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WO2014183666A1 - Forme cristalline ii dérivée d'oxazolidinone, son procédé de préparation et son utilisation - Google Patents

Forme cristalline ii dérivée d'oxazolidinone, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2014183666A1
WO2014183666A1 PCT/CN2014/077667 CN2014077667W WO2014183666A1 WO 2014183666 A1 WO2014183666 A1 WO 2014183666A1 CN 2014077667 W CN2014077667 W CN 2014077667W WO 2014183666 A1 WO2014183666 A1 WO 2014183666A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
thiophene
methyl
carboxamide
chloro
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.)
Ceased
Application number
PCT/CN2014/077667
Other languages
English (en)
Chinese (zh)
Inventor
黄长江
张士俊
刘旭圆
袁静
付晓丽
商倩
刘鹏
刘登科
徐为人
汤立达
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Institute of Pharmaceutical Research Co Ltd
Original Assignee
Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tianjin Institute of Pharmaceutical Research Co Ltd filed Critical Tianjin Institute of Pharmaceutical Research Co Ltd
Publication of WO2014183666A1 publication Critical patent/WO2014183666A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P9/06—Antiarrhythmics
    • 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 invention belongs to the technical field of medicine, relates to an oxazolidinone derivative crystal form, a preparation method and use thereof, and in particular to a (S)-5-chloro-indole-((2-oxo) Form II of -3-(4-(2-oxo-2-indole-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide Its preparation method and use. Background technique
  • Thrombosis is an abnormal coagulation of blood in a flowing state due to activation of platelets and activation of blood coagulation factors.
  • Blood coagulation is originally a protective mechanism of organisms. There are antagonistic coagulation systems and anticoagulant systems in the blood. Their dynamic balance ensures the potential coagulability of blood and always ensures the fluid state of blood. .
  • thromboembolic disease is the most serious disease in cardiovascular disease and the first killer of human health. In China, with the improvement of living standards and the aging of the population, the incidence, mortality and disability of these diseases have increased year by year.
  • antithrombotic diseases are classified into antiplatelet drugs, anticoagulant drugs, and fibrinolytic drugs.
  • anticoagulant drugs are the main content of antithrombotic therapy.
  • Xa is the best target for the development of new anticoagulant drugs.
  • the coagulation process is usually divided into an endogenous coagulation pathway and an exogenous coagulation pathway.
  • Many blood coagulation factors are involved in the coagulation process, and each inactive factor converts the next inactive coagulation factor precursor into an activated form.
  • the final summary of the endogenous and exogenous pathways is the conversion of factor X to Xa. Therefore, in theory, direct inhibition of factor Xa activity should result in highly effective anticoagulant effects without the side effects of thrombin inhibitors.
  • platelets Because it directly inhibits the activity of factor Xa, it has the least effect on the normal hemostatic reaction/regulation process. For example, platelets remain capable of responding to low levels of catalytically active thrombin and thus do not affect platelet thrombosis and minimize the risk of hemorrhagic syndrome.
  • Patent CN201110337461.4 provides a novel compound having the structure of formula (I), which is a low molecular weight orally administrable inhibitor of factor Xa, which can be used for preventing/treating diseases, preferably thromboembolic diseases and/or thrombosis. Embolism complications, especially deep vein thrombosis, pulmonary embolism, heart Muscle infarction and so on.
  • An object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Form II of -oxazolidin-5-yl)methyl)thiophene-2-carboxamide.
  • Measured by D/Max-2500 X-ray diffractometer the measurement conditions were: CuKa, 40KV, 100 mA, and the X-ray powder diffraction characteristic absorption peak (2 ⁇ ) values of the crystal form were: 6.96, 9.68, 13.46, 13.94, 15.16, 15.50, 19.42, 20.60, 21.44, 22.72, 23.20, 24.66, 25.72, 27.32, 27.78; 2 ⁇ Measurement error is ⁇ 0.2.
  • the crystal form X-ray powder diffraction has a diffraction angle (2 ⁇ ) and a crystal plane spacing (d value) as shown in Table 1, and the measurement error of 2 ⁇ is ⁇ 0.2, as shown in Table 1.
  • Table 1 Crystalline X-ray powder diffraction diffraction angle and interplanar spacing results
  • Another object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1, Process for the preparation of Form II of 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide.
  • the present invention provides (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Process for the preparation of crystalline form II of alk-5-yl)methyl)thiophene-2-carboxamide, which comprises (S) -5 -chloro-N-((2-oxo-3-(4-) (2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- 5 -yl)methyl)
  • the thiophene-2-carboxamide is crystallized in a crystallization solvent, wherein the crystallization solvent is hydrazine, hydrazine-dimethylformamide and ethanol, or the crystallization solvent is hydrazine, hydrazine-dimethylformamide and water.
  • the preparation method may include: (S)-5-chloro-indole-((2-oxo-3-(4-(2-oxo-2-indole-pyridin-1-yl)phenyl)) -1,3-oxazolidine-5-yl;)methyl)thiophene-2-carboxamide is added to hydrazine, hydrazine-dimethylformamide, dissolved by stirring, and then added with ethanol or water to precipitate a solid.
  • the amount of the crystallization solvent is as follows: ⁇ , ⁇ -dimethylformamide has a volume of the corresponding (S) -5 -chloro-indole-((2-oxo-3-(4-(2-) Oxy-2-pyridin-1-yl)phenyl)-1,3-oxazolidine- 5 -yl)methyl) thiophene-2-carboxamide 5 to 10 times the mass; ethanol or water volume corresponding (S)-5-chloro-indole-((2-oxo-3-(4-(2-oxo-2-indole-pyridin-1-yl)phenyl)-1,3-oxazolidine-5 -Based on 10 to 20 times the mass of methyl)thiophene-2-carboxamide.
  • the multiple is a volume-to-mass ratio and its unit is mL/g.
  • the heating and dissolving temperature may be from 60 ° C to 100 ° C.
  • Still another object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Use of crystalline form II of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation of a medicament for preventing/treating a thromboembolic disease and/or thromboembolic complications and for preventing/treating thromboembolism Use in sexually transmitted diseases and/or thromboembolic complications.
  • the present invention provides the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Use of Form II of -oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation of a medicament for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.
  • the present invention also provides the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1, Use of Form II of 3-oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.
  • thromboembolic disease includes, inter alia, diseases such as myocardial infarction with ST-segment elevation (STEMI) and without ST-segment elevation (without STEMI), stable/unstable angina, coronary interventional therapy For example, re-occlusion and restenosis after angioplasty or aortic coronary artery bypass surgery, peripheral vascular occlusive disease, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attack, and thrombosis and thrombosis Embolism type stroke.
  • diseases such as myocardial infarction with ST-segment elevation (STEMI) and without ST-segment elevation (without STEMI), stable/unstable angina, coronary interventional therapy
  • re-occlusion and restenosis after angioplasty or aortic coronary artery bypass surgery peripheral vascular occlusive disease, pulmonary embolism, deep vein thrombosis and renal vein thro
  • the thromboembolic disease also includes cardiac thromboembolism, such as stroke, cerebral ischemia, systemic thromboembolism, and ischemia, and also, for example, acute, intermittent or persistent cardiac arrhythmia, cardioversion, valvular heart disease or Artificial heart valve.
  • cardiac thromboembolism such as stroke, cerebral ischemia, systemic thromboembolism, and ischemia
  • acute, intermittent or persistent cardiac arrhythmia cardioversion, valvular heart disease or Artificial heart valve.
  • the thromboembolic diseases also include atherosclerotic vascular diseases and inflammatory diseases (such as Thrombosis of the respiratory system caused by other diseases such as diabetes, neoplastic diseases, especially those undergoing major surgical intervention or radiotherapy/chemotherapy.
  • the thromboembolic disease also includes diffuse invasive coagulation (DIC).
  • DIC diffuse invasive coagulation
  • the thromboembolic complications include microvascular hemolytic anemia, complications such as hemodialysis and heart valve repair in the context of extracorporeal blood circulation.
  • Figure 1 is (S) -5 -chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine
  • Figure 2 is (S) -5 -chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline II de (S)-5-chlorine-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-group)-1,3-oxazolidine-5-group)méthyl)thiophène-2-formamide, son procédé de préparation et son utilisation. La forme cristalline II préparée de (S)-5-chlorine-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-group)-1,3-oxazolidine-5-group)méthyl)thiophène-2-formamide est représentée par le diagramme de diffraction de rayons X sur poudres.
PCT/CN2014/077667 2013-05-17 2014-05-16 Forme cristalline ii dérivée d'oxazolidinone, son procédé de préparation et son utilisation Ceased WO2014183666A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310182806.2 2013-05-17
CN201310182806.2A CN103232446B (zh) 2013-05-17 2013-05-17 一种噁唑烷酮衍生物晶型ⅱ及其制备方法和用途

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Publication Number Publication Date
WO2014183666A1 true WO2014183666A1 (fr) 2014-11-20

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CN (1) CN103232446B (fr)
WO (1) WO2014183666A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232446B (zh) * 2013-05-17 2015-09-23 天津药物研究院 一种噁唑烷酮衍生物晶型ⅱ及其制备方法和用途
CN103242307B (zh) * 2013-05-17 2015-08-12 天津药物研究院有限公司 一种噁唑烷酮类衍生物晶型ⅰ及其制备方法和用途
CN106478661A (zh) * 2015-08-25 2017-03-08 华北制药集团新药研究开发有限责任公司 苯并恶唑并恶嗪酮类化合物wa1-089的晶型e及其制备方法
CN116265459A (zh) * 2021-12-17 2023-06-20 天津药业集团有限公司 一种噁唑烷酮类衍生物的晶型ⅲ及其制备方法和用途

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WO2008155069A2 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substituées et leur utilisation
WO2008155032A1 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft (oxazolidinon-5-yl-méthyl)-2-thiophène-carboxamides substitués et leur utilisation dans le domaine de la coagulation sanguine
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CN103242307A (zh) * 2013-05-17 2013-08-14 天津药物研究院 一种噁唑烷酮类衍生物晶型ⅰ及其制备方法和用途
CN103626749A (zh) * 2012-08-21 2014-03-12 苏州泽璟生物制药有限公司 取代的噁唑烷酮化合物和包含该化合物的药物组合物及其用途

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DE10342570A1 (de) * 2003-09-15 2005-04-14 Bayer Healthcare Ag Verfahren zur Herstellung von 4-(4-Aminophenyl)-3-morpholinon
CN1763018B (zh) * 2005-09-30 2012-11-21 天津药物研究院 噁唑烷酮类化合物
CN101220002B (zh) * 2007-12-28 2011-07-13 天津药物研究院 作为抗菌剂的噁唑烷酮类化合物
EP2451816A4 (fr) * 2009-07-06 2013-02-27 Glenmark Generics Ltd Forme cristalline d'hydrobromure de prasugrel et son procédé de préparation
CN102050819B (zh) * 2009-11-10 2012-05-23 天津药物研究院 噁唑烷酮衍生物及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008155069A2 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substituées et leur utilisation
WO2008155032A1 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft (oxazolidinon-5-yl-méthyl)-2-thiophène-carboxamides substitués et leur utilisation dans le domaine de la coagulation sanguine
CN102464658A (zh) * 2010-11-03 2012-05-23 天津药物研究院 噁唑烷酮衍生物及其制备方法和用途
CN103626749A (zh) * 2012-08-21 2014-03-12 苏州泽璟生物制药有限公司 取代的噁唑烷酮化合物和包含该化合物的药物组合物及其用途
CN103232446A (zh) * 2013-05-17 2013-08-07 天津药物研究院 一种噁唑烷酮衍生物晶型ⅱ及其制备方法和用途
CN103242307A (zh) * 2013-05-17 2013-08-14 天津药物研究院 一种噁唑烷酮类衍生物晶型ⅰ及其制备方法和用途

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CN103232446B (zh) 2015-09-23

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