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Compound for treating and/or preventing hepatitis B virus infection as well as preparation method and application thereof

A compound and selected technology, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc., to achieve the effects of good in vivo efficacy, good safety, and excellent pharmacokinetic properties

Active Publication Date: 2021-02-02
SHANGHAI ZHIMENG BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] According to reports, some compounds can effectively reduce the level of HBsAg in serum by inhibiting the secretion of HBsAg, but so far there is no drug with this mechanism of action for the clinical treatment of HBV patients

Method used

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  • Compound for treating and/or preventing hepatitis B virus infection as well as preparation method and application thereof
  • Compound for treating and/or preventing hepatitis B virus infection as well as preparation method and application thereof
  • Compound for treating and/or preventing hepatitis B virus infection as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] The preparation of embodiment 1 compound EXP 1

[0176]

[0177] 1) Synthesis of compound 2

[0178] Compound 1 (10 g, 64.1 mmol, 1.0 eq) was dissolved in DMF (100 mL), then sodium carbonate (17 g, 160.2 mmol, 2.5 eq) and benzyl bromide (8.4 mL, 70.5 mmol, 1.1 eq) were added. The reaction solution was stirred at 60°C for 16 hours. After cooling to room temperature, add water (300mL) to the reaction solution and extract with EA (80mL x2), combine the organic phases, wash with saturated brine (150mL), then dry with anhydrous sodium sulfate, concentrate, and the residue is subjected to silica gel column chromatography Compound 2 (9.6 g, 61%) was obtained as a white solid after purification (petroleum ether / ethyl acetate=10 / 1). LCMS:[M+H] + = 247.1.

[0179] 2) Synthesis of compound 3

[0180] Compound 2 (9.6g, 39mmol, 1.0eq) was dissolved in DMF (100mL), then NCS (8.34g, 62.4mmol, 1.6eq) was added, and the reaction solution was stirred overnight at 80°C. After coo...

Embodiment 2

[0213] The preparation of embodiment 2 compound EXP 2

[0214]

[0215] Compound EXP 1 (200 mg) was dissolved in ethyl acetate (1 mL), n-hexane (10 mL) was added, the resulting solution was filtered to obtain a solid, and compound EXP 2 (150 mg, yield 75%) was obtained after drying under reduced pressure.

[0216] LCMS:[M+H] + =422.1

[0217] 1 H NMR (400MHz, DMSO) δ15.78(s,1H),8.94(s,1H),7.23(s,1H),5.10–5.03(m,1H),4.83-4.82(m,1H),4.65- 4.64(m,2H),4.10-4.07(m,1H),3.16(s,3H),2.41–2.31(m,4H),0.76(s,9H).

Embodiment 3

[0218] The preparation of embodiment 3 compound EXP 3

[0219]

[0220] 1) Synthesis of compound 2

[0221] Compound 1 (1.1g, 5.7mmol, 1.0eq) was dissolved in methanol (30mL), then palladium on carbon (10%, 500mg) was added, hydrogen was replaced and reacted at room temperature for 18 hours. After the reaction was complete, palladium carbon was removed by filtration, and concentrated to obtain compound 2 (500 mg, 86%) as a colorless oil.

[0222] 2) Synthesis of Compound 4

[0223] Compound 3 (500mg, 3.0mmol, 1.0eq) was dissolved in tetrahydrofuran (20mL), then compound 2 (306mg, 3.0mmol, 1.0eq) and triphenylphosphine (1.18g, 4.5mmol, 1.5eq) were added, ice The bath was cooled to zero degrees Celsius, and a solution of DIAD (909mg, 4.5mmol, 1.5eq) in tetrahydrofuran (5mL) was added slowly, followed by reaction at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chroma...

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Abstract

The invention relates to a compound for treating and / or preventing hepatitis B virus infection as well as a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure shown as a formula I, and the definitions of all groups and substituents are as described in the specification. The compound has higher activity, better in-vivo drug effect, better safety, better pharmacokinetic property and better druggability.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a class of compounds used for treating and / or preventing hepatitis B virus infection and its preparation method and application. Inhibit the replication of HBV virus. Background technique [0002] More than 240 million people worldwide are chronically infected with HBV, and among those chronically infected, up to 40% are at risk of developing liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. The surface antigen clearance of hepatitis B patients is an important biomarker for clinical diagnosis and treatment. One of the key diagnostic symptoms of chronic HBV is the high serum level of HBsAg, and the serological clearance of HBsAg is considered to be one of the clinical criteria for hepatitis B cure. [0003] It is reported that some compounds can effectively reduce the level of HBsAg in serum by inhibiting the secretion of HBsAg, but so far there is no drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14A61P31/20
CPCA61P31/20C07D471/14A61K31/4985
Inventor 梁波金秋陈焕明张志军夏天华波刘刚
Owner SHANGHAI ZHIMENG BIOPHARMA CO LTD
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