Phosphoramidate derivatives of nucleoside compounds and uses of derivatives

A compound and alkyl technology, applied in the field of compounds and pharmaceutical compositions for the prevention or treatment of viral infections, enteroviridae viral infections, to achieve good metabolic stability, less toxic and side effects, and good bioavailability

Active Publication Date: 2020-12-01
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research work on anti-new coronavirus drugs is still in its infancy, and there is no clinically effective anti-new coronavirus drug

Method used

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  • Phosphoramidate derivatives of nucleoside compounds and uses of derivatives
  • Phosphoramidate derivatives of nucleoside compounds and uses of derivatives
  • Phosphoramidate derivatives of nucleoside compounds and uses of derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Example 1 Methyl (((((2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methoxy Synthesis of (phenoxy)phosphoryl)-L-alanine ester

[0168]

[0169] Step 1) Synthesis of (chloro(phenoxy)phosphoryl)-L-alanine methyl ester

[0170]

[0171] Weigh (2S)-2-alanine methyl ester hydrochloride (400mg, 2.87mmol) in a 50mL two-necked bottle, add dichloromethane (10 mL) under nitrogen protection and stir at -78°C for 2 minutes, drop Add triethylamine (0.87mL, 6.30mmol), and stir for another two minutes, then dissolve dichlorophosphoryloxybenzene (0.428mL, 2.86mmol) in dichloromethane (10mL), and slowly add it dropwise to the reaction flask, Then keep stirring at -78°C for 30 minutes, warm up to ice bath temperature, and directly use in the next reaction.

[0172] Step 2) Synthesis of ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester

[0173]

[0174] Under ice bath, dissolve 2,3,4,5,6-pentafluorophenol (527mg, 2.86mmol) and t...

Embodiment 2

[0216] Example 2 Isopropyl (((((2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methyl Synthesis of oxy)(phenoxy)phosphoryl)-L-alanine ester

[0217]

[0218]Weigh (2R,3S,4R,5R)-2-(6-amino-9H-purin-9-yl)-4-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol (55mg, 0.20mmol) In a 50mL two-necked flask, add N,N-dimethylformamide (3mL) under nitrogen protection, cool to ice bath temperature, add dropwise a tetrahydrofuran solution of tert-butylmagnesium chloride (0.22mL, 0.22mmol, 1.0mol / L) , stirred at room temperature for 10 minutes after dropping, and added ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (110mg, 0.24mmol) into the reaction flask at ice bath temperature , then returned to room temperature and stirred for 2 hours to stop the reaction, added saturated ammonium chloride aqueous solution (3mL) to quench the reaction, then added ethyl acetate (30mL), washed with water (10mL×3), dried over anhydrous sodium sulfate and conc...

Embodiment 3

[0221] Example 3 Benzyl (((((2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methoxy Synthesis of (phenoxy)phosphoryl)-L-alanine ester

[0222]

[0223] Step 1) Synthesis of (chloro(phenoxy)phosphoryl)-L-alanine benzyl ester

[0224]

[0225] Weigh (2S)-2-alanine benzyl ester hydrochloride (800mg, 3.71mmol) in a 50mL two-necked bottle, add dichloromethane (20 mL) under nitrogen protection and stir at -78°C for 2 minutes, drop Add triethylamine (1.10mL, 7.90mmol), and stir for another two minutes, then dissolve dichlorophosphoryloxybenzene (0.55mL, 3.71mmol) in dichloromethane (10mL), and slowly add it dropwise to the reaction flask, Then keep stirring at -78°C for 30 minutes, warm up to ice bath temperature, and directly use in the next reaction.

[0226] Step 2) Synthesis of ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine benzyl ester

[0227]

[0228] Under ice bath, dissolve 2,3,4,5,6-pentafluorophenol (682mg, 3.71mmol), triet...

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Abstract

The invention belongs to the technical field of medicines, and relates to phosphoramidate derivatives of nucleoside compounds, uses of the phosphoramidate derivatives, and a pharmaceutical compositioncontaining the compounds. The derivatives and pharmaceutical composition can be used as an antiviral reagent, especially an anti-novel coronavirus (SARS-CoV-2) reagent. The invention also relates toa method for preparing the compounds and the pharmaceutical composition, and the use of the derivatives and pharmaceutical composition to prevention or treatment of viral infections, including but notlimited to, Flaviviridae viral infections, Filoviridae viral infections, Enteroviridae viral infections, Orthomyxoviridae viral infections, Paramyxoviridae viral infections, coronaviridae viral infections, particularly novel coronaviridae (SARS-CoV-2) infections.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating viral infections, and methods and uses thereof. Specifically, the present invention relates to phosphoramidate derivatives of nucleoside compounds and pharmaceutical compositions thereof, methods for preparing such compounds and pharmaceutical compositions, and their use in the prevention or treatment of viral infections, including but not limited to, yellow Viridae virus infection, Filoviridae virus infection, Enteroviridae virus infection, Orthomyxoviridae virus infection, Paramyxoviridae virus infection, Coronaviridae virus infection. In particular, the compounds of the present invention and their pharmaceutical compositions are used to prevent or treat novel coronavirus (SARS-CoV-2) infection. Background technique [0002] The virological classification of coronavirus (Coronavirus, CoV) belongs to the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/207A61K31/7076A61K45/06A61P11/08A61P29/00A61P31/16A61P31/14
CPCC07H19/207A61K45/06A61P11/08A61P29/00A61P31/16A61P31/14
Inventor 金传飞钟文和
Owner SUNSHINE LAKE PHARM CO LTD
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