Coumarin 3-formamide neuraminidase inhibitor as well as preparation method and application thereof

A neuraminidase and formamide technology, applied in the field of biomedicine, can solve the problems of expensive raw materials for production of Tamiflu, complex synthesis process, etc., and achieves good neuraminidase inhibitory activity, simple synthesis method, and excellent neuraminic acid. Effect of enzyme inhibitory effect

Pending Publication Date: 2021-10-01
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 v...

Method used

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  • Coumarin 3-formamide neuraminidase inhibitor as well as preparation method and application thereof
  • Coumarin 3-formamide neuraminidase inhibitor as well as preparation method and application thereof
  • Coumarin 3-formamide neuraminidase inhibitor as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0038] Described preparation method specifically comprises the following steps:

[0039] (1) forming a reaction system with salicylaldehyde and diethyl malonate, and obtaining the intermediate of formula (II) through aftertreatment after the reaction;

[0040] (2) The formula (II) intermediate obtained in step (1) and the substituted aniline are dissolved in an organic solvent to form a reaction system, and after the reaction, the coumarin 3-carboxamides shown in the formula (I) are obtained through post-treatment. agent;

[0041] In step (1), piperidine and acetic acid are used as catalysts, and absolute ethanol is used as the organic solvent.

[0042] In step (1), the temperature of the reaction system is 77-79°C, preferably 78°C, and the reaction time is 8-10h, preferably 8h.

[0043] In step (1), the post-treatment process specifically includes: taking out the reaction system for cooling, adding 50 ml of ice water to the reaction system in an ice-water bath for dilution....

Embodiment 1

[0052] A preparation method containing coumarin 3-carboxamide neuraminidase inhibitor, its structural formula is as follows:

[0053]

[0054] Concrete synthetic steps are as follows:

[0055](1) Accurately measure 1.83g (15mmoL) of salicylaldehyde and 2.88g (18mmoL) of diethyl malonate with a graduated cylinder, pour them into a 100ml round bottom flask, pour 30mL of absolute ethanol, and stir. 0.15 mL of piperidine was added, and 2 drops of acetic acid were added dropwise. Place in an oil bath and heat and stir at 78° C. for 8 hours. After the reaction is over, dilute the reaction system with 50 ml of ice water in an ice-water bath, and a large amount of solids are produced in the system solution. Filter the solid to obtain a filter cake, wash the filter cake with ice water, and then dry the filter cake at room temperature to obtain the intermediate of formula (II).

[0056] (2) Take 0.64g (3mmoL) of the intermediate of formula (II) and 0.55g (3.6mmoL) of 3,4-dimethoxya...

Embodiment 2

[0086] A preparation method of coumarin 3-carboxamide neuraminidase inhibitor, its structural formula is as follows, and it is prepared by a method similar to Example 1.

[0087] N-(3-methoxy-4-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxamide

[0088]

[0089] Yellow solid, 5% yield, IC 50 The value is 35.56 μM.

[0090] 1 H NMR (500MHz, DMSO-d 6 )δ13.37(s,1H),9.25(s,1H),8.88(s,1H),7.62(d,J=5.9Hz,1H),7.38(t,J=7.0Hz,1H),6.93( m,5H), 3.81(s,3H). 13 C NMR (125MHz, DMSO-d 6 )δ161.43, 160.64, 147.74, 147.62, 141.42, 133.15, 132.78, 119.83, 119.45, 116.92, 114.03, 113.11, 112.94, 108.74, 40.49.

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Abstract

The invention relates to a coumarin 3-formamide neuraminidase inhibitor as well as preparation and an application thereof. The inhibitor has a structure as shown in a formula (I). The preparation method specifically comprises the following steps: (1) reacting salicylaldehyde and diethyl malonate, and performing post-treatment to obtain an intermediate as shown in a formula (II); and (2) dissolving the intermediate in the formula (II) and substituted aniline in an organic solvent, reacting, and performing post-treatment to obtain the inhibitor as shown in the formula (I). The compound is novel in structure, and experimental results 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 coumarin 3-carboxamide neuraminidase inhibitor and a preparation method and application thereof. 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, pyrrolidine...

Claims

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Application Information

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IPC IPC(8): C07D311/12C07D405/12A61P31/16A61K31/352A61K31/4709A61K31/4433
CPCC07D311/12C07D405/12A61P31/16A61K31/352A61K31/4709A61K31/4433
Inventor 孔苓权余微程利平
Owner SHANGHAI INST OF TECH
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