GSK-3beta/ChE double inhibitor as well as preparation method and application thereof

A technology of inhibitors and solvates, applied in the field of medicine, can solve problems such as reduction and loss of binding effects

Pending Publication Date: 2020-04-14
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The binding of hyperphosphorylated tau protein (PHF-Tau) to tubulin is reduced to one-tenth of the normal level, thereby losing the function of promoting microtubule assembly, and it can also compete with tubulin for binding Normal tau protein and other macromolecular microtubule-associated proteins, and capture these proteins, resulting in normal microtubule depolymerization, abnormal hyperphosphorylated tau protein aggregates itself and forms PHF / NFTs structure, which leads to Alzheimer's disease

Method used

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  • GSK-3beta/ChE double inhibitor as well as preparation method and application thereof
  • GSK-3beta/ChE double inhibitor as well as preparation method and application thereof
  • GSK-3beta/ChE double inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxylic acid ethyl ester ( 2a)

[0113]

[0114] Compound 4 (666mg, 2mmol) and 9i (727mg, 3mmol) were dissolved in 55mL THF, triphenylphosphine (1.57g, 6mmol) was added, and DIAD (1.2mL, 6mmol) was slowly added dropwise under the protection of argon under ice bath conditions. ), and reacted at room temperature for 24 hours after the addition was completed and the ice bath was removed. The reaction solution was spin-dried, dissolved in DCM and separated by column chromatography to obtain the product (DCM / MeOH=30 / 1, v / v). The product was a light yellow solid with a yield of 52%. 1 H NMR (300MHz, DMSO-d 6 ,δppm): 11.04(s,1H,-CONH-),8.51(m,1H,-NHCH 2 -),8.42(m,2H,Ar-H),7.41-7.77(m,3H,Ar-H),7.41-7.49(m,2H,Ar-H),4.16(m,2H,-OCH 2 CH 3 ), 4.18(t, J=9.1Hz, 2H, -CH 2 NH-),3.29(m,2H,-CH 2 NH-),2.99(m,2H,Ar-CH 2 -),2.60(m,2H,Ar-CH 2 -),2.07(m,1H,-CHCO-),1.76(m,4H,-(CH ...

Embodiment 2

[0116] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxylic acid (2b)

[0117]

[0118] Dissolve 2a (55.7mg, 0.1mmol) in 3mL THF / MeOH mixed solution (THF / MeOH=2 / 1, v / v), add LiOH solution (400μL, 1.5mmol / mL) dropwise under ice bath, remove the ice React at room temperature for 7 hours after bathing. The completion of the reaction was detected by TLC, THF in the reaction solution was removed by rotary evaporation at low temperature, 2 times the amount of water was added, the acid was adjusted to precipitate a solid, and suction filtration was obtained to obtain a pale yellow crystalline product (60.1 mg), with a yield of 87%. 1 H NMR (300MHz, DMSO-d 6 ,δppm):10.94(s,1H,-CONH-),8.45(m,1H,-NHCH 2 -),8.39(m,1H,Ar-H),7.89(m,1H,Ar-H),7.78(m,1H,Ar-H),7.69(t,J=8.2Hz,1H,Ar-H ),7.57(m,1H,Ar-H),7.38(t,J=8.2Hz,2H,Ar-H),4.83(t,J=8.2Hz,2H,-NHCH 2 -),4.29(m,2H,-NHCH 2 -), 2.95(t, J=8.2Hz, 2H, Ar-CH 2 -), 2.66(t, J=8.2Hz, 2H, Ar...

Embodiment 3

[0120] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxamide (2c)

[0121] 2b (55.7mg, 0.1mmol) was dissolved in 8mL DMF, DIPEA (49.5μL, 0.3mmol) and HATU (53.2mg, 0.14mmol) were added, activated at room temperature for 3 hours under the protection of argon, and then NH 4 Cl (31.8 mg, 0.6 mmol) was reacted at room temperature under the protection of argon for 18 hours. The completion of the reaction was detected by TLC. The reaction solution was spin-dried, sanded, and separated by column chromatography to obtain a yellow solid product (DCM / MeOH=10 / 1, v / v), with a yield of 38%. 1 H NMR (300MHz, DMSO-d 6,δppm):11.00(s,1H,-CONH-),8.44(m,1H,-NHCH 2 -),8.31-8.42(m,3H,Ar-H),7.81(d,J=6.1Hz,1H,Ar-H),7.68(m,2H,-CONH 2 ),7.30-7.40(m,2H,Ar-H),6.97(s,1H,Ar-H),4.81(t,J=8.2Hz,2H,-NHCH 2 -), 4.28 (d, J=6.1Hz, 2H, -NHCH 2 -), 2.91(t, J=8.2Hz, 2H, Ar-CH 2 -), 2.65(d, J=8.2Hz, 2H, Ar-CH 2 -), 2.03(m, 1H, -CHCO-), 1.73(d, J=8.2Hz, 4...

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Abstract

The invention discloses a GSK-3beta / ChE double inhibitor with the structural formula shown as formula (I), or pharmaceutically acceptable salts and solvates of formula (I). The chemical small molecules involved in the invention can effectively inhibit the enzyme activity of GSK-3 beta, AChE and BChE, have the effects of improving cognition, reducing tau protein phosphorylation and reducing neuroinflammation, and have important application value in the preparation of drugs for preventing or treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a GSK-3β / AChE dual inhibitor and a preparation method thereof, and the application of the compound in the preparation of drugs for treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is a very complex neurodegenerative syndrome of the brain, and so far there is no conclusion about its exact etiology. At present, it is believed that AD is the result of a combination of multiple etiologies, and more than a dozen AD theories have been proposed from the perspective of pathogenesis, such as the cholinergic theory, the amyloid (β-amyloid, Aβ) cascade theory, the tau protein theory, and the metalloid theory. Ion theory, oxidative stress theory, immune inflammation theory, nerve cell apoptosis theory, glutamate function theory, etc. A large number of cholinergic neurons in the basal layer and cerebral cortex of AD patients are destroyed, resulting in ...

Claims

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Application Information

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IPC IPC(8): C07D417/04C07D417/14A61P25/28A61P25/00A61K31/473
CPCC07D417/04C07D417/14A61P25/28A61P25/00Y02P20/55
Inventor 孙昊鹏冯锋蒋学阳王洋周俊廷邢才轶柳文媛曲玮张杰徐健
Owner CHINA PHARM UNIV
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