Pyridine derivative, composition thereof and application of pyridine derivative and composition as anti-influenza virus drug

A derivative, pyridone technology, applied in the direction of antiviral agents, active ingredients of silicon compounds, active ingredients of heterocyclic compounds, etc., can solve the problems of doubtful efficacy of neuraminidase inhibitors and ineffectiveness in severe patients

Active Publication Date: 2019-07-23
JIANGXI CAISHI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The neuraminidase inhibitors Oseltamivir and Zanamivir can suppress viral budding and release, but the clinical efficacy of neuraminidase inhi...

Method used

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  • Pyridine derivative, composition thereof and application of pyridine derivative and composition as anti-influenza virus drug
  • Pyridine derivative, composition thereof and application of pyridine derivative and composition as anti-influenza virus drug
  • Pyridine derivative, composition thereof and application of pyridine derivative and composition as anti-influenza virus drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Embodiment 1: Preparation (I-1)

[0104]

[0105] Preparation of Compound 1b: Compound 1a (2.0 g, 8.1 mmol), DBU (1.85 g, 12.2 mmol) and ethyl iodide (2.28 g, 14.6 mmol) were reacted in 20 mL of DMF at room temperature for 16 hours. Then add 100mL water to dilute and extract with EA. The organic phases were combined, washed successively with sodium thiosulfate, 0.5N HCl and saturated brine, dried over anhydrous sodium sulfate and spin-dried to obtain 2.1 g of an oily product.

[0106] The preparation of compound 1c: compound 1b (2.1g, 7.7mmol), Boc hydrazine (1.53g, 11.6mmol) and pyridine p-toluenesulfonate (5.78g, 23.1mmol) in N,N-dimethylacetamide (20mL ) at 60°C for 16 hours. After the reaction was completed, 100 mL of water was added to the reaction liquid, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by colu...

Embodiment 2

[0113] Embodiment 2: Preparation (I-26)

[0114]

[0115] Preparation of compound 26b: Compound 1d (360 mg, 1 mmol), 26a (116 mg, 1.2 mmol), TEA (303 mg, 3.0 mmol) and HATU (570 mg, 1.5 mmol) were stirred overnight in DCM at room temperature, then diluted with water, and extracted with DCM. The organic phases were combined, washed with saturated brine, dried and concentrated, and separated by column chromatography to obtain 320 mg of white solid. ESI-MS m / z 440.2(M+H) +

[0116] Preparation of compound 26c: Compound 26b (320 mg, 0.73 mmol) was dissolved in 4 mL of DCM, 1 mL of TFA was added and reacted at 0° C. for 6 hours. Spin dry, add 1N NaOH to adjust to basicity, and extract with DCM / iPrOH. The organic phases were combined, washed with saturated brine, dried and concentrated to obtain 195 mg of an oil, which was directly used in the next step.

[0117] Preparation of Compound 26d: Compound 26c (195 mg, 0.57 mmol) was dissolved in 5 mL of toluene, 30 mg of paraforma...

Embodiment 3

[0120] Embodiment 3: Preparation (I-27)

[0121]

[0122] Preparation of compound 27b: Compound 1d (360mg, 1mmol), 27a (136mg, 1.2mmol), TEA (303mg, 3.0mmol) and HATU (570mg, 1.5mmol) were stirred overnight in DCM at room temperature, then diluted with water, and extracted with DCM. The organic phases were combined, washed with saturated brine, dried and concentrated, and separated by column chromatography to obtain 345 mg of a yellow solid. ESI-MS m / z 456.2(M+H) +

[0123] Preparation of Compound 27c: Compound 27b (345 mg, 0.76 mmol) was dissolved in 4 mL of DCM, 1 mL of TFA was added and reacted at 0° C. for 6 hours. Spin dry, add 1N NaOH to adjust to basicity, and extract with DCM / iPrOH. The organic phases were combined, washed with saturated brine, dried and concentrated to obtain 170 mg of oil, which was directly used in the next step.

[0124] Preparation of Compound 27d: Compound 27c (170 mg, 0.48 mmol) was dissolved in 5 mL of toluene, 30 mg of paraformaldehyde ...

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PUM

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Abstract

The invention belongs to the antiviral field of medical chemistry and relates to a novel pyridine derivative shown in a formula (I), a stereisomer, pharmaceutical salt, a solvent compound or a crystalof the pyridine derivative and an application of the pyridine derivative and the stereisomer, pharmaceutical salt, the solvent compound or the crystal in preparing drugs for preventing or treating viral infection diseases such as influenza A and/or influenza B, particularly in preparing a cap dependent endonuclease inhibitor in preventing or treating influenza A and/or influenza B viral infectiondiseases. The compound has remarkable activity for inhibiting influenza endonuclease and influenza DNA, can be independently used or can be combined with a neuraminidase inhibitor, nucleoside medicines, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor or other anti-influenza drugs, the influenza infection time is notably shortened, the death rate is remarkably reduced, and the pyridine derivative has very good clinical application prospects.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, in particular to a class of novel pyridone derivatives or their stereoisomers, pharmaceutical compositions containing the aforementioned pyridone derivatives or their stereoisomers and their use as antiviral drugs, especially Use as a medicament for preparing cap dependent endoclease inhibitor (Cap dependent endoclease inhibitor) for the prevention and / or treatment of influenza virus infection, specifically for the preparation of prevention and / or treatment of influenza virus type A and influenza virus B The use of drugs for type infections. Background technique [0002] Influenza is an acute respiratory infection caused by influenza virus. Influenza can kill thousands of people every year, and large flu outbreaks can kill millions worldwide. Although influenza vaccine and amantadine can be used to prevent and treat influenza, their prevention and efficacy are very limited, and a broa...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00C07D498/20C07D498/22C07D471/14C07D498/14C07D487/04C07D471/22C07F7/10A61K31/53A61K31/5383A61K31/5386A61K31/519A61K31/5025A61K31/695A61P31/16
CPCC07D471/04C07D519/00C07D498/20C07D498/22C07D471/14C07D498/14C07D487/04C07D471/22C07F7/0816
Inventor 陈力邵庆武进薛晓剑
Owner JIANGXI CAISHI PHARMA TECH CO LTD
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