Antiviral drug and preparation method therefor

Abstract

The invention discloses an antiviral drug and a preparation method therefor. The invention discloses a peramivir ester derivative and the preparation method therefor. The chemical name of the peramivir ester derivative is: (1S,2S,3R,4R)-1'-carboxylic acid-3'[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino cyclopentyl-2'-oxo-{5-[1,4,8,11-tetraazaheterocyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazaheterocyclotetradecyl]}-R-carboxylate. The peramivir ester derivative disclosed by the invention has an obviously higher activity (EC50) and a selectivity index (SI = EC50 / CC50) by comparison with the peramivir, and also is a more potent anti-flu drug.

Description

technical field

[0001] The invention relates to an anti-influenza virus drug, especially a derivative ester of peramivir, specifically an ester of peramivir and plerixafor-N-alkanoic acid; the invention also relates to a preparation method of the anti-viral drug. Background technique

[0002] Influenza (abbreviated as influenza) is an acute respiratory infection caused by influenza virus, and it is also a highly contagious and fast-spreading disease. 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 mutation, is highly contagious...

Examples

Embodiment 1

[0047] Example 1 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-valerate

[0048]

[0049] (1) (1S,2S,3R,4R)-2-hydroxy-3-[(1S)-1-acetamido-2-ethyl]butyl-4-diBoc-guanidinocyclopentan-1- Benzyl carboxylate

[0050]

[0051] 32.8g (100mmol) of peramivir, 21.3g (112mmol) of p-toluenesulfonic acid, 54.1g (500mmol) of benzyl alcohol, add 500mL of toluene and reflux for 24 hours (using a water trap). After the reaction is complete, Add ethyl acetate to freeze crystallization, filter with suction, wash with ethyl acetate, add 200mL tetrahydrofuran to dissolve the filter cake, add 30.3g (300mol) of triethylamine, add 109.1g (500mmol) of di-tert-butyl dicarbonate (BOC anhydride) ), the reaction was stirred at room temperature for 24 hours. After the reaction was completed, 400 mL of dichloromethane was added, and the pH was adjusted to 2-...

Embodiment 2

[0067] Example 2 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-octadecanoate

[0068]

[0069] Prepared in the same manner as in Example 1, replacing ethyl 5-bromopentanoate in step (3) with ethyl 18-bromo-octadecanoate to obtain the target compound; high resolution mass spectrum (+ESI, m / z): 1096.6419 [M+H] + .

Embodiment 3

[0070] Example 3 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-methyl-phenyl-valerate

[0071]

[0072] Prepared as in Example 1, replacing 5-bromovalerate ethyl ester in step (3) with p-bromomethyl-phenylvalerate ethyl ester to obtain the target compound; high resolution mass spectrum (+ESI, m / z): 1004.4098 [M+H] + .

[0073] The following test examples are used to further compare and illustrate the selectivity index and death protection rate of peramivir derivative esters provided by the present invention.

technical field

[0001] The invention relates to an anti-influenza virus drug, especially a derivative ester of peramivir, specifically an ester of peramivir and plerixafor-N-alkanoic acid; the invention also relates to a preparation method of the anti-viral drug. Background technique

[0002] Influenza (abbreviated as influenza) is an acute respiratory infection caused by influenza virus, and it is also a highly contagious and fast-spreading disease. 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 mutation, is highly contagious...

Examples

Embodiment 1

[0047] Example 1 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-valerate

[0048]

[0049] (1) (1S,2S,3R,4R)-2-hydroxy-3-[(1S)-1-acetamido-2-ethyl]butyl-4-diBoc-guanidinocyclopentan-1- Benzyl carboxylate

[0050]

[0051] 32.8g (100mmol) of peramivir, 21.3g (112mmol) of p-toluenesulfonic acid, 54.1g (500mmol) of benzyl alcohol, add 500mL of toluene and reflux for 24 hours (using a water trap). After the reaction is complete, Add ethyl acetate to freeze crystallization, filter with suction, wash with ethyl acetate, add 200mL tetrahydrofuran to dissolve the filter cake, add 30.3g (300mol) of triethylamine, add 109.1g (500mmol) of di-tert-butyl dicarbonate (BOC anhydride) ), the reaction was stirred at room temperature for 24 hours. After the reaction was completed, 400 mL of dichloromethane was added, and the pH was adjusted to 2-...

Embodiment 2

[0067] Example 2 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-octadecanoate

[0068]

[0069] Prepared in the same manner as in Example 1, replacing ethyl 5-bromopentanoate in step (3) with ethyl 18-bromo-octadecanoate to obtain the target compound; high resolution mass spectrum (+ESI, m / z): 1096.6419 [M+H] + .

Embodiment 3

[0070] Example 3 (1S, 2S, 3R, 4R)-1'-carboxylic acid-3'-[(1S)-1''-acetamido-2''-ethyl]butyl-4'-guanidino Cyclopenta-2'-oxo-{5-[1,4,8,11-tetraazacyclotetradecyl]methyl}phenyl)-1,4,8,11-tetraazacyclotetradecyl Alkyl]}-methyl-phenyl-valerate

[0071]

[0072] Prepared as in Example 1, replacing 5-bromovalerate ethyl ester in step (3) with p-bromomethyl-phenylvalerate ethyl ester to obtain the target compound; high resolution mass spectrum (+ESI, m / z): 1004.4098 [M+H] + .

[0073] The following test examples are used to further compare and illustrate the selectivity index and death protection rate of peramivir derivative esters provided by the present invention.

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