3,4-dihydroxyacetophenone derivative, preparation method, application and pharmaceutical composition thereof

A derivative, the technology of qingxinone, which is applied in the direction of drug combination, carbon-based compound preparation, organic compound preparation, etc., can solve the problems restricting clinical application and so on

Active Publication Date: 2019-01-18
WEIFANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This shortcoming seriously restricts the clinical application

Method used

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  • 3,4-dihydroxyacetophenone derivative, preparation method, application and pharmaceutical composition thereof
  • 3,4-dihydroxyacetophenone derivative, preparation method, application and pharmaceutical composition thereof
  • 3,4-dihydroxyacetophenone derivative, preparation method, application and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1 Preparation of 3,4-dihydroxyacetophenone fatty acid ester derivative (I)

[0064] The preparation method of the derivative comprises the following steps: the feeding concentration of 3,4-dihydroxyacetophenone is 0.01-0.1mol / L; the molar ratio of 3,4-dihydroxyacetophenone, acid chloride and triethylamine is 1 : 2~8: 2~8, the reaction temperature is 10~100°C, the reaction time is 3~10 hours, the reaction process is monitored by high performance liquid chromatography, ODS C18 chromatographic column (250×4.60mm, 5μm), sample loading Volume 20μL, flow rate 1mL / min, column temperature at room temperature, mobile phase composition, methanol / water (60:40, volume ratio), 254nm ultraviolet detection; after the reaction, filter to obtain the filtrate; the filtrate was evaporated to dryness under reduced pressure, and ethyl acetate was added Dissolved, washed with water and saturated NaCl solution successively. The ethyl acetate phase was dried overnight with anhydrous m...

Embodiment 2

[0073] Example 2 Preparation of 3,4-dihydroxyacetophenone benzyl ether derivative (II)

[0074] The preparation method of the derivative comprises the following steps: the feeding concentration of 3,4-dihydroxyacetophenone is 0.1~1mol / L, 3,4-dihydroxyacetophenone, 4-substituted benzyl bromide and anhydrous K 2 CO 3 The molar ratio is 1:0.5~2:0.5~2, the reaction temperature is 10~100°C, the reaction time is 1~5 hours, and the reaction process is monitored by high performance liquid chromatography, ODS C18 chromatographic column (250×4.60mm, 5μm), sample volume 20μL, flow rate 1mL / min, column temperature at room temperature, mobile phase composition, methanol / water (60:40, volume ratio), 254nm UV detection. After the reaction was completed, the filtrate was obtained by filtration. The filtrate was diluted with five times the volume of ethyl acetate, washed with water and saturated NaCl solution successively. The ethyl acetate phase was dried overnight with anhydrous magnesium...

Embodiment 3

[0083] Example 3 Preparation of the polyethylene glycol sustained-release body (Ⅲ) of 3,4-dihydroxyacetophenone

[0084] The preparation method of this derivative comprises the steps:

[0085] In the first step, 3,4-dihydroxyacetophenone (also known as Qingxinone) is used as a starting material in anhydrous organic solvents including acetonitrile, N,N-dimethylformamide, acetone, dichloro Among methane and methyl tert-butyl ether, the following basic reagents include triethylamine, pyridine, 4-dimethylaminopyridine, anhydrous K 2 CO 3 As a catalyst, react with dianhydride to obtain the corresponding intermediate products (IV) and (V).

[0086] In the second step, N-hydroxysuccinimide and diphenylphosphinyl chloride, in the following anhydrous organic solvents including acetonitrile, N,N-dimethylformamide, acetone, dichloromethane, methyl tert-butyl In ether, the following basic reagents include triethylamine, pyridine, 4-dimethylaminopyridine, anhydrous K 2 CO 3 As a catal...

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Abstract

The invention discloses a 3,4-dihydroxyacetophenone derivative, a preparation method, an application and a pharmaceutical composition. The 3,4-dihydroxyacetophenone derivative comprises a 3,4-resacetophenone fatty acid derivative (I), a 3,4-resacetophenone benzyl ether derivative (II) and a polyethylene glycol slow release body (III) of 3,4-resacetophenone. The preparation method is mild in condition, high in yield, few in step, easy to operate, simple to post-treat and easier to achieve industrial production. The half life of the drug is greatly prolonged compared with that of 3,4-resacetophenone. The oral bioavailability is higher than that of the 3,4-resacetophenone. The 3,4-dihydroxyacetophenone derivative is expected to be further developed to an oral drug for treating cardiovasculardisease induced by platelet aggregation.

Description

technical field [0001] The present invention relates to the technical field of compounds, in particular to a carbinone derivative, its preparation method, application and a pharmaceutical composition with the derivative as an active ingredient. Background technique [0002] 3,4-dihydroxyactophenone (3,4-dihydroxyactophenone), also known as green heart ketone, is an active substance isolated from the leaves of Ilepubescens Hook.et Arn.var.glaber Chang. It can improve heart disease angina pectoris, and has anti-platelet aggregation, anti-atherosclerosis and anti-inflammatory activities. In the early 1980s, as a new drug for treating coronary heart disease, injections were developed and promoted clinically. [0003] However, the half-life of 3,4-dihydroxyacetophenone is very short. Animal experiment data show that the intravenous injection is only 5-6 minutes, and the intramuscular injection and oral administration are 8-9 minutes. This shortcoming seriously restricts the cli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/16C07C49/84C07C67/14C07C45/64A61K31/222A61K31/122A61K31/77A61P7/02C08G65/333
CPCA61P7/02C07C45/64C07C49/84C07C67/14C07C69/16C08G65/33341
Inventor 段煜孙娜曲梅王梦雨王峰李志坚郭健
Owner WEIFANG MEDICAL UNIV
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