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Pyridone-site alkyne amine modified derivative as well as preparation method and application thereof

A technology of pyridone and its derivatives, which can be applied in drug combination, organic chemistry, nervous system diseases, etc., and can solve problems such as oxidative stress

Active Publication Date: 2021-03-19
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, high concentrations of redox-active metal ions may act as catalysts to participate in the generation of reactive oxygen species (ROS), leading to oxidative stress

Method used

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  • Pyridone-site alkyne amine modified derivative as well as preparation method and application thereof
  • Pyridone-site alkyne amine modified derivative as well as preparation method and application thereof
  • Pyridone-site alkyne amine modified derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] The preparation method of 1-(2-(benzyl(propargyl)amino)ethyl)-2-methyl-3-hydroxypyridin-4(1H)-one (b1)

[0072] Add maltol (41.58g, 330mmol), benzyl bromide (67.72g, 396mmol), anhydrous potassium carbonate (68.31g, 495mmol), acetone 600mL into a 2000mL single-necked bottle, react at 60°C for 4h, stop the reaction, and concentrate under reduced pressure The reaction solution was dissolved in 600mL of water, extracted with 600mL×4 dichloromethane, the organic layers were combined, washed 3 times with saturated brine, finally dried with anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid 2-methyl-3- Benzylpyran-4-one (68.77g), yield 96.5%.

[0073] Pyrone (64.80g, 300mmol), ethylenediamine (21.60g, 360mmol), sodium hydroxide (14.40g, 360mmol), ethanol (400mL), water (300mL), and React at 75°C for 1.5h. After the reaction, concentrate the reaction solution under reduced pressure, purify it by silica gel column chromatography (dichloromethane: methanol: am...

Embodiment 2

[0081] The preparation method of 1-(2-(2-fluorobenzyl(propargyl)amino)ethyl)-2-methyl-3-hydroxypyridin-4(1H)-one (b2)

[0082] Get the formula 3 intermediate (0.52g, 2mmol) obtained from the reaction of Example 1, anhydrous potassium carbonate (0.41g, 3mmol) is dissolved in DMF (4mL), get 3-bromopropyne (0.21g, 1.8mmol) and use DMF (2mL) was diluted in a constant pressure dropping funnel, added dropwise at 40°C for 6 hours, then concentrated the reaction solution under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol:ammonia=20:1:0.1 for washing deagent), concentrated under reduced pressure to obtain formula 5 (0.37g), yield 69.4%

[0083] Add the intermediate of formula 5 (0.30g, 1mmol), potassium hydroxide (0.11g, 2mmol), 2-fluorobenzyl bromide (0.28g, 1.5mmol), tetrahydrofuran (15mL) into a 50mL single-necked bottle, and reflux at 69°C Reaction 20h. After the reaction, the reaction solution was concentrated, purified by silica g...

Embodiment 3

[0088] The preparation method of 1-(2-(2-chlorobenzyl (propargyl) amino) ethyl) -2-methyl-3-hydroxypyridin-4 (1H)-one (b3)

[0089] Get the formula 3 intermediate (1.29g, 5mmol) obtained by the above-mentioned embodiment 1 reaction, anhydrous potassium carbonate (1.03 g, 7.5mmol) is dissolved in DMF (10mL), take 3-bromopropyne (0.53g, 4.5mmol ) and diluted with DMF (7.5mL) in a constant pressure dropping funnel, added dropwise at 40°C for 6h, then concentrated the reaction solution under reduced pressure, purified by silica gel column chromatography (dichloromethane:methanol:ammonia=20:1: 0.1 as eluent), concentrated under reduced pressure to obtain formula 5 (0.96g), yield 72.1%.

[0090] Add the intermediate of formula 5 (0.30g, 1mmol), potassium hydroxide (0.11g, 2 mmol), 2-chlorobenzyl bromide (0.31g, 1.5mmol), tetrahydrofuran (15mL) into a 50mL single-necked bottle, and at 69°C After 20 hours of reflux reaction, the reaction solution was concentrated, purified by silica ...

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PUM

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Abstract

The invention provides a pyridone one-site alkyne amine modified derivative shown as a formula (I), pharmaceutically acceptable salt of the pyridone one-site alkyne amine modified derivative, a preparation method of the pyridone one-site alkyne amine modified derivative and application of the pyridone one-site alkyne amine modified derivative to preparation of medicines for preventing or treatingrelated diseases by inhibiting monoamine oxidase, chelating metal iron ions, resisting A beta and resisting oxidation. According to the invention, a series of novel small-molecular multi-target anti-AD active compounds are synthesized, and the pyridone derivative with iron ion chelating activity and propynylamine with MAOB irreversible inhibition activity are creatively and organically combined together, so that the compounds have remarkable advantages on Alzheimer's disease with complex pathogenesis. In addition, compared with a natural product derivative inhibitor, these novel small molecules have excellent drug-likeness.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of multi-target anti-Aβ aggregation and anti-oxidation agents with azirynyl and pyridone derivatives that have the ability to chelate iron ions and inhibit monoamine oxidase B. Anti-Alzheimer's disease pyridone one-alkyne amine modified derivative and preparation method thereof and the pyridone one-alkyne amine modified derivative or its pharmaceutically acceptable salt in the preparation of drugs for preventing or treating Alzheimer's disease in the application. Background technique [0002] Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and language decline, among other cognitive impairments. Although the etiology of AD is unknown, several factors are thought to play important roles in the pathophysiology of AD, such as cholinergic dysfunction, tau protein aggregation, β-amyloid (A...

Claims

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Application Information

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IPC IPC(8): C07D213/69A61P25/16A61P25/28
CPCC07D213/69A61P25/16A61P25/28
Inventor 谢媛媛郭嘉楠张雨佳张婧祺吕杨静
Owner ZHEJIANG UNIV OF TECH
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