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Pharmaceutical compound as well as preparation and application thereof

A compound and drug technology, applied in the field of pharmaceutical compounds and their preparation and use, can solve the problems of no real hydrolysis, absorption, reduction of TXA2/PGI2 ratio, damage to intestinal mucosal barrier, etc. in the body, so as to avoid gastrointestinal bleeding , reduce resistance effect, reduce release effect

Active Publication Date: 2019-02-26
SHANGHAI HUAIFENG BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, aspirin can also damage the intestinal mucosal barrier, eventually leading to ulcers
(2) Biological toxicity: after absorption, aspirin inhibits cyclooxygenases when passing through the gastrointestinal tract during the distribution and absorption process of the whole body, weakens their protective effect, and leads to the reduction of the production of prostaglandins (prostaglandins) that regulate gastric acid secretion and blood flow, Injury to the mucous membrane of the digestive tract
[0014] It can be seen that the current aspirin drugs have the following problems: low efficiency, low safety, short-acting, poor stability
[0026] Although the formation of aspirin and flavone esters as prodrugs faces great challenges, natural flavone products can improve platelet function, adjust the balance of PGI2 and TXA2, increase PGI2 levels, reduce the ratio of TXA2 / PGI2, inhibit platelet aggregation, and promote damaged blood vessels. Restoring endothelial function, forming aspirin and flavonoids to achieve synergistic antithrombotic effect is still very attractive for clinical research and development, but so far, there is no real hydrolysis, absorption, and metabolism in the body that meet the requirements of antiplatelet therapy. Aggregation Design Requires Aspirin Ester Drug Study Success

Method used

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  • Pharmaceutical compound as well as preparation and application thereof
  • Pharmaceutical compound as well as preparation and application thereof
  • Pharmaceutical compound as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] Example 1: Preparation of 3-O-((2-acetoxy)-benzoyl)-3',4',7-tri(-O-hydroxyethyl)quercetin

[0155] 1) Troxerutin (10g=10.9mmol, troxerutin chromatographic purity 85%, content 81%) was dissolved in 380ml of water, then added 20ml of concentrated sulfuric acid, heated to reflux for 3 hours, stopped the reaction and cooled down, and cooled to After filtering at room temperature, and then washing with water until neutral, the filter cake was obtained, and vacuum-dried at 65°C to obtain 5.66 g of 3′,4′,7-tris(-O-hydroxyethyl)quercetin with a chromatographic purity of 90.2%. Yield 56.6%.

[0156] 2) In a 100ml three-necked reaction flask, anhydrous 3′,4′,7-tris(-O-hydroxyethyl)quercetin (2g=4.6mmol, water content less than 0.1%) was stirred and dissolved at room temperature in In DMF (40ml), add aspirin (1.66g=9.2mmol) again, then add DCC (1.9g=9.2mmol) and 10% DMAP therein, stir reaction at -5~5 ℃, after 12 hours, reaction finishes, The reaction solution was filtered, and ...

Embodiment 2

[0159] Example 2: Preparation of 3-O-((2-acetoxy)-benzoyl)-3',4',7-tri(-O-hydroxyethyl)quercetin

[0160] (1) Troxerutin (100g=119.9mmol, troxerutin chromatographic purity 92%, content 89%) was dissolved in 3800ml water, then added 200ml concentrated sulfuric acid, heated to reflux for 3 hours, stopped the reaction, and kept warm for 90 Filtrate above ℃, wash with hot water until neutral to obtain a filter cake, and dry it in vacuum at 65℃ to obtain 55.4g of 3′,4′,7-tris(-O-hydroxyethyl)quercetin with a chromatographic purity of 93.8%. Yield 55.4%.

[0161] (2) In a 500ml glass reaction vial, dissolve 10g (23.0mmol) of 3′,4′,7-tris(-O-hydroxyethyl)quercetin obtained in (1) in DMF (200ml) for later use, Add 12.4g (68.9mmol) of aspirin, add 12g of DCC and 12% DMAP to it, stir the reaction at -5~-15°C, after 18 hours, the reaction is completed, the reaction solution is filtered, and the filtrate is added with 15 times saturated ice salt water, stirred, and precipitated The soli...

Embodiment 3

[0163] Example 3: Preparation of 3-O-((2-acetoxy)-benzoyl)-3',4',7-tri(-O-hydroxyethyl)quercetin

[0164] (1) Troxerutin (100g=121.3mmol, troxerutin chromatographic purity 93%, content 90%) was dissolved in 3800ml water, then added 200ml concentrated sulfuric acid, heated to reflux for 3 hours, stopped the reaction, and kept warm for 80 Filtrate above ℃, then wash with hot water until neutral to obtain a filter cake, add 4500ml of ethanol-water (40:60) mixed solvent to the filter cake, stir and heat to reflux for 30 minutes, heat filter, and vacuum-dry the filter cake at 65 °C to obtain 3' , 4', 7-tris(-O-hydroxyethyl) quercetin 53.1g, chromatographic purity 95.1%, yield 53.1%.

[0165] (2) In a 500ml glass reaction vial, dissolve 10g (23.0mmol) of 3′,4′,7-tris(-O-hydroxyethyl)quercetin obtained in (1) in DMF (200ml) for later use, Add 8.3g (46.1mmol) of aspirin, then add 15g of DCC and 15% DMAP to it, and stir the reaction at -15~-25°C. After 26 hours, the reaction is comple...

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PUM

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Abstract

The invention relates to a drug, in particular to a pharmaceutical compound as well as preparation and an application thereof. The compound, or pharmaceutically acceptable salt, or a 5-hydroxy complex and 4-keto complex, or a solvate of the compound has the structure shown in the description, wherein R1 is (CH2) n, R2 and R3 are selected from H or O-(CH2)n-OH, and R4 is selected from H or (CH2)n-OH, and n is an integer of 1-10.

Description

technical field [0001] The invention relates to a medicine, in particular to a medicine compound and its preparation and application. Background technique [0002] Cardiovascular disease is the first killer of human beings. In 2016, the number of deaths from cardiovascular diseases in the world was 17.65 million, far exceeding the number of tumors (various tumors) (8.93 million). In China, the death toll of ischemic heart disease (coronary heart disease) and ischemic stroke is much higher than the death toll of all cancers, and the situation in the United States is similar. Although the clinical effect of antiplatelet drugs is positive, bleeding side effects are the biggest problem of existing antiplatelet drugs. Existing antiplatelet drugs all have different degrees of bleeding side effects. On the one hand, severe bleeding side effects (such as intracranial hemorrhage) can be fatal and more harmful than the blood clot itself. On the other hand, bleeding side effects lim...

Claims

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Application Information

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IPC IPC(8): C07D311/30A61K31/625A61P29/00A61P37/02A61P27/16A61P1/16A61P27/12A61P15/00A61P15/04A61P25/28A61P35/00A61P9/00A61P9/10A61P25/00A61P7/02A61P39/06A61P9/12A61P3/06A61P31/04A61P31/10A61P31/12A61P37/08A61P7/10A61P19/10
CPCA61P1/16A61P3/06A61P7/02A61P7/10A61P9/00A61P9/10A61P9/12A61P15/00A61P15/04A61P19/10A61P25/00A61P25/28A61P27/12A61P27/16A61P29/00A61P31/04A61P31/10A61P31/12A61P35/00A61P37/02A61P37/08A61P39/06C07D311/30
Inventor 李大鹏
Owner SHANGHAI HUAIFENG BIOTECHNOLOGY CO LTD
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