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Anti-influenza virus compound as well as preparation method and application thereof

A technology for anti-influenza virus and compounds, applied in antiviral agents, organic chemical methods, organic chemistry, etc.

Active Publication Date: 2018-07-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This structure has not been reported in the prior art

Method used

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  • Anti-influenza virus compound as well as preparation method and application thereof
  • Anti-influenza virus compound as well as preparation method and application thereof
  • Anti-influenza virus compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of anti-influenza virus compound (II)

[0034] Step (1) (3R, 4R, 5S)-4-acetamide-5-(chloromethoxycarbonyl)amino-3-(1-propoxyethyl ester)-1-cyclohexane-1-carboxylic acid ethyl ester (I) Preparation

[0035] The reaction equation is:

[0036]

[0037] Acetonitrile (30mL), oseltamivir (3.12g, 10.0mmol), chloromethyl chloroformate (1.94g, 15.0mmol) and N,N-dimethylethylamine (1.10g, 15.0mmol) were successively added to the flask ), stirred at 20°C for 3 hours, after the reaction was completed, the reaction solution was poured into 30 mL of water for extraction, the organic phase was collected, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtrate, and evaporate the organic solvent under reduced pressure to obtain 3.45 g of white solid, which is (3R, 4R, 5S)-4-acetamide-5-(chloromethoxycarbonyl)amino-3-(1-propoxyethyl ester) -1-cyclohexane-1-carboxylate ethyl ester (I) crude product, this product...

Embodiment 2

[0042] Embodiment 2: the preparation of anti-influenza virus compound (II)

[0043] Step (1) (3R, 4R, 5S)-4-acetamide-5-(chloromethoxycarbonyl)amino-3-(1-propoxyethyl ester)-1-cyclohexane-1-carboxylic acid ethyl ester (I) Preparation

[0044] The reaction equation is:

[0045]

[0046] Tetrahydrofuran (30ml), oseltamivir (3.12g, 10.0mmol), chloromethyl chloroformate (1.29g, 10.0mmol) and N,N-diisopropylethylamine (1.94g, 15.0 mmol), stirred at room temperature for 5 hours, the reaction was completed, the reaction solution was poured into 30ml of water for extraction, the organic phase was collected, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtrate, and evaporate the organic solvent under reduced pressure to obtain 3.82 g of white solid, which is (3R, 4R, 5S)-4-acetamide-5-(chloromethoxycarbonyl)amino-3-(1-propoxyethyl ester) - 1-Cyclohexane-1-carboxylate ethyl ester (I) crude product, this product is directly used in the n...

Embodiment 3

[0051] Example 3: In vitro antiviral activity test of compound (II) containing oseltamivir and favipiravir structures

[0052] (1) Test method

[0053] Chicken embryo fibroblasts were inoculated in 96-well culture plates, and the culture solution containing influenza virus and the compound to be tested was added, and the cells were incubated at 37°C, 5% CO 2 After culturing in medium for 48 hours, 10 μL of cck-8 reagent and 90 μL of DMEM matrix containing 1% FBS were added, and the culture was continued for 90 minutes at 37° C. to observe cytopathic changes (CPE) to determine the inhibitory effect of each compound on influenza virus. Oseltamivir carboxylate was used as a positive control.

[0054] (2) Test results

[0055] Table 1 Compound II in vitro antiviral activity test results

[0056]

[0057] It can be seen from the above table that Compound II has different degrees of inhibitory effects on H5N2, H5N6, and H5N8, and has better antiviral activity on H5N2 in vitro....

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Abstract

The invention relates to an anti-influenza virus compound as well as a preparation method and an application thereof, and belongs to the technical field of pharmaceutical synthesis. The compound contains oseltamivir and favipiravir structures and has the structure shown in the formula II in the description. The method comprises the following steps: oseltamivir and methyl chloroformate are subjected to condensation reaction, a compound (I) (3R,4R,5S)-4-acetamido-5-[chloromethoxycarbonyl]amino-3-(1-propoxyethyl)- -1-cyclohexane-1-carboxylic ethyl ester is obtained; the compound (I) and favipiravir are linked by nucleophilic substitution reaction, and a target compound (II) is obtained. The compound (II) has different degrees of inhibiting effects on H5N2, H5N6 and H5N8, and has better antiviral activity on H5N2 in vitro. Therefore, the invention also provides the application of the compound shown in the formula II in preparation of anti-influenza virus medicines.

Description

technical field [0001] The invention relates to an anti-influenza virus compound and a preparation method thereof, and experiments on its anti-virus activity and metabolic stability have been carried out, and belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Influenza (abbreviated as influenza) is an acute respiratory infection caused by influenza virus, and it is also a disease with strong contagion and fast transmission speed. It is mainly spread through droplets in the air, person-to-person contact or contact with contaminated items. Typical clinical symptoms are: sudden onset of high fever, general pain, significant fatigue and mild respiratory symptoms. Generally, autumn and winter are the high-incidence period, and the complications and death caused by it are very serious. The disease is caused by influenza virus, which can be divided into three types: A (A), B (B), and C (C). Type A virus often undergoes antigenic variation, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24A61K31/4965A61P31/16
CPCC07B2200/07C07D241/24
Inventor 刘新泳张涛展鹏张健鞠翰
Owner SHANDONG UNIV
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