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WO2014183667A1 - Solvate d'acide acétique de dérivé d'oxazolidinone, procédé de préparation dudit solvate, et application associée - Google Patents

Solvate d'acide acétique de dérivé d'oxazolidinone, procédé de préparation dudit solvate, et application associée Download PDF

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Publication number
WO2014183667A1
WO2014183667A1 PCT/CN2014/077668 CN2014077668W WO2014183667A1 WO 2014183667 A1 WO2014183667 A1 WO 2014183667A1 CN 2014077668 W CN2014077668 W CN 2014077668W WO 2014183667 A1 WO2014183667 A1 WO 2014183667A1
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WO
WIPO (PCT)
Prior art keywords
oxo
methyl
acetic acid
carboxamide
phenyl
Prior art date
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Ceased
Application number
PCT/CN2014/077668
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English (en)
Chinese (zh)
Inventor
黄长江
袁静
付晓丽
张士俊
商倩
刘旭圆
刘登科
徐为人
汤立达
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Publication of WO2014183667A1 publication Critical patent/WO2014183667A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P9/06—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, and relates to an acetic acid solvate of an oxazolidinone derivative, a preparation method thereof and use thereof, in particular, the invention relates to (S)-5-chloro-N-((2- Acetic acid solvent of oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide And 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 (A), 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.
  • 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-pyridyl)phenyl)-1,3-oxazole Acetic acid solvate of ⁇ -5-yl)methyl)thiophene-2-carboxamide, represented by the chemical formula (I): Wherein n is selected from the group consisting of 0.5 to 1.5, such as 0.5, 0.6, 07, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5; preferably 0.5 1.2, most preferably 0.8.
  • the measurement conditions were as follows: CuKa, 40 KV, 100 mA, and the solvate X-ray powder diffraction characteristic absorption peak (2 ⁇ ) value was 3.60, 7.04, 10.50, 14.00, measured by D/Max-2500 X-ray diffractometer. 17.48, 20.12, 21.00, 23.86, 24.56, 26.42, 28.12; 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 results
  • the invention (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1)
  • the differential thermal analysis of the acetic acid solvate of 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is shown in Figure 2.
  • the test results show that the solvate has an endotherm at 155 °C. And with about 10% weight loss, it was proved that the solvate crystal form contained about 10% by weight of acetic acid.
  • 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 acetic acid solvates 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 an acetic acid solvate 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-oxazolidin-5-yl)methyl)thiophene-2-carboxamide crystallized in a crystallization solvent, wherein the crystallization The solvent is acetic acid.
  • the preparation method may include: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)) -1,3-oxazolidine-5-yl)methyl)thiophene-2-carboxamide is added to acetic acid, dissolved by heating, allowed to stand for crystallisation, filtered and dried to give (S)-5-chloro-N- ((2-Oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5-yl)methyl)thiophene-2-methyl Acetate solvate of amide.
  • the amount of the crystallization solvent is as follows:
  • the volume of acetic acid is the corresponding (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-) 10) to 10 times, preferably 25 to 40 times the mass of the phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, the multiple being a volume-to-mass ratio,
  • the unit is mL/g.
  • the heating and dissolving temperature may be from 80 ° C to reflux temperature, preferably from 80 to 110 ° 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 an acetic acid solvate of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation of a medicament for preventing/treating a thromboembolic disease and/or a thromboembolic complication and for preventing/treating a thrombus Use in embolic disease 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 an acetic acid solvate 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)-1,3 Use of an acetic acid solvate of -oxazolidin-5-yl)methyl)thiophene-2-carboxamide for the prevention/treatment of thromboembolic diseases 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, Heart valve disease or artificial heart valve.
  • cardiac thromboembolism such as stroke, cerebral ischemia, systemic thromboembolism, and ischemia
  • acute, intermittent or persistent cardiac arrhythmia such as cardioversion, Heart valve 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).
  • atherosclerotic vascular diseases and inflammatory diseases such as motor system rheumatic diseases
  • other diseases such as diabetes, tumor diseases, especially 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- ⁇ -2H-pyridine-1-yl)phenyl)-1,3-oxazolidine- Acetic acid solvated 4 X-ray powder diffraction pattern of 5-yl)methyl)thiophene-2-carboxamide;
  • Figure 2 is (S)-5-chloro-indole-((2-oxo-3-(4-(2- ⁇ -2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- Ei' differential thermal analysis of 5-yl)methyl)thiophene-2-carboxamide.

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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)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (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 concerne un solvate d'acide acétique de (S) 5-chloro-N-((2-oxo-3-(4-(2-oxo-2 H-pyridin-1-yl)phényl)-1,3-oxazolidine -5-yl) méthyl) thiophène -2-carboxamide, un procédé de préparation dudit solvate et une application correspondante. Le solvate d'acide acétique préparé de (S)-5-chloro-N-((2-oxo -3-(4-(2-oxo-2H-pyridin-1-yl)phényl)-1,3-oxazolidine -5-yl) méthyl) thiophène -2-carboxamide est caractérisé par un diagramme de diffraction de puissance X.
PCT/CN2014/077668 2013-05-17 2014-05-16 Solvate d'acide acétique de dérivé d'oxazolidinone, procédé de préparation dudit solvate, et application associée Ceased WO2014183667A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310185328.0 2013-05-17
CN201310185328 2013-05-17

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1434822A (zh) * 1999-12-24 2003-08-06 拜尔公司 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
CN101743244A (zh) * 2007-06-20 2010-06-16 拜耳先灵制药股份公司 取代的*唑烷酮类及其用途
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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2069339B1 (fr) * 2006-09-25 2011-05-18 Wockhardt Research Centre Pipéridinophényloxazolidinones substituées
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
CN1434822A (zh) * 1999-12-24 2003-08-06 拜尔公司 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
CN101743244A (zh) * 2007-06-20 2010-06-16 拜耳先灵制药股份公司 取代的*唑烷酮类及其用途
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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