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Benzofuran derivative as well as preparation method and medical application thereof

A technology of compounds and mixtures, applied in the field of medicine, can solve problems such as hemorrhage and cerebral hemorrhage patients who cannot be used

Active Publication Date: 2020-06-30
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antithrombotic drugs that target the PAR-1 receptor often cause bleeding, so Vorapaxar cannot be used in patients with cerebral hemorrhage

Method used

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  • Benzofuran derivative as well as preparation method and medical application thereof
  • Benzofuran derivative as well as preparation method and medical application thereof
  • Benzofuran derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] 4-(4-(4-(((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo Furan-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzyl)morpholine 1

[0220]

[0221] first step

[0222] 2-Bromo-5-methylthiazole-4-carboxylic acid methyl ester 1b

[0223] Under an argon atmosphere, 2-bromo-5-methylthiazole-4-carboxylic acid 1a (700mg, 3.15mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in 15mL of methanol, and concentrated sulfuric acid (10mg, 102.04mmol) was added For the above reaction system, the oil bath was heated to 65° C., and the stirring reaction was continued for 18 hours. The reaction was cooled, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1b (744 mg), which was directly subjected to the next reaction without purification.

[0224] MS m / z(ESI):236.1[M+1]

[0225] second step

[0226] 2-(4-Formylphenyl)-5-methylthiazole-4-carboxylic acid methyl ester 1d

[0227] In an argon atmospher...

Embodiment 2

[0255] Cyclopropyl(4-(4-(4-(((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazole-6- Base) benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)benzyl)piperazin-1-yl)methanone 2

[0256]

[0257]

[0258] first step

[0259] (2-Bromo-5-methylthiazol-4-yl)methanol 2b

[0260] Dissolve ethyl 2-bromo-5-methylthiazole-4-carboxylate 2a (1.25g, 4.99mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) in 10mL THF, stir the reaction solution to clarify, and cool to -78°C , add diisobutylaluminum hydride (1.5M, 9.95mmol) dropwise, continue to react for 1 hour, slowly add 1M hydrochloric acid (70mL) dropwise, add 60mL water and stir, add ethyl acetate (60mL×2) for extraction, and combine organic phase, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (390 mg, yield: 37.5%).

[0261] MS m / z(ESI):208.0[M+1]

[...

Embodiment 3

[0287] 4-(4-(4-(((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo Furan-4-yl)oxy)methyl)thiazol-2-yl)benzyl)morpholine 3

[0288]

[0289] first step

[0290] 2-(4–(morpholinemethyl)phenyl)thiazole-4-carboxylic acid ethyl ester 3b

[0291] Under an argon atmosphere, ethyl 2-(4-formylphenyl)thiazole-4-carboxylate 3a (200 mg, 0.77 mmol, prepared by the method disclosed in the patent application "US6200978 (B1)") was dissolved in 20 mL di In methyl chloride, compound 1e (67mg, 0.77mmol) was added, and sodium triacetoxyborohydride (324mg, 1.53mmol) was added, and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain crude compound 3b (254 mg, and the product was directly subjected to the next reaction without purification.

[0292] MS m / z(ESI):333.1[M+1]

[0293] second step

[0294] 2-(4-(morpholinomethyl)phenyl)thiazol-4-yl)methanol 3c

[0295] Crude compound 3b (254 mg, 0.77 mmol) was dissolved in 10 mL of tetrahy...

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Abstract

The invention relates to benzofuran derivatives, and a preparation method and medical application thereof. Specifically, the present invention relates to a new benzofuran derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the composition as a therapeutic agent, especially as a PAR-4 antagonist, wherein each substituent of general formula (I) is as defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a new benzofuran derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a PAR-4 Use of antagonists. Background technique [0002] Protease-activated receptors (PARs) are a kind of G protein-coupled receptors on the cell surface and belong to the G protein-coupled receptor superfamily. Like other types of G protein-coupled receptors, protease-activated receptors also have a single-chain seven-transmembrane property. As one of the main receptors on the surface of platelets, four protease-activated receptors in this family have been discovered so far, named PAR-1, PAR-2, PAR-3 and PAR-4. Human platelets express PAR-1 and PAR-4, whereas murine platelets express PAR-3 and PAR-4 but not PAR-1. [0003] Scientific researchers discovered PAR-4 in 1998 and further cloned the ge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61P7/02A61P9/10A61K31/5377A61K31/433A61K31/496
CPCC07D513/04A61P7/02A61P9/10
Inventor 杨方龙张羚贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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