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Benzofuran endothelin receptor antagonist and use

An endothelin receptor and benzofuran technology, which is applied in the field of medicine and chemical industry, can solve the problems of limiting the application of cardiovascular diseases, low oral bioavailability of peptide antagonists, etc.

Inactive Publication Date: 2014-08-06
蔡进
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Peptide ET antagonists with strong effects have been found, including BQ123, BQ160, FR2139317, etc., but the low oral bioavailability of peptide antagonists limits their application in cardiovascular diseases requiring long-term medication

Method used

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  • Benzofuran endothelin receptor antagonist and use
  • Benzofuran endothelin receptor antagonist and use
  • Benzofuran endothelin receptor antagonist and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Ethyl 1-(2-acetyl-3-hydroxy)phenoxyacetate

[0021] With 15.2g (0.1mol) 2,6-dihydroxyacetophenone, 41.4g (0.3mol) K 2 CO 3 Mix in 200ml of acetone, slowly drop in 20g (0.12mol) of ethyl bromoacetate, reflux for 3 hours after dropping, cool to room temperature, filter, wash the filter cake with 20ml of acetone, after the filtrate is concentrated, add an appropriate amount of water, and white Flaky crystals were filtered, the product was washed with 50% acetone-water solution, and dried to obtain 14.6 g of the product, yield 61%, mp80-82°C.

Embodiment 2

[0022] Example 2 1-Methyl-4-hydroxybenzofuran-2-carboxylic acid ethyl ester

[0023] Add 13.6g (0.057mol) ethyl 1-(2-acetyl-3-hydroxy)phenoxyacetate to a sodium ethoxide solution made of 2.7g (0.118mol) sodium metal and 180ml absolute ethanol, then Heating to reflux for 9 hours, cooling to room temperature, pouring the reaction solution into a large amount of ice water, adjusting the pH to 3 with concentrated HCl, granular solids precipitated, and suction filtering after standing, the filter cake was washed with water, dried, and the product was washed with a flash column Chromatography (eluent: petroleum ether: ethyl acetate = 2:1 (v / v)) purified to give 4.5 g of white powdery solid, yield 36%, mp 158-159 °C. 1 H-NMR (CDCl 3 )δ1.44 (t, 3H, -OCH 2 C H 3 ), 2.78 (s, 3H, 3-CH 3 ), 4.45 (q, 2H, -OC H 2 CH 3 ), 6.6 (d, 1H, 5-H), 7.12 (d, 1H, J=4Hz, 7-H), 7.26 (t, 1H, J=4Hz, 6-H).

Embodiment 3

[0024] Example 3 4-(3-phenylallyloxy)-3-methylbenzofuran-2-carboxylic acid (Ⅰ 1 )

[0025] Dissolve 0.9g (3.6mmol) ethyl 1-methyl-4-hydroxybenzofuran-2-carboxylate in 20ml DMF, add 3.5g K 2 CO 3 , 0.5g KI, add 1ml of phenyl allyl bromide under mechanical stirring, then heat to 60°C, the reaction solution changes from yellow-green fluorescence to colorless, then stir for 0.5hr, cool to room temperature, pour the reaction solution into ice In water, the precipitated oil was solidified and then recrystallized from methanol to obtain 0.76 g of colorless granular crystal 4-(3-phenylallyloxy)-3-methylbenzofuran-2-carboxylic acid ethyl ester.

[0026] Dissolve 0.7g (3mmol) ethyl 4-(3-phenylallyloxy)-3-methylbenzofuran-2-carboxylate in 30ml ethanol, add 10ml NaOH, reflux for 1hr, cool to room temperature , adjusted pH=3 with 10% HCl under cooling, recrystallized the precipitated solid with 75% ethanol to obtain light yellow granular crystals, yield 67%, mp191-193°C. Anal.C 19 h ...

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Abstract

The invention discloses a class of benzofuran endothelin receptor antagonists, which have the structure of general formula I: wherein, R represents -CH2CH=CHPh, 4-CH3C6H4OCH2CH2-, 3-ClC6H4OCH2CH2-,,,, or. The compound of the present invention has strong endothelin receptor antagonistic activity, has good inhibitory effect on rat thoracic aorta deendothelial vascular ring contraction induced by ET-1 (2nmol / L), and can be used for the preparation and treatment of cardiovascular and cerebrovascular diseases , tumors, diabetes, kidney disease, asthma, hyperthyroidism and other disease drugs.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a class of benzofuran endothelin receptor antagonists and their application. Background technique [0002] The mortality rate of cardiovascular and cerebrovascular diseases ranks first among all kinds of diseases, and the final causes of death are mostly myocardial hypertrophy, heart failure (heart failure), stroke and fatal arrhythmia. Especially in recent years, the fatality rate of severe heart failure has remained high, which has become a difficult problem in the international medical community. These diseases currently lack effective therapeutic drugs. [0003] Endothelin (endothclin, ET) is an active polypeptide containing 21 amino acids synthesized and secreted by vascular endothelial cells, cardiac muscle, smooth muscle, etc. Injury factors play an important role in the pathogenesis of many heart, brain, lung, kidney and vascular diseases. ET ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/343A61K31/4025A61K31/433A61K31/4245C07D307/85C07D417/12C07D413/12A61P9/00A61P35/00A61P3/10A61P13/12A61P11/06A61P5/16
Inventor 蔡进吉民
Owner 蔡进
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