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Condensed polycyclic pyridone derivative and application thereof

A technology of polycyclic pyridone and derivatives, applied in the directions of active ingredients of heterocyclic compounds, organic chemistry, antiviral agents, etc., can solve the problems of low immunity and low efficacy in young children

Active Publication Date: 2021-06-04
HUNAN NANXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Influenza vaccination is the main preventive method and is highly effective, but it has the disadvantage that it must be injected once a year and is less effective for immunocompromised and high-risk adults and young children
However, influenza virus drug resistance will inevitably appear, and small molecules with different chemical structures targeting the same target may have different drug resistance, so it is still necessary to develop new influenza virus nuclease endonuclease inhibitors

Method used

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  • Condensed polycyclic pyridone derivative and application thereof
  • Condensed polycyclic pyridone derivative and application thereof
  • Condensed polycyclic pyridone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and 2

[0191] (2S, 4aS, 14aR, 14bR)-14-((S)-10-fluoro-6-hydrogen-11-deuterodibenzo[b,e]thieheptin-11-yl)-9-hydroxyl-1 , 3,4,5,6,14,14a,14b-octahydro-2H-2,4a-epoxypyrido[1',2':1,6][1,2,4]triazino[ 3,4-a]isoquinoline-8,10-dione [compound 1] and (2S,4aS,14aR,14bR)-14-((R)-10-fluoro-6-hydrogen-11-deuterodione Benzo[b, e]thieheptin-11-yl)-9-hydroxyl-1,3,4,5,6,14,14a,14b-octahydro-2H-2,4a-epoxypyrido[ 1',2': 1,6][1,2,4]triazino[3,4-a]isoquinoline-8,10-dione [compound 2]

[0192] The synthetic route is as follows:

[0193]

[0194] Step 1: DMF (300 mL) intermediate 1-1 (50 g, 521 mmol) and nitromethane (32 g, 521 mmol) were added to a round bottom flask. NaOH (62.4 g, 1.56 mmol) was added at 0°C. Stirring of the resulting mixture was continued at room temperature for 2 hours. The reaction was quenched with water, then concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and ...

Embodiment 3 and 4

[0210] (2S, 4aS, 14aR, 14bR)-14-((S)-10-fluoro-6,6-dideutero-11-hydrodibenzo[b,e]thiepin-11-yl)-9- Hydroxy-1,3,4,5,6,14,14a,14b-octahydro-2H-2,4a-epoxypyrido[1',2':1,6][1,2,4]tri Azino[3,4-a]isoquinoline-8,10-dione [compound 3] and (2S,4aS,14aR,14bR)-14-((R)-10-fluoro-6,6-di Deuterium-11-hydrodibenzo[b,e]thieheptin-11-yl)-9-hydroxy-1,3,4,5,6,14,14a,14b-octahydro-2H-2,4a -epoxypyrido[1',2':1,6][1,2,4]triazino[3,4-a]isoquinoline-8,10-dione [Compound 4]

[0211] The synthetic route is as follows:

[0212]

[0213] Step 1: Add Intermediate 1-14 (200 mg, 0.41 mmol) and Intermediate 3-1 (300 mg, 0.41 mmol) to a round bottom flask A stirred solution of T3P (1.8 mL) and EtOAc (2 mL) was added methanesulfonic acid ( 39 mg, 0.41 mmol). Stirred at 50 °C for 24 hours. Quenched the reaction with H2O. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure t...

Embodiment 5 and 6

[0216] (2S, 4aS, 14aR, 14bR)-14-((S)-10-fluoro-6,6-dideutero-11-deuterodibenzo[b,e]thiepin-11-yl)-9- Hydroxy-1,3,4,5,6,14,14a,14b-octahydro-2H-2,4a-epoxypyrido[1',2':1,6][1,2,4]tri Azino[3,4-a]isoquinoline-8,10-dione [compound 5] and (2S,4aS,14aR,14bR)-14-((R)-10-fluoro-6,6-di Deuterium-11-deuterodibenzo[b,e]thieheptin-11-yl)-9-hydroxy-1,3,4,5,6,14,14a,14b-octahydro-2H-2,4a -epoxypyrido[1',2':1,6][1,2,4]triazino[3,4-a]isoquinoline-8,10-dione [Compound 6]

[0217] The synthetic route is as follows:

[0218]

[0219] Step 1: Intermediate 1-14 (150 mg, 0.31 mmol) and Intermediate 5-1 (225 mg, 0.31 mmol) were added to a round bottom flask A stirred solution of T3P (1.35 mL) and EtOAc (1.5 mL) was added methanesulfonic acid (30 mg, 0.31 mmol). Stirred at 50°C for 24 hours. Quenched the reaction with H2O. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduce...

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Abstract

The invention belongs to the field of medicines, and particularly relates to a fused polycyclic pyridone derivative as shown in a formula I, pharmaceutically acceptable salts, solvates, including hydrates, polycrystals, prodrugs, eutectics, tautomers and stereoisomers thereof, and application of the fused polycyclic pyridone derivative and the pharmaceutically acceptable salts, the solvates, the tautomers and the stereoisomers. Particularly, the compound provided by the invention can be used as an anti-influenza drug with a CEN inhibition effect.

Description

[0001] field of invention [0002] The invention belongs to the field of medicines, in particular to a fused polycyclic pyridone derivative and its application. More specifically, the compounds described in the present invention can be used as anti-influenza drugs with CEN inhibitory effect. Background technique [0003] Influenza is a highly contagious respiratory disease caused by influenza viruses. Among them, influenza A virus has the widest host range, which can infect both poultry and mammals, and can easily cause a worldwide pandemic. There have been four major influenza outbreaks (1918, 1957, 1968, 2009) in the past century. Among them, the "Spanish flu" (H1N1) that broke out in 1918 directly caused about 50 million deaths, which was the flu outbreak with the largest number of deaths in human history. The most recent "Mexican flu" (A / 2009 / H1N1) that broke out in 2009 spread rapidly to 214 countries around the world, killing about 200,000 people within 12 months of th...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/53A61P31/16A61P31/12
CPCA61P31/12A61P31/16C07D491/22
Inventor 王永钢林寨伟廖辉胡双华张世喜杨文逊
Owner HUNAN NANXIN PHARMA CO LTD
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