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Thiomorpholine-containing pyrrole derivatives and their preparation method and use

A technology of drugs and compounds, applied in the field of medicine, can solve problems such as weak alkalinity, limitation, and difficulty in purification, and achieve the effect of obvious platelet aggregation and inhibition of platelet aggregation

Active Publication Date: 2012-11-28
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since clopidogrel is an oily substance with a very weak alkalinity, it needs to be mixed with a strong acid to form a salt, but it is unstable in the presence of moisture, so that the free base is precipitated, and there are certain difficulties in purification.
And because of its strong acidity, it is subject to certain restrictions in preparation

Method used

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  • Thiomorpholine-containing pyrrole derivatives and their preparation method and use
  • Thiomorpholine-containing pyrrole derivatives and their preparation method and use
  • Thiomorpholine-containing pyrrole derivatives and their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0057] Preparation of intermediate Ⅲ-1

[0058]

[0059] Add 22.1g (0.01mol) 4-acetyl-1-cyclopropane-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (II) into a reaction flask equipped with stirring, condenser and thermometer, Dissolve it with 100ml of thionyl chloride, stir, and reflux for 4 hours (the plates show that the reaction is complete). Thionyl chloride was evaporated to dryness to obtain a white solid (HPLC: 99.6%). HRMS(m / z)[M+H] + : 222.1085.

Embodiment 1

[0061] Preparation of 1-(1-cyclopropyl-2,5-dimethyl-4-(thiazolidine-3-carbonyl)-1H-pyrrol-3-yl)ethanone (compound Ⅰ-1)

[0062]

[0063] Add 24.0 g (0.01 mol) of intermediate III-1 to a reaction flask equipped with stirring, a condenser, and a thermometer, dissolve it with 150 ml of dichloromethane, and add 20.2 g (0.2 mol) of triethylamine while stirring. 8.9 g of thiazolidine was added to the reaction system. After the addition, the reaction was continued for 5h under reflux (the plate showed that the reaction was complete). Wash the reaction solution with 3×50ml water, dry the dichloromethane layer fully with anhydrous sodium sulfate, filter, and evaporate the dichloromethane under reduced pressure to obtain a pale yellow solid, which is separated by column [mobile phase: v (petroleum ether): v (ethyl acetate)=1:2] to obtain a white solid (HPLC: 99.7%). HRMS(m / z)[M+H] + : 293.1279.

[0064] Referring to Example 1, compounds I-2~I-3 can be synthesized.

[0065]

...

Embodiment 2

[0068] Compound Ⅰ-1 hydrochloride: take 2.9 g of white solid Ⅰ-1 and dissolve it in 15 mL of absolute ethanol. Cool in an ice-water bath to 5°C, add 11.1% ethanol hydrochloric acid solution dropwise until the pH is 2, and continue stirring for about 1 h in an ice-water bath. Filter to obtain light yellow solid, vacuum dry, m.p.>230°C.

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Abstract

The invention belongs to the technical field of antiplatelet drugs and provides thiomorpholine-containing pyrrole derivatives and pharmaceutically acceptable salts thereof. The thiomorpholine-containing pyrrole derivatives have a general structural formula I. In the general structural formula I, m and R are defined in the patent specification. The invention relates to a preparation method of the thiomorpholine-containing pyrrole derivatives, discloses a drug composition containing the thiomorpholine-containing pyrrole derivatives or their pharmaceutically acceptable salts as active ingredients, and also discloses a use of the thiomorpholine-containing pyrrole derivatives and their pharmaceutically acceptable salts in antiplatelet drugs.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and more specifically, relates to a class of compounds with anti-platelet aggregation and their preparation methods, pharmaceutical compositions containing them and their use as anti-platelet drugs. Background technique [0002] In recent years, the incidence of thromboembolic diseases, mainly coronary thrombosis and cerebral thrombosis, has been on the rise, seriously endangering human health. Platelet aggregation is a key link in the normal coagulation mechanism, and the adhesion, aggregation, and release reactions of platelets lead to thrombus formation. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombosis have always been a research hotspot. [0003] Clinically, aspirin is widely used as an antiplatelet aggregation drug. Although aspirin can be tolerated by most people, sometimes even a small dose may cause gastrointestinal discom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D207/34A61K31/541A61K31/427A61P7/02A61P9/10
Inventor 刘登科刘颖田军祁浩飞路亮吴疆
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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