WO2016019848A1 - Dérivé thioester du dabigatran, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé thioester du dabigatran, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2016019848A1
WO2016019848A1 PCT/CN2015/086021 CN2015086021W WO2016019848A1 WO 2016019848 A1 WO2016019848 A1 WO 2016019848A1 CN 2015086021 W CN2015086021 W CN 2015086021W WO 2016019848 A1 WO2016019848 A1 WO 2016019848A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
methyl
stereoisomer
acceptable salt
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/CN2015/086021
Other languages
English (en)
Chinese (zh)
Inventor
魏用刚
邱关鹏
雷柏林
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.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco Pharmaceutical 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 Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Priority to CN201580036779.5A priority Critical patent/CN107027308A/zh
Publication of WO2016019848A1 publication Critical patent/WO2016019848A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • cardiovascular disease is one of the main causes of death in humans.
  • One of its main aspects is thrombosis, which is caused by a series of complex reactions.
  • Blood coagulation is a protective mechanism of the organism whereby the defect of the vessel wall can be "sealed” quickly and reliably, thus avoiding blood loss or minimizing it. Maintaining normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.
  • X 2 is O; R 2 is n-hexyl;
  • R 1 , R 2 , X 1 and X 2 are identical to those defined in the above formula (I).
  • the suspension of the group prototype drug was collected from the eyelids, anticoagulated by heparin, and centrifuged at 3000C for 10 min at 4 ° C for 5 min before administration (0 h) and 5 min, 15 min, 30 min, 1.0, 2.0, 4.0, 8.0, 24.0 h after administration.
  • the plasma was separated and stored at -80 ° C for testing. Take 30ul of rat plasma at each time point, add 200ul of internal standard solution (7.5ng/ml verapamil), vortex for 1min, centrifuge at 13000rpm for 10min at 4°C, and take 190ul of supernatant for LC-MS/MS (Shimadzu Company lc-20A Technology Co., Ltd., API4000+) analysis.
  • the main pharmacokinetic parameters were analyzed by WinNonlin 6.3 software non-compartmental model. The results are shown in Table 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un dérivé thioester du dabigatran tel qu'indiqué dans la formule (I), un stéréoisomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci et une utilisation de celui-ci dans la préparation de médicaments destinés à la prévention et au traitement de maladies thromboemboliques, X1, X2, R1, and R2 étant tels que définis dans la description.
PCT/CN2015/086021 2014-08-06 2015-08-04 Dérivé thioester du dabigatran, son procédé de préparation et son utilisation pharmaceutique Ceased WO2016019848A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580036779.5A CN107027308A (zh) 2014-08-06 2015-08-04 一种达比加群硫酯衍生物及其制备方法和在药学上的用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410383909.X 2014-08-06
CN201410383909 2014-08-06
CN201510201580 2015-04-27
CN201510201580.5 2015-04-27

Publications (1)

Publication Number Publication Date
WO2016019848A1 true WO2016019848A1 (fr) 2016-02-11

Family

ID=55263150

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/086021 Ceased WO2016019848A1 (fr) 2014-08-06 2015-08-04 Dérivé thioester du dabigatran, son procédé de préparation et son utilisation pharmaceutique

Country Status (2)

Country Link
CN (1) CN107027308A (fr)
WO (1) WO2016019848A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1248251A (zh) * 1997-02-18 2000-03-22 贝林格尔英格海姆法玛公司 二取代双环杂环,其制备法及作为药物的用途
CN1675193A (zh) * 2002-08-02 2005-09-28 贝林格尔英格海姆法玛两合公司 1－甲基－2－(4－脒基苯基氨甲基)－苯并咪唑－5－基－羧酸－(n－2－吡啶基－n－2－羟基羰基乙基－酰胺的新颖前药，其制法及其作为药物制剂的用途
WO2012174856A1 (fr) * 2011-06-24 2012-12-27 合肥医工医药有限公司 Inhibiteur de thrombine à usage oral, son procédé de préparation et utilisation médicale
CN103554087A (zh) * 2013-11-19 2014-02-05 南京工业大学 达比加群衍生物、及其制备方法和抗血栓用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2550966T3 (en) * 2011-07-25 2017-02-06 Dritte Patentportfolio Beteili Dabigatran amidoxic acid esters as prodrugs and their use as a drug
CN102766134B (zh) * 2012-07-19 2014-06-25 北京普禄德医药科技有限公司 达比加群的酯衍生物及其制备方法和用途
CN102875533B (zh) * 2012-11-06 2015-06-17 中国药科大学 达比加群衍生物、其制法及抗血栓用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1248251A (zh) * 1997-02-18 2000-03-22 贝林格尔英格海姆法玛公司 二取代双环杂环,其制备法及作为药物的用途
CN1675193A (zh) * 2002-08-02 2005-09-28 贝林格尔英格海姆法玛两合公司 1－甲基－2－(4－脒基苯基氨甲基)－苯并咪唑－5－基－羧酸－(n－2－吡啶基－n－2－羟基羰基乙基－酰胺的新颖前药，其制法及其作为药物制剂的用途
WO2012174856A1 (fr) * 2011-06-24 2012-12-27 合肥医工医药有限公司 Inhibiteur de thrombine à usage oral, son procédé de préparation et utilisation médicale
CN103554087A (zh) * 2013-11-19 2014-02-05 南京工业大学 达比加群衍生物、及其制备方法和抗血栓用途

Also Published As

Publication number Publication date
CN107027308A (zh) 2017-08-08

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