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Pyridone hexa-alkyne amine modified derivative and preparation method and application thereof

A technology of pyridone and its derivatives, which is applied in the field of pyridone modified derivatives of six-alkyne amine and its preparation and application, and can solve the problems that cannot be effectively and completely cured

Active Publication Date: 2021-03-26
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, the only four clinically available drugs, Donepezil, Galantamine, Rivastigmine and Memantine, are not effective in completely curing the disease

Method used

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  • Pyridone hexa-alkyne amine modified derivative and preparation method and application thereof
  • Pyridone hexa-alkyne amine modified derivative and preparation method and application thereof
  • Pyridone hexa-alkyne amine modified derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] The preparation method of 1-methyl-2-((benzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a1)

[0087] Kojic acid (12.78g, 90mmol), benzyl bromide (23.08g, 135mmol), and potassium carbonate (24.84g, 180mmol) were added to a 500mL single-necked bottle, and reacted at 60°C for 5h under the condition of ethanol as the solvent (250mL). After the reaction, the reaction system was concentrated under reduced pressure to obtain the crude product as a light yellow solid, which was washed with water and dried to obtain a white solid (18.75 g), with a yield of 89.8%.

[0088] Take the above white solid (13.92g, 60mmol), dissolve it in ethanol (150mL), then add sodium hydroxide (4.80g, 120mmol), 9.30g methylamine aqueous solution (mass fraction: 40%; methylamine 120mmol), at 50 The reaction was carried out at ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:meth...

Embodiment 2

[0095]The preparation method of 1-methyl-2-((3-chlorobenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a2)

[0096] 3-Chlorobenzylamine (0.28g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (10mL) were added to a 50mL single-necked bottle, and then 3 -Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (2mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (20mL) was added , extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1), collected the The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.14 g), with a yield of 77.8%.

[0097] Take the above-mentioned bright yellow transparent liquid (0.1...

Embodiment 3

[0101] The preparation method of 1-methyl-2-((3-fluorobenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a3)

[0102] 3-Fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.34g, 2.5mmol) and N,N-dimethylformamide (9mL) were added to a 50mL single-necked bottle respectively, and the 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (3mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL ), extracted with 20mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1 elution), the collection containing The eluate of the target compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.11 g), with a yield of 67.5%.

[0103] Take the above-mentioned bright yellow transp...

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Abstract

The invention relates to a pyridone hexa-alkyne amine modified derivative as shown in a formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, application of the pyridone hexa-alkyne amine modified derivative or the pharmaceutically acceptable salt thereof to preparation of drugs for preventing or treating related diseases, especially Alzheimer's disease and Parkinson's disease, by inhibiting monoamine oxidase, chelating metal iron ions, resisting Abeta and resisting oxidation. According to the invention, a series of novel single-molecule multi-target anti-ADactive compounds are synthesized, and pyridone derivatives with iron ion chelating activity and propynylamine with MAOB inhibitory activity are creatively and organically combined together, so that the compounds have remarkable advantages on Alzheimer's disease with complex pathogenesis; and the combined molecules are far superior to CP20 (deferiprone) in the aspect of iron ion chelating activity.

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 hexa-alkyne amine modified derivatives and its preparation method and its application in the preparation of drugs for the treatment of Alzheimer's disease and other diseases. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease that affects the physical and mental health of tens of millions of elderly people around the world, causing patients to show symptoms such as memory loss and cognitive decline. As global aging intensifies, the number of people living with AD is expected to increase to 131 million by 2050. [0003] The cause of AD is a mystery. Case analysis shows that the etiology of AD is closely r...

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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