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Soluble epoxide hydrolase inhibitor

An epoxide and hydrolase technology, applied in the fields of organic chemistry, drug combination, sulfonic acid amide preparation, etc., can solve the problems of poor water solubility, low bioavailability, limited druggability and clinical application, etc., and achieves a short synthetic route, Wide range of biological effects and less toxic and side effects

Active Publication Date: 2013-08-28
YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inherent physical properties of urea functional groups determine that such compounds have poor water solubility and low bioavailability, which greatly limit their druggability and clinical application.

Method used

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  • Soluble epoxide hydrolase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Synthesis of 3-(4-trifluoromethylsulfonyl)phenylcarbamoyl-1-sulfonyl chloride

[0060] In a 250mL three-necked flask, add 3-chlorosulfonylbenzoyl chloride (5.84g, 24.4mmol) into dry dichloromethane (16.6mL), stir in an ice bath at -10°C, and then add triethylamine ( 3.4mL, 24.4mmol) and 4-trifluoromethylsulfonanilide (5g, 22.2mmol), stirred overnight at room temperature to obtain a crude product.

Embodiment 2

[0062] Synthesis of 3-(morpholinylsulfonyl)-N-(4-(trifluoromethylsulfonyl)phenyl)benzamide (1a)

[0063] Take 2 mL of the crude product obtained in the previous step reaction, add it to 10 mL of dichloromethane, then add triethylamine (0.5 mL, 3.47 mmol) and morpholine (232 mg, 2.67 mmol) in sequence, continue the reaction at room temperature for 3 h, remove the solvent by rotary evaporation, and use silica gel The product was purified by column chromatography (PE:EA=3:1) to obtain 750 mg of white product with a yield of 71%. Product purity: 98%, 1 HNMR (ppm) 8.62-7.91 (m, 9H), 3.67 (t, 4H), 2.9 (t, 4H). MS (M + +1) 479, elemental analysis (%): calculated value C, 45.18; H, 3.58; F, 11.91; N, 5.85; O, 20.06; S, 13.40; found value C, 45.15; ; N, 5.87; O, 20.05; S, 13.41.

Embodiment 3

[0065] Synthesis of 3-(N-(2-methoxyethyl)aminosulfonyl)-N-(4-trifluoromethylsulfonyl)phenyl)benzamide (1b)

[0066] Take 2 mL of the crude product obtained in the previous step reaction, add it to 10 mL of dichloromethane, then add triethylamine (0.5 mL, 3.47 mmol) and 2-methoxyethylamino (200 mg, 2.67 mmol) successively, continue the reaction at room temperature for 6 h, spin The solvent was evaporated, and the product was purified by silica gel column chromatography (PE:EA=4:1) to obtain 800 mg of a yellow product with a yield of 77.3%. Product purity: 97.8%, 1 HNMR (ppm) 8.51-7.31 (m, 9H), 2.4 (br, 1H), 3.3 (t, 2H). 3.6 (t, 2H). 3.2 (s, 3H). MS (M + +1) 467, elemental analysis (%): calculated value C, 43.77; H, 3.67; F, 12.22; N, 6.01; O, 20.58; S, 13.75; found value C, 43.78; ; N, 6.02; O, 20.55; S, 13.73.

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Abstract

The invention provides a soluble epoxide hydrolase inhibitor, which has the following structural formula I, wherein R1 is N-R2R3; R2 and R3 are hydrogen, C1-C4 alkyl, aromatic ring, aromatic heterocyclic ring, or C1-C4 alkyl connected with the aromatic ring or the aromatic heterocyclic ring respectively; and the R2 can also be connected with the R3 to form a ring, then R1 is a quinary, hexahydricor heptabasic heterocyclic ring containing 1 nitrogen atom or 1 oxygen atom, and the nitrogen atom can be directly connected with the hydrogen and can also be connected with the C1-C4 alkyl. Rat experiment group results in an anesthesia state and a non-anesthesia state show that the inhibitor has certain blood pressure reducing effect, can be used for preparing medicaments for preventing and treating cardiovascular diseases, and has broad clinical application prospect. The invention provides a preparation method.

Description

technical field [0001] The invention relates to pharmaceutical preparations, in particular to a soluble epoxide hydrolase inhibitor. Background technique [0002] The morbidity and mortality of cardiovascular diseases have surpassed neoplastic diseases and leapt to the first place. Drug therapy is an extremely important component of a comprehensive approach to the successful management of cardiovascular disease. There are many varieties of cardiovascular drugs and the sales market is large, ranking first in the world's drugs. However, the side effects and adverse reactions of existing drugs are becoming increasingly prominent, and the development of new drugs, especially safe and effective innovative drugs based on new mechanisms of action, is still a key development area of ​​the pharmaceutical industry. [0003] Soluble epoxide hydrolase (sEH) widely exists in mammalian tissues and plays an important role in the metabolism of lipid epoxy compounds in vivo, mainly respons...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/66C07D295/26A61K31/5375C07C311/17C07C303/38C07D213/73C07D213/42A61K31/167C07C311/18A61K31/341A61K31/4409A61P9/00A61P9/12A61P43/00
Inventor 谢雨礼李成杨琼峰苏红唐开勇
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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