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Donepezil-BHT heterozygotes and preparation method and application thereof in treatment of Alzheimer's disease

A technology of donepezil and -BHT, which is applied in the field of donepezil-BHT hybrid, its preparation and its use in the treatment of Alzheimer's disease, and can solve the problems of inhibiting the pathological process of Alzheimer's disease

Inactive Publication Date: 2019-01-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs targeting a single target can only regulate one of the physiological pathways, but cannot fundamentally inhibit the pathological process of Alzheimer's disease

Method used

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  • Donepezil-BHT heterozygotes and preparation method and application thereof in treatment of Alzheimer's disease
  • Donepezil-BHT heterozygotes and preparation method and application thereof in treatment of Alzheimer's disease
  • Donepezil-BHT heterozygotes and preparation method and application thereof in treatment of Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Preparation of 4-(N-1-benzylpiperidine)amino-2,4-di-tert-butyl-p-hydroxybenzamide (3a).

[0077] Dissolve 100mg (0.39mmol, 1eq) of the raw material 2,4-di-tert-butyl p-hydroxybenzoic acid (1a) in 6ml of anhydrous dichloromethane, and add condensing agent 1-hydroxybenzotriazole (HOBT) 49.74mg (0.36 mmol, 1.1eq) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) 69.62mg (0.36mmol, 1.1eq), drop triethylamine 151μl (1.09 mmol, 3eq), after stirring and reacting under ice bath for 1 hour, add 4-amino-1-benzylpiperidine (2a) 69.1mg (0.36mmol, 1eq) dropwise in dichloromethane solution to react overnight, monitor the reaction until the amine is complete , washed three times with saturated sodium bicarbonate, washed three times with saturated sodium chloride until HOBT was cleaned, the organic phase was combined and mixed and passed through a silica gel column, and the dichloromethane / methanol product system was obtained to obtain about 140 mg of the target pro...

Embodiment 2

[0079] Preparation of 4-(N-1-benzylpiperidine)aminomethyl-2,4-di-tert-butyl-p-hydroxybenzamide (3b)

[0080] The preparation process is the same as 1, but the raw material 4-amino-1-benzylpiperidine (2a) is replaced with 4-aminomethyl-1-benzylpiperidine (2b), the yield is 82%; white solid, m.p.217-218 °C, 1 H NMR (500MHz, DMSO) δ8.27(d, J=7.7Hz, 1H), 7.60(s, 2H), 7.31(m, 5H), 3.45(s, 2H), 3.13(t, J=6.2Hz , 2H), 2.81(d, J=11.0Hz, 2H), 1.90(t, J=11.0Hz, 2H), 1.64(d, J=12.2Hz, 2H), 1.54(d, J=6.2Hz, 1H ), 1.41(s, 18H), 1.22-1.11(m, 2H); 13 C NMR (126MHz, DMSO) δ167.51, 156.51, 139.24, 138.64, 129.20, 128.56, 127.24, 126.45, 124.43, 62.91, 53.46, 45.20, 36.33, 35.03, 30.71, 30.36. ESI-MS m / z [: 437 M+H] + ;HRMS(ESI)m / z: 437.3164[M+H] + (calcd for 437.3163, C 28 h 41 N 2 o 2 ).

Embodiment 3

[0082] Preparation of 4-(N-1-benzylpiperidine)aminoethyl-2,4-di-tert-butyl p-hydroxybenzamide (3c)

[0083] The preparation process is the same as 1, the raw material 4-amino-1-benzylpiperidine (2a) is replaced with 4-aminoethyl-1-benzylpiperidine (2c), the yield is 75%; white solid, m.p.182-183 °C, 1 H NMR (500MHz, CDCl3) δ7.61(s, 2H), 7.42-7.33(m, 4H), 7.32(s, 1H), 5.99(s, 1H), 5.57(s, 1H), 3.60(s, 2H), 3.51(dd, J=14.1, 6.4Hz, 2H), 2.98(d, J=10.3Hz, 2H), 2.06(s, 2H), 1.78(d, J=10.3Hz, 2H), 1.61( d, J=6.4Hz, 2H), 1.50(s, 18H), 1.43(s, 2H), 1.32(d, J=14.1Hz, 1H); 13 C NMR (126MHz, DMSO) δ167.95, 156.51, 135.96, 129.56, 128.31, 126.04, 123.98, 53.30, 37.76, 36.50, 34.43, 33.62, 31.54, 30.20. ESI-MS m / z: 451.3 [M+H] + ;HRMS(ESI)m / z: 451.3317[M+H] + (calcd for 451.3319, C 29 h 43 N 2 o 2 ).

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Abstract

The invention relates to the field of medicinal chemistry, in particular to a class of donepezil-BHT heterozygotes. The donepezil-BHT heterozygotes serving as multifunctional acetylcholinesterase (AChE) inhibitors and monoamine oxidase B (MAO-B) inhibitors have a great in-vitro antioxidation effect and have a great neuroprotective effect on hydrogen peroxide (H2O2)-induced oxidative damage of PC12nerve cells and bacterial lipopolysaccharide (LPS) stimulated BV-2 inflammatory injuries, it is proved by animal experiments that the donepezil-BHT heterozygotes have a great effect on improvement ofthe cognitive function, and it is considered that the donepezil-BHT heterozygotes can be used as drug candidates for treatment of Alzheimer's disease. A most preferred compound structure is shown inthe description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of donepezil-BHT hybrids, which are multifunctional acetylcholinesterase (AChE) inhibitors and monoamine oxidase B (MAO-B) inhibitors, and have good in vitro anti-inflammatory properties. Oxidation, for hydrogen peroxide (H 2 o 2 ) induces oxidative damage of PC12 nerve cells and bacterial lipopolysaccharide (LPS) stimulates BV-2 inflammatory damage, has better neuroprotective effects, and has been proved to have a better effect on improving cognitive function in animal experiments, which can be considered drug candidates for the treatment of Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease in the elderly. The pathogenesis of AD is complex. So far, the pathological mechanism of Alzheimer's disease is not completely clear. Its cause is not only related to the decrease of c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/26C07D211/58A61K31/445A61K31/4468A61P25/28A61P39/06A61P25/00
CPCC07D211/26C07D211/58
Inventor 孔令义王小兵蔡佩
Owner CHINA PHARM UNIV
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