-05-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014209092A1 (fr) 2013-06-28 2014-12-31 Tetra, Sia Correcteur de dysfonction endothéliale
WO2017173494A1 (fr) * 2016-04-06 2017-10-12 Csl Limited Méthode de traitement de l'athérosclérose

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113929735B (zh) * 2020-06-29 2023-08-01 首都医科大学 Gly-Pro-Arg-Pro-NHCH2CH2NH-华法林,其合成,活性和应用

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WO2010151096A1 (fr) * 2009-06-25 2010-12-29 Tetra, Sia Combinaisons thérapeutiques d'acide nicotinique et de meldonium
WO2010151095A1 (fr) 2009-06-25 2010-12-29 Tetra, Sia Nouveaux sels de l'acide acétylsalicylique

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WO1991017258A1 (fr) 1990-05-10 1991-11-14 Cetus Corporation Inhibiteurs de l'activation du facteur xii et leurs applications
WO1994020535A1 (fr) 1992-12-11 1994-09-15 Corvas International, Inc. ECOTINE UTILISEE EN TANT QU'INHIBITEUR DU FACTEUR Xa, XIa ET XIIa
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014209092A1 (fr) 2013-06-28 2014-12-31 Tetra, Sia Correcteur de dysfonction endothéliale
WO2017173494A1 (fr) * 2016-04-06 2017-10-12 Csl Limited Méthode de traitement de l'athérosclérose
CN109071629A (zh) * 2016-04-06 2018-12-21 杰特有限公司 治疗动脉粥样硬化的方法
US11174321B2 (en) 2016-04-06 2021-11-16 Csl Limited Method of treating atherosclerosis

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