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Butyrylcholine esterase selective inhibitor and preparation method and application thereof

A technology for selecting and compounding compounds, applied in the field of medicine, can solve the problems of poor selectivity, small quantity, lack of structural novelty and diversity, etc.

Active Publication Date: 2019-01-25
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 BuChE inhibitors are accompanied by the emergence of AChE inhibitors, and they have the disadvantages of small number, lack of structural novelty and diversity, and poor selectivity.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-1,2,5-oxadiazol-3-amine (Intermediate 1)

[0034] Take 2-cyanomethylbenzimidazole (1g, 6.36mmol) in an eggplant-shaped bottle, dissolve it with acetic acid (10ml), add an aqueous solution of sodium nitrite (0.44g, 6.36mmol) dropwise under an ice bath, and a solid is formed, After stirring in an ice bath for 40 minutes, it was suction filtered, and the filter cake was washed once with water and twice with diethyl ether. Take another eggplant-shaped bottle, add hydroxylamine hydrochloride (0.53g, 7.63mmol) in an ice bath, add water as a solvent, add potassium hydroxide (0.54g, 9.54mmol), and then add diglyme (6ml) , and finally add the filter cake of the previous step, return the reaction system to room temperature and start heating, reflux for 6 hours, and cool to room temperature; a large number of golden pink crystals precipitate, filter with suction, wash the filter cake once with water, wash twice with ether, and dry to o...

Embodiment 2

[0042] 2-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-N-(quinolin-6-yl)ethyl Synthesis of amides:

[0043] With reference to the synthetic method of Example 1, the intermediate 2 in Example 1 is replaced by 2-chloro-N-(quinolin-6-yl)acetamide to obtain a milky white solid compound, which is 2-(2-(4 -Amino-1,2,5-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-N-(quinolin-6-yl)acetamide (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-d6):δ10.95(s,1H N H CO),8.80(s,1H,ArH),8.33(s,1H,ArH),8.24(d,J=8.34Hz,1H,ArH),8.02(d,J=9.39Hz,1H,ArH),7.91 -7.81(m,3H,ArH,N H 2 )7.49-7.38(m,3H,ArH),7.05(s,2H,ArH),5.69(s,2H,C H 2 ).MS(ESI):calcd.for C 20 h 15 N 7 o 2 [M+H + ]386.1365found 386.1359.

Embodiment 3

[0045] 3-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-N-(quinolin-6-yl)propane Synthesis of amides:

[0046]With reference to the synthetic method of Example 1, the intermediate 2 in Example 1 is replaced by 3-chloro-N-(quinolin-6-yl) propanamide to obtain a milky white solid compound, which is 3-(2-(4 -Amino-1,2,5-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-N-(quinolin-6-yl)propionamide (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(300MHz,DMSO-d6):δ10.40(s,1H,N H CO), 8.76(dd, J=1.56, 4.14Hz, 1H, ArH), 8.21-8.25(m, 2H, ArH), 7.91(d, J=9.06Hz, 1H, ArH), 7.65(d, J= 8.13Hz, 1H, ArH), 7.81 (d, J = 7.89Hz, 1H, ArH), 7.65 (dd, J = 2.28, 9.06Hz, 1H, ArH), 7.47 (q, J = 3.54Hz, 1H, ArH) ,7.40(d,J=7.26Hz,1H,ArH) 7.32(t,J=7.38Hz,1H,ArH),7.01(s,2H,N H 2 ),5.02(t,J=6.66Hz,2H,C H 2 Cl), 3.03(t, J=6.54Hz, 2H, C H 2 CO).HR-MS(ESI):calcd.for C 21 h 17 N 7 o 2 [M+H +...

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Abstract

The invention discloses a butyrylcholine esterase selective inhibitor and a preparation method and application thereof. The invention discloses a compound shown in a formula (I), and also discloses application of the compound in preparation of medicines for preventing or treating Alzheimer's disease. An inventor uses the inhibiting activity of butyrylcholine esterase, selective screening and Morris water maze experiment as carriers to evaluate the function of the compound in the formula (I) for treating the Alzheimer's disease (especially medium and severe Alzheimer's disease), the good in-vitro and in-vivo activities and higher selectivity are found, and the compound can be further developed into a precursor substance which can selectively inhibit the butyrylcholine esterase to reach thefunction of treating the Alzheimer's disease. The formula (I) is shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a butyrylcholinesterase selective inhibitor and a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD) is a systemic brain neurodegenerative syndrome, clinically manifested as central cognitive decline, mental and motor disorders. At present, with the aging of the population has become a global problem, AD has posed a huge threat to the life and health of the elderly and the overall medical resources of the society. According to the "World Alzheimer's Disease Report 2016", there were 46.8 million AD patients worldwide in 2015, and by 2050, this number will reach 132 million. In the past five years, the global investment in AD treatment has increased by more than 35%, reaching 818 billion US dollars in 2015, and will exceed one trillion US dollars in 2018. This series of shocking figures clearly reveals the severe situation of AD prevention and...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D413/04A61P25/28A61K31/4709A61K31/4245
CPCA61P25/28C07D413/04C07D413/14
Inventor 孙昊鹏李琦卢鑫陈瑶冯锋邢帅帅李启航曲玮
Owner CHINA PHARM UNIV
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