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A kind of anti-hepatitis B virus compound and its preparation method and application

A compound and anti-hepatitis B technology, applied in antiviral agents, organic chemistry, pharmaceutical formulations, etc., can solve the problems of low HBsAg clearance rate, difficult to achieve functional cure of hepatitis B virus, etc. Low effect on hepatotoxicity

Active Publication Date: 2022-07-01
SOUTH CHINA UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nucleoside analogs directly act on viral replication by inhibiting the reverse transcription process of the virus from pre-genomic RNA to DNA; long-term nucleotide analog therapy can improve liver diseases, inhibit liver metabolic decompensation, and reduce the incidence and mortality of liver cancer. However, nucleotide analogs do not directly act on the cccDNA pool, and cannot affect viral transcription and production of related viral proteins. Therefore, even with long-term treatment with nucleotide analogs, the clearance rate of HBsAg is very low (0-5%) , and these drugs can only functionally inhibit hepatitis B disease, and it is difficult to achieve a functional cure for hepatitis B virus

Method used

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  • A kind of anti-hepatitis B virus compound and its preparation method and application
  • A kind of anti-hepatitis B virus compound and its preparation method and application
  • A kind of anti-hepatitis B virus compound and its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0038] This embodiment provides a 5-fluoro-2-phenyl-11-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene The preparation method of -8-ketone comprises the following steps:

[0039] Step (1): Preparation of Compound 11

[0040] 3.492g of compound 10 (10mmol) was dissolved in 30mL of DMF, cooled to 0°C, 1.961g of NBS (11mmol) in DMF was added dropwise, stirred for 30 minutes, transferred to 25°C to react, after the reaction was complete, a saturated solution was added. It was quenched with sodium sulfite solution and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was obtained by filtration. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 3.270 g of pale Compound 11 as a yellow solid. The yield was 77%.

[0041] The structural characterization data of compound 11 are as follows:

[0042] 1 H NMR (60...

Embodiment 2

[0048] The present embodiment provides a preparation method of compound 12a:

[0049] The preparation method of embodiment 2 is compared with embodiment 1, and the difference is only:

[0050] In step (2), 0.087g compound 11 (0.20mmol), 0.030g phenylboronic acid (0.24mmol), 0.007g bistriphenylphosphine palladium dichloride (0.01mmol) and 0.085g potassium carbonate (0.6mmol) were added. Into the reaction flask, add 4mL of THF and 1mL, and pass argon protection, react overnight at a temperature of 50 ° C, stop heating, cool to room temperature, filter to obtain a filtrate, and concentrate the filtrate under reduced pressure to obtain a residue, the residue is filtered through silica gel Purification by column chromatography gave 0.051 g of compound 12a in 60% yield.

Embodiment 3

[0052] The present embodiment provides a preparation method of compound 12a:

[0053] The preparation method of embodiment 3 is compared with embodiment 1, and the difference is only:

[0054] In step (2), 0.085g compound 11 (0.2mmol), 0.034g phenylboronic acid (0.24mmol), 0.007g 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.01mmol) and 0.082g g potassium carbonate (0.6 mmol) was added to the reaction flask, 4 mL of N,N-dimethylformamide and 1 mL of water were added, and protected by argon, the reaction was carried out at a temperature of 50 ° C overnight, and the heating was stopped and cooled to room temperature, The filtrate was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 0.049 g of compound 12a with a yield of 58%.

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Abstract

The invention discloses an anti-hepatitis B virus compound and a preparation method and application thereof; the preparation method comprises the following steps: (1) 5-fluoro-11-(pyrrolidine-1-yl)-8H-dibenzo[ 3,4;6,7]cyclohepta[1,2-b]thiophen-8-ketone was dissolved in the first organic solvent, cooled to 0°C, added NBS, stirred evenly, and then transferred to 25°C for reaction 5-fluoro-2-bromo-11-(pyrrolidin-1-yl)-8H-dibenzo[3,4;6,7]cyclohepta[1,2-b]thiophen-8-one; ( 2) 5-fluoro-2-bromo-11-(pyrrolidine-1-yl)-8H-dibenzo[3,4;6,7]cyclohepta[1,2-b]thiophen-8-ketone , an alkali reagent, a catalyst and a boric acid compound are dissolved in the second organic solvent, and a coupling reaction occurs at 25°C-100°C to obtain an anti-hepatitis B virus compound. The compounds prepared by the present invention have inhibitory effect on HBV cccDNA in hepatocytes after biological activity detection, and have low toxicity to normal liver cells, and can be used for preventing, treating, treating or alleviating viral infectious diseases of hepatitis B patients.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an anti-hepatitis B virus compound and a preparation method and application thereof. Background technique [0002] Hepatitis B, referred to as hepatitis B, is a disease caused by the infection of the body by the hepatitis B virus. The continuous replication of hepatitis B virus in the human body can cause liver lesions and seriously endanger the health of patients. Although the birth of the hepatitis B vaccine has greatly reduced the risk of contracting hepatitis B, a large number of people around the world are still infected with the hepatitis B virus every year. Various types of liver diseases caused by hepatitis B virus infection, including hepatitis B, hepatitis B-related cirrhosis, and primary liver cancer, are preliminarily referenced in the list of carcinogens published by the World Health Organization International Agency for Research on Cancer. infection) in the list...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/80C07D409/04A61P31/20A61K31/4025
CPCC07D333/80C07D409/04A61P31/20
Inventor 张雷曾春梅李晶
Owner SOUTH CHINA UNIV OF TECH