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A class of compounds with antithrombotic effect

A compound and pharmaceutical technology, applied in the field of medicine, can solve the problems of high bleeding risk and excessive bleeding in patients, and achieve the effect of inhibiting platelet aggregation

Active Publication Date: 2016-06-01
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results of its clinical controlled trial with clopidogrel also show that it can effectively reduce the death caused by non-fatal heart disease and stroke, but it leads to more bleeding in patients
Because this product still has some adverse reactions closely related to its clinical efficacy, especially due to the higher risk of bleeding, although the FDA approved prasugrel for marketing, it requires it to add a black box warning on the new drug label To warn of the risk of bleeding and advise against use in patients with active pathological bleeding, history of transient ischemic attack or stroke, or recent need for surgery including coronary artery bypass surgery

Method used

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  • A class of compounds with antithrombotic effect
  • A class of compounds with antithrombotic effect
  • A class of compounds with antithrombotic effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Compound Ⅳ-1

[0049]

[0050] Take compound Ⅱ-1 (10g, 61mmol) and dissolve it in 50mL of dichloromethane. Stir well to dissolve. Cool down to 0°C. A dichloromethane solution of bromoacetyl bromide (III, 13.6 g, 67 mmol) was added dropwise. After dropping, keep the temperature and react for 4h. After the reaction was detected by TLC, the reaction solution was washed three times with water (30mL×3), the organic layer was separated, dried, filtered, and rotary evaporated. Wait until the light yellow oil, without refining, can be used for the next reaction. The quality of the obtained product is 16.5g, the yield is 95%, the purity is 98.3% (HPLC normalization method), MS (m / z) [M+H] + : 284.0.

[0051] With reference to Example 1, the following compounds can be obtained

[0052]

Embodiment 2

[0054] Compound Ⅵ-1

[0055]

[0056] Dissolve compound IV-1 (10g, 35mmol) in 50mL of ethanol, add potassium acetate (10.3g, 105mmol) after fully dissolved, heat to reflux, react for 6h, TLC detects that the reaction is complete. The reaction solution was left to cool, poured into water, and a solid precipitated out. Filter, dry, and recrystallize with ethyl acetate and petroleum ether 1:2 to obtain 10.5g of product, yield 80.8%, purity 99.1% (HPLC normalization method), MS(m / z)[M+H] + : 371.1.

[0057] With reference to Example 2, the following compound can be obtained

[0058]

Embodiment 3

[0060] Compound Ⅰ-1

[0061]

[0062] Take compound IV-1 (5g, 13.5mmol) and fully dissolve it with 30mL of dichloromethane. Decrease to 0°C, add triethylamine (2g, 20mmol), dropwise add acetic anhydride (2.1g, 20mmol), keep the temperature for 3h. TLC detects that the reaction is complete. The reaction solution was poured into 30 mL of water, the organic phase was separated and washed three times with water (30 mL×3). The organic layer was dried, filtered and evaporated to dryness to give a brown oil. Stir with ethanol at room temperature to obtain a white solid, which is filtered, and the filter cake is rinsed with cold ethanol to obtain 4.3 g of the product. Yield 77.2%, purity 99.4% (HPLC normalization method), MS(m / z)[M+H] + : 413.1.

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Abstract

The invention discloses compounds with antithrombotic effects with the structure of formula I and pharmaceutically acceptable salts thereof. According to the compound, R can be hydrogen, methyl, ethyl, propyl, isopropyl, nitro, cyano, halogen and trifluoromethyl. The invention also discloses a method for preparing the compounds, a pharmaceutical composition by taking the compounds and the pharmaceutically acceptable salts as active ingredients, and application of serving as antiplatelet drugs, particularly for preparation of medicines for preventing or treating the coronary syndrome, myocardial infarction, myocardial ischemia and other cardiovascular and cerebrovascular diseases caused by platelet aggregation.

Description

technical field [0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of compounds with antithrombotic effect, their preparation method, pharmaceutical composition containing them and their use as antithrombotic drugs. Background technique [0002] The incidence of thromboembolic diseases, mainly coronary thrombosis and cerebral thrombosis, is on the rise, seriously endangering human health. Platelet aggregation is a key link in the normal coagulation mechanism, so drugs that inhibit platelet aggregation have become a hot spot in the research of antithrombotic drugs. [0003] Ticlopidine, developed and marketed by Sanofi in France, is the first ADP receptor antagonist antiplatelet drug, which inhibits the activation of ADP receptors by binding to P2Y-type special sulfhydryl receptors, thereby preventing platelet aggregation. effect. Because ticlopidine not only inhibits a certain platelet aggregation activating factor, but a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14A61K31/496A61P7/02A61P9/00A61P9/10
Inventor 刘登科刘颖穆帅张士俊张大帅黄阳侯佳佳
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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