Compound with mother nucleus of 3-phenyl-1,2,4-oxadiazole as well as preparation method and application thereof

A compound, the technology of oxadiazole, which is applied in the field of medicine, can solve the problems of immunosuppression and lack of specificity, and achieve the effect of reducing inflammatory damage, simple preparation method, and improving the inflammatory microenvironment

Active Publication Date: 2021-08-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, some progress has been made in the research on NLRP3 inflammasome and the development of its inhibitors. However, most inhibitors target the downstream products of NLRP3 inflammasome activation. This method does not directly target NLRP3 inflammasome. Body, lack of specificity, easy to cause immunosuppression

Method used

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  • Compound with mother nucleus of 3-phenyl-1,2,4-oxadiazole as well as preparation method and application thereof
  • Compound with mother nucleus of 3-phenyl-1,2,4-oxadiazole as well as preparation method and application thereof
  • Compound with mother nucleus of 3-phenyl-1,2,4-oxadiazole as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Embodiment 1 synthetic compound III

[0094] Weigh hydroxylamine hydrochloride (3.9g, 0.06mol) in reaction bottle, add ethanol 70ml to it successively, sodium bicarbonate (4.8g, 0.06mol), add 4-(trifluoromethoxy) benzonitrile (5.8ml, 0.04mol), reflux reaction at 75°C for 4h, and the disappearance of raw materials was monitored by TLC. The solvent was removed under reduced pressure, extracted with ethyl acetate, washed with water, and the organic phase was collected and dried over anhydrous sodium sulfate. Silica gel column purification, the solvent was removed under reduced pressure to obtain 5.7 g of white solid, yield: 64.8%. 1 H NMR (300MHz, DMSO-d 6 )δ9.78(s,1H),7.87–7.68(m,2H),7.38(dq,J=7.9,1.1Hz,2H),5.92(s,2H). 13 C NMR (75MHz, DMSO-d 6 )δ150.28, 149.09, 133.14, 127.82, 122.21, 121.15. HRMS (ESI) calcd for C 8 h 7 f 3 N 2 o 2 [M+H] + 221.0532, found 221.0535. HPLC (10%-100% methanol in water), t R = 11.22 min, >98.17%.

Embodiment 2

[0095] Embodiment 2 synthetic compound IV

[0096] Weigh compound III (4.4g, 0.02mol) in the reaction flask, add acetone 50mL, potassium carbonate (3g, 0.02mol) to it, add chloroacetyl chloride (3.25ml, 0.04mol) dropwise, reflux at 55°C for 8h, TLC monitored disappearance of starting material. The solvent was removed under reduced pressure, tetrahydrofuran was added, the reaction was refluxed at 70°C, and the disappearance of the starting material was monitored by TLC. The solvent was removed under reduced pressure, extracted with ethyl acetate, washed with water, and the organic phase was collected and dried over anhydrous sodium sulfate. Silica gel column purification, the solvent was removed under reduced pressure. 2.3 g of light yellow oil was obtained with a yield of 41.4%. 1 H NMR (300MHz, Chloroform-d) δ8.33–8.04 (m, 2H), 7.36 (dp, J=7.9, 1.1Hz, 2H), 4.78 (s, 2H). 13 C NMR (75MHz, Chloroform-d) δ174.65, 167.88, 151.54, 129.29, 124.72, 122.07, 121.17, 33.29. HRMS (ES...

Embodiment 3

[0097] Embodiment 3 synthetic compound I-1

[0098] 5-(((1H-imidazol-2-yl)thio)methyl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (I-1)

[0099] Taking compound I-1 as an example, weigh compound IV (200mg, 0.72mmol) in a reaction flask, add tetrahydrofuran 10mL, potassium carbonate (160mg, 1.16mmol), and then add 1H-imidazole-2-thiol (100mg , 1 mmol), reacted overnight at room temperature, and TLC monitored the disappearance of the starting material. The reaction solution was sequentially extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purify with a silica gel column to obtain 203 mg, yield: 82.5%.

[0100]5-(((1H-imidazol-2-yl)thio)methyl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (I-1) .White solid, yield 82.5%, m.p.152.1-153.0℃. 1 H NMR (300MHz, DMSO-d6) δ12.48(s,1H), 8.13–8.05(m,2H), 7.60–7.53(m,2H), 7.09(s,2H), 4.60(s,2H). 13 C NMR (75MHz, DMSO-d6) δ178.17, 167.21, 15...

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Abstract

The invention discloses a compound with a mother nucleus of 3-phenyl-1, 2, 4-oxadiazole as well as a preparation method and application thereof. The provided compound with a mother nucleus of 3-phenyl-1,2,4-oxadiazole is simple in preparation method and novel in structure. The compound can specifically inhibit the activation of NLRP3 inflammasome, so that maturation and secretion of IL-1[beta] are reduced, inflammatory injury is relieved, and the inflammatory micro-environment is improved. Therefore, the compound has remarkable anti-inflammatory activity and has no obvious toxicity to THP-1 cells. The disclosed compound can be prepared into an anti-inflammatory drug and used for treating inflammation-related diseases, including diabetes, atherosclerosis, rheumatic arthritis, rheumatoid arthritis, chronic blocking lung diseases, gout, chronic kidney diseases, neurodegenerative diseases, cryopyrin-associated periodic syndromes, non-alcoholic fatty liver disease, and inflammatory intestinal diseases.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a compound whose mother nucleus is 3-phenyl-1,2,4-oxadiazole and its preparation method and application. Background technique [0002] The inflammasome is a high molecular weight complex that mediates the activation of effector proteins caspases and is part of innate immunity. Different pattern recognition receptors (pattern recognition receptors, PRRs) recognize pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) or damage-associated molecular patterns (damage associated molecular patterns, DAMPs), thereby forming a variety of different inflammatory small body. So far, several PRRs have been proposed to form inflammasomes, including nucleotide-binding oligomerization domain (NOD)-like receptors. Among the inflammasomes formed by NOD-like receptors, the NOD like receptor containing pyrin domain 3 (NLRP3) inflammasome has the most typical characteristic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D413/12C07D271/06A61K31/428A61K31/4439A61K31/4245A61K31/433A61P3/10A61P9/10A61P19/02A61P11/00A61P19/06A61P13/12A61P1/16A61P1/00A61P25/28A61P29/00A61P25/16A61P25/14
CPCC07D417/12C07D413/12C07D271/06A61P3/10A61P9/10A61P19/02A61P11/00A61P19/06A61P13/12A61P1/16A61P1/00A61P25/28A61P25/16A61P29/00A61P25/14
Inventor 徐莉莉狄斌赵旎
Owner CHINA PHARM UNIV
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