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Benzoxazole compound as well as preparation method, pharmaceutical composition and application thereof

A technology for benzoxazole and compounds, which is applied in the field of benzoxazole compounds and their preparation, can solve the problems of low bioavailability and poor stability, and achieve the effect of simple and easy preparation method and excellent therapeutic effect

Active Publication Date: 2022-05-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: Aiming at the shortcomings of existing compounds such as low bioavailability and poor stability, the present invention aims to provide a class of benzoxazole compounds that effectively antagonize P2Y6 receptors and their preparation methods, pharmaceutical compositions and applications

Method used

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  • Benzoxazole compound as well as preparation method, pharmaceutical composition and application thereof
  • Benzoxazole compound as well as preparation method, pharmaceutical composition and application thereof
  • Benzoxazole compound as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of 2-(1-(tert-butyl)-5-(furan-2-yl)-1H-pyrazol-3-yl)benzo[d]oxazole

[0045]

[0046] Place 2.8g of potassium tert-butoxide in 11mL of THF to form a suspension, and cool in an ice bath at 0°C; dissolve 1.1g of acetylfuran and 2.7mL of diethyl oxalate in 11mL of ethylene glycol dimethyl ether, and dissolve this The solution was added dropwise to the suspension of potassium tert-butoxide at 0°C; the mixture was stirred at room temperature for 1 hour. After all the acetylfuran was consumed as monitored by TLC, 7.5 mL of 1M HCl solution was added. The crude product was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (4:1) to obtain 4-(furan-2 -yl)-2,4-dioxobutanoic acid ethyl ester.

[0047] 1.4 g of ethyl 4-(furan-2-yl)-2,4-dioxobutyrate was dissolved in ethanol, 0.9 g of tert-but...

Embodiment 2

[0054] Example 2: Synthesis of 2-(1-(tert-butyl)-5-(furan-2-yl)-1H-pyrazol-3-yl)-5-methylbenzo[d]oxazole

[0055]

[0056] Using o-amino-p-cresol as a raw material, see Example 1 for the synthesis method.

[0057] The NMR data are as follows:

[0058] 1 H NMR (400MHz, DMSO-d6) δ7.92(s, 1H), 7.66(d, J=8.3Hz, 1H), 7.57(s, 1H), 7.23(d, J=8.3Hz, 1H), 7.15 (s,1H),6.80(d,J=3.3Hz,1H),6.68(d,J=2.6Hz,1H),2.44(s,3H),1.53(s,9H).

[0059] 13 C NMR(101MHz,DMSO-d6)δ158.21,148.51,144.48,142.95,141.90, 137.33,134.68,134.21,126.86,119.96,113.31,112.25,112.12,110.82,62.76,40.62, 40.42,40.21,40.00,39.79,39.58 ,39.37,34.94,31.60,30.28,29.96,21.46.

Embodiment 3

[0060] Example 3: Synthesis of 2-(1-(tert-butyl)-5-(furan-2-yl)-1H-pyrazol-3-yl)-5-chlorobenzo[d]oxazole

[0061]

[0062] Using 4-chloro-2-aminophenol as raw material, see Example 1 for the synthesis method.

[0063] The NMR data are as follows:

[0064] 1 H NMR (400MHz, DMSO-d6) δ8.07 (dd, J = 7.5, 1.6Hz, 1H), 7.84–7.72 (m, 2H), 7.40 (dd, J = 7.5, 1.5Hz, 1H), 7.27– 7.16(m,2H),6.98(t,J=7.5Hz,1H),1.46(s,10H).

[0065] 13 C NMR (101MHz, DMSO-d6) δ158.07, 152.16, 150.75, 142.66, 140.52, 131.95, 131.20, 130.80, 126.55, 119.50, 112.14, 111.51, 104.50, 60.49, 28.94.

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PUM

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Abstract

The invention discloses a benzoxazole compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is as shown in formula (I), and the compound comprises pharmaceutically acceptable salts thereof. The benzoxazole compound and the pharmaceutical composition thereof can effectively antagonize a P2Y6 receptor, the optimal in-vitro antagonism rate reaches 100%, and the optimal IC50 value reaches the picomolar concentration level; in-vivo inhibition of mouse colon length shortening, body weight reduction and DAI score increase can be realized. The compound can be used for preparing drugs for treating inflammatory diseases related to P2Y6 receptors, the prepared drugs can exert drug effects at the cellular level and the animal level, the application is wide, and the synthesis method of the compound is simple and easy to implement.

Description

technical field [0001] The present invention relates to a class of benzoxazole compounds and their preparation methods, pharmaceutical compositions and applications, in particular to a class of compounds that can be prepared as P2Y 6 A benzoxazole compound of a receptor antagonist drug, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] P2Y 6 receptor (P2Y 6 R) is the eight subtypes of the P2Y receptor family (P2Y 1 R, P2Y 2 R, P2Y 4 R. P2Y 6 R, P2Y 11 R, P2Y 12 R, P2Y 13 R and P2Y 14 A member of R), expressed in various organs and tissues such as immune organs, cardiovascular system, and nervous tissue, P2Y 6 The endogenous ligand of the receptor is an extracellular nucleotide molecule, which specifically activates phospholipase C (PLC) through its selective agonist UDP and upregulates intracellular Ca 2+ Concentration, to achieve the purpose of transmitting intercellular signals and regulating various phy...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D413/04A61K31/422A61P29/00A61P25/00A61P19/00A61P1/00A61P9/10
CPCC07D413/14C07D413/04A61P29/00A61P25/00A61P19/00A61P1/00A61P9/10
Inventor 胡庆华李环球冷海峰周梦泽
Owner CHINA PHARM UNIV
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