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Novel heterocyclic compounds and medicinal application of same as anti-influenza virus inhibitors

A kind of technology of heterocyclic compound and medicinal salt, applied in the application field of medicine

Inactive Publication Date: 2019-02-26
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the analysis of the inhibition of the virus in the lung by the two inhibitors, it is doubtful whether neuraminidase inhibition is effective, but the PB2 inhibitor has a significant inhibitory effect

Method used

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  • Novel heterocyclic compounds and medicinal application of same as anti-influenza virus inhibitors
  • Novel heterocyclic compounds and medicinal application of same as anti-influenza virus inhibitors
  • Novel heterocyclic compounds and medicinal application of same as anti-influenza virus inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1: Preparation of (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylpyrimidine-4- base)amino)-4,4-dimethylpentanoic acid (I-1)

[0089]

[0090] Preparation of compound 2: N-bromosuccinimide (NBS, 5.29g, 29.7mmol) was added to a solution of compound 1 (4.50g, 33mmol) in dichloromethane (100mL) and reacted at room temperature for 19 hours, After the reaction was completed, saturated sodium bisulfite solution (200ml) was added, the layers were separated, the organic layer was washed with 20% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain 4.62g of crude product.

[0091] Preparation of Compound 3: Compound 2 (4.40 g, 20.4 mmol) was dissolved in 30 mL of dry DMF, sodium hydrogen (1.30 g, 32.6 mol) was added and stirred for 30 minutes. Then p-toluenesulfonyl chloride (TsCl, 5.78 g, 30.6 mmol) was added and reacted for 4 hours. After the reaction was completed, it wa...

Embodiment 2

[0099] Example 2: Preparation of (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)- 4,4-Dimethyl-N-(methylsulfonyl)pentanamide (I-65)

[0100]

[0101] Preparation of Compound 11: Compound 4 (1.40g, 3.36mmol), 2-chloro-4-thiomethyl-5-fluoropyrimidine (0.50g, 2.80mmol), Pd2(dba)3 (0.26g, 0.28mmol), X-phos (0.67g, 1.4mmol) and sodium carbonate (0.89g, 8.40mmol) were dissolved in 25mL of ethylene glycol dimethyl ether and 5mL of water, nitrogen bubbling for 30 minutes to remove the oxygen in the system, heated to reflux for 19 hours, cooled After reaching room temperature, the reaction solution was poured into 100 mL of water, filtered, the filter cake was washed with water, and then recrystallized with acetonitrile to obtain 1.10 g of the product. Yield: 75.7%.

[0102] Preparation of Compound 12: At 0°C, m-chloroperoxybenzoic acid (MCPBA, 85%, 0.71g, 3.48mmol) was added in batches to a solution of Compound 11 (0.60g, 1.39mmol) in dichlorometh...

Embodiment 3

[0108] Example 3. In vitro biological activity studies and cytotoxicity studies

[0109] Compounds to be tested: compounds of the present invention: compound I-1, compound I-65; reference compound: VX-787.

[0110] Test method for in vitro biological activity research: MDCK cells were seeded into 384-well cell culture plates at a density of 2,000 cells per well, and then placed at 37°C, 5% CO 2 Incubate overnight in the incubator. The next day, the compounds were diluted and added to the cell wells (3-fold dilution, 8 test concentration points), and then the influenza virus A / PR / 8 / 34 (H1N1) strain was added to the cell culture wells at 2*TCID90 per well , the final concentration of DMSO in the medium was 0.5%. Place the cell plate at 37°C, 5% CO 2 Cultured in the incubator for 5 days. After 5 days of culture, the cell viability was detected using the cell viability detection kit CCK8. The original data was analyzed by nonlinear fitting of the inhibitory rate and cytotoxic...

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Abstract

The invention provides heterocyclic compounds represented by a formula (I) as described in the specification or a pharmaceutically acceptable salt thereof, a preparation method thereof, and application of the heterocyclic compounds to the preparation of medicines used for treating or preventing influenza A viruses. The compounds can inhibit the transcription and synthesis of RNAs of influenza viruses and are a PB2 inhibitor.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of heterocyclic compounds, heterocyclic compound salts, preparation methods thereof and application as medicines for treating and preventing influenza virus. Background technique [0002] Influenza is a potentially fatal infectious disease with high morbidity and mortality and a significant burden on the healthcare system. Every year, 5-20% of the population is infected with influenza virus, causing other complications such as breathing or heart, causing hundreds of thousands of deaths worldwide every year, and millions of people may die in the event of an influenza pandemic. Influenza in the 20th century Big eruptions have killed tens of millions of people. These pandemic flus are all caused by mutations in influenza viruses in animals, which spread from animal species to humans. [0003] Influenza viruses belong to the RNA viruses of the family Orthomyxo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D401/04C07D403/04C07D519/00A61K31/506A61K31/4985A61K31/519A61K31/4439A61K31/444A61P31/16
CPCC07D401/04C07D403/04C07D471/04C07D487/04C07D519/00
Inventor 陈力邵庆江涛武进
Owner GINKGO PHARMA
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