WO2014183665A1 - Forme cristalline i d'un dérivé d'oxazolidinone, et son procédé de préparation et son utilisation - Google Patents

Forme cristalline i d'un dérivé d'oxazolidinone, et son procédé de préparation et son utilisation Download PDF

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Publication number
WO2014183665A1
WO2014183665A1 PCT/CN2014/077666 CN2014077666W WO2014183665A1 WO 2014183665 A1 WO2014183665 A1 WO 2014183665A1 CN 2014077666 W CN2014077666 W CN 2014077666W WO 2014183665 A1 WO2014183665 A1 WO 2014183665A1
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WO
WIPO (PCT)
Prior art keywords
oxo
thiophene
chloro
phenyl
methyl
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Application number
PCT/CN2014/077666
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English (en)
Chinese (zh)
Inventor
黄长江
袁静
商倩
刘鹏
王成港
付晓丽
刘欢
张士俊
靳文仙
徐为人
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天津药物研究院
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Application filed by 天津药物研究院 filed Critical 天津药物研究院
Publication of WO2014183665A1 publication Critical patent/WO2014183665A1/fr

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    • 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
    • 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
    • A61P9/10—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 I and a preparation method and use thereof, and more particularly to a (S)-5-chloro-N-((2- Crystal form of oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide I and its preparation method and use.
  • Background technique is referred to the technical field of medicine, relates to an oxazolidinone derivative crystal form I and a preparation method and use thereof, and more particularly to a (S)-5-chloro-N-((2- Crystal form of oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide I and its preparation method and use.
  • 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 I of -oxazolidine-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: 4.04, 8.08, 12.16, 13.96, 17.14, 19.40, 19.76, 20.30, 23.80, 24.46, 28.60, 32.26; 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.
  • Table 1 Crystalline X-ray powder diffraction diffraction angle and interplanar spacing
  • 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 I of 3-oxazolidine-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 I 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)thiophene-2-carboxamide crystallized in a crystallization solvent, wherein the crystallization
  • the solvent is a mixed solution of an aqueous solution of formic acid and ethanol.
  • the preparation method may include: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-) Pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is added to the mixed solution, dissolved by stirring and heated to room temperature to precipitate crystals. Filtration and drying gave (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3- Form I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide.
  • the mixed solution is composed of a formic acid aqueous solution having a concentration of 80% to 95% and ethanol in a volume ratio of 1:0.5 to 1.5.
  • the mixed solution is composed of a formic acid aqueous solution having a concentration of 85% to 90% and ethanol in a volume ratio of 1: 0.8 to 1.2.
  • the mixed solution consists of a concentration of 88% aqueous formic acid and ethanol in a volume ratio of 1:1.
  • the mixed solution is used in an amount of: the total volume of the mixed solution is the corresponding (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine)- 15- to 6 -phenyl)-1,3-oxazolidine- 5 -yl)methyl)thiophene-2-carboxamide 15 to 25 times the mass, the multiple is the volume-to-mass ratio, the unit is mL/g .
  • 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 Form I 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 I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the manufacture 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 I of 3-oxazolidin-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 motor system rheumatic diseases), as well as other diseases (such as diabetes, tumor diseases, especially major surgical intervention or radiotherapy/chemotherapy).
  • the patient caused by thromboembolism 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 X-ray powder diffraction pattern of Form I of -5-yl)methyl)thiophene-2-carboxamide. The best way to implement the invention

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (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)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur la forme cristalline I du (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phényl)-1,3-oxazolidin-5-yl)méthyl)thiophène-2-formamide, et sur son procédé de préparation et son utilisation. La forme cristalline I préparée du (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phényl)-1,3-oxazolidin-5-yl)méthyl)thiophène-2-formamide est caractérisée par un diffractogramme aux rayons X par la méthode des poudres.
PCT/CN2014/077666 2013-05-17 2014-05-16 Forme cristalline i d'un dérivé d'oxazolidinone, et son procédé de préparation et son utilisation WO2014183665A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310183080.4 2013-05-17
CN201310183080.4A CN103242307B (zh) 2013-05-17 2013-05-17 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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* Cited by examiner, † Cited by third party
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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
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
CN106562981A (zh) * 2015-10-13 2017-04-19 孙双勇 一种由知非沙班与人参皂苷Rb3组成的药物组合物及应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1772751A (zh) * 1999-12-24 2006-05-17 拜耳医药保健股份公司 取代的噁唑烷酮和其在血液凝固领域中的应用
WO2008155069A2 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substituées et leur utilisation
CN101772496A (zh) * 2007-06-20 2010-07-07 拜耳先灵制药股份公司 取代的*唑烷酮类和其用途
CN101821259A (zh) * 2007-06-20 2010-09-01 拜耳先灵制药股份公司 取代的(*唑烷酮-5-基-甲基)-2-噻吩-酰胺和其在血液凝固领域中的应用
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

Family Cites Families (1)

* 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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1772751A (zh) * 1999-12-24 2006-05-17 拜耳医药保健股份公司 取代的噁唑烷酮和其在血液凝固领域中的应用
WO2008155069A2 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substituées et leur utilisation
CN101772496A (zh) * 2007-06-20 2010-07-07 拜耳先灵制药股份公司 取代的*唑烷酮类和其用途
CN101821259A (zh) * 2007-06-20 2010-09-01 拜耳先灵制药股份公司 取代的(*唑烷酮-5-基-甲基)-2-噻吩-酰胺和其在血液凝固领域中的应用
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

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