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Derivatives of anti-influenza and anti-avian influenza medicament and application thereof

A technology of derivatives and uses, applied in the field of pharmaceutical compounds, can solve the problems of low oral bioavailability and difficulty in permeating small intestinal epithelial cells after oral administration

Inactive Publication Date: 2012-07-25
董慧珍
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the acuteness of this compound is very large, and it is difficult to pass through the small intestinal epithelial cells after oral administration, and the oral bioavailability is very low, and the oral bioavailability in male ferrets is only 2.5%.
, the oral bioavailability in rats is only 3%

Method used

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  • Derivatives of anti-influenza and anti-avian influenza medicament and application thereof
  • Derivatives of anti-influenza and anti-avian influenza medicament and application thereof
  • Derivatives of anti-influenza and anti-avian influenza medicament and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: (1S,2S,3R,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1 - Carboxylic acid L-valine ester (compound 1-1)

[0032]

[0033] Preparation Process:

[0034] The first step: 3285 mg (10 mmol) of compound A, 10.9 g of di-tert-butyl dicarbonate and 8340 mg of potassium carbonate were added to 100 ml of ethyl acetate solution. After stirring at room temperature for 12 hours, add 100 ml of water until the solid is completely dissolved, collect the organic layer, then wash the organic layer with water, dry over anhydrous sodium sulfate, and distill off the solvent to obtain a colorless oil.

[0035] Step 2: Add carbonyldiimidazole (5 mmol) to tetrahydrofuran, then add 2640 mg (5 mmol) of the oil obtained in the first step, stir at 25 °C for 1.5 hours, then stir at 45 °C 1 hour. Under stirring conditions, L-valine in anhydrous dimethylformamide (DMF) solution was reacted at 80° C. for 2 hours in the above solution. Evaporate DMF under...

Embodiment 2

[0037] Example 2 (1S, 2S, 3R, 4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4-guanidino-2-hydroxyl-cyclopentyl-1- Carboxylic acid L-isoleucine ester (compound 1-2)

[0038]

[0039] The synthetic method is the same as above, and the yield is 48.1%.

Embodiment 3

[0040] Example 3 In vivo pharmacokinetic studies

[0041] Experimental animals: Sprague-Dawley rats,

[0042] Administration method: Compounds A, 1-1 and 1-2 were intragastrically administered to rats at a dose of 15 mg / kg.

[0043] Rats were injected with Compound A through the tail vein at a dose of 4 mg / kg. The doses are all calculated according to compound A.

[0044] The concentration of Compound A in the plasma was determined after blood was taken from the rats. The results are shown in the table below:

[0045] The experimental results are shown in the table below. Average AUC after intravenous injection of Compound A (4 mg / kg) in rats 0-t It is 25.24 μg·h / mL. It can be seen from the table that after oral administration of compounds 1-1 and 1-2 to rats, the oral bioavailability of compound A was 61.2% and 43.1%, respectively.

[0046] Table 1 Pharmacokinetic parameters after oral administration of compound A, compound 1-1 and 1-2 in rats

[0047]

...

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PUM

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Abstract

The invention relates to an anti-influenza and anti-avian influenza medicament, wherein the chemical name is (1S, 2S, 3R, 4R)-3-((1S)-1-acetamido-2-ethyl-butyl)-4-guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid, the structure is as shown in the figure (the compound is called compound A for short), and different groups are connected on carboxyl or / and amino of the compound A in the research to get the derivatives of the compound A. The derivatives can be combined with pharmaceutically acceptable excipients to be used for treating and / or preventing influenza and avian influenza.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compounds, specifically it is a new (1S,2S,3R,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4- A derivative of guanidino-2-hydroxy-cyclopentyl-1-carboxylic acid, and a pharmaceutical composition using this derivative as an active ingredient, used in the preparation of medicines for treating and / or preventing influenza and avian influenza application. Background technique [0002] The chemical name is (1S,2S,3R,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4-guanidino-2-hydroxy-cyclopentyl-1- The structure of the carboxylic acid (Compound A) is as follows. [0003] [0004] Compound A [0005] The compound is a cyclopentane derivative neuraminidase inhibitor jointly developed by American BioCryst Pharmaceuticals and RW Johnson Institute of Drug Research. It has the advantages of good acceptance and low toxicity, and is a promising anti-influenza chemotherapeutic drug. [0006] However, the acuteness...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/18C07C277/08A61K31/198A61P31/16
Inventor 董慧珍
Owner 董慧珍
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