Heterocyclic compounds, their compositions and their use as anti-influenza virus drugs

A heterocyclic compound and composition technology, applied in the field of medicinal chemistry, can solve problems such as poor water solubility, increased activity, complex structure, etc., and achieve the effects of improved activity, strong druggability, and enhanced interaction

Active Publication Date: 2021-02-26
SUZHOU YUANZHI PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the prior art, although some PB2 inhibitors have been reported in the literature, their structures are relatively complex, their water solubility is poor, and their activity needs to be further improved.

Method used

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  • Heterocyclic compounds, their compositions and their use as anti-influenza virus drugs
  • Heterocyclic compounds, their compositions and their use as anti-influenza virus drugs
  • Heterocyclic compounds, their compositions and their use as anti-influenza virus drugs

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0084] Preparation of compound 2:

[0085] Maleic anhydride (10g, 0.1mol) was dissolved in chloroform (100mL), cooled to 0°C in an ice bath, and 1,3-cyclohexadiene (11.2mL, 0.11mol) was added dropwise to the reaction solution. Warm to room temperature and stir overnight in the dark. The reaction solution was concentrated, methanol (70 mL) was added, heated to 50 °C, stirred for 10 min, cooled to 0 °C in ice bath, stirred for 30 min, filtered and dried to obtain compound 2 (14 g, 71%) as a white solid. 1 H NMR (400MHz, CDCl 3 ):δ6.31-6.32(m,2H),3.21-3.22(m,2H),3.14-3.16(m,2H),1.60-1.64(m,2H),1.59-1.60(m,2H). 13 C NMR (100MHz, CDCl 3 )δ: 172.9, 133.1, 44.6, 31.6, 22.8.

[0086] Preparation of Compound 3:

[0087] Compound 2 (24.6g, 138.0mmol) and quinine (49.2g, 151.6mmol) were suspended in anhydrous toluene (92mL), the reaction solution was cooled to -16°C, absolute ethanol (52.4mL, 898.6mmol) was added dropwise, React at -20°C for 20 h, filter, wash the filter cake with ...

Embodiment 1

[0102]Example 1: Preparation of (2S, 3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylpyrimidine- 4-yl)amino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (I-1)

[0103]

[0104] Preparation of compound 1b:

[0105] Add methylmagnesium bromide (27mL, 0.027mol, 1M tetrahydrofuran solution) into the there-necked flask, cool to 0°C, add compound 1a (2.990g, 0.018mol) in tetrahydrofuran solution (10mL), and stir at 10-15°C for 1h after dropping ; Cooled to 0 ° C, added dropwise successively triethylamine (2.5mL, 0.018mol) and I 2 (4.960 g, 0.018 mol) in THF (60 mL), after the addition, keep stirring at this temperature for 1 h, and then stir overnight at room temperature. Add sodium bisulfite solution to wash, extract with ethyl acetate (150mL) for 3 times, combine the ethyl acetate layers, wash with water (200mL) and saturated brine (200mL) successively, dry over anhydrous sodium sulfate and concentrate, the crude product is washed with silica gel Purified by...

Embodiment 2

[0115] Example 2: Preparation of (2S, 3S)-3-(6-cyclopropyl-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidine -4-yl)amino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (I-7)

[0116]

[0117] Preparation of compound 7b:

[0118] Add cyclopropylmagnesium bromide (27mL, 27.000mmol, 1M tetrahydrofuran solution) into the there-necked flask, cool to 0°C, add compound 1a (2.980g, 17.850mmol) in tetrahydrofuran solution (20mL), and stir at 10-15°C for 1h after dropping , cooled to 0°C, added dropwise triethylamine (2.5mL, 17.850mmol) and I 2 (4.960g, 17.850mmol) in THF (60mL), keep stirring at this temperature for 1h after addition, and then stir overnight at room temperature. Add sodium bisulfite solution for washing, extract with ethyl acetate (150mL) for 3 times, combine the ethyl acetate layers, wash with saturated brine (200mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (PE / EA=100 / 5) was pur...

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Abstract

The present invention provides a class of heterocyclic compounds represented by formula (I) or pharmaceutically acceptable salts thereof, their preparation methods and their application in the preparation of medicines for treating or preventing influenza virus. As novel viral polymerase inhibitors, these compounds can inhibit the transcription and synthesis of type A influenza virus RNA. Compared with existing viral polymerase inhibitors, the compounds of the present invention have significantly better activity and better water solubility And the structure is simpler.

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 deadly infectious disease with high morbidity and mortality. 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 are antisense RNA viruses belonging to the family of Orthomyxoviridae, including five species: A virus, B viru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/506A61P31/16A61P31/12
CPCA61P31/12A61P31/16C07D471/04
Inventor 陈力邵庆甘立斌
Owner SUZHOU YUANZHI PHARM TECH CO LTD
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