Liyustrazine acyl piperazine derivative, and its preparing method and medicinal composition and use

A technology of ligustrazinylpiperazine and derivatives, which is applied in the field of Ligusticum derivatives medicines, and can solve the problems of large toxic side effects and poor specificity

Inactive Publication Date: 2006-05-24
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are many drugs used to treat cardiovascular and cerebrovascular diseases clinically, but they generally have shortcomings such as poor specificity and high toxicity and side effects.

Method used

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  • Liyustrazine acyl piperazine derivative, and its preparing method and medicinal composition and use
  • Liyustrazine acyl piperazine derivative, and its preparing method and medicinal composition and use
  • Liyustrazine acyl piperazine derivative, and its preparing method and medicinal composition and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1. the preparation of intermediate 2-chloromethyl-3,5,6-trimethylpyrazine hydrochloride (2)

[0063] A mixture of Ligustrazine trihydrate (30.4g, 160mmol), glacial acetic acid (40ml) and 30% hydrogen peroxide (18ml, 160mmol) was heated at 70°C for 4h, and 30% hydrogen peroxide (18ml, 160mmol) was added , continue to react for 4h, TLC monitors until the reaction is complete, cool to room temperature, adjust pH=10 with 50% sodium hydroxide solution, extract with chloroform, dry over anhydrous sodium sulfate, filter, evaporate chloroform to obtain ligustrazine mono Crude nitrogen oxides. Then add acetic anhydride (15.1ml, 160mmol), heat to reflux for 2.5h, monitor by TLC until the reaction is complete, evaporate excess acetic anhydride under reduced pressure to obtain black slurry ligustrazine acetylate, add 20% sodium hydroxide solution after cooling (155ml), left overnight, extracted with chloroform (150ml, 30ml×5 times), dried over anhydrous sodium sulfate, ...

Embodiment 2

[0065] Embodiment 2. Preparation of intermediate N-acylpiperazine (3)

[0066] Take carboxylic acid (100mmol) and thionyl chloride (200mmol) into a round-bottomed flask, install a condenser tube and a drying tube, heat and reflux for 5h, evaporate excess thionyl chloride, and carry out vacuum distillation on the residue to obtain the acid chloride derivative things.

[0067] Put piperazine hexahydrate (11.7g, 60mmol) in a round-bottomed flask, add glacial acetic acid (50ml), stir until dissolved, add the above-synthesized acid chloride (50mmol) dropwise at room temperature, after completion of the dropwise addition, stir for 2h, add to the reaction Add water (50ml) to the solution, then adjust the pH=12 with sodium hydroxide solution, place it under cooling, remove a small amount of bisacylated product by filtration, extract the filtrate 5 times with chloroform, combine the extracts, wash with water until neutral, and use Dry over sodium sulfate, evaporate chloroform to get a...

Embodiment 3

[0068] Example 3. Preparation of intermediate 2-(1-piperazinylmethyl)-3,5,6-trimethylpyrazine (4)

[0069] Anhydrous piperazine (50g, 580mmol) was dissolved in chloroform (300ml), and 2-chloromethyl-3,5,6-trimethylpyrazine hydrochloride ( 20.7g, 100mmol) of chloroform (100ml) solution, react at room temperature for 5h, TLC monitors that the reaction is complete, the reaction solution is washed with 4mol / L ammonia water (100ml×3 times), the organic layer is dried with anhydrous sodium sulfate, filtered, evaporated After removing the solvent, 19 g of crude black oil was obtained with a yield of 86%, which could be directly used in the synthesis of the final product without purification. A small amount of the crude product was recrystallized with n-hexane to obtain the white crystalline intermediate 2-(1-piperazinylmethyl)-3,5,6-trimethylpyrazine (4).

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Abstract

The invention relates to Ligustrazine acylpiperazine ramifications and their preparing method as well as their medicine combination and the application, belonging to the technical field of Ligusticum wallichi acrylpiperazine remification medicine. The invention alkylates piperazine cycle of 2-chloromethyl-3, 5, 6-trimethyl pyrazine hydrochloride with N-acylperazine to obtain Ligustrazine acylpiperazine ramifications A6-8, 16-28, 30, and 32-36, and acylates the perazine cycle of 2-chloromethyl-3, 5, 6-trimethyl pyrazine hydrochloride with 2-(1- piperazine methyl)-3, 5, 6-trimethyl pyrazine to obtain Ligustrazine acylpiperazine ramifications A1-5, 9-15, 29, 31, 37, and 38, and ammonolyzes the compound A1 with water to obtain another Ligustrazine acylpiperazine ramification A39. These ramifications and medicine auxiliaries are made into different forms of medicine combinations, used to prepare a medicine for repairing and protecting blood vessel endodermis cells or resisting blood platelet coacervation.

Description

(1) Technical field [0001] The invention relates to a drug for treating cardiovascular and cerebrovascular diseases and a preparation method, in particular to a ligustrazinylpiperazine derivative, a preparation method and a pharmaceutical composition composed of the derivative and an auxiliary agent, and belongs to the technical field of Ligusticum derivative drugs. (2) Background technology [0002] Cardiovascular and cerebrovascular diseases are common and frequently-occurring diseases that seriously endanger human health. With the aging of the social population, the incidence rate is increasing day by day. What is worrying is that with the increasingly fierce social competition, the age of onset of cardiovascular and cerebrovascular diseases is getting younger and younger, and it is no longer the patent of the elderly. According to statistics, 16 million people around the world die from various cardiovascular and cerebrovascular diseases every year. It is the number one k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12A61K31/496A61P3/06A61P7/02A61P9/10C07D401/14
Inventor 刘新泳徐文方程先超李锦
Owner SHANDONG UNIV
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