Pyridone derivative and composition thereof, and application of pyridone derivative as anti-influenza virus medicine

A kind of derivative, pyridone technology, applied in pyridone derivative, its composition and application field as anti-influenza virus drug, can solve the problem such as suspicious curative effect of severe patients

Pending Publication Date: 2020-06-19
JIANGXI CAISHI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Neuraminidase inhibitors Oseltamivir (Oseltamivir) and Zanamivir (Zanamivir) can suppress virus budding and release, but the clinical efficacy of neuraminidase inhibitors for severe patients is doubtful, and there are widely The drug resistance of neuraminidase inhibitors is also a problem that must be considered

Method used

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  • Pyridone derivative and composition thereof, and application of pyridone derivative as anti-influenza virus medicine
  • Pyridone derivative and composition thereof, and application of pyridone derivative as anti-influenza virus medicine
  • Pyridone derivative and composition thereof, and application of pyridone derivative as anti-influenza virus medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Embodiment 1: preparation compound I-1

[0161]

[0162] 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, namely compound 1b.

[0163] 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 prod...

Embodiment 2

[0170] Embodiment 2: preparation compound 1-5

[0171]

[0172] Preparation of compound 2b: compound 1h (180mg, 0.49mmol) and 2a (264mg, 1.0mmol) were reacted in a solution of T3P in ethyl acetate at 100°C for 3 hours in a sealed manner. Cool, add saturated NaHCO 3 The aqueous solution was diluted and extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and separated on a preparative plate to obtain 190 mg of product. ESI-MS m / z 612.2(M+H) + .

[0173] Preparation of compound I-5: compound 2b (190 mg, 0.31 mmol) and lithium chloride (50 mg, 1.18 mmol) were reacted in 5 mL DMA at 100° C. for 3 hours. After the reaction is complete, add 10 mL of water to dilute, and adjust the pH to 5-6 with 2N hydrochloric acid. After filtration, the solid was sucked dry to obtain 136 mg of product. 1 HNMR (400MHz, CDCl 3 )δ: 7.04-7.12(m, 3H), 7.00-7.02(d, 1H, J=7.6Hz), 6.90-6.93(m, 1H), 6.79-6.83(m, 1H), 6.63-6.64(d, 1H, J=7.2Hz), 5.74-5.76(d, 1H, J=7...

Embodiment 3

[0174] Embodiment 3: preparation compound I-7

[0175]

[0176] Preparation of compound 3b: Compound 3a (5.0g, 27.8mmol) was added into n-butyl vinyl ether (10mL), then palladium trifluoroacetate (100mg, 0.3mmol), triethylamine (3.03g, 30mmol) and DPPP (124mg, 0.3mmol), closed the reaction, stirred overnight at 75°C, TLC showed that the reaction was complete. Add 50mL of water, extract twice with ethyl acetate, wash the organic phase with saturated brine and dry over anhydrous sodium sulfate, concentrate and separate by column chromatography to obtain 4.8g of the product, which is directly used in the next step.

[0177] Preparation of compound 3c: Compound 3b (4.8g, 23.3mmol) was dissolved in 50mL of anhydrous toluene, and 1N diethylzinc solution (70mL, 70mmol) was added at -40°C under nitrogen protection. After the addition was completed, the reaction was stirred for 1 h, and chloroiodomethane (8.22 g, 46.6 mmol) was added. After the addition, continue to stir the react...

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PUM

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Abstract

The invention belongs to the field of medical chemistry antivirus, and relates to a novel pyridone derivative represented by formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, and application of the novel pyridone derivative or the stereoisomer, the pharmaceutically acceptable salt, the solvate or the crystal thereof in preparation of drugs for prevention or treatment of influenza A type or / and influenza B type and other viral infection diseases, particularly application as a PA subunit cap dependent endonuclease inhibitor in prevention or treatment of influenza A type or / and influenza B type viral infection diseases. The compound disclosed by the invention has remarkable activity of inhibiting influenza incision enzyme and influenza DNA, canbe used alone or in combination with a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, an M2 inhibitor or other anti-influenza drugs, significantly shortens the time ofinfluenza infection and reduces the mortality, and has excellent 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 medicine for preparing cap dependent endonuclease inhibitor (Cap dependent endonuclease 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 infectious disease caused by infection with influenza virus. Influenza can kill thousands of people every year, and large flu outbreaks can kill millions worldwide. Although influenza vaccines and antiviral drugs such as amantadine can be used to prevent and treat influenza, their p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D498/20C07D498/22C07D498/14C07D471/14C07D471/22C07D491/22C07D519/00C07F9/6561A61K31/53A61K31/5365A61K31/537A61K31/675A61K31/683A61P31/12A61P31/16
CPCC07D471/04C07D498/20C07D498/22C07D498/14C07D471/14C07D471/22C07D491/22C07D519/00C07F9/65616A61P31/12A61P31/16
Inventor 陈力邵庆翟培斌武进薛晓剑李晓闻
Owner JIANGXI CAISHI PHARMA TECH CO LTD
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