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2-thio-n-hydroxycytosine ribonucleoside phosphate and its use in antiviral drugs

A technology of hydroxycytosine ribonucleoside phosphate and thiolation, applied in the field of medicinal chemistry, can solve problems such as long survival period, virus rebound, drug resistance, etc., and achieve high product yield, good inhibitory effect, and simple steps Effect

Active Publication Date: 2022-05-17
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

Nucleoside drugs do have anti-HBV infection effects, but the biggest problem is the emergence of drug-resistant virus strains, virus resistance and rebound after treatment stops
Due to the relatively long survival period of viral DNA in infected liver cells, and the drug will cause HBV polymerase to mutate and produce drug resistance, etc., making it difficult to completely eliminate HBV virus

Method used

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  • 2-thio-n-hydroxycytosine ribonucleoside phosphate and its use in antiviral drugs
  • 2-thio-n-hydroxycytosine ribonucleoside phosphate and its use in antiviral drugs
  • 2-thio-n-hydroxycytosine ribonucleoside phosphate and its use in antiviral drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The synthetic method of N-hydroxyl 2-thio-N-hydroxycytosine ribonucleoside phosphate, its synthetic route is as follows:

[0040]

[0041] Compound A (10 g), hexamethyldisilazane (300 mL), trimethylchlorosilane (7.71 g) and ammonium sulfate (412 mg) were mixed, N 2Under protection, stir at 126 °C for 18 hours to make the solution clear, concentrate the reaction solution, then drain it with an oil pump, add 1,2-dichloroethane (200 mL), compound B (27.6 g) to the reaction solution, and finally add Tin tetrachloride (27.0 g), stirred at room temperature for 1 h. Add saturated sodium bicarbonate solution dropwise to quench, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter to remove anhydrous sodium sulfate, concentrate the filtrate, and dry it with an oil pump to obtain compound C (33.7 g , white solid), compound C was directly used in the next step without further purification.

[0042] Compound C (4 ...

Embodiment 2

[0051] Example 2 In vitro anti-HBV activity research

[0052] The prepared compound and the positive control drugs telbivudine and lamivudine were used for in vitro anti-HBV efficacy evaluation test.

[0053] Telbivudine (Shanghai Titan Technology Co., Ltd.), Lamivudine (Shanghai Titan Technology Co., Ltd.), HepG2.2.15 cells (provided by the Antiviral Drug Research Laboratory, School of Pharmacy, Fudan University), fetal bovine serum (FBS) (Thermo Fisher Biochemicals Co., Ltd.), DMEM medium (Thermo Fisher Biochemicals Co., Ltd.), carbon dioxide incubator (Thermo Fisher Biochemicals Co., Ltd.), fluorescent quantitative PCR (Thermo Fisher Murphy Fisher Biochemical Co., Ltd.).

[0054] Detection of drug antiviral activity: take a bottle of well-grown HepG2.2.15 cells, digest with trypsin, make a single cell suspension, count with a cell counting plate, and adjust the cells with DMEM medium containing 10% FBS serum. Density to 2 x 10 5 Individual / mL, inoculated in culture plate...

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Abstract

The invention discloses a 2-thio-N-hydroxycytosine ribonucleoside phosphate, the structural formula is: The compound disclosed by the invention has a good inhibitory effect on the secretion of HBV DNA by HepG2.2.15 cells, and has anti-hepatitis virus activity , provides a good choice for the treatment of viral hepatitis, and is also of great significance to the development of more ideal drugs for the treatment of hepatitis B.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to 2-thio-N-hydroxycytosine ribonucleoside phosphate and its antiviral application. Background technique [0002] Persistent HBV infection is the main cause of hepatitis B chronicity, and can lead to disease progression, deterioration, and HBV-related hepatocellular carcinoma. In addition to inoculating hepatitis B vaccine for immune prophylaxis, the anti-HBV drugs currently approved for clinical use mainly include two types, namely interferon and nucleoside drugs. Some marketed immunomodulators and traditional Chinese medicines can also be used as auxiliary methods for hepatitis B. treat. Interferon is a class of cytokines that can regulate the immune function of the body, and has antiviral and antitumor effects. In terms of anti-hepatitis B virus, interferon mainly acts on the interferon receptor of the cell, thereby producing a large number of protein ki...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H1/00C07H1/06A61P31/20
CPCC07H19/10C07H1/00C07H1/06A61P31/20
Inventor 鲍甫义袁仁涛王小明周伟柳惠陈锋刘志东杨丽彭盛叶小新
Owner 南京颐媛生物医学研究院有限公司