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Nucleoside compound and application thereof

A compound, selected technology, applied in the field of prodrugs and/or pharmaceutically acceptable salts thereof, nucleoside compounds and derivatives thereof, capable of solving the problems of low bioavailability orally

Pending Publication Date: 2022-04-08
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Later, through the pharmacokinetic analysis of GS-441524, it was found that its oral bioavailability is very low, and it can only be used in the form of injection

Method used

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  • Nucleoside compound and application thereof
  • Nucleoside compound and application thereof
  • Nucleoside compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] Embodiment 1. Synthesis of compound 1

[0237]

[0238] Dissolve 5.62g of compound GS-441524 in 30mL of acetone, add 11.50mL of 2,2-dimethoxypropane and 1.34mL of 98% sulfuric acid, stir at 45°C for half an hour, cool to room temperature, and remove by rotary evaporation Organic solvents. Extract with 100 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution, repeat the extraction three times, combine the ethyl acetate layers, add anhydrous sodium sulfate to dry, and filter to remove sodium sulfate. The organic solvent was removed by rotary evaporation, and separated by column chromatography (eluent: petroleum ether / ethyl acetate (V / V)=1 / 2) to obtain 6.20 g of compound 1 (white solid, yield 97%). Get obtained compound 1 to detect proton spectrum, the result is as follows:

[0239] 1 H NMR (400MHz, Chloroform-d) δ7.95(s, 1H), 7.11(d, J=4.7Hz, 1H), 6.69(dd, J=4.8, 2.4Hz, 1H), 5.77(s, 2H) , 5.42 (d, J=6.6Hz, 1H), 5.24 (dd, J=6.6, 2.4Hz, 1H), 4.67 (...

Embodiment 2

[0240] Embodiment 2. Synthesis of compound 2

[0241]

[0242] Dissolve 1.50g of compound 1 in 15ml of dichloromethane, then add 0.42mL of tetrahydro-2H-pyran-4-carboxylic acid and 0.27g of 4-dimethylaminopyridine, stir for 10min, then add 1.1g of Dicyclohexylcarbodiimide, stirred at room temperature for 4h. After separation by column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1), 1.9 g of compound 2 (white solid, yield 95%) was obtained, ESI-MS: m / z 444.5[M+H] + .

Embodiment 3

[0243] Example 3. Compound ((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4 Synthesis of -dihydroxytetrahydrofuran-2-yl)methyl tetrahydro-2H-pyran-4-carboxylate (ATV2001)

[0244]

[0245] Dissolve 1.50 g of compound 2 in 10 mL (6.7 V) of formic acid and 5 mL (3.3 V) of water, stir at room temperature for 30 hours, evaporate the excess formic acid to dryness, dissolve the residue in ethyl acetate, and wash with saturated aqueous sodium carbonate Adjust the pH to 8, separate the organic layer, extract the aqueous layer twice with EA, combine the organic layers, wash with saturated brine, dry over sodium sulfate, filter and evaporate to dryness, and the crude product is separated by column chromatography (the eluent is : DCM / MeOH (V / V)=10 / 1), to obtain 0.96 g of compound ATV2001 (white solid, yield 70%). The obtained compound ATV2001 detects hydrogen spectrum and carbon spectrum, and the results are as follows:

[0246] 1 H NMR (600MHz, DMSO-d 6 ...

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Abstract

The invention relates to a nucleoside compound and application thereof, in particular to a compound shown in a formula I, a prodrug thereof and / or pharmaceutically acceptable salt thereof, and a preparation method, a composition and application thereof. The compound and the composition have the application of preventing, relieving and / or treating coronavirus infection, or replication or reproduction of homologous variant viruses of the coronavirus infection, and cytopathic effects generated by the coronavirus infection or the replication or reproduction of the homologous variant viruses of the coronavirus infection.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to the fields of pharmaceutical technology and virus infection disease technology. It specifically relates to a nucleoside compound and its derivative, prodrug and / or its pharmaceutically acceptable salt, and its preparation method and application. Background technique [0002] 2019 Novel Coronavirus (2019Novel Coronavirus, 2019-nCoV, Novel Coronavirus), also known as Severe Acute Respiratory Syndrome Coronavirus 2 (Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2), Novel Coronavirus is a positive-sense single-stranded RNA viruses with a methylated cap at the 5' end and a polyA tail at the 3' end. The new coronavirus genome consists of at least 10 open reading frames (open reading frame, ORF) and some regulatory genes, which encode structural proteins (nucleocapsid protein N, transmembrane protein M, envelope protein E and spike protein S) and Nonstructural proteins (chymotr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61K45/06A61P31/14
CPCA61P31/14A61P29/00A61P11/14A61P11/04A61P11/00A61K31/53A61P31/04C07D487/04Y02A50/30
Inventor 李迎君曹流周启璠陈其姝徐铁凤李官官杨斯迪朱调珍杨彧鉴冀彦锡郭德银张绪穆
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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