Triazole neuraminidase inhibitor as well as preparation method and application thereof

A technology of neuraminidase and inhibitors, applied in antiviral agents, organic chemistry, etc., can solve the problems of expensive raw materials and complex synthesis process of Tamiflu, achieve good neuraminidase inhibitory effect, simple synthesis method, Effect of excellent neuraminidase inhibitory activity

Active Publication Date: 2021-11-05
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently the most widely used anti-influenza drug is Tamiflu, but with the widespread use of drugs, the resistance of influenza virus to Tamiflu also appears, and the resistance of Tamiflu also appears, and the resistance of Tamiflu also appears. The production raw materials are extremely expensive and the synthesis process is complicated

Method used

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  • Triazole neuraminidase inhibitor as well as preparation method and application thereof
  • Triazole neuraminidase inhibitor as well as preparation method and application thereof
  • Triazole neuraminidase inhibitor as well as preparation method and application thereof

Examples

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preparation example Construction

[0042] Described preparation method specifically comprises the following steps:

[0043] (1) Form a reaction system with substituted aniline and chloroacetyl chloride, and obtain the intermediate of formula (II) through post-treatment after the reaction;

[0044] (2) dissolving furoyl chloride and thiosemicarbazide in an organic solvent to form a reaction system, after the reaction, an intermediate of formula (Ⅲ) is obtained through post-processing;

[0045] (3) The intermediate of formula (Ⅲ) obtained in step (2) is dissolved in sodium hydroxide solution to form a reaction system, and the reaction is processed to obtain the intermediate of formula (Ⅳ);

[0046] (4) get the formula (IV) intermediate that step (3) obtains and the formula (II) intermediate that step (1) obtains and sodium hydroxide solution are dissolved in the organic solvent, react and obtain formula (I) through aftertreatment indicated inhibitors.

[0047] In step (1), triethylamine is used as the acid-bind...

Embodiment 1

[0054] A preparation method of triazole neuraminidase inhibitor, its structural formula is as shown in formula I:

[0055]

[0056] Concrete synthetic steps are as follows:

[0057] (1) Accurately weigh 0.61g (5mmol) of 3-ethylaniline and 0.51g (5mmol) of triethylamine in a 50mL round bottom flask, add 10mL of dichloromethane, use nitrogen protection, add 0.56g (5mmol) of chloroacetyl chloride ), placed in an ice-water bath at 0°C and stirred for 4 hours, then added 20 mL of dichloromethane to dilute the reaction, washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine, and removed the dichloromethane by rotary evaporation to obtain the intermediate of formula (II) body.

[0058] (2) Accurately weigh 0.65g (5mmol) of 2-furoyl chloride and 0.46g (5mmol) of thiosemicarbazide into a 50mL round bottom flask, add 20mL of dichloromethane, place in an ice-water bath at 0°C and stir for 16 hours. Upon completion, the dichloromethane is remov...

Embodiment 2

[0090] A method for preparing a triazole neuraminidase inhibitor, its structural formula is as follows, and it is prepared by a method similar to Example 1.

[0091] N-(3,4-Dimethoxyphenyl)-2-((5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide

[0092]

[0093] White solid, 67% yield, IC 50 The value was 1.43 μM. 1 H NMR(500MHz,DMSO)δ14.46(s,1H),10.19(s,1H),7.87(s,1H),7.28(s,1H),7.07(d,J=10.0Hz,1H),6.99 (s, 1H), 6.88 (d, J=5.0Hz, 1H), 6.67 (s, 1H), 4.08 (s, 2H), 3.71 (s, 6H). 13C NMR (125MHz, DMSO) δ 165.67, 148.64, 145.09, 144.54, 143.81, 132.52, 112.14, 112.06, 111.16, 110.32, 104.36, 55.77, 55.39, 36.53. HRMS(ESI):361.0966[M-H]+

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Abstract

The invention relates to a triazole neuraminidase inhibitor and a preparation method and application thereof. The inhibitor has a structure as shown in a formula (I), and the preparation method comprises the following steps: (1) forming a reaction system from substituted aniline and chloroacetyl chloride to obtain an intermediate as shown in a formula (II); (2) dissolving furanyl acyl chloride and thiosemicarbazide in an organic solvent to form a reaction system, so as to obtain an intermediate shown in a formula (III); (3) dissolving the intermediate in the formula (III) obtained in the step (2) in a sodium hydroxide solution to form a reaction system, so as to obtain an intermediate in a formula (IV); and (4) dissolving the intermediate in the formula (IV) obtained in the step (3), the intermediate in the formula (II) obtained in the step (1) and a sodium hydroxide solution in an organic solvent, conducting reacting, and performing post-treatment to obtain the inhibitor shown in the formula (I). The compound is novel in structure, and experiments show that the compound has good neuraminidase inhibitory activity and can be used for preparing drugs for inhibiting neuraminidase activity.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a triazole neuraminidase inhibitor and its preparation method and application. Background technique [0002] Neuraminidase is an important functional glycoprotein embedded in the envelope surface of influenza virus. Its main function in the replication process of influenza virus is to cleave glycosidic bonds, so that the virus can escape from the host cell and achieve the purpose of transmission. Therefore, neuraminidase is one of the important targets for the development of anti-influenza virus drugs. Anti-influenza drugs developed by targeting neuraminidase can be divided into the following categories according to structure: neuraminic acid analogues, cyclohexenes, cyclopentanes, benzoates, pyrrole rings to indole alkaloids Classes, multimers, fusion proteins and polycyclic compounds, etc. Currently the most widely used anti-influenza drug is Tamiflu, but with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D405/14A61P31/16
CPCC07D405/04C07D405/14A61P31/16
Inventor 程利平石林庞婉
Owner SHANGHAI INST OF TECH
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