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4-thiouracil deoxynucleoside phosphate and application thereof to antiviral drugs

A technology of deoxynucleoside phosphate and thiouracil, which is applied in the direction of antiviral agents, phosphorus organic compounds, sugar derivatives, etc., can solve the problems of weak drug efficacy, drug resistance, and relapse after drug withdrawal

Active Publication Date: 2021-10-15
南京颐媛生物医学研究院有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many types, most of the drugs have different degrees of drug withdrawal rebound phenomenon after continued use, so that the phenomenon of "relapse after drug withdrawal" appears in the treatment of hepatitis B, and all of them will produce drug resistance, and the drug effect is not good. Strong, still need to find new drugs

Method used

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  • 4-thiouracil deoxynucleoside phosphate and application thereof to antiviral drugs
  • 4-thiouracil deoxynucleoside phosphate and application thereof to antiviral drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the synthesis of compound B

[0035] .

[0036] 1) Compound A (25 g, 178.48 mmol) was dissolved in acetonitrile (250 mL), the reaction mixture was replaced with argon and protected by argon, and then trimethyl phosphate (107.5 g, 713.93 mmol), Sodium iodide (80 g, 535.45 mmol) and 4A molecular sieves were added completely, and the temperature of the reaction liquid oil bath was raised to 90°C and stirred overnight. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate=15 / 1~5 / 1) to obtain compound B (50.7 g, colorless and transparent Oil, yield: 65%).

[0037] 2) Compound A (11.2 g, 79.96 mmol) was dissolved in acetonitrile (100 mL), the reaction mixture was replaced with argon and protected by argon, and then trimethyl phosphate (41.15 g, 279.86 mmol)...

Embodiment 2

[0038] Embodiment 2: the synthesis of compound C

[0039] .

[0040] 1) Compound B (50.7 g, 115.11 mmol) was dissolved in acetonitrile (250 mL), and then lithium bromide (10 g, 115.11 mmol) was added to the reaction solution, the reaction mixture was replaced with argon, and the temperature of the oil bath was raised Reaction at 90°C for 16h. The reaction solution naturally cooled to room temperature, and a large amount of solids precipitated out. After filtration, the filter cake was washed with petroleum ether, and the filter cake was dried to obtain compound C (26.6 g, white solid, yield: 71.9%).

[0041] 2) Compound B (23.9 g, 54.27 mmol) was dissolved in acetonitrile (150 mL), and then lithium bromide (4.7 g, 54.27 mmol) was added to the reaction solution, and the reaction mixture was replaced by argon under argon protection, and the oil bath The temperature was raised to 90°C for 16h. The reaction solution was naturally cooled to room temperature and concentrated un...

Embodiment 3

[0043] 1) Synthesis of Compound E

[0044] .

[0045] Compound D (5 g, 21.91 mmol) and acetic anhydride (4.92 g, 48.2 mmol) were dissolved in pyridine (50 mL), the reaction mixture was replaced with argon and protected by argon, and stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure, diluted with dichloromethane (200 mL), washed the organic phase with saturated citric acid (80 mLx2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the compound E (7.57 g, white solid).

[0046] 2) Synthesis of Compound E

[0047] .

[0048] Compound D (5 g, 21.91 mmol) and acetic anhydride (4.92 g, 48.2 mmol) were dissolved in acetonitrile (50 mL), the reaction mixture was replaced with argon and protected by argon, stirred for 10 min, and triethylamine ( 4.88 g, 48.2 mmol), stirred at room temperature for 16h. The reaction soluti...

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Abstract

The invention discloses 4-thiouracil deoxynucleoside phosphate, the structural formula of which is Q06, and a new drug molecule not only has a new choice for hepatitis B treatment drugs, but also has important significance for developing more ideal hepatitis B treatment drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to 4-thiouracil deoxynucleoside phosphate and its application as an antiviral drug. Background technique [0002] Hepatitis B (HBV) virus infection is the main pathogenic factor of viral hepatitis, and then causes liver cirrhosis, liver cancer, and severe cases are life-threatening. China is a large hepatitis B infection country in the world. Although the use of vaccines is very successful, due to the large population base and high past infection rate, the carrier rate of hepatitis B virus and the incidence of hepatitis B are at a high level. For viral hepatitis with certain indications, antiviral therapy has a good clinical effect. Anti-HBV drugs mainly include interferon and nucleoside (acid) drugs, and nucleoside (acid) anti-HBV drugs are widely used in clinical practice and account for a large market share. Although there are many types, most of the dru...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00C07H1/06A61P31/20A61K31/7068C07F9/09C07H19/073
CPCC07H19/10C07H1/00C07H1/06A61P31/20C07F9/091C07H19/073
Inventor 佟有恩李时悦周光泉马丁潘永利杨丽袁仁涛时洪艳江海明李润峰杨梦琪
Owner 南京颐媛生物医学研究院有限公司
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