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Selective butyrylcholinesterase inhibitor, preparation method and use

A technology of butyrylcholinesterase and selectivity, which is applied in the direction of pharmaceutical formulations, organic active ingredients, and medical preparations containing active ingredients, etc., can solve the problems of severe AD patients' lack of drugs and patients with no available drugs, etc., to achieve The effect of high selectivity and good in vitro activity

Active Publication Date: 2020-12-11
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned drugs can only be effective for mild and moderate AD, and the drugs for severe AD patients are still very scarce, and many patients are in a situation where no drugs are available

Method used

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  • Selective butyrylcholinesterase inhibitor, preparation method and use
  • Selective butyrylcholinesterase inhibitor, preparation method and use
  • Selective butyrylcholinesterase inhibitor, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (1) 6-(tert-butyl) 3-methyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (intermediate 1 )Synthesis

[0050] Take N-tert-butoxycarbonyl-4-piperidone (2g, 10.4mmol) in an eggplant-shaped bottle, dissolve it with ethanol (20mL), add methyl cyanoacetate (1.09g, 11.04mmol), and settle sulfur (0.39g , 12.05mmol) and morpholine (1.75g, 20.08mmol), heated to reflux for 3 hours, cooled to room temperature and stirred overnight, a large amount of solids were precipitated, filtered, the filter cake was washed twice with ice ethanol, dried to obtain intermediate 6- (tert-butyl) 3-methyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (2.42g, yield 77% ).

[0051] (2) 6-(tert-butyl)3-methyl 2-(benzenesulfonamido)-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid Synthesis of Esters (Intermediate 2)

[0052] Take 6-(tert-butyl) 3-methyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (intermediate 1, 0.5 g, 1.60mmol) in a...

Embodiment 2

[0057] Example 2: 6-Benzyl-2-(((4-methylphenyl)sulfonamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxy Synthesis of methyl esters:

[0058] With reference to the synthetic method of Example 1, the intermediate 2 in Example 1 is replaced by 6-(tert-butyl) 3-methyl 2-(((4-methylphenyl)sulfonyl)-4,7- Dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, a yellow solid compound, namely 6-benzyl-2-(((4-methylphenyl)sulfonyl Amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid methyl ester (compound 2).TLC detects as one point, there is a dark spot under the ultraviolet lamp 254nm, 365nm No fluorescence. 1 H NMR (500MHz, CDCl 3 ): δ7.79(d, J=8.2Hz, 2H), 7.40-7.30(m, 6H), 7.27(s, 1H), 3.79(s, 3H), 3.70(s, 2H), 3.52(s, 2H), 2.79(t, J=5.7Hz, 2H), 2.75(t, J=5.7Hz, 2H), 2.42(s, 3H).HRMS(ESI)m / zcalcd.for C 23 h 24 N 2 o 4 S 2 [M+H] + 456.1177, found 456.1172.

Embodiment 3

[0059] Example 3: 6-Benzyl-2-(((4-(tert-butyl)phenyl)sulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- Synthesis of methyl 3-carboxylate:

[0060] With reference to the synthetic method of Example 1, intermediate 2 in Example 1 is replaced by 6-(tert-butyl) 3-methyl 2-(((4-(tert-butyl)phenyl)sulfonamido)-4 , 7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, to obtain a yellow solid compound, which is 6-benzyl-2-(((4-(tert-butyl base) phenyl) sulfonamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid methyl ester (compound 3).TLC detects as one point, UV lamp 254nm There are dark spots below and no fluorescence at 365nm. 1 H NMR (500MHz, CDCl 3 ): δ7.93(d, J=8.5Hz, 2H), 7.62(s, 1H), 7.45(d, J=8.5Hz, 2H), 7.41(t, J=6.4Hz, 3H), 7.32-7.29 (m, 2H), 4.75(s, 2H), 3.81(s, 3H), 3.55(t, J=8.3Hz, 2H), 3.26(t, J=8.4Hz, 2H), 1.32(s, 9H) .HRMS(ESI)m / z calcd.for C 26 h 30 N 2 o 4 S 2 [M+H] + 499.1647, found 499.1650.

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Abstract

The invention discloses a selective butyrylcholine esterase inhibitor with a structure represented by a general formula (I), a preparation method and applications thereof. According to the invention,by evaluating the effect of the selective butyrylcholine esterase inhibitor to a butyrylcholine esterase target through the cholinesterase inhibition activity and the selectivity, the results show that the selective butyrylcholine esterase inhibitor has good in-vitro activity and extremely high selectivity, and is further developed to be used in preparation of drugs for preventing or treating Alzheimer's disease.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a selective butyrylcholinesterase inhibitor, a preparation method and application. Background technique [0002] Alzheimer's disease (AD) is a severe and irreversible degenerative syndrome of the central nervous system, clinically manifested as memory loss, cognitive deficits, and mental and motor disorders. [0003] The pathological causes of AD are extremely complex and involve multiple systems and links such as nerves, immunity, and blood circulation. So far, people have not yet concluded its exact cause. At present, researchers believe that AD is the result of a combination of multiple etiologies, and put forward more than a dozen AD theories from the perspective of pathogenesis, such as the cholinergic theory, the amyloid (β-amyloid, Aβ) cascade theory, and the tau protein theory. , metal ion theory, oxidative stress theory, immune inflammation theory, nerve cel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61P25/28A61K31/4709A61K31/4365
CPCA61P25/28C07D495/04Y02P20/55
Inventor 孙昊鹏陈霆恺杨鸿瑜杜晨曦刘弈君陈瑶冯锋柳文媛徐桔唐旭王旻宇郭凡蒋学阳
Owner CHINA PHARM UNIV
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