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1,4-disubstituted piperazine derivatives and their preparation method and use

A technology of piperazine and compounds, applied in the field of anti-platelet drugs, compounds with anti-platelet aggregation and their preparation, can solve the problems of clopidogrel resistance and achieve the effect of inhibiting 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

[0009] One object of the present invention is to develop a novel 1,4-disubstituted piperazine derivative and its medicinal salt in order to solve the problem of clopidogrel resistance

Method used

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  • 1,4-disubstituted piperazine derivatives and their preparation method and use
  • 1,4-disubstituted piperazine derivatives and their preparation method and use
  • 1,4-disubstituted piperazine derivatives and their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] 2-(4-(3-Chloropyridin-2-yl)piperazin-1-yl)-2-oxoethyl nitrate (compound Ⅰ-1-1)

[0085]

[0086] Add intermediate III-1 (2.4g, 0.01mol) to the reaction flask equipped with stirring, condenser and thermometer, dissolve in anhydrous acetonitrile (20m1), and add anhydrous acetonitrile solution of silver nitrate (2.0g, 0.012mol) (10m1), refluxed for 5h under stirring in the dark, TLC showed that the reaction was complete and cooled to room temperature, and the solvent was evaporated to dryness under reduced pressure. Dichloromethane (20ml) was added to the residue, stirred for 10min, filtered, and the filtrate was evaporated to dryness under reduced pressure. Add absolute ethanol (30ml), evaporate to dryness under reduced pressure after activated carbon decolorization, and dry under reduced pressure at room temperature overnight to obtain light yellow transparent oil Ⅰ-1-1 (2.6g, yield 90%), purity 98.5% (HPLC method ). HRMS(m / z)[M+H] + : 302.0596.

[0087] Referring...

Embodiment 2

[0090] 2-(4-(3-Chloropyridin-2-yl)piperazin-1-yl)ethyl nitrate (compound Ⅰ-2-1)

[0091]

[0092] Mix 6.5ml of fuming nitric acid and 19.5ml of acetic anhydride in a reaction flask equipped with stirring, condenser and thermometer, and control the temperature at -15°C, and dropwise add intermediate IV-1 (2.9g, 0.01mol) Tetrahydrofuran (100ml) solution was added dropwise, then slowly raised to room temperature, reacted for 4h, and ice water was added dropwise to stop the reaction. The reaction mixture was dissolved in 200ml of ethyl acetate, washed successively with 200ml of water, 200ml of saturated sodium bicarbonate solution, and then washed with 200ml of water and 200ml of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, the crude product was purified by column chromatography (v (petroleum ether): v (ethyl acetate) = 1:2] to obtain 1.4 g of yellow oil with a yield of 50% and a purity o...

Embodiment 3

[0096] Compound Ⅰ-1-1 into hydrochloride: Take 3.2 g of the light yellow oily substance of Ⅰ-1-1 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 a light yellow solid, which is dried in vacuo.

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PUM

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Abstract

The invention belongs to the technical field of antiplatelet drugs and provides 1,4-disubstituted piperazine derivatives and pharmaceutically acceptable salts thereof. The 1,4-disubstituted piperazine derivatives have a general structural formula I. In the general structural formula I, x, y, m, R1, R2, R3 and R4 are defined in the patent specification. The invention relates to a preparation method of the 1,4-disubstituted piperazine derivatives, discloses a drug composition containing the 1,4-disubstituted piperazine derivatives or their pharmaceutically acceptable salts as active ingredients, and also discloses a use of the 1,4-disubstituted piperazine 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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IPC IPC(8): C07D213/75C07D261/04C07D213/74A61K31/496A61P7/02A61P9/00
Inventor 刘登科刘颖路亮张力婉解晓帅田军侯佳佳邹美香
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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