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Thienopyridine derivatives, and preparation methods and medical use thereof

A use and drug technology, applied in the field of thiophenepyridine derivatives and their preparation, can solve the problems of cardiovascular events and increased mortality, and achieve the effects of good anti-platelet aggregation effect, solving resistance problems and high bioavailability

Active Publication Date: 2014-04-02
WUHAN QR PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After the occurrence of clopidogrel resistance, the consequences are very serious, with a significant increase in cardiovascular events and mortality

Method used

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  • Thienopyridine derivatives, and preparation methods and medical use thereof
  • Thienopyridine derivatives, and preparation methods and medical use thereof
  • Thienopyridine derivatives, and preparation methods and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] 2-(3,5,6-Trimethylpiperazineformyloxy)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-C]pyridine- 5-base) the preparation method of methyl acetate, its synthetic route is as follows:

[0069]

[0070] Dissolve QR02000-IN-07 (10mmol, 1.0eq) in 20mL methanol, add QR02000-IN-08 (10mmol, 1.0eq) and NaHCO 3 (20mmol, 2.0eq), heated to 70°C, reacted for 6h. Cool to room temperature, filter to remove inorganic salts, evaporate the solvent under reduced pressure, add 100mL ethyl acetate and 30mL water, separate the organic layer, wash the organic layer twice with water, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and use a flash column The product QR02000-IN-09 was purified.

[0071] Add thionyl chloride (60mmol, 2.0eq) dropwise to 60mL of dichloromethane solution in which QR02000-IN-02 (30mmol, 1.0eq) was dissolved in ice-cooling, add to room temperature and stir for 2h, evaporate to dryness under reduced pressure The product acid chloride w...

Embodiment 2

[0073] 2-(3,5,6-Trimethylpiperazineacetoxy-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-C]pyridine-5- Base) the preparation of methyl acetate:

[0074]

[0075] Add oxalyl chloride (60mmol, 2.0eq) dropwise to 60mL of dichloromethane solution in which QR02000-IN-03 (30mmol, 1.0eq) was dissolved in an ice bath. in anhydrous dichloromethane; add this solution dropwise to a solution of QR02000-IN-09 (15mmol, 0.5eq) and triethylamine (180mmol, 3.0eq) in dichloromethane at 0°C, add After the completion, the temperature of the reaction system was controlled at about 0° C., the stirring was continued for 0.5 hours, and the temperature was raised to room temperature and stirred for 2 hours. Pour the reaction solution into 60 mL of ice water, extract with ethyl acetate (100 mL×3), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, concentrate and evaporate to dryness, and obtain the target product QR02002 by flash column chrom...

Embodiment 3

[0077] 2-(3,4,5-trihydroxycyclohexenecarboxy)-3,5,6-trimethylpiperazineacetoxy-2-(2-chlorophenyl)-2-(6, Preparation of 7-dihydrothieno[3,2-C]pyridin-5-yl)methyl acetate:

[0078]

[0079] Oxalyl chloride (60mmol, 2.0eq) was added dropwise to a solution of QR02000-IN-05 (30mmol, 1.0eq) and triethylamine (120mmol, 3.0eq) in 60mL of dichloromethane solution in an ice bath, and the addition was completed to Stir at room temperature for 2h, concentrate to dryness, and then dissolve in anhydrous dichloromethane; add the solution dropwise to a solution of QR02000-IN-09 (15mmol, 0.5eq) and triethylamine (180mmol, 3.0 In the dichloromethane solution of eq), after the addition, the temperature of the reaction system was controlled at about 0° C., and the stirring was continued for 0.5 hours, and the temperature was raised to room temperature and stirred for 2 hours. The reaction solution was poured into 60 mL of ice water, extracted with ethyl acetate (100 mL×3), the organic phases ...

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Abstract

The invention belongs to the field of pharmaceutical chemistry technology, and particularly discloses thienopyridine derivatives, and preparation methods and a medical use thereof. Through structural modification of clopidogrel and prasugrel, a series of new thienopyridine derivative compounds are synthesized and mainly include derivatives esterified with ligustrazine formic acid and shikimic acid; the compounds go into a body, then are rapidly metabolized into effective metabolites and ligustrazine formic acid or shikimic acid, successfully keep away from metabolism of CYP2C19 enzyme, can be directly metabolized into active compounds to play a pharmacological function, thereby solving the clopidogrel resistance problem, effectively improving the compound antithrombotic activity, and also having no significant effect on hemorrhage risk; and the compounds have relatively ideal protective function on liver and kidney, and also have potential therapeutic significance for other cardiovascular diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a class of thienopyridine derivatives, a preparation method and a medical application thereof. Background technique [0002] Thrombotic diseases are various diseases in which the stenosis and occlusion of the vascular lumen caused by thrombus lead to ischemia and infarction of major organs, resulting in various diseases. Factors leading to thrombosis include adhesion and aggregation of platelets on the surface of the damaged vessel wall, stasis of blood flow, activation of coagulation factors to promote the formation of thrombin and low fibrinolytic activity. Drugs clinically used in the treatment of thrombosis can be divided into three categories: antiplatelet drugs, anticoagulant drugs and thrombolytic drugs. Antiplatelet drugs have both therapeutic and preventive effects, and are the main category of antithrombotic drugs. Antiplatelet drugs refer to d...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P7/02
CPCC07D495/04
Inventor 葛建马建义项光亚王朝东
Owner WUHAN QR PHARMA CO LTD
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