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2-hydroxy-4-oxo-2-butenoic acid compound and pharmaceutical application thereof

A technology of compound and hydroxyl, which is applied in the field of preparation of intermediates or prodrugs of compounds, anti-influenza pharmaceutical applications, and can solve problems such as unclear mechanism of action, complex and changeable traditional Chinese medicine ingredients, and poor reproducibility

Inactive Publication Date: 2013-06-19
TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For chemically synthesized compounds, most of them have problems such as poor reproducibility and difficult synthesis. On the other hand, the ingredients of traditional Chinese medicine are complex and changeable. There can be hundreds of compounds extracted from a single Chinese medicine, and the active ingredients against avian influenza are often dozens of kinds. , the mechanism of action is unclear

Method used

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  • 2-hydroxy-4-oxo-2-butenoic acid compound and pharmaceutical application thereof
  • 2-hydroxy-4-oxo-2-butenoic acid compound and pharmaceutical application thereof
  • 2-hydroxy-4-oxo-2-butenoic acid compound and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of compound 4-[(1-tert-butoxycarbonyl-4-benzenesulfonyl)-piperidin-4-yl]-2-hydroxy-4-oxo-2-butenoic acid

[0065] A. Sodium chloride (4.2g, 0.105mmol) was dissolved in 10ml chloroform and 12.5ml water, and pipecolic acid ethyl ester (2.48g, 15.8mmol) and di-tert-butyl dicarbonate (3.63g, 16.6mmol), heated to reflux and stirred for 2.5h, cooled to room temperature, separated the organic phase, extracted the aqueous phase with chloroform (2×35ml), combined the organic phases, dried overnight with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a light yellow oily liquid 1 .

[0066] B. Preparation of fresh LDA. Add a certain amount of dry diisopropylamine solvent, cool to -78°C, add an equal amount of n-butyllithium, continue stirring at this temperature for 0.5h, and add a certain amount of dry tetrahydrofuran during the reaction. Fresh LDA (2.31mmol) was dissolved in 10ml of dry tetrahydrofuran, cooled to -78°C, and 1-tert-butyloxyc...

Embodiment 2

[0084]Preparation of compound 4-[(1-benzyl-4-benzenesulfonyl)-piperidin-4-yl]-2-hydroxy-4-oxo-2-butenoic acid

[0085] A. Sodium chloride (4.2g, 0.105mmol) was dissolved in 10ml chloroform and 12.5ml water, and pipecolic acid ethyl ester (2.48g, 15.8mmol) and di-tert-butyl dicarbonate (3.63g, 16.6mmol), heated to reflux and stirred for 2.5h, cooled to room temperature, separated the organic phase, extracted the aqueous phase with chloroform (2×35ml), combined the organic phases, dried overnight with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a light yellow oily liquid 1 .

[0086] B. Preparation of fresh LDA. Add a certain amount of dry diisopropylamine solvent, cool to -78°C, add an equal amount of n-butyllithium, continue stirring at this temperature for 0.5h, and add a certain amount of dry tetrahydrofuran during the reaction. Fresh LDA (2.31mmol) was dissolved in 10ml of dry tetrahydrofuran, cooled to -78°C, and 1-tert-butyloxycarbonyl pipeco...

Embodiment 3

[0105] Preparation of compound 4-[(1-tert-butoxycarbonyl-4-p-fluorobenzenesulfonyl)-piperidin-4-yl]-2-hydroxy-4-oxo-2-butenoic acid

[0106] A. Sodium chloride (4.2g, 0.105mmol) was dissolved in 10ml chloroform and 12.5ml water, and pipecolic acid ethyl ester (2.48g, 15.8mmol) and di-tert-butyl dicarbonate (3.63g, 16.6mmol), heated to reflux and stirred for 2.5h, cooled to room temperature, separated the organic phase, extracted the aqueous phase with chloroform (2×35ml), combined the organic phases, dried overnight with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a light yellow oily liquid 1 .

[0107]B. Preparation of fresh LDA. Add a certain amount of dry diisopropylamine solvent, cool to -78°C, add an equal amount of n-butyllithium, continue stirring at this temperature for 0.5h, and add a certain amount of dry tetrahydrofuran during the reaction. Fresh LDA (2.31mmol) was dissolved in 10ml of dry tetrahydrofuran, cooled to -78°C, and 1-tert-bu...

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PUM

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Abstract

The invention discloses a compound shown as a general formula (I) with an anti-influenza effect, an active pharmaceutical ingredient of a pharmaceutically acceptable salt of the compound, and a preparation method of the compound. The compound shown as the general formula (I) can directly inhibit activity of endonuclease for a PA_N target, can kill influenza virus fundamentally, and is used for preparing anti-influenza drugs.

Description

technical field [0001] The present invention relates to a 2-hydroxy-4-oxo-2-butenoic acid compound and a pharmaceutically acceptable salt thereof, as a compound for inhibiting endonuclease activity and an anti-influenza preparation aimed at the PA_N target, and Pharmaceutical use for anti-influenza use alone or in combination with other active compounds. The invention further relates to processes for the preparation of these compounds, with respect to compounds of general formula (VIII), which serve as intermediates or prodrugs for the preparation of compounds of formula (I). Background technique [0002] Influenza virus belongs to the Orthomyxoviridae family and is an enveloped single-stranded RNA virus, which can be divided into three parts: envelope, matrix protein (M protein) and core from outside to inside. The influenza virus genome contains 8 RNA segments known to encode 11 viral proteins. Among them, the polymerase complex composed of three subunits, PA, PB1 and PB...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/54A61K31/445A61P31/16
Inventor 饶子和杨诚娄智勇路支超杨猛王丽君姚伟利刘伟
Owner TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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