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Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof

An arylpentadienamide, aldehyde dehydrogenase technology, applied in the directions of anti-inflammatory agents, antitoxic agents, drug combinations, etc., can solve problems such as limited curative effect, achieve improved activity and water solubility, good druggability, and good development Foreground effect

Pending Publication Date: 2022-03-08
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the most commonly used clinical drugs for the treatment of alcoholism include opioid receptor antagonists such as naloxone and naltrexone, which can only provide symptomatic and supportive treatment to improve symptoms of intoxication, with limited curative effect

Method used

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  • Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof
  • Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof
  • Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Preparation of N-(benzo[d][1,3]dioxol-5-ylmethyl)anthracene-9-carboxamide

[0090]

[0091] Anthracene-9-carboxylic acid (114 mg, 0.51 mmol) was dissolved in anhydrous DMF, HATU (235 mg, 0.6 mmol), 1 mL DIEA were added, and after stirring for 5 minutes, piperine (79 mg, 0.52 mmol) was added and reacted at room temperature for 24 h. TLC monitoring, after the reaction of the raw materials was completed, the reaction solution was poured into 50mL of 1N dilute hydrochloric acid solution, a large amount of white solids were precipitated, the mixed solution was allowed to stand overnight, filtered, and dried to obtain compound 1 with a yield of 84.1%.

Embodiment 2-4

[0093] Example 1 was repeated, with the difference that different raw materials were used to obtain compounds 2, 14, and 27 in Table 1. The details are as follows: Use 1-naphthoic acid to replace the raw material anthracene-9-carboxylic acid in Example 1 to obtain compound 2; use 2,5-dichlorobenzoic acid and 2,4-dichloronicotinic acid to replace the raw materials in Example 1 Anthracene-9-carboxylic acid and (6-methoxypyridin-3-yl)methanamine were used instead of the raw material piperine in Example 1 to prepare compounds 14 and 27, respectively.

Embodiment 5

[0095] Preparation of 2-((benzo[d][1,3]dioxol-5-ylmethyl)carbamoyl)-3-chlorobenzoic acid

[0096]

[0097] 1) Preparation of 2-chloro-6-((2-ethoxy-2-oxoethyl)carbamoyl)benzoic acid

[0098] 4-Chloroisobenzofuran-1,3-dione (274mg, 1.5mmol) was dissolved in 10mL ethyl acetate, stirred at room temperature to dissolve, and 2-aminoacetate ethyl ester (155mg, 1.5mmol) was added dropwise, Can produce a large amount of white solids immediately, TLC monitors, and after the reaction is completed, stand and filter, and dry to obtain the intermediate 2-chloro-6-((2-ethoxyl-2-oxoethyl)carbamoyl)benzoic acid , 90% yield.

[0099] 2) Preparation of methyl 2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)carbamoyl)-3-chlorobenzamido)acetate

[0100] Dissolve the intermediate 2-chloro-6-((2-ethoxy-2-oxoethyl)carbamoyl)benzoic acid (213mg, 0.51mmol) in anhydrous DMF, add HATU (235mg, 0.6mmol ), 1mL DIEA, stirred for 5 minutes, added piperine (79mg, 0.52mmol), reacted at room temperature for 24h, mon...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an amide aldehyde dehydrogenase agonist as well as a synthesis method and application thereof. The amide compounds provided by the invention show relatively high agonistic activity to ALDH2, so that the compounds have the potential of preparing medicines for treating diseases related to ALDH2 activity; compared with a positive control, the amide compound has the advantages that the activity and the water solubility are obviously improved, and the druggability is better. Therefore, the compound provided by the invention has a good development prospect.

Description

[0001] This application is a divisional application of the invention patent application submitted on June 4, 2018 with the application number 2018105625623 and the title of the invention is "amide-type aldehyde dehydrogenase agonist, its synthesis method and use". technical field [0002] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a class of aryl pentadienamide aldehyde dehydrogenase inhibitors, a synthesis method and application thereof. Background technique [0003] Aldehyde dehydrogenase 2 (ALDH2) is responsible for the detoxification of acetaldehyde produced by exogenous alcohol metabolism in the body and acrolein in environmental pollution; it is also responsible for the endogenous oxidative stress of lipid peroxidation end product 4- The detoxification of hydroxynonenal (4-HNE) and malondialdehyde (MDA) is an important part of the oxidative stress defense system in the body (Physiol Rev.2014, 94(1):1-34; Cardiovasc ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/182C07D213/64A61K31/4453A61K31/4545A61P35/00A61P9/00A61P25/00A61P3/10A61P7/06A61P25/04A61P29/00A61P19/10A61P17/00A61P35/04A61P9/10A61P9/04A61P39/02
CPCA61P3/10A61P7/06A61P9/00A61P9/04A61P9/10A61P17/00A61P19/10A61P25/00A61P29/00A61P35/00A61P35/04C07D213/64C07D295/182A61P25/04A61P39/02
Inventor 郑灿辉朱驹田巍胡剑周若兰
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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