Pyridone derivative, composition thereof and application thereof as Anti-influenza drug

一种衍生物、吡啶酮的技术，应用在吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用领域，能够解决重症患者疗效可疑等问题

Active Publication Date: 2019-12-31
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, composition thereof and application thereof as Anti-influenza drug
  • Pyridone derivative, composition thereof and application thereof as Anti-influenza drug
  • Pyridone derivative, composition thereof and application thereof as Anti-influenza drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Embodiment 1: preparation compound I-1

[0193]

[0194] 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.

[0195]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 pro...

Embodiment 2

[0202] Embodiment 2: preparation compound 1-5

[0203]

[0204] 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) + .

[0205] 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

[0206] Embodiment 3: preparation compound I-7

[0207]

[0208] 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 at 75°C overnight, 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.

[0209] 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 and the reaction was stirred for 1 h, chloroiodomethane (8.22 g, 46.6 mmol) was added. After the addition, continue to stir the reacti...

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PUM

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Abstract

The present invention relates to the field of medical chemistry, and relates to a novel pyridone derivative represented by formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, asolvate or a crystal thereof, and an application thereof in the preparation of a drug for preventing or treating viral infectious diseases such as influenza A or / and influenza B, in particular an application thereof as a PA subunit cap-dependent endonuclease inhibitor for preventing or treating influenza A and / or influenza B viral infectious diseases. The compound of the present invention has significant activity in inhibiting influenza endonuclease and influenza DNA, and may be used alone or in combination with a neuraminidase inhibitor, a nucleoside drug, a PB2 inhibitor, a PB1 inhibitor, anM2 inhibitor or other anti-influenza drugs, significantly shortening the time of influenza infection, reducing mortality, and having excellent clinical application prospects.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a novel pyridone derivative or its stereoisomer, pharmaceutically acceptable salt, solvate or crystal, containing the aforementioned pyridone derivative or its stereoisomer, pharmaceutically acceptable salt , solvates or crystalline pharmaceutical compositions and their use as antiviral drugs, especially as a drug for the preparation of cap-dependent endonuclease inhibitors (Cap dependent endonuclease inhibitor) for the prevention and / or treatment of influenza virus infection Uses, specifically, for example, the use for preparing medicines for preventing and / or treating influenza virus type A and influenza virus type B 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. A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D471/22C07D498/14C07D498/20C07D498/22C07D491/22C07F9/6561A61K31/53A61K31/5383A61K31/5386A61K31/675A61K31/685A61P31/16
CPCC07D471/04C07D498/20C07D498/22C07D498/14C07D471/14C07D471/22C07D491/22C07D519/00C07F9/65616A61P31/12A61P31/16A61K45/06A61K31/53A61K2300/00A61K31/5365
Inventor 陈力邵庆翟培彬武进薛晓剑李晓闻
Owner JIANGXI CAISHI PHARMA TECH CO LTD
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