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Butyrylcholine esterase selective inhibitor as well as preparation method and application thereof

A technology for butyrylcholinesterase and butyrylcholine, which is applied in the field of butyrylcholinesterase selective inhibitors and its preparation, can solve the problems of lack of structural novelty, poor diversity selectivity, and small quantity , to achieve good in vitro activity

Active Publication Date: 2021-06-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the existing BChE inhibitors are accompanied by the emergence of AChE inhibitors, and they have the disadvantages of small number, lack of structural novelty, diversity and poor selectivity.

Method used

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  • Butyrylcholine esterase selective inhibitor as well as preparation method and application thereof
  • Butyrylcholine esterase selective inhibitor as well as preparation method and application thereof
  • Butyrylcholine esterase selective inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of N-(4-(4-benzylpiperazin-1-yl)quinolin-3-yl)benzamide

[0037] (1) Synthesis of 4-(4-benzylpiperazin-1-yl)-3-aminoquinoline (intermediate 1)

[0038] Take 4-chloro-3-nitroquinoline (350mg, 1.678mmol) in an eggplant-shaped flask, dissolve it with acetonitrile (4mL), slowly add 1-benzylpiperazine (295.7mg, 1.678mmol) and triethylamine dropwise (350μL, 2.517mmol), start heating, reflux for 2 hours, cool to room temperature, and spin dry to obtain a large amount of yellow solid, namely 4-(4-benzylpiperazin-1-yl)-3-nitroquinoline (526mg , the yield was 90.07%). Take 4-(4-benzylpiperazin-1-yl)-3-nitroquinoline (526mg, 1.510mmol) in an eggplant-shaped flask, dissolve it with ethanol, and add 9M hydrochloric acid (30mL ), then drop by drop the ethanol solution (50mL) of tin protochloride (1145mg, 6.039mmol), drop and finish heating and reflux for 6 hours, cool to room temperature; Ethanol is removed, and the remaining solution is oxidized with hydrogen under ice b...

Embodiment 2

[0044] Synthesis of N-(4-(4-benzylpiperazin-1-yl)quinolin-3-yl)-4-fluorobenzamide:

[0045] With reference to the synthetic method of Example 1, the raw material of intermediate 2 in Example 1 was replaced by 4-fluorobenzoic acid to obtain a yellow solid, which was N-(4-(4-benzylpiperazin-1-yl)quinone (Phenol-3-yl)-4-fluorobenzamide (Compound 2). TLC detection is one point, there are dark spots under the ultraviolet lamp at 254nm, and there is no fluorescence at 365nm. 1 H NMR (300MHz, DMSO-d 6 ):δ10.28(s,1H),8.57(s,1H),8.18(d,J=5.6Hz,1H),8.16–8.10(m,2H),8.00(d,J=8.2Hz,1H) ,7.73(q,J=5.8,4.3Hz,1H),7.64(q,J=7.8,7.4Hz,1H),7.46(t,J=8.8Hz,2H),7.34–7.25(m,5H), 3.57(s,2H),3.32(t,J=7.1Hz,4H),2.93(t,J=7.1Hz,4H).

Embodiment 3

[0047] Synthesis of N-(4-(4-benzylpiperazin-1-yl)quinolin-3-yl)-2-chlorobenzamide:

[0048] With reference to the synthetic method of Example 1, the raw material of Intermediate 2 in Example 1 is replaced by 2-chlorobenzoic acid to obtain a light yellow solid, which is N-(4-(4-benzylpiperazin-1-yl) Quinolin-3-yl)-2-chlorobenzamide (Compound 3). TLC detection is one point, there are dark spots under the ultraviolet lamp at 254nm, and there is no fluorescence at 365nm. 1 H NMR (400MHz, CDCl 3 ):δ9.98(s,1H),8.65(s,1H),8.11(dd,J=8.5,1.5Hz,1H),7.98(dd,J=8.4,1.3Hz,1H),7.77–7.72( m,1H),7.69(td,J=7.5,1.5Hz,1H),7.48–7.40(m,2H),7.40(ddd,J=7.1,6.0,2.9Hz,1H),7.45–7.34(m, 6H), 3.74(s, 2H), 3.31(t, J=7.0Hz, 4H), 2.91(t, J=7.1Hz, 4H).

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PUM

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Abstract

The invention discloses a butyrylcholine esterase selective inhibitor as well as a preparation method and application thereof. The inhibitor is a compound shown as a formula (I). The invention also discloses application of the compound in preparation of drugs for preventing or treating Alzheimer's disease. Experiments such as butyrylcholine esterase inhibitory activity, selective screening, Nrf2 activation activity, Morris water maze and the like are used as carriers to evaluate the treatment of Alzheimer's disease (especially moderate and severe Alzheimer's disease) by the compound shown in the formula (I), and the compound is found to have good in-vitro and in-vivo activity and extremely high selectivity. The compound can be used as a precursor substance for further development of Alzheimer's disease by selectively inhibiting butyrylcholine esterase.

Description

technical field [0001] The invention relates to a class of butyrylcholinesterase inhibitors and their preparation methods and uses, in particular to a class of butyrylcholinesterase selective inhibitors and their preparation methods and uses. Background technique [0002] Alzheimer's disease (AD) is a systemic brain neurodegenerative syndrome with a slow course, difficult to detect and irreversible. Clinical manifestations include central cognitive impairment, mental and motor disturbances, etc. Since the incidence of AD will increase with age, in today's society where population aging is getting worse, AD has posed a huge threat to the life and health of the elderly and the overall medical resources of the society, and has become a global medical problem. . According to the "2019 World Alzheimer's Disease Report" statistics, in 2019, there were more than 50 million AD patients worldwide, and by 2050, this number is expected to reach 152 million, which is equivalent to 1 p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46C07D401/12A61K31/496C07D405/12A61P25/28
CPCC07D215/46C07D401/12C07D405/12A61P25/28
Inventor 孙昊鹏陈颖李琦陈瑶冯锋柳文媛
Owner CHINA PHARM UNIV
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