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Beta-carboboline GSK3beta/DYRK1A dual inhibitor and preparation method thereof and application of beta-carboboline GSK3beta/DYRK1A dual inhibitor in resisting Alzheimer's disease

A carboline, general formula technology, applied in the field of organic compound synthesis and medical application, can solve problems such as affecting axonal transport function, reducing acetylcholine content, affecting cognitive function and the like

Active Publication Date: 2021-07-06
GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the activation of GSK-3β causes hyperphosphorylation of tau protein, depolymerizes tubulin, affects axonal transport function, and promotes the expression of acetylcholinesterase, thereby greatly reducing the content of acetylcholine and affecting cognition. Knowledge function

Method used

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  • Beta-carboboline GSK3beta/DYRK1A dual inhibitor and preparation method thereof and application of beta-carboboline GSK3beta/DYRK1A dual inhibitor in resisting Alzheimer's disease
  • Beta-carboboline GSK3beta/DYRK1A dual inhibitor and preparation method thereof and application of beta-carboboline GSK3beta/DYRK1A dual inhibitor in resisting Alzheimer's disease
  • Beta-carboboline GSK3beta/DYRK1A dual inhibitor and preparation method thereof and application of beta-carboboline GSK3beta/DYRK1A dual inhibitor in resisting Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] N-(4-Bromopyridin-2-yl)cyclopropanecarboxamide (Compound 2)

[0069]

[0070] Compound 4-bromo-2-aminopyridine (5g, 28.90mmol) and pyridine (3.43g, 43.35mmol) were dissolved in THF (50ml), and cyclopropanecarbonyl chloride (3.63g, 34.68mmol) was slowly added dropwise under ice-cooling After reacting for 4 hours, the reaction liquid was evaporated to dryness, then ice water was added thereto, and filtered by suction to obtain compound 2 as a white solid with a yield of 90%.

Embodiment 2

[0072] N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclopropanecarboxamide (Compound 3)

[0073]

[0074] Compound 2 (3g, 12.44mmol) and bipinacol borate (3.79g, 14.93mmol) were dissolved in anhydrous dioxane (50ml), and KOAc (3.66g, 37.33mmol) and Pd(dppf ) Cl 2 , N 2 Under protection, after reacting at 90° C. for 12 h, the reaction solution was concentrated, water was added thereto and filtered with suction, and the filter cake was washed with petroleum ether and acetonitrile in sequence to obtain compound 3 as an off-white solid with a yield of 80%.

Embodiment 3

[0076] N-(4-(4-fluoro-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (Compound 4a)

[0077]

[0078] Dissolve compound 3 (0.2g, 0.9mmol) and 2-bromo-5-fluoronitrobenzene (0.31g, 1.09mmol) in dioxane / water (8ml:2ml), add CS 2 CO 3 (0.37g, 2.73mmol) and Pd(dppf)Cl 2 , N 2 Under protection, after reacting at 95°C for 10 h, the reaction liquid was concentrated, ethyl acetate was added, extracted, and the concentrated intermediate obtained was purified by silica gel column to obtain the pure compound 4a as a light yellow solid with a yield of 85%.

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PUM

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Abstract

The invention discloses a beta-carboline GSK3beta / DYRK1A dual inhibitor as shown in a general formula I, a preparation method of the beta-carboline GSK3beta / DYRK1A dual inhibitor and application of the beta-carboline GSK3beta / DYRK1A dual inhibitor in resistant the Alzheimer's disease. A novel beta-carboline derivative has GSK3beta / DYRK1A dual inhibition activity, and a preparation method of the beta-carboline derivative serving as the GSK3beta / DYRK1A dual inhibitor is provided. Meanwhile, the invention also discloses application of the beta-carboline derivative in preparation of a medicine for treating the Alzheimer's disease. The beta-carboline derivative can provide a theoretical basis for discovery of a novel AD treatment drug.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a β-carbomorph GSK-3β / DYRK1A dual inhibitor, a preparation method thereof and an anti-Alzheimer's disease application. Background technique [0002] Alzheimer's disease (AD) is a common progressive neurodegenerative disease, clinically manifested as progressive decline of memory function, cognitive dysfunction, language and social function decline, and even personality changes and life ability loss of symptoms. Due to the limited understanding of the molecular basis of its pathobiology, there is no effective treatment to date. If no effective drugs are found in recent years, it will bring a heavy medical burden to the society. Currently, only cholinesterase (ChE) inhibitors and N-methyl-D-aspartic acid (N-methyl-D-aspartic acid) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD. acid, NMDA)...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/444A61P25/28
CPCC07D471/04A61P25/28
Inventor 赵庆春刘文武刘欣蒋晓文丁怀伟许子华刘文杰
Owner GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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