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Phosphoramidate derivative of nucleoside compound and application thereof

A compound and alkyl technology, applied in the field of compounds and pharmaceutical compositions for the prevention or treatment of viral infection, enteroviridae viral infection, to achieve good metabolic stability, good safety, and good clinical application prospects

Active Publication Date: 2020-12-11
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 derivative of nucleoside compound and application thereof
  • Phosphoramidate derivative of nucleoside compound and application thereof
  • Phosphoramidate derivative of nucleoside compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] Example 1 (((((2S,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorus Synthesis of Acyl)-L-Alanine Methyl Ester

[0159]

[0160] Step 1) Synthesis of (chloro(phenoxy)phosphoryl)-L-alanine methyl ester

[0161]

[0162] Weigh (2S)-methyl 2-alanine hydrochloride (400mg, 2.87mmol) into a 50mL double-necked round bottom flask, add dichloromethane (10mL) under nitrogen protection and stir at -78°C for 2 minutes, Add triethylamine (0.87mL, 6.30mmol) dropwise, and stir for another 2 minutes, then dissolve dichlorophosphoryloxybenzene (0.428mL, 2.86mmol) in dichloromethane (10mL), and slowly add dropwise to the reaction flask , and then kept stirring at -78°C for 30 minutes, warmed to ice bath temperature, and was directly used in the next reaction.

[0163] Step 2) Synthesis of ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester

[0164]

[0165] Under ice bath, dissolve 2,3,4,5,6-pentafluorophenol (527mg, 2.86m...

Embodiment 2

[0173] Example 2 (((((2S,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorus Synthesis of Acyl]-L-Alanine Ethyl Ester

[0174]

[0175] Step 1) Synthesis of (chloro(phenoxy)phosphoryl)-L-alanine ethyl ester

[0176]

[0177] Weigh (2S)-ethyl 2-alanine hydrochloride (500mg, 3.26mmol) in a 50mL double-necked round bottom flask, add dichloromethane (15mL) under nitrogen protection and stir at -78°C for 2 minutes, Triethylamine (0.99mL, 7.10mmol) was added dropwise, and stirred for another two minutes, then dichlorophosphoryloxybenzene (0.486mL, 3.25mmol) was dissolved in dichloromethane (10mL), and slowly added dropwise to the reaction flask , and then kept stirring at -78°C for 30 minutes, warmed to ice bath temperature, and was directly used in the next reaction.

[0178] Step 2) Synthesis of ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester

[0179]

[0180] Under ice bath, dissolve 2,3,4,5,6-pentafluorophenol (...

Embodiment 3

[0188] Example 3 (((((2S,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorus Synthesis of Acyl]-L-Alanine Isopropyl Ester

[0189]

[0190] Weigh ((2S, 4S, 5R)-5-(6-amino-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methanol (127mg, 0.50mmol) in a 50mL double-necked round bottom flask bottle, add N,N-dimethylformamide (3mL) under nitrogen protection, heat up to 50°C to completely dissolve the raw materials, then cool in an ice bath, add dropwise a tetrahydrofuran solution of tert-butylmagnesium chloride (0.55mL, 0.55mmol, 1.0mol / L), stirred at room temperature for 10 minutes after dropping, added ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (249mg, 0.55mmol) to the reaction flask under ice cooling Then move to room temperature and stir for 2 hours to stop the reaction, add saturated ammonium chloride aqueous solution (3mL) to quench the reaction, then add ethyl acetate (50mL), wash with water (20mL×3), dry over anh...

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Abstract

The invention belongs to the technical field of medicines, and relates to a phosphoramidate derivative of a nucleoside compound and application thereof, and a pharmaceutical composition containing thecompound. The phosphoramidate derivative can be used as an antiviral reagent, especially an anti-SARS-CoV-2 reagent. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in preventing or treating viral infection, including but not limited to flaviviridae viral infection, filamentousvirology viral infection, enterovirus viral infection, orthomyxoviridae viral infection, paramyxoviridae viral infection and coronavirus viral infection, especially SARS-CoV-2 infection.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, and relates to a compound and a pharmaceutical composition for preventing or treating viral infection, as well as its application method and application. 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 (Coronaviru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/207A61K31/7076A61K45/06A61P31/12A61P31/14
CPCC07H19/207A61K45/06A61P31/12A61P31/14
Inventor 金传飞钟文和张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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