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Pyridinone derivatives as selective cytotoxic agents against HIV infected cells

A technology of dihydropyridine and compound, applied in the direction of antiviral agents, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of virus resistance, rapid rebound of viremia, and incurable solutions.

Pending Publication Date: 2022-02-08
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treated patients are at risk of acquiring mutations that make the virus in their bodies resistant to available therapies and seeing a rapid rebound in viremia when off treatment, suggesting that current regimens are not curative

Method used

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  • Pyridinone derivatives as selective cytotoxic agents against HIV infected cells
  • Pyridinone derivatives as selective cytotoxic agents against HIV infected cells
  • Pyridinone derivatives as selective cytotoxic agents against HIV infected cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0426]

[0427] 5-Chloro-2-fluoro-3-((1-((6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo Substituent-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0428] Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-(methoxymethyl)pyridin-3-yl)methyl)-6-oxo Substituent-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0429] To 3-(chloromethyl)-2-methoxy-6-(methoxymethyl)pyridine, C15 (30 mg, 0.149 mmol), 5-chloro-2-fluoro-3-((6-oxo Dioxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile AB04 (35 mg, 0.086 mmol) in DMF (1 mL) K was added to the stirred solution of 2 CO 3 (23.81 mg, 0.172 mmol) and lithium bromide (11.22 mg, 0.129 mmol). The resulting mixture was stirred at 15 °C for 1 h. TLC showed that the reaction was complete and the mixture was washed with H 2 Dilute with O (10 mL) and extract with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), washed wi...

Embodiment 14

[0438]

[0439] 5-(difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( 1, 1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0440] Step 1: 5-(Difluoromethyl)-3-((1-((5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo Substitute-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)-2-methylbenzonitrile

[0441] To 5-(difluoromethyl)-2-methyl-3-((6-oxo-4-(1,1,2,2-tetrafluoroethyl)-1,6-dihydropyrimidine at room temperature -5-yl)oxy)benzonitrile, AB01 (30 mg, 0.080 mmol) and 3-(chloromethyl)-5-fluoro-2-methoxypyridine, C20 (15.36 mg, 0.087 mmol) in NMP ( 795 µL) was added potassium carbonate (21.98 mg, 0.159 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water (3 mL), and extracted with EtOAc (3 mL). The organic layer was concentrated under reduced pressure to give the title compound which was used in the next step without further purification. MS: 517.1 (M+1...

Embodiment 21

[0448]

[0449] 5-chloro-2-fluoro-3-((1-((6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-oxo-4-( Complete Fluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0450] Step 1: 5-Chloro-2-fluoro-3-((1-((2-methoxy-6-methylpyridin-3-yl)methyl)-6-oxo-4-(perfluoro Ethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile

[0451] To 5-chloro-2-fluoro-3-((6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile, AB06 (50 mg, 0.130 mmol) and (2-methoxy-6-methylpyridin-3-yl)methanol, C17 (20.0 mg, 0.13 mmol) in DCM (1303 µL) was added dropwise to an ice-cold solution of DIAD (25.3 µL, 0.130 mmol). The resulting mixture was warmed to room temperature, then washed with saturated NaHCO 3 The aqueous solution was diluted and extracted with DCM. The organic layer was washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / hexanes) to give the title compound. MS: 519....

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Abstract

The present disclosure is directed to pyridinone derivatives of Formula I and their use for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV nave cells, and for the treatment of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC).

Description

[0001] Background of the invention [0002] Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). In the absence of viral suppression, HIV-infected individuals exhibit severe immunodeficiency, making them highly susceptible to debilitating and ultimately fatal opportunistic infections. There are a variety of clinically approved antiretroviral drugs available that exhibit multi-log reductions in viral load. Treated patients are at risk of acquiring mutations that make the virus in their bodies resistant to available therapies and seeing a rapid rebound in viremia when off treatment, suggesting that current regimens are incurable. [0003] HIV is a retrovirus whose life cycle involves the reverse transcription of the viral RNA genome into DNA by an enzyme called reverse transcriptase, and the subsequent integration of that DNA copy into host chromosomal DNA by the virus-encoded integrase. The viral RNA is transcribed and the vira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D403/06A61K31/4412
CPCC07D401/06A61P31/18A61K31/513C07D401/14A61K2300/00A61K45/06A61K31/506
Inventor A·康弗索A·埃尔 马鲁尼A·富尔斯特J·L·弗里D·N·亨特王澄D·王
Owner MERCK SHARP & DOHME BV
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