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Oxamide neuraminidase inhibitor and preparation method and application thereof

A technology of neuraminidase and oxamide, which is applied in the field of biomedicine, can solve the problems of Tamiflu’s expensive raw materials, serious virus resistance, and complicated synthesis process, and achieve good druggability, low toxicity, and simple molecular structure Effect

Active Publication Date: 2021-10-08
ZHEJIANG JIANFENG PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In recent years, due to the wide application of neuraminidase inhibitors in clinical practice, drug-resistant virus strains have appeared. Tamiflu is the most widely used oral preparation, but the drug resistance of the virus is also the most serious. It is extremely expensive and the synthesis process is complicated, and drug-resistant strains of zanamivir, peramivir and laninamivir are also beginning to appear

Method used

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  • Oxamide neuraminidase inhibitor and preparation method and application thereof
  • Oxamide neuraminidase inhibitor and preparation method and application thereof
  • Oxamide neuraminidase inhibitor and preparation method and application thereof

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preparation example Construction

[0048]The preparation method of above-mentioned oxamide neuraminidase inhibitor, the equation of preparation method is as follows:

[0049]

[0050] Described preparation method specifically comprises the following steps:

[0051] (1) form a reaction system with substituted aniline, monoethyl oxalyl chloride, triethylamine and ethyl acetate, and obtain the intermediate of formula (II) through after-treatment after the reaction;

[0052] (2) dissolving the intermediate of formula (II) obtained in step (1) in an organic solvent, adding potassium hydroxide to form a reaction system, and obtaining the intermediate of formula (III) after the reaction;

[0053] (3) Dissolve the intermediate of formula (III) obtained in step (2) in an organic solvent, add 1-hydroxybenzotriazole (HOBt) and 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (EDCl) forms a reaction system, and after the reaction, the oxamide inhibitors shown in the formula (I) are obtained through aftertre...

Embodiment 1

[0084] N 1 -(3-Chlorobenzyl)-N 2 -(3-hydroxyl-4-methoxyphenyl) oxalamide, its structural formula is as shown in formula I:

[0085]

[0086] Concrete synthetic steps are as follows:

[0087] (1) Accurately weigh 2.83g (20mmoL) of 3-chlorobenzylamine in a 150ml round bottom flask, add 4.17mL (30mmoL) of triethylamine and 80.00mL of ethyl acetate, and then use a constant pressure dropping funnel at 0°C Slowly add 3.36mL (30mmoL) monoethyl oxalyl chloride dropwise to the system, and stir the reaction at room temperature 25°C for 6 hours, after the reaction is completed. Add 100mL of distilled water to the reaction system, adjust the pH to 3 with concentrated hydrochloric acid, then add 150mL of ethyl acetate to the reaction solution for extraction and liquid separation, take the organic phase, and then carry out vacuum distillation on the organic phase to obtain the intermediate of formula (II) The crude product of the body was purified by column chromatography to obtain a ...

Embodiment 2

[0094] N 1 -(3-Chlorobenzyl)-N 2 -(3,4,5-trimethoxyphenyl)oxalamide, whose structural formula is as follows, was prepared by a method similar to Example 1.

[0095]

[0096] White solid, 81% yield, IC 50 The value is 0.24±0.11 μM, and the melting point is 215.5-215.7°C.

[0097] 1 H NMR (400MHz, DMSO-d 6 )δ10.55(s,1H),9.59(t,J=6.4Hz,1H),7.42–7.29(m,6H),4.42(d,J=6.4Hz,2H),3.77(s,6H), 3.66(s,3H). 13 C NMR (100MHz, DMSO-d 6 )δ160.75, 158.67, 153.11, 141.66, 134.82, 134.11, 133.46, 130.71, 127.71, 127.43, 126.54, 98.79, 60.58, 56.23, 42.58.

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Abstract

The invention relates to an oxamide neuraminidase inhibitor and preparation and application thereof. The structural formula of the inhibitor is shown in the specification. The preparation method specifically comprises the following steps of: (1) forming a reaction system from substituted aniline, oxalyl chloride monoethyl ester, triethylamine and ethyl acetate, and performing post-treatment after reaction to obtain an intermediate shown in a formula (II); (2) dissolving the intermediate in the formula (II) in an organic solvent, adding potassium hydroxide to form a reaction system, and reacting to obtain an intermediate in a formula (III); and (3) dissolving the intermediate shown in the formula (III) in an organic solvent, adding 1-hydroxybenzotriazole (HOBt) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) to form a reaction system, and carrying out post-treatment after the reaction 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 an oxamide-type neuraminidase inhibitor and a preparation method and application thereof. Background technique [0002] Neuraminidase is a glycoprotein distributed on the envelope of influenza virus, which hydrolyzes the glycosidic bond between sialic acid and glycoprotein on the surface of host cells during virus infection, and promotes the release of mature viruses from the surface of infected cells to continue Infect new cells. At the same time, it can prevent the aggregation of progeny virus particles after they are released from the host cell, and can also hydrolyze the sialic acid in the respiratory mucosa, thereby preventing the inactivation of progeny virus particles and promoting the spread of the virus in the respiratory tract. Neuraminidase has played an important role, so neuraminidase is one of the important targets for the development and design of ...

Claims

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Application Information

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IPC IPC(8): C07C233/56C07C231/02C07C231/12C07C231/14C07D317/58A61P31/16
CPCC07C233/56C07C231/02C07C231/12C07C231/14C07D317/58A61P31/16
Inventor 程利平张兴永钟志坚
Owner ZHEJIANG JIANFENG PHARM CO LTD
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