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Influenza virus replication inhibitor and uses thereof

A technology of solvates and compounds, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc., to achieve excellent in vivo pharmacodynamic properties, good influenza virus, and good druggability

Active Publication Date: 2020-04-24
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to all these drugs, influenza viruses have developed resistance

Method used

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  • Influenza virus replication inhibitor and uses thereof
  • Influenza virus replication inhibitor and uses thereof
  • Influenza virus replication inhibitor and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0286] Example 1: (R)-12-((S)-9,10-difluoro-6,11-dihydrobenzo[e]thieno[3',2':5,6]benzo[1 ,2-b]thiepan-6-yl)-7-hydroxyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[ 2,1-f][1,2,4]triazine-6,8-dione and (S)-12-((R)-9,10-difluoro-6,11-dihydrobenzo[e ]thieno[3',2':5,6]benzo[1,2-b]thiepan-6-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- Mixture of [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8dione Mixture:

[0287]

[0288] Step 1): 7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] Synthesis of [1,2,4]triazine-6-,8-dione

[0289]

[0290] The title compound was prepared by referring to the synthesis method disclosed in the patent application WO 2016175224.

[0291] Step 2): Synthesis of benzo[b]thiophene-7-thiol

[0292] 7-Bromobenzothiophene (5.00g, 23.5mmol) was added into THF (50mL), cooled to -78°C, sulfur powder (0.79g, 25mmol) was added, and stirred at this temperature for 0.5 hours. A tetrahydrofuran solution of tert-butyllithium (3...

Embodiment 2

[0315] Example 2 (R)-12-((S)-9,10-difluoro-6,11-dihydrobenzo[e]thieno[3',2':5,6]benzo[1, 2-b]thiepan-6-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2 ,1-f][1,2,4]triazine-6,8 dione (2-1) and (R)-12-((R)-9,10-difluoro-6,11-dihydro Benzo[e]thieno[3',2':5,6]benzo[1,2-b]thiepan-6-yl)-7-hydroxy-3,4,12,12a-tetra Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2-2)

[0316]

[0317] Step 1): (R)-7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, Synthesis of 1-f][1,2,4]triazine-6,8-dione

[0318]

[0319] The title compound was prepared by referring to the synthesis method disclosed in the patent application WO 2017221869.

[0320] Step 2): (12aR)-7-(benzyloxy)-12-(9,10-difluoro-6,11-dihydrobenzo[e]thieno[3', 2':5,6]benzo[1,2-b]thiepan-6-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3, 4-c]pyrido Synthesis of [2,1-f][1,2,4]triazine-6,8-dione

[0321] 9,10-difluoro-6,11-dihydrobenzo[e]thieno[3',2':5,6]benzo[1...

Embodiment 3

[0331] Example 3 (R)-12-((S)-9,10-difluoro-6,11-dihydrobenzo[5,6]thiepano[3,2-g]benzofuran- 6-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4] Triazine-6,8-dione (3-1) and (R)-12-((R)-9,10-difluoro-6,11-dihydrobenzo[5,6]sulfur Heptacyclo[3,2-g]benzofuran-6-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4- c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (3-2)

[0332]

[0333] Step 1): Synthesis of Benzofuran-7-thiol

[0334] Dissolve 7-bromobenzofuran (7.00g, 35.50mmol), sulfur (1.19g, 37.20mmol) in THF (5mL), under nitrogen protection, stir at -78°C for 20 minutes, then add tert-butyllithium (55.00 mL, 72.00 mmol, 1.30 mol / L) was slowly added dropwise to the above reaction solution, and the reaction was continued at this temperature for 1 hour. Stop the reaction, add the reaction solution into saturated ammonium chloride solution (50mL), extract with diethyl ether (50mL×2), combine the organic phase, extract the obtained organic phase w...

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Abstract

The invention belongs to the field of medicines, and particularly relates to a new compound serving as an influenza virus replication inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in the treatment of influenza. The compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the compound shown in the formula (I). The compound can well inhibit influenza viruses, and / or has lowercytotoxicity, more excellent in-vivo metabolic dynamics properties and in-vivo pharmacodynamic properties.

Description

[0001] field of invention [0002] The invention belongs to the field of medicine, and specifically relates to a novel compound as an influenza virus replication inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound and the pharmaceutical composition in treating influenza. More specifically, the compounds of the present invention can be used as inhibitors of influenza virus cap-dependent endonuclease (cap-dependent endonuclease). Background technique [0003] Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously endangers human health. It is caused by influenza virus and has the characteristics of high prevalence, widespread prevalence and rapid transmission. Influenza viruses can cause severe symptoms, such as pneumonia or heart and lung failure, in the elderly and children with weakened immune systems and some patients with immune disorders. The f...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/53A61P31/16
CPCC07D519/00A61P31/16C07D498/14A61K45/06
Inventor 罗慧超任青云殷俊俊吴春林范钰新莫玉峰张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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