Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds

A technology of pyridone and coumarin, applied in the direction of organic active ingredients, organic chemistry, medical preparations containing active ingredients, etc., can solve the problem of increasing neurotransmitters in the brain

Active Publication Date: 2019-09-10
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs only act on a single target, prevent neurotransmitter enzymes from metabolizing neurotransmitters and temporarily increase the amount of neurotransmitters in the brain, which cannot fundamentally cure AD, but can only control or improve the cognitive and functional symptoms of patients6- 12 months, delay the progression of the disease
Studies have shown

Method used

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  • Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds
  • Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds
  • Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] 2-Methyl-3-hydroxy-1-((coumarin-3-yl)methyl)pyridin-4(1H)-one (1a)

[0059] Add maltol (7.56g, 60mmol), acetone 100mL, and methyl iodide (9.37g, 66mmol) into a 250mL single-necked bottle, heat and reflux for 6 hours, cool to room temperature after the reaction, spin to dry the solvent, add 100mL water to dissolve, and Methyl chloride (50 mL) was extracted 4 times, the organic layer was dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain 2-methyl-3-methoxypyrone. Yield 98%.

[0060] Add the pyrone (8.65g, 40mmol) obtained by the above reaction into a 250mL one-mouth bottle, 60mL of 25% ammonia water, 50mL of ethanol, heat and reflux at 75°C for 12h, cool to room temperature after the reaction is completed, spin the solvent to obtain a brown oily liquid, and use Acetone / ethyl acetate recrystallization gave 2-methyl-3-methoxypyridone as a light yellow solid. Yield 75%.

[0061] Add salicylaldehyde (7.33g, 60mmol), propionic anhydride (3...

Embodiment 2

[0070] The preparation method of 2-methyl-3-hydroxyl-1-((7-methoxy-coumarin-3-yl)methyl)pyridin-4(1H)-one (1b)

[0071]

[0072]Add maltol (7.56g, 60mmol), acetone 100mL, and methyl iodide (9.37g, 66mmol) into a 250mL single-necked bottle, heat and reflux for 6 hours, cool to room temperature after the reaction, spin to dry the solvent, add 100mL water to dissolve, and Methyl chloride (50 mL) was extracted 4 times, the organic layer was dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain 2-methyl-3-methoxypyrone. Yield 98%.

[0073] Add the pyrone (8.65g, 40mmol) obtained by the above reaction into a 250mL one-mouth bottle, 60mL of 25% ammonia water, 50mL of ethanol, heat and reflux at 75°C for 12h, cool to room temperature after the reaction is completed, spin the solvent to obtain a brown oily liquid, and use Acetone / ethyl acetate recrystallization gave 2-methyl-3-methoxypyridone as a light yellow solid. Yield 75%.

[0074] Add 2-hydro...

Embodiment 3

[0082] The preparation method of 2-methyl-3-hydroxyl-1-((7-propargyloxy-coumarin-3-yl)methyl)pyridin-4(1H)-one (1c)

[0083]

[0084] Add maltol (7.56g, 60mmol), acetone 100mL, and benzyl bromide (11.29g, 66mmol) into a 250mL single-necked bottle, heat and reflux for 6 hours, cool to room temperature after the reaction, spin the solvent, add 100mL water to dissolve, and Methyl chloride (50 mL) was extracted 4 times, the organic layer was dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain 2-methyl-3-benzyloxypyrone. Yield 98%.

[0085] Add the pyrone (8.65g, 40mmol) obtained by the above reaction into a 250mL one-mouth bottle, 60mL of 25% ammonia water, 50mL of ethanol, heat and reflux at 75°C for 12h, cool to room temperature after the reaction is completed, spin the solvent to obtain a brown oily liquid, and use Acetone / ethyl acetate recrystallization gave 2-methyl-3-benzyloxypyridone as a light yellow solid. Yield 75%.

[0086] Add 2,...

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Abstract

The invention discloses coumarin/pyridone heterozygous derivatives represented by a formula (I) shown in the description or a pharmaceutically-acceptable salt of the derivatives. The preparation method of the coumarin/pyridone heterozygous derivatives comprises the following steps: one pyridone derivative represented by a formula 3 shown in the description is obtained by a series of synthesis by using one hydroxypyrone with different substituent groups represented by a formula 1 shown in the description as a raw material; and a compound represented by a formula 4 shown in the description is subjected to a condensation reaction to obtain a compound represented by a formula 5 shown in the description, one-step bromination is performed to obtain a compound represented by a formula 6 shown inthe description, the compound represented by the formula 6 and the pyridone derivative represented by the formula 3 are subjected to a one-step nucleophilic substitution reaction to obtain a compoundrepresented by a formula 7 shown in the description, and finally an alkyl protecting group in a pyridone structure is removed to obtain one target compound represented by the formula (I). The compounds provided by the invention are a novel series of single-molecular multi-target series drugs, and have iron chelation, targeted MAO-B inhibitory activity, antioxidant activity, unique advantages for an Alzheimer disease with complicated pathogenesis, a clear mechanism of action and excellent activity.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of coumarin hybrid pyridone compounds with monoamine oxidase B inhibitory effect and metal iron ion chelating ability and antioxidant activity and its preparation method and anti-Alzheimer's effect. use in mutism. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset, complex etiology, and progressive development. The clinical manifestations are persistent mental decline, aphasia, loss of judgment ability, and movement disorders. AD patients will cause a heavy economic and nursing burden to the family and the society. There are only five drugs currently on the market and used clinically: Donepezil, Rivastigmine, Galantamine, and Tacrine, four acetylcholinesterase inhibitors (AChEi). ), and the N-methyl-D-aspartate receptor (NMDA) inhibitor Memantine. These drugs only act on a single target, p...

Claims

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Application Information

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IPC IPC(8): C07D405/06A61K31/4433A61P25/28A61P25/16A61P39/04
CPCA61P25/16A61P25/28A61P39/04C07D405/06Y02P20/55
Inventor 谢媛媛张长俊袁圣利韩家鑫米治胜蒋筱莹
Owner ZHEJIANG UNIV OF TECH
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