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Sialic acid analog and application thereof to preparation of anti-influenza-virus medicaments

An analogue, sialic acid technology, applied in the field of chemistry, can solve problems such as poor bioavailability and rapid excretion

Inactive Publication Date: 2011-07-20
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its main disadvantages include: poor oral bioavailability and easy to be excreted rapidly, clinically, it can only be administered through nasal or oral inhalation; its common adverse reactions are nose and throat discomfort, nausea and diarrhea, headache, cough, dizziness, epistaxis, etc.

Method used

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  • Sialic acid analog and application thereof to preparation of anti-influenza-virus medicaments
  • Sialic acid analog and application thereof to preparation of anti-influenza-virus medicaments
  • Sialic acid analog and application thereof to preparation of anti-influenza-virus medicaments

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0046] Preparation Example 1: Preparation of (3R, 4S)-3-acetamide-4-azido-2-formaldehyde-3,4-dihydro-2H-pyran-6-carboxylic acid methyl ester a) (4S, 5R) - Preparation of 5-acetylamino-4-azido-6-formyl-5,6-dihydro-4H-pyran-2-carboxylic acid methyl ester

[0047] For the preparation method, see J.CHEM.PERKIN TRANS I 1995.1173-1180.

[0048] b) Preparation of (3R, 4S)-3-acetamide-4-azido-2-carbaldehyde-3,4-dihydro-2H-pyran-6-carboxylic acid methyl ester

[0049]

[0050] The compound N-acetyl-2,4-dideoxy-2,3-dehydro-4α-azido-D-neuraminic acid methyl ester was added to methanol / water (v / v=3:1) mixture , stirred in an ice-water bath until completely dissolved, and slowly added NaIO 4 Afterwards, allow the temperature to rise slowly to room temperature and continue to stir for about 16 hours. TLC (dichloromethane / methanol=9:1, v / v) traces the disappearance of the raw material. Add anhydrous methanol after evaporating the solvent, and use anhydrous magnesium sulfate After dryin...

Embodiment 1

[0052] Example 1: Preparation of (2S, 3R, 4S)-3-acetylamino-4-amino-2-(piperidine-1-methyl)-3,4-dihydro-2H-pyran-6-carboxylic acid

[0053] a) (2S, 3R, 4S)-3-acetylamino-4-azido-2-(piperidine-1-methyl)-3,4-dihydro-2H-pyran-6-carboxylic acid methyl ester preparation of

[0054] (3R,4S)-3-acetamide-4-azido-2-formyl-3,4-dihydro-2H-pyran-6-carboxylic acid methyl ester 200mg (0.75mmol) and hexahydropyridine 76.5mg (0.9mmol) into a 25ml round bottom flask, add 5ml of anhydrous methanol, stir at room temperature under nitrogen protection until the solid dissolves, add 1 drop of glacial acetic acid, continue stirring for 10min, add NaBH 3 CN 57mg (0.9mmol), stirred at room temperature for 16 hours, TLC (dichloromethane / methanol=9:1, v / v) tracked the disappearance of raw materials, added a small amount of saturated NaHCO 3 Aqueous solution, after extraction with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation to obtain a ye...

Embodiment 2

[0068] Example 2: (2S, 3R, 4S)-3-acetylamino-4-amino-2-(4-hydroxypiperidine-1-methyl)-3,4-dihydro-2H-pyran-6- Preparation of formic acid

[0069] a) (2S, 3R, 4S)-3-acetylamino-4-azido-2-(4-hydroxypiperidine-1-methyl)-3,4-dihydro-2H-pyran-6- Preparation of methyl formate

[0070] compound

[0071] (2S, 3R, 4S)-3-Acetamido-4-azido-2-(4-hydroxypiperidine-1-methyl)-3,4-dihydro-2H-pyran-6-carboxylic acid The ester is implemented with reference to the intermediate (3R, 4S)-3-acetamide-4-azido-2-formyl-3,4-dihydro-2H-pyran-6-carboxylic acid methyl ester and 4-hydroxypiperidine Obtained by the experimental operation of Example 1(a), the yield was 22.6% under silica gel column chromatography purification conditions (dichloromethane / methanol=13:1, v / v).

[0072] ESI-MSm / z: 354.4 (M+H) +

[0073] 1 H-NMR (400MHz, CDCl 3. )δppm 6.24-6.22 (d, NH, J=8.2Hz) 5.98-5.97 (d, 3-CH, J=12.4Hz), 4.36-4.22 (m, 6-CH), 4.17-4.15 (m, NCH 2 CH 2 C H O), 3.80(s, COOC H 3 ), 3.68-3.66 (m, 5-...

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Abstract

The invention provides a sialic acid analog with obvious activity of inhibiting influenza virus and application of the sialic acid analog to preparation of anti-influenza-virus medicaments. Zanamivir serves as a lead compound; and a C6 position side chain in the molecular structure is modified, so that a novel zanamivir analog of which the C6 position is provided with an amino side chain and a C6position side chain is provided with hydrophilic hydroxyl is obtained. A vitro anti-virus activity research is performed on the compound. The result shows that the compound in vitro has obvious activity of inhibiting the influenza virus. Therefore, the sialic acid analog is expected to be applied to preparation of the anti-influenza-virus medicaments.

Description

[0001] This patent application is a divisional application of CN200810198787.1. The filing date of the original application CN200810198787.1 is September 26, 2008. The name of the invention is: sialic acid analogs and their application in the preparation of anti-influenza virus drugs. technical field [0002] The invention relates to the technical field of chemistry, in particular to a group of sialic acid analogues; the invention also relates to the application of the compounds in the preparation of antiviral drugs. Background technique [0003] Influenza is a common respiratory disease that can debilitate the patient and cause various complications, sometimes requiring hospitalization and possibly death. It is highly contagious, and it is easy for the elderly and infirm with weaker resistance to infect each other , causing a certain range of popularity. Annual influenza epidemics can cause 3 to 5 million severe cases and result in 300,000 to 500,000 deaths. People older t...

Claims

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Application Information

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IPC IPC(8): C07D309/28C07D405/08C07D407/06A61K31/5377A61K31/453A61K31/4025A61P31/16A61P11/00
Inventor 张健存仪明君刘燕赵宇陈凌
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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