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Nitric oxide donor endothelin receptor antagonist as well as preparation method and application thereof

An endothelin receptor and nitric oxide technology, which is applied in the field of medicine and chemical industry, can solve the problems of restricting the application of cardiovascular diseases, low oral bioavailability of peptide antagonists, etc., and achieves significant therapeutic effect and strong endothelin receptor antagonism. active effect

Active Publication Date: 2014-11-12
SOUTHEAST UNIV
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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 to include 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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  • Nitric oxide donor endothelin receptor antagonist as well as preparation method and application thereof
  • Nitric oxide donor endothelin receptor antagonist as well as preparation method and application thereof
  • Nitric oxide donor endothelin receptor antagonist as well as preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0020] Preparation of 5-isopropoxy-2-hydroxyacetophenone: Weigh 15.2 grams (0.1mol) of 2,5-dihydroxyacetophenone, 36.92 grams (0.3mol) of 2-bromopropane, 3.7 grams of potassium iodide, 16.6 Add gram (0.12mol) of potassium carbonate to a 150mL conical flask, then add 60mL of acetone, reflux for 24 hours under stirring, filter, spin the filtrate, and pass the residue through the column (petroleum ether: ethyl acetate = 10:1 mixed solvent was the eluent), and 13.6 grams of yellow oil was obtained, with a yield of 70%; the preparation of 5-benzyloxy-2-hydroxyacetophenone: weigh 1.9 grams (12.5 mmol) of 2,5 - Dihydroxyacetophenone, 3.45 grams (25 mmol) of potassium carbonate, 1.6 grams (12.5 mmol) of benzyl chloride, and 3.7 grams of potassium iodide were added to a 150 mL ground-mouth Erlenmeyer flask, and then 60 mL of acetone was added, slowly dripping Add an acetone solution containing 1.6 g (12.5 mmol) of benzyl chloride, after the addition is complete, reflux for 24 hours und...

Embodiment 1

[0026] Example 1: Preparation of 2-(3,4-methylenedioxyphenyl)-4-chloro-6-isopropoxy-2H-chromene-3-carboxylic acid

[0027] The first step, prepare 2,5-dihydroxyacetophenone:

[0028]Add 110 g (1.0 mol) of hydroquinone, 206 g (2.02 mol) of acetic anhydride and 2 mL of concentrated sulfuric acid into a 1-liter beaker, stir the reaction mixture by hand, the reaction proceeds quickly and exotherms, continue to stir for ten minutes Finally, the reaction mixture was transferred to a 2-liter beaker containing 200 grams of crushed ice, stirred, and after the ice had completely melted, suction filtered, washed with water, and dried to obtain 170 grams of white solid powder, which was recrystallized with absolute ethanol to obtain White crystal hydroquinone diacetate 140 grams, yield 72%, Mp.120-122 ℃; To the 500mL round bottom flask equipped with the reflux condenser with calcium chloride drying tube, add 50 grams (0.257 mol) of hydroquinone diacetate and 116 grams (0.87mol) of powder...

Embodiment 2

[0037] Example 2: 2-(3,4-methylenedioxyphenyl)-4-[(4-methoxy)phenoxy]-6-isopropoxy-2H-chromene-3-carboxy acid preparation

[0038] The first step, prepare 2,5-dihydroxyacetophenone:

[0039] Operation with reference to the first step in Example 1;

[0040] The second step, preparation of 5-isopropoxy-2-hydroxyacetophenone:

[0041] Operation with reference to the second step in Example 1;

[0042] The third step is to prepare 2-(3,4-methylenedioxyphenyl)-6-isopropoxy-2,3-dihydro-4-chromone:

[0043] Operation with reference to the third step in Example 1;

[0044] The fourth step is to prepare 2-(3,4-methylenedioxyphenyl)-4-chloro-6-isopropoxy-2H-chromene-3-carboxylic acid:

[0045] Operation with reference to the fourth step in Example 1;

[0046] The fifth step is to prepare the target product:

[0047] Add 4 g (0.01 mol) of 2-(3,4-methylenedioxyphenyl)-4-chloro-6-isopropoxy-2H-chromene-3-carboxylic acid into a 250 mL Erlenmeyer flask , add 50mL of anhydrous DMF to d...

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PUM

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Abstract

The invention discloses a nitric oxide donor endothelin receptor antagonist (1) with a structure in a general formula (1). In the general formula (1), R1 represents -CH(CH3)2, or R2 represents C1 or R3 represents H or -(CH2)4ONO2. The compound disclosed by the invention has strong endothelin receptor antagonistic activity, and can be used for preparing a drug for treating heart and cerebral vessels, tumors, diabetes mellitus, nephrosis, asthma and hyperthyroidism.

Description

technical field [0001] The present invention belongs to the field of medicine and chemical industry, and specifically relates to a nitric oxide donor-type endothelin receptor antagonist, also relates to the preparation method of the nitric oxide-donor type endothelin receptor antagonist, and finally relates to the nitric oxide-donor type endothelin receptor antagonist use of receptor antagonists. 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 ...

Claims

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Application Information

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IPC IPC(8): A61K31/357C07D407/04A61P9/00A61P35/00A61P3/10A61P13/12A61P11/06A61P5/14
Inventor 蔡进吉民
Owner SOUTHEAST UNIV
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