Uridine monophosphate analogue, and preparation method and applications thereof

A technology for uracil nucleotides and analogs, applied in the field of uracil nucleotide analogs and their preparation, can solve the problems of unfavorable virus clearance, anti-hepatitis C products on the market, too large molecules, and the like

Inactive Publication Date: 2015-07-08
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

40KD macromolecular pegylated interferon is too large to distribute in blood vessels and liver, which is not good for extrahepatic virus clearance
[0011] 近年来研究该类核苷单磷酸酯类似物的专利主要有PHARMASSET公司开发的WO2008121634A2、WO2010075517A2,CHIMERIX公司开发的WO2010135520A1,ALIOS BIOPHARMA公司开发的WO2012040127A1、WO2012088155A1,MERCK SHARP&DOHME CORP公司开发的WO2012142075A1、WO2012142085A1、WO2013009737A1 , but, so far, there is no related anti-hepatitis C products on the market, therefore, further development of this class of nucleoside monophosphate analogues has become an important strategy

Method used

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  • Uridine monophosphate analogue, and preparation method and applications thereof
  • Uridine monophosphate analogue, and preparation method and applications thereof
  • Uridine monophosphate analogue, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] The first step of preparation of isopropyl ((2-cyclopropylphenoxy)(4-nitrophenoxy)phosphoryl)-L-alanine ester

[0144]

[0145] 4-Nitrophenylphosphorus dichloride (320mg, 1.25mmol) was dissolved in CH 2 Cl 2 (2.5mL), cooled to -78°C, CH 2 Cl 2 (2.5mL) solution was added dropwise, reacted at this temperature for 30 minutes and gradually warmed up to 0°C, and the reaction solution was added dropwise to cooled L-alanine isopropyl ester hydrochloride (210mg , 1.25mmol) of CH 2 Cl 2 (2.5mL) solution, then TEA (366L, 2.63mmol) was added dropwise to the reaction system, stirred at 0°C for 1 hour, the reaction solution was concentrated under reduced pressure, EtOAc (20mL) was added to the reaction flask, the white solid was filtered, and the filtrate Concentration gave a yellow oily liquid. Column chromatography (eluent: PE:EtOAc=5:1) afforded the title compound isopropyl((2-cyclopropylphenoxy)(4-nitrophenoxy)phospho)-L-alanine acid ester (395mg, 70%).

[0146] 1 H ...

Embodiment 2

[0154] The first step of preparation of isopropyl ((3-cyclopropylphenoxy)(4-nitrophenoxy)phosphoryl)-L-alanine ester

[0155]

[0156] 4-Nitrophenylphosphorus dichloride (1.950g, 7.62mmol) was dissolved in CH 2 Cl 2 (15mL), cooled to -78°C, CH 2 Cl 2 (15mL) solution was added dropwise, reacted at this temperature for 30 minutes and gradually warmed up to 0°C, and the reaction solution was added dropwise to L-alanine isopropyl hydrochloride (1.279g ,7.63mmol) of CH 2 Cl 2 (15mL) solution, then TEA (2.23mL, 16.0mmol) was added dropwise to the reaction system, stirred at 0°C for 1 hour, the reaction solution was concentrated under reduced pressure, EtOAc (30mL) was added to the reaction flask, the white solid was filtered, and the filtrate Concentration gave a yellow oily liquid. Column chromatography (eluent: PE:EtOAc=4.5:1) afforded the title compound isopropyl((3-cyclopropylphenoxy)(4-nitrophenoxy)phospho)-L-alanine Ester (2.905g, 85%).

[0157] 1 H NMR (400MHz, CD...

Embodiment 3

[0165] The first step of preparation of isopropyl ((2-cyclopropyl-6-methylphenoxy)(4-nitrophenoxy)phosphoryl)-L-alanine ester

[0166]

[0167] 4-Nitrophenylphosphorous dichloride (1.950g, 7.62mmol) was dissolved in CH 2 Cl 2 (15mL), cooled to -78°C, CH 2 Cl 2 (15mL) solution was added dropwise, reacted at this temperature for 30 minutes and gradually warmed up to 0°C, and the reaction solution was added dropwise to L-alanine isopropyl hydrochloride (1.279g ,7.63mmol) of CH 2 Cl 2 (15mL) solution, then TEA (2.23mL, 16.0mmol) was added dropwise to the reaction system, stirred at 0°C for 1 hour, the reaction solution was concentrated under reduced pressure, EtOAc (30mL) was added to the reaction flask, the white solid was filtered, and the filtrate Concentration gave a yellow oily liquid. Column chromatography (eluent: PE:EtOAc=5:1~3:1) gave the title compound isopropyl ((2-cyclopropyl-6-methylphenoxy)(4-nitrophenoxy )phospho)-L-alaninate (2.880 g, 82%).

[0168] 1 H...

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PUM

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Abstract

The invention relates to uracil nucleotide analogs, preparation methods therefor and uses thereof. Specifically, the invention provides uracil nucleotide analogic compounds having the following formula (I), stereoisomers or pharmaceutically acceptable salts thereof, preparation methods therefor and uses thereof. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection in mammals. The compounds have a wide application prospect and are hopeful to be developed into a new generation of antiviral drugs.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a uracil nucleotide analogue and its preparation method and application. Background technique [0002] The viruses of the Flaviviridae family include at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; and flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever and the genus hepaciviruses, the only member of which is HCV. The Flavivirus genus includes more than 68 members, grouped based on serological relatedness. Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever. Flaviviruses of global concern for association with human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus, and Japanese encephalitis virus. Because the HCV genome is similar to human flaviviruses and pestiviruses in structure and phenotypic characteristics, it is cl...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00A61K31/7072A61P31/12A61P31/14
CPCA61K31/7072C07H19/10C07H1/00A61P31/12A61P31/14C07H19/06
Inventor 钟慧娟岑均达马建斌谭松良高鹏喻红平徐耀昌马景毅王听中吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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