Ligustrazine derivative and preparation method and medical application thereof

A technology of ligustrazine and its derivatives, applied in the field of medicinal chemistry, can solve the problems of weak clinical physiological activity of ligustrazine, limited wide use, and poor water solubility of ligustrazine

Active Publication Date: 2020-10-27
泰州学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003]Because the clinical physiological activity of Ligustrazine is weak, in order to improve its curative effect, it is often used in combination with other drugs clinically; meanwhile, Ligustrazine has poor water solubility, which also limits Its widespread use in clinical

Method used

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  • Ligustrazine derivative and preparation method and medical application thereof
  • Ligustrazine derivative and preparation method and medical application thereof
  • Ligustrazine derivative and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of target compound

[0047] (1) Synthesis of 5-p-hydroxyphenyl-3H-1,2-dithiole-3-thione (ADTOH)

[0048]

[0049] Weigh ADT (8g, 33mmol) and pyridine hydrochloride (23g, 200mmol) into a 250ml three-neck flask, heat at 215°C for 0.5h in a constant temperature stirrer, and monitor the completion of the reaction by TLC. After cooling down to 100°C, filter with hot water and take the filter cake. Dissolve the filter cake in 200ml 10% NaOH solution, and stir at room temperature for 4h. The reaction solution was filtered, and the filter cake was taken. Dissolve the filter cake in water, adjust the pH to 2-3 with hydrochloric acid while stirring, and a red precipitate is formed at this time. Continue to filter, wash the filter cake until neutral, and dry to obtain orange-yellow solid ADTOH with a yield of 64%.

[0050] (2) Synthesis of (3,5,6-trimethylpyrazin-2-yl)methanol (3)

[0051]

[0052] Ligustrazine (500mg, 0.027mmol) and 2ml of h...

Embodiment 2

[0071] Example 2: Evaluation of anti-platelet aggregation activity

[0072] Take 2 rabbits, use lidocaine for local anesthesia, surgically separate the common carotid artery, take blood, take 3.8% sodium citrate 1:9 anticoagulation, and centrifuge at 500r / min for 10min to prepare platelet-rich plasma (PRP). Part of it was centrifuged at 3000r / min to prepare platelet-poor plasma (PPP), and the platelet aggregation experiment was carried out by turbidimetric method. Add 240 μL of PRP and 30 μL of different concentrations of test drugs into the measurement tube, and incubate for 5 min. ) (final concentration 1mmol / L) as the inducer, observe and record the maximum aggregation rate within 5min. Using normal saline (NS) as a control, calculate the inhibitory rate (%) or IC of each test compound 50 value. Inhibition rate (%) = [the maximum aggregation rate within 5 minutes of the control group - the maximum aggregation rate within 5 minutes of the test sample group] / [the maximum...

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Abstract

The invention discloses a ligustrazine derivative and a preparation method and medical application thereof. The invention synthesizes and prepares three ligustrazine derivatives with novel structures,and provides a preparation method of the ligustrazine derivatives. Pharmacological results show that the inhibitory activity of the three ligustrazine derivatives I-2, I-4 and I-6 on ADP-induced or AA-induced platelet aggregation is superior to that of a parent compound ligustrazine (TMP); compared with clinically common medicines with anticoagulant effects, the activity of the ligustrazine derivatives I-2, I-4 and I-6 in inhibition of ADP-induced platelet aggregation is equivalent to that of a positive drug thilopyrazine, and the inhibition activity of the ligustrazine derivatives I-2, I-4 and I-6 in inhibition of AA-induced platelet aggregation is obviously superior to that of a positive control drug aspirin.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a ligustrazine derivative, a preparation method and a medical application. Background technique [0002] Ligustrazine is the main active ingredient extracted from the natural product Ligusticum chuanxiong. Its chemical composition is tetramethylpyrazine (TMP), which has a relatively stable chemical structure and rich pharmacological activity. It has excellent performance in system protection, improvement of brain circulation and anti-cancer, and is widely used in drug synthesis. It is estimated that nearly 24 million people will die from cardiovascular diseases such as ischemic heart disease and stroke in 2030, and the incidence rate may increase by 48% from 2012 to 2030 (He Yuanzhi, Hou Xuefeng, Liu Ying, Feng Nianping. Recent progress in the synthesis, structural diversity and emerging applications of cyclodextrin-based metal-organic frameworks. Journal of materia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12A61P7/02A61K31/497
CPCC07D409/12A61P7/02
Inventor 文帅牟伊陈龙李玉秀余思思王燕韩雪涛
Owner 泰州学院
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