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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: 2015-06-24
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 a stirrer, a condenser and a thermometer. Dissolve it with 100ml of thionyl chloride, stir, and react under reflux for 4h (the plate layer shows that the reaction is complete). The thionyl chloride was evaporated to dryness to obtain a white solid (HPLC: 99.6%). HRMS(m / z)[M+H] + : 240.0793.

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 24.0g (0.01mol) of Intermediate III-1 into a reaction flask equipped with a stirrer, condenser and thermometer, dissolve it with 150ml of dichloromethane, and add 20.2g (0.2mol) of triethylamine with stirring. 8.9 g of thiazolidine was added to the reaction system. After adding, continue to react for 5h under reflux (the plate layer shows that the reaction is complete). The reaction solution was washed with 3×50ml water, the methylene chloride layer was fully dried with anhydrous sodium sulfate, filtered, and the methylene chloride was evaporated under reduced pressure to obtain a pale yellow solid, which was separated by column [mobile phase: v (petroleum ether): v (Ethyl acetate)=1:2], a white solid (HPLC: 99.7%) can be obtained. HRMS(m / z)[M+H] + : 293.1279.

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

[0065]...

Embodiment 2

[0068] Compound I-1 into hydrochloride: Take 2.9 g of I-1 white solid and dissolve it in 15 mL of absolute ethanol. Cool to 5°C in an ice-water bath, add 11.1% hydrochloric acid ethanol solution dropwise to pH 2, and continue to stir in an ice-water bath for about 1 hour. After filtration, a light yellow solid was obtained, which was dried in vacuum, 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 invention belongs to the technical field of medicine, and more specifically, it relates to a class of compounds with anti-platelet aggregation effect, a preparation method thereof, a pharmaceutical composition containing them, and use as an anti-platelet medicine. 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. The adhesion, aggregation, and release reactions of platelets lead to thrombosis. Therefore, drugs that inhibit platelet aggregation play an important role in the treatment of thrombosis and have always been a hot research topic. [0003] Clinically, aspirin is widely used as an anti-platelet aggregation drug. Although aspirin can be tolerated by most people, sometimes even small doses may cause gastrointestinal discomfort in s...

Claims

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Application Information

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Patent Type & Authority Patents(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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