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Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative

A technology of coumarin and pyridone, applied in the direction of anti-toxins, drug combinations, nervous system diseases, etc., can solve the problems of vague pathogenic mechanism, low pertinence, and incomplete cure

Active Publication Date: 2020-02-18
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The pathogenesis of Alzheimer's disease is very complicated. Although the human research on Alzheimer's disease has never stopped, the pathogenic mechanism of the disease is still unclear. Deposition of β-amyloid protein, metal ions, hyperphosphorylation of tau protein Many factors, such as oxidation, oxidative stress, synaptic damage and reduction of acetylcholine levels, β-secretase, and monoamine oxidase, may be closely related to the pathogenesis of AD.
Therefore, the research and development of anti-AD drugs is also very difficult. At present, there is still a lack of effective therapeutic drugs. There are only 5 anti-Alzheimer's drugs approved by the FDA, namely Tacrine and Donepezil. , Galantamine, Rivastigmine and Memantine, these drugs can only reduce or inhibit the disease, but cannot completely cure the disease
Due to the complex pathogenesis, single-target drugs have a single effect and are not highly targeted, while multi-target drugs can play a role in different pathophysiological links of the disease to enhance the curative effect and make up for the shortcomings of single drugs. They are anti-AD drugs. R & D direction

Method used

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  • Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative
  • Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative
  • Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] N-(2-(2-methyl-3-hydroxy-1(4H)-4-oxopyridyl)ethyl)-2-oxo-2H-chromene-3-carboxamide (a1b1) preparation method

[0064]Add maltol (7.56g, 60mmol), methyl iodide (25.56g, 180mmol), anhydrous potassium carbonate (24.84g, 180mmol), acetone (100mL) into a 250mL single-necked bottle, heat and reflux for 3h, monitor the reaction by TLC, and wait for the raw material After the conversion is complete, stop the reaction, concentrate the reaction solution to obtain a solid, add 100mL water to dissolve, extract with 100mL×4 dichloromethane, combine the organic layers, dry the organic layer with anhydrous sodium sulfate, and concentrate to obtain a yellow oily liquid 2-methyl- 3-methoxypyran-4-one (8.35 g), yield 99.4%.

[0065] Pyrone (2.80g, 20mmol), ethylenediamine (1.26g, 21mmol), sodium hydroxide (0.72g, 18mmol), ethanol (20mL), water (18mL), and Heat at reflux at 70°C for 1.5h. After the reaction, concentrate the reaction solution and purify it by silica gel column chromatogr...

Embodiment 2

[0074] N-(2-(6-methyl-3-hydroxy-1(4H)-4-oxopyridyl)ethyl)-2-oxo-2H-chromene-3-carboxamide (a1b2) preparation method

[0075] Add kojic acid (21.3g, 150mmol) and thionyl chloride (85mL) into a 250mL single-necked bottle, connect the reaction bottle to a gas absorption device, and stir at room temperature for 2h. After the reaction, suction filtration was performed, and the filter cake was washed with petroleum ether until the filtrate was colorless. The filter cake was recrystallized with water to obtain a white solid (21.7 g), with a yield of 90.3%. Add the above-mentioned white solid (21.7g, 135.5mmol) and distilled water (100mL) into a 500mL two-necked flask, heat up to 50°C, then add zinc powder (17.6g, 271mmol), measure concentrated hydrochloric acid (40.9mL) and place in constant In the pressure dropping funnel, slowly add dropwise, control the temperature between 70-80°C, after dropping, control the temperature at 75°C for 4 hours. After the reaction, the reaction solu...

Embodiment 3

[0086] The preparation method of N-(2-(3-hydroxyl-1(4H)-4-oxopyridyl)ethyl)-2-oxo-2H-benzopyran-3-carboxamide (a1b3)

[0087]Kojic acid (14.2g, 100mmol), methyl iodide (42.6g, 300mmol), anhydrous potassium carbonate (41.4g, 300mmol) and acetone (100mL) were added to a 100mL single-necked bottle, and the reaction was refluxed for 3h. After the reaction, concentrate the reaction solution to obtain a solid, add 150mL of water, extract with 150mL×3 methylene chloride, combine the organic layers, wash with 150mL×2 saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a yellow solid (14.35g ), yield 92%.

[0088] Add the above yellow solid (6.24g, 40mmol) and acetone (600mL) into a 1000mL four-necked flask, stir mechanically, and heat up to reflux. Put Jones reagent (45mL) in a constant pressure dropping funnel, add it dropwise slowly, after dropping, reflux reaction for 40min, monitor the reaction by TLC, stop the reaction after the conversion of the raw ma...

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Abstract

The invention discloses a coumarin hybrid pyridinone amide derivative and a preparation method and application thereof. The coumarin hybrid pyridinone amide derivative and pharmacologically acceptablesalt thereof are shown in the formula (I) and the formula (II), and the derivative can be used for preparing drugs for resisting the Alzheimer's disease, the Parkinson's disease or treating other diseases or symptoms by suppressing monoamine oxidase, chelating metallic iron ions, resisting A<beta> and resisting oxidation.

Description

technical field [0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of coumarin complexes that have both iron ion chelating ability and monoamine oxidase B inhibitory effect, and synergistically realize anti-Aβ and anti-oxidation multi-target anti-Alzheimer's disease. A pyridone amide derivative, a preparation method thereof, and an application in the treatment of Alzheimer's disease. Background technique [0002] Alzheimer's Disease (AD) was first proposed by German psychiatrist and neuropathologist Alzheimer in 1906. Alzheimer's disease, also known as senile dementia, is a degenerative disease of the central nervous system with insidious onset and progressive development. It is the most common type of dementia, and its incidence is increasing among the elderly. Its clinical symptoms include daily behavior difficulties, cognitive impairment, memory impairment, time and space orientation impairment, withd...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61P25/28A61P25/16A61P39/06
CPCA61P25/16A61P25/28A61P39/06C07D405/12
Inventor 谢媛媛蒋筱莹姚传胜郭嘉楠吕杨静
Owner ZHEJIANG UNIV OF TECH
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