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A kind of pyridone-alkynylamine modified derivative and its preparation method and application

A technology of pyridone and its derivatives, which is applied in drug combination, organic chemistry, nervous system diseases, etc., can solve problems such as oxidative stress, and achieve the effect of excellent drug-like properties

Active Publication Date: 2022-07-19
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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  • A kind of pyridone-alkynylamine modified derivative and its preparation method and application
  • A kind of pyridone-alkynylamine modified derivative and its preparation method and application
  • A kind of pyridone-alkynylamine modified derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] 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, 396 mmol), anhydrous potassium carbonate (68.31g, 495mmol), acetone 600mL, 60 ℃ of reaction after 4h to stop the reaction, concentrated under reduced pressure in 2000mL single-neck flask The reaction solution was dissolved in 600 mL of water, extracted with 600 mL × 4 dichloromethane, the organic layers were combined, washed three times with saturated brine, and finally dried over anhydrous sodium sulfate and concentrated to obtain a yellow oily liquid 2-methyl-3- Benzylpyran-4-one (68.77 g), 96.5% yield.

[0073] In a 2000mL single-neck flask, add the pyrone (64.80g, 300mmol) obtained by the above reaction, ethylenediamine (21.60g, 360mmol), sodium hydroxide (14.40g, 360mmol), ethanol (400mL), water (300mL), The reaction was carried out at 75°C for 1.5 h. After the reaction was completed, the reaction solutio...

Embodiment 2

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

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

[0083] In a 50mL single-necked flask, add intermediate of formula 5 (0.30g, 1mmol), potassium hydroxide (0.11g, 2mmol), 2-fluorobenzyl bromide (0.28g, 1.5mmol), tetrahydrofuran (15mL), reflux at 69°C Reaction for 20h. After the reacti...

Embodiment 3

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

[0089] Take the intermediate of formula 3 (1.29 g, 5 mmol) obtained from the reaction in the above Example 1, anhydrous potassium carbonate (1.03 g, 7.5 mmol) was dissolved in DMF (10 mL), and 3-bromopropyne (0.53 g, 4.5 mmol) was taken. ) and diluted with DMF (7.5 mL) in a constant pressure dropping funnel, added dropwise at 40°C for 6 h, concentrated under reduced pressure, and 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] In a 50mL single-neck flask, add intermediate of formula 5 (0.30g, 1mmol), potassium hydroxide (0.11g, 2 mmol), 2-chlorobenzyl bromide (0.31g, 1.5mmol), tetrahydrofuran (15mL), at 69 ° C After refluxing for 20h, the reaction solution was concentrated, purified by silica gel column chromatography (dichl...

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Abstract

The present invention provides a pyridone-alkynylamine modified derivative represented by formula (I) and a pharmaceutically acceptable salt thereof and a preparation method thereof. and anti-oxidation to prevent or treat related diseases, the invention synthesizes a series of novel small molecule multi-target anti-AD active compounds, innovatively combines pyridone derivatives with iron ion chelating activity with pyridone derivatives with iron ion chelating activity MAO-B irreversibly inhibits the activity of propargyl amine organically combined, which has significant advantages for Alzheimer's disease with complex pathogenesis. And this series of novel small molecules have better drug-like properties than natural product derivative inhibitors.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of multi-targets that have both iron ion chelating ability and monoamine oxidase B inhibitory effect, and use aziridine and pyridone derivatives to synergistically achieve anti-intracerebral Aβ aggregation and anti-oxidation A pyridone-alkynamine-modified derivative of point anti-Alzheimer's disease and a preparation method thereof, and the pyridone-alkynamine-modified derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating Alzheimer's disease applications in . Background technique [0002] Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss and decline in language ability and other cognitive impairments. Although the etiology of AD is unclear, several factors are thought to play an important role in the pathophysiology of AD, such a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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