1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as preparation method and application thereof

A technology of oxadiazoles and activators, applied in 1 field, can solve the problems of complex etiology and difficult to achieve treatment, and achieve the effects of high activity, small molecular weight and high selectivity

Pending Publication Date: 2021-11-05
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since AD ​​is a systemic disease with complex etiology, it is difficult to achieve the purpose of treatment only by targeting individual links in its many disease processes.

Method used

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  • 1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as preparation method and application thereof
  • 1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as preparation method and application thereof
  • 1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Synthesis of 3-(3-(6-methylpyridyl))-5-(3-hydroxyphenyl)-1,2,4-oxadiazole (intermediate 1)

[0042] Dissolve 3-benzyloxybenzoic acid and N,N'-carbonyl-diimidazole in N,N'-dimethylformamide, and stir at room temperature for 45 minutes. Add 6-methyl-N-hydroxy-3-pyridinecarboxamidine into the reaction flask, then raise the temperature to 110°C and stir for 5h. The reaction solution was cooled to room temperature, poured into saturated aqueous sodium bicarbonate solution, and a white solid precipitated out. Suction filtration, the filter cake washed twice. Dried to white powder. Dissolve the white powder in ethanol, add concentrated hydrochloric acid, and reflux overnight at 105°C. After cooling to room temperature, a white solid precipitated out. Suction filtration, washed twice with water and twice with petroleum ether. After drying, a white solid was obtained. 1 H NMR (300MHz, DMSO-d6): δ10.12(s, 1H), 9.11(d, J=1.9Hz, 1H), 8.31(dd, J=8.1, 2.1Hz, 1H), 7.62(d, J ...

Embodiment 2

[0052] N-(6-(5-(5-(6-(2-methylpyridyl))1,2,4-oxadiazolyl)-2-methyl-phenoxy)hexyl)-9-amino -Synthesis of 1,2,3,4-tetrahydroacridine

[0053] With reference to the synthetic method of Example 1, intermediate 1 in Example 1 is replaced by 3-(3-(6-methylpyridyl))-5-(4-methyl-3-hydroxyphenyl)-1, 2,4-Oxadiazole, to obtain a light brown oil, which is N-(6-(5-(5-(6-(2-methylpyridyl))1,2,4-oxadiazolyl) -2-Methyl-phenoxy)hexyl)-9-amino-1,2,3,4-tetrahydroacridine. 1 H NMR (300MHz, CDCl 3 )δ9.29 (d, J=2.0Hz, 1H), 8.33 (dd, J=8.1, 2.2Hz, 1H), 7.97 (dd, J=10.6, 8.9Hz, 2H), 7.74 (dd, J=7.7 , 1.0Hz, 1H), 7.58(dd, J=14.3, 4.3Hz, 2H), 7.38(d, J=7.3Hz, 1H), 7.31(d, J=7.8Hz, 2H), 4.12(t, J =6.2Hz, 2H), 3.55(t, J=7.1Hz, 2H), 3.09(s, 2H), 2.73(s, 2H), 2.67(s, 3H), 2.31(s, 3H), 1.93(s , 6H), 1.80-1.72(m, 2H), 1.62-1.52(m, 4H). HRMS(ESI): found 548.3024, calcd for C 34 h 38 N 5 o 2 [M+H] + 548.3020.

Embodiment 3

[0055] N-(6-(5-(5-(6-(2-methylpyridyl))1,2,4-oxadiazolyl)-2-methoxy-phenoxy)hexyl)-9- Synthesis of Amino-1,2,3,4-tetrahydroacridine

[0056] With reference to the synthetic method of Example 1, intermediate 1 in Example 1 is replaced by 3-(3-(6-methylpyridyl))-5-(4-methoxy-3-hydroxyphenyl)-1 , 2,4-Oxadiazole, to obtain a light brown oil, namely N-(6-(5-(5-(6-(2-methylpyridyl)) 1,2,4-oxadiazolyl )-2-methoxy-phenoxy)hexyl)-9-amino-1,2,3,4-tetrahydroacridine. 1 H NMR (300MHz, CDCl 3 )δ9.27(s, 1H), 8.32(d, J=7.6Hz, 1H), 8.15(d, J=7.8Hz, 1H), 8.06(d, J=8.4Hz, 1H), 7.84(d, J=8.3Hz, 2H), 7.68(s, 1H), 7.65-7.58(m, 1H), 7.40(d, J=7.6Hz, 1H), 7.31(d, J=8.1Hz, 1H), 7.01( d, J=8.3Hz, 1H), 4.16(t, J=6.3Hz, 2H), 3.95(s, 3H), 3.71(t, J=7.0Hz, 2H), 3.16(s, 2H), 2.66( s, 5H), 1.91 (s, 6H), 1.86-1.77 (m, 2H), 1.59 (s, 4H). HRMS (ESI): found 564.2967, calcd for C 34 h 38 N 5 o 3 [M+H] + 564.2969.

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Abstract

The invention discloses a 1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as a preparation method and application thereof. The structure of the compound is shown in the specification. According to the 1, 2, 4-oxadiazole Nrf2 activator-tacrine spliced product as well as the preparation method and application thereof of the invention, acetylcholin esterase inhibitory activity, Nrf2 activation activity, selective screening and Morris water maze experiments are used as carriers to evaluate the treatment of the Alzheimer's disease (especially moderate and severe Alzheimer's disease) by the compounds shown in the general formulas I, II and III, and the compounds have good in-vitro and in-vivo activity and extremely high selectivity, and can be used as precursor substances for further development of an anti-Alzheimer's disease effect by selectively inhibiting acetylcholin esterase and activating Nrf2.

Description

technical field [0001] The invention relates to chemical industry and medicine, in particular to a 1,2,4-oxadiazole Nrf2 activator-tacrine combination product and its preparation method and application. Background technique [0002] Alzheimer's disease (AD) is the most common cause of dementia, accounting for an estimated 60%-70% of cases worldwide. Approximately 10% of persons aged ≥65 years are considered to have AD; this figure rises to 32% in persons >85 years of age, where the annual incidence of AD is estimated to be 6.48%. People with AD experience progressive loss of memory and cognitive functions involving language, visuospatial, and executive domains. Alzheimer's disease pathology in the brain is characterized by amyloid (Aβ) plaques and abnormal tau protein tangles. Based on the temporal appearance of amyloid and tauopathies and the evidence that Aβ overproduction leads to AD, the amyloid cascade hypothesis was proposed, which postulates that Aβ accumulation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/473A61P25/28
CPCC07D413/14A61K31/473
Inventor 孙昊鹏李琦王园园林宏智乔玉婷冯锋柳文媛曲玮
Owner CHINA PHARM UNIV
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