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4-thiodeoxythymidine derivatives and their pharmaceutical application against hepatitis B virus

A technology of thiodeoxythymidine and derivatives, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problem of drug resistance, drug resistance needs to be improved, and hepatitis B virus cannot be completely eliminated. problem, to achieve the effect of cheap raw materials, easy large-scale production, and clever design

Active Publication Date: 2021-12-10
南京颐媛生物医学研究院有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have a common shortcoming, that is, drug resistance will appear after being used for a period of time, and the hepatitis B virus cannot be completely eliminated.
In view of the drug resistance and efficacy of existing anti-HBV drugs to be improved, the development of new anti-HBV drugs is still an important issue in the treatment of viral hepatitis

Method used

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  • 4-thiodeoxythymidine derivatives and their pharmaceutical application against hepatitis B virus
  • 4-thiodeoxythymidine derivatives and their pharmaceutical application against hepatitis B virus
  • 4-thiodeoxythymidine derivatives and their pharmaceutical application against hepatitis B virus

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthetic route is as follows:

[0039] ;

[0040] Thymine (26 g, 205.7 mmol) in hexamethyldisilazane (320 mL, 1.48 mol) and trimethylchlorosilane (42 mL, 321 mmol), N 2 Under protection, stir at 130°C for 3h. After cooling to room temperature, the reaction solution was concentrated, and the oil pump was drained. Dichloromethane (500 mL, anhydrous) was added to the crude product, and then compound A (CAS: 141846-57-3) (80 g, 205.7 mmol) and trifluoro Trimethylsilyl methanesulfonate (2.25 mL, 12.3 mmol), stirred at room temperature for 1 h. After the reaction was completed, slowly add saturated sodium bicarbonate solution to the reaction solution under stirring, extract with dichloromethane, wash the organic phase with saturated brine, separate the organic phase, dry over anhydrous sodium sulfate, filter to remove anhydrous sodium sulfate, and the filtrate Concentration gave a crude product, which was separated by column chromatography (petroleum ether: ethyl ac...

Embodiment 2

[0054] The synthetic route is as follows:

[0055] ;

[0056] Intermediate compound 1 (2 g, 3.8 mmol) and compound I (3.4 g, 7.5 mmol, CAS: 1354823-36-1) were dissolved in MeCN (100 mL), magnesium chloride (359 mg, 3.8 mmol) was added, and at 50 °C Stir for 10 min, then add DIEA (1.22 g, 9.4 mmol), and stir overnight at 50°C. After the reaction, cool to room temperature, add dichloromethane (200 mL) to dilute, wash the reaction solution with citric acid (1N), wash the organic phase with saturated ammonium chloride in turn, then wash with saturated sodium bicarbonate, and then with saturated brine, and wash the organic phase with It was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, the filtrate was concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10 / 1-1 / 1) to obtain compound J (2.3 g, yellow solid).

[0057] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.76 (s, 1H), 7.42 (d,5H), 7.36 (dd, 4...

Embodiment 3

[0061] The synthetic route is as follows:

[0062] ;

[0063] Chloromethyl pivalate (48.2 g, 320 mmol), trimethyl phosphate (11.2 g, 80 mmol) and sodium iodide (36 g, 240 mmol) were mixed in acetonitrile (100 mL, anhydrous), and added to the reaction solution Add a few grains of 4A molecular sieve, N 2 90 under protection o C was refluxed overnight, after the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, the filter residue was washed with ethyl acetate, the filtrate was concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10 / 1-5 / 1) to obtain Product L (28.3 g, colorless liquid).

[0064] Compound L (6 g, 13.6 mmol) and lithium bromide (1.2 g, 13.6 mmol) were dissolved in acetonitrile (50 mL, dry), 90 o C was refluxed and stirred overnight. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed wi...

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Abstract

The invention discloses a 4-thiodeoxythymidine derivative and its anti-hepatitis B virus pharmaceutical application. The present invention provides 4-thiodeoxythymidine derivatives or pharmaceutically acceptable salts thereof, the structures of which are shown in structural formula I or structural formula II. The present invention proves that 4-thiodeoxythymidine derivatives or pharmaceutically acceptable salts thereof have anti-HBV activity through in vitro cytotoxicity tests and in vitro anti-HBV virus efficacy tests, and have anti-hepatitis B drug development prospects. Hepatitis offers a potential option.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of 4-thiodeoxythymidine derivatives and their anti-hepatitis B virus pharmaceutical 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. Therefore, antiviral therapy is the key to the treatment of chronic hepatitis B. Currently, commonly used anti-HBV drugs are divided into immunomodulatory drugs and nucleoside analogs. In addition, Chinese herbal medicine and its active ingredients also play an important role in the anti-HBV treatment. Interferon is a common immunomodulator for HBV treatment. Interferon has broad-spectrum antiviral properties, long-lasting therapeutic effect and high virus surface antigen clearance rate, but its acceptance rate is low and side effects are large. Nucleoside analogues mai...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H19/10C07H1/00A61P1/16A61P31/20A61P35/00A61K31/7068
CPCC07H19/073C07H19/10C07H1/00A61P1/16A61P31/20A61P35/00C07B2200/07
Inventor 冯力杨子峰陆冬晓马丁陈锋杨丽彭盛周明唐秀春叶小新刘红宁
Owner 南京颐媛生物医学研究院有限公司
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