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1, 3, 4-oxadiazole neuraminidase inhibitor as well as preparation method and application thereof

A technology of neuraminidase and oxadiazoles, which is applied in the field of biomedicine, can solve the problems of expensive raw materials and complex synthesis process of Tamiflu, and achieve good neuraminidase inhibitory activity, simple synthesis method and excellent neuraminidase. Effect of Acidase Inhibitory Effect

Active Publication Date: 2021-10-01
ZHEJIANG JIANFENG PHARM CO LTD
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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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  • 1, 3, 4-oxadiazole neuraminidase inhibitor as well as preparation method and application thereof
  • 1, 3, 4-oxadiazole neuraminidase inhibitor as well as preparation method and application thereof
  • 1, 3, 4-oxadiazole neuraminidase inhibitor as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0051] Described preparation method specifically comprises the following steps:

[0052] (1) After aniline, chloroacetyl chloride and triethylamine are reacted, the intermediate of formula (II) is obtained through aftertreatment;

[0053] (2) benzohydrazide, carbon disulfide and potassium hydroxide are reacted to obtain the intermediate of formula (III) through aftertreatment;

[0054] (3) dissolving the intermediates of formula (II) and intermediates of formula (III) in an organic solvent, and post-processing after the reaction to obtain the 1,3,4-oxadiazole inhibitors shown in formula (I);

[0055] In step (1), triethylamine is used as a catalyst, the organic solvent is dichloromethane, the temperature of the reaction system is 0-20°C, preferably 15°C, and the reaction time is 8-24h, preferably 24h, the post-treatment process is as follows: After the reaction is completed, use 1moL -1Hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine wash...

Embodiment 1

[0061] A preparation method of 1,3,4-oxadiazole neuraminidase inhibitor, its structural formula is as shown in formula I:

[0062]

[0063] Concrete synthetic steps are as follows:

[0064] (1) Accurately weigh 0.7g (5mmol) of 3-fluorophenethylamine and 0.51g (5mmol) of triethylamine in a 250ml round bottom flask, pour 30ml of dichloromethane into it, protect it under nitrogen, and stir in an ice bath, Then, 0.37 mL (5 mmol) of chloroacetyl chloride was added dropwise with a 1 ml disposable syringe. After the dropwise addition was completed, the reaction was stirred at 15°C for 24 hours. After the reaction was completed, 1 moL -1 Wash with hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine, dry the organic phase with anhydrous sodium sulfate, and remove the solvent in vacuo to obtain the intermediate of formula (II).

[0065] (2) Accurately weigh 0.76g (5mmol) of 4-hydroxybenzoic hydrazide, 0.28g (5mmol) of potassium hydroxide in a 250ml...

Embodiment 2

[0096]A preparation method of 1,3,4-oxadiazole neuraminidase inhibitor, its structural formula is as follows, and it is prepared by a method similar to Example 1.

[0097] 2-(N-(3,4-dichlorobenzyl)carbonylmethylenemercapto)-5-(4-chlorophenyl)-1,3,4-oxadiazole

[0098]

[0099] Pale yellow solid, yield 35%, IC 50 The value is 0.032 μM.

[0100] 1 H NMR (500MHz, DMSO-d 6 )δ8.92(t, J=6.1Hz, 1H), 7.93(d, J=8.2Hz, 2H), 7.64(d, J=8.2Hz, 2H), 7.50(d, J=9.5Hz, 2H) ,7.24(d,J=8.4Hz,1H),4.32(d,J=6.0Hz,2H),4.18(s,2H). 13 C NMR (125MHz, DMSO-d 6 )δ166.88, 164.79, 164.08, 140.70, 137.19, 131.38, 130.83, 130.00, 129.63, 128.54, 128.03, 122.28, 42.03, 35.98.

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Abstract

The invention relates to a 1, 3, 4-oxadiazole neuraminidase inhibitor as well as a preparation method 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 aniline, chloroacetyl chloride and triethylamine, and performing post-treatment to obtain an intermediate as shown in a formula (II); (2) performing reaction on benzoyl hydrazine, carbon disulfide and potassium hydroxide, and performing post-treatment to obtain an intermediate as shown in a formula (III); and (3) dissolving the intermediate shown in the formula (II) and the intermediate shown in the formula (III) 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 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 1,3,4-oxadiazole 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, pyrrolidines, ben...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/113C07D413/12C07D417/12A61P31/16A61K31/4245A61K31/4709A61K31/4725A61K31/517A61K31/498A61K31/433A61K31/428
CPCC07D271/113C07D413/12C07D417/12A61P31/16A61K31/4245A61K31/4709A61K31/4725A61K31/517A61K31/498A61K31/433A61K31/428
Inventor 程利平余微庞婉
Owner ZHEJIANG JIANFENG PHARM CO LTD
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