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SEH inhibitor or pharmaceutically acceptable composition thereof as well as preparation method and application thereof

A technology of inhibitors and compositions, applied in the field of medicine, can solve the problems of short retention time of sEH inhibitors and poor efficacy in vivo, and achieve long efficacy in vivo, excellent therapeutic effect and high yield

Active Publication Date: 2021-09-17
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned sEH inhibitors have a short residence time and poor efficacy in vivo

Method used

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  • SEH inhibitor or pharmaceutically acceptable composition thereof as well as preparation method and application thereof
  • SEH inhibitor or pharmaceutically acceptable composition thereof as well as preparation method and application thereof
  • SEH inhibitor or pharmaceutically acceptable composition thereof as well as preparation method and application thereof

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preparation example Construction

[0042] The present invention provides the preparation method of the sEH inhibitor described in the above technical scheme, comprising the following steps:

[0043] The compound II, the chlorination reagent, the catalyst and the soluble compound II solvent are mixed and then chlorinated to obtain an acid chloride intermediate; the acid chloride intermediate, ammonia solution, ice and the soluble acid chloride intermediate solution are mixed to carry out Acylation reaction to obtain the sEH inhibitor with the structure shown in formula I;

[0044]

[0045] In the present invention, unless otherwise specified, all raw material components are commercially available commodities well known to those skilled in the art.

[0046] In the present invention, the preparation method of compound II preferably comprises the following steps:

[0047] (1) compound 1, (S)-piperidine-3-carboxylic acid ethyl ester, organic base and soluble compound 1 solvent are mixed and then acylated to obtain...

Embodiment 1

[0091] (1) Preparation of (S)-ethyl 1-(3-fluoro-4-nitrobenzoyl)piperidine-3-carboxylate (compound 2)

[0092] Add 0.14mol 3-fluoro-4-nitrobenzoic acid, 150mL dry tetrahydrofuran and 0.014mol DMF to a 500mL single-neck flask to obtain a mixed solvent; 0.16mol thionyl chloride is dissolved in 50mL dry tetrahydrofuran to obtain chlorination Sulfoxide solution; add the thionyl chloride solution dropwise to the mixed solution under stirring conditions, after the dropwise addition, the temperature is raised to 60°C for chlorination reaction for 3 hours, and the tetrahydrofuran and the residual thionyl chloride are removed by distillation under reduced pressure to constant weight to obtain 3-fluoro-4-nitrobenzoyl chloride. Dissolve in 100 mL of dry tetrahydrofuran to obtain 3-fluoro-4-nitrobenzoyl chloride solution.

[0093] Under stirring conditions, 0.14mol (S)-piperidine-3-ethyl carboxylate, 0.41mol triethylamine and 150mL dry tetrahydrofuran were added to a 500mL three-necked fla...

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Abstract

The invention provides an sEH inhibitor or a pharmaceutically acceptable composition thereof as well as a preparation method and application thereof, and belongs to the technical field of medicine. According to the sEH inhibitor or a pharmaceutically acceptable composition thereof provided by the invention, the sEH inhibitor has a structure as shown in a formula I in the specification. The sEH inhibitor provided by the invention can stabilize an endogenous substance epoxy fatty acid with wide physiological activity, and has a very strong inhibition effect on human recombinant sEH. Neuropathic pain can be remarkably relieved by regulating the generation of various pro-inflammatory cytokines, relieving endoplasmic reticulum stress, preventing or reversing endothelial dysfunction and stabilizing multiple action mechanisms of mitochondrial functions, and target-related adverse reactions can be effectively avoided. Moreover, the structure of the sEH inhibitor provided by the invention does not contain free carboxyl, so that adverse reactions such as gastrointestinal irritation caused by oral administration can be avoided, and the sEH inhibitor is small in adverse reaction, high in bio-availability, excellent in analgesic effect and small in administration dosage.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a sEH inhibitor or a pharmaceutically acceptable composition thereof, and a preparation method and application thereof. Background technique [0002] Soluble epoxide hydrolase (sEH) is widespread in mammalian tissues, especially in liver, kidney, lung, intestine and blood vessels. sEH inhibitors can stabilize endogenous epoxidized fatty acids (EETs) with a wide range of physiological activities. EETs are a class of endogenous lipid epoxies with potent biological activity. It has anti-inflammatory, analgesic, anti-apoptotic, anti-fibrotic, and anti-ischemic effects, while showing protective effects on organs such as the heart, lung, kidney, and brain. Therefore, sEH inhibitors have received extensive attention. [0003] Currently, the central pharmacophore of sEH inhibitors includes butamide, carbamate, and urea. The retention time of the sEH inhibitor on the target enzyme (t ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60A61P25/04A61P29/00A61P9/00A61P25/00A61P3/00A61P13/12A61P31/04A61P1/00A61P1/04A61P19/02A61P9/12A61P9/10A61P3/10A61P19/06A61P21/00A61P25/16A61P25/28A61P25/14
CPCC07D211/60A61P25/04A61P29/00A61P9/00A61P25/00A61P3/00A61P13/12A61P31/04A61P1/00A61P1/04A61P19/02A61P9/12A61P9/10A61P3/10A61P19/06A61P21/00A61P25/16A61P25/28A61P25/14
Inventor 陈国良杜芳瑜刘中博曹若琳陈露傅扬
Owner SHENYANG PHARMA UNIVERSITY
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