Preparation method and medical application of water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives

A solvate and drug technology, which is applied to the preparation of water-soluble 2-hydroxytetrahydrothienopyridine derivatives and the field of medical application thereof, and can solve the problems of slow onset, poor water solubility and the like

Active Publication Date: 2015-03-18
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the shortcomings of poor water solubility and slow onset of the existing oral antiplatelet drugs, and to de

Method used

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  • Preparation method and medical application of water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives
  • Preparation method and medical application of water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives
  • Preparation method and medical application of water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0079] (S)-(5-(1-(2-chlorophenyl)-2-methoxy-2-carbonylethyl)-4,5,6,7-tetrahydrothieno[3,2-c] Preparation of Sodium Pyridin-2-yloxy)methylphosphate (Formula I-1a Compound)

[0080]

[0081] Step 1: Di-tert-butyl (5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yloxy)methylphosphate (formula XII-1 compound) preparation

[0082] Under nitrogen protection, 5-trityl-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one (compound of formula X, 3.98g, 10mmol) and sodium iodide (100mg) were added into anhydrous tetrahydrofuran (50mL), and a solution of sodium hexamethyldisilazide in tetrahydrofuran (1M, 11.0mL, 11.0mmol) was added dropwise at 0°C. Stir at room temperature for 1 hour, then add di-tert-butyl chloromethyl phosphate (compound of formula XI-1, 3.10 g, 12 mmol), continue to stir at room temperature for 30 minutes, then heat to 80 ° C, keep warm until the raw material disappears (TLC detection ). The solvent was evaporated under reduced pressure, water (50 mL) was added...

Embodiment 2

[0089] (S)-(5-(1-(2-chlorophenyl)-2-methoxy-2-carbonylethyl)-4,5,6,7-tetrahydrothieno[3,2-c] Preparation of Sodium Pyridin-2-yloxy)methylphosphate (Formula I-1a Compound)

[0090]

[0091] Step 1: (S)-2-(2-(Chloromethoxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chloro The preparation of phenyl) methyl acetate (formula III-1 compound)

[0092] Under nitrogen protection, (2S)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(2 -Chlorophenyl)-methyl acetate (compound of formula II, 3.38g, 10mmol) (prepared with reference to the method described in Chinese patent application 201010624329.7), chlorobromomethane (10g, 78mmol), potassium iodide (50mg) and potassium tert-butoxide (1.34 g, 12 mmol) was added into tetrahydrofuran (50 mL), stirred at room temperature for 1 hour, then heated to 40° C., and kept warm until the raw material disappeared (TLC detection). The solvent was evaporated under reduced pressure, water (50 mL) was added to the residue, extracte...

Embodiment 3

[0096] (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-carbonylethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Preparation of -2-base sodium phosphate (compound of formula I-2a)

[0097]

[0098] Step 1: Preparation of 5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl di-tert-butyl phosphate (compound of formula XVI-1)

[0099] 5-trityl-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one (compound of formula X, 3.98g, 10mmol), DBU (3.3mL , 22mmol) and DMAP (0.12g, 1mmol) were dissolved in anhydrous tetrahydrofuran (30mL), and the phosphorylation reagent formula XV-1 compound (5.65g, 20.75mmol) (prepared according to the method described in WO2005063777) was added dropwise at 0°C Tetrahydrofuran (5 mL) solution was added after dropping, slowly warmed to room temperature and stirred overnight. Add saturated sodium bicarbonate solution (5mL) to quench the reaction, evaporate the organic solvent under reduced pressure, add water (20mL) to the residue, extract with ethyl acetate (50mL x...

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Abstract

The invention relates to the field of pharmacy and specifically relates to water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives as well as a preparation method of the derivatives and application of the derivatives in pharmacy, and specifically relates to application of the water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives in preparation of drugs for preventing or treating thrombus and embolism related diseases, and in particular to application of the water-soluble 2-hydroxyl tetrahydrothienopyridine derivatives in prevention and treatment of acute ST segment elevation type myocardial infarction as injections.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to water-soluble 2-hydroxytetrahydrothienopyridine derivatives and their preparation method and application in pharmacy, in particular to water-soluble 2-hydroxytetrahydrothienopyridine derivatives in the preparation of prevention or treatment The use in medicines for thrombosis and embolism-related diseases, especially the use as an injection in the prevention and treatment of acute ST-segment elevation myocardial infarction. Background technique [0002] Clopidogrel as irreversible P2Y 12 Receptor antagonists are currently the most widely used anti-platelet aggregation drugs. It is clinically used to treat atherosclerotic diseases, acute coronary syndrome and thrombotic complications. Clinical studies have found that the oral bioavailability of clopidogrel is very low, and its onset is slow. Circulation, 2004, 109:166). [0003] Prasugrel (Prasugrel) is a newly listed oral antiplatelet...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61K9/08A61P7/02A61P9/10
Inventor 孙宏斌张秀玲龚彦春吕伏生
Owner JIANGSU VCARE PHARMATECH
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