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2-aminothiophene neuraminidase inhibitor, preparation method and application thereof

A technology of neuraminidase and aminothiophene, which is applied in the field of biomedicine, can solve the problems of expensive raw materials for Tamiflu production and complicated synthesis process, and achieve excellent inhibitory effect, simple synthesis method, and good neuraminidase inhibitory activity

Active Publication Date: 2021-05-28
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 the drug, the resistance of influenza viruses to Tamiflu also appears, and the production raw materials of Tamiflu are extremely expensive and the synthesis process is complicated

Method used

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  • 2-aminothiophene neuraminidase inhibitor, preparation method and application thereof
  • 2-aminothiophene neuraminidase inhibitor, preparation method and application thereof
  • 2-aminothiophene neuraminidase inhibitor, preparation method and application thereof

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preparation example Construction

[0045] Described preparation method specifically comprises the following steps:

[0046] (1) methyl acetoacetate, sublimed sulfur and ethyl cyanoacetate form a reaction system, and after the reaction, obtain the intermediate of formula (II);

[0047] (2) The intermediate of formula (II) obtained in step (1) is dissolved in an organic solvent and forms a reaction system with chloroacetyl chloride, and the intermediate of formula (III) is obtained after the reaction;

[0048] (3) The intermediate of formula (III) obtained in step (2) and the substituted aromatic phenol are dissolved in an organic solvent to form a reaction system, and after the reaction, the 2-aminothiophene inhibitor shown in formula (I) is obtained through aftertreatment;

[0049] In step (1), diethylamine is used as the catalyst, absolute ethanol is used as the organic solvent, the temperature of the reaction system is 25-80°C, preferably 25°C, and the reaction time is 14-48h, preferably 26h, the post-treatm...

Embodiment 1

[0079] 4-Ethyl-2-methyl-5-(2-(5-bromo-2-methylphenoxy)acetamido)-3-methylthiophene-2,4-dicarboxylate, its structural formula is as follows Shown in formula I:

[0080]

[0081] Concrete synthetic steps are as follows:

[0082] (1) Accurately measure 10.78mL (100mmoL) methyl acetoacetate and 10.65mL (100mmoL) ethyl cyanoacetate with a graduated cylinder, pour them into a 50ml round bottom flask, and then accurately weigh 3.21g (100mmoL) of sublimed sulfur into the round Bottom flask, pour 20mL absolute ethanol, stir. Add 8 mL of diethylamine dropwise with a constant pressure dropping funnel. After the dropwise addition, the constant-pressure funnel was removed, and placed at room temperature at 25° C. for a stirring reaction for 26 hours. After the reaction, a large amount of solids were produced in the system solution. The solid was filtered to obtain a filter cake, which was washed several times with 50% ethanol aqueous solution, and then dried at normal temperature to ...

Embodiment 2

[0089] 4-Ethyl-2-methyl-5-(2-(quinoline-6-acyloxy)-acetamido)-thiophene-2,4-dicarboxylate, its structural formula is as follows, similar to Example 1 prepared by the method.

[0090]

[0091] White solid, 94% yield, IC 50 The value is 0.035 μM.

[0092] 1 H NMR (500MHz, CDCl 3)δ12.58(s,1H),8.87–8.82(m,1H),8.11(t,J=9.5Hz,2H),7.63(dd,J=9.5,3.0Hz,1H),7.42(dd,J =8.0,4.0Hz,1H),7.17(d,J=2.5Hz,1H),4.89(s,2H),4.45(q,J=7.0Hz,2H),3.88(s,3H),2.79(s ,3H),1.44(t,J=7.0Hz,3H). 13 C NMR (125MHz, CDCl 3 )δ165.99,165.85,163.21,154.97,151.00,148.85,144.97,135.07,131.62,128.98,122.02,121.70,120.36,117.76,115.34,106.97,615.12,614.29,

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Abstract

The invention relates to a 2-aminothiophene neuraminidase inhibitor, preparation and application thereof, wherein the structural formula of the inhibitor is shown in the specification. The preparation method specifically comprises the following steps: (1) carrying out reaction on methyl acetoacetate, sublimed sulfur and ethyl cyanoacetate, and then carrying out post-treatment to obtain an intermediate shown in a formula (II); (2) dissolving the intermediate in the formula (II) in an organic solvent, and reacting with chloroacetyl chloride to obtain an intermediate in a formula (III) after the reaction; and (3) dissolving the intermediate shown in the formula (III) and substituted aromatic phenol in an organic solvent, reacting, and performing post-treatment to obtain the inhibitor shown in the formula (I). Compared with the prior art, the compound of the invention 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 2-aminothiophene neuraminidase inhibitor and its preparation method and application. Background technique [0002] Neuraminidase is a glycoprotein distributed on the envelope of influenza virus, which can assist mature influenza virus to escape from the original host cells and infect new cells. Therefore, neuraminidase is one of the important targets for the development of anti-influenza virus drugs one. [0003] Currently, there are only 6 anti-influenza virus drugs approved by the U.S. FDA, 2 M2 proton channel inhibitors (amantadine and rimantadine), 3 neuraminidase inhibitors (zanamivir, oseltamivir, etc.) Wei and peramivir) and an RNA-dependent RNA polymerase inhibitor (Sofruza). Anti-influenza drugs developed by targeting neuraminidase can be divided into the following categories according to their structures: cyclohexenes, pyrans, pyrrolidines, benzoic a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38C07D409/12A61P31/16A61K31/381A61K31/4709
CPCA61P31/16C07D333/38C07D409/12
Inventor 程利平钟志坚张兴永庞婉郭玲玲
Owner SHANGHAI INST OF TECH
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