Hepatitis b core protein modulators

An ethyl and compound technology, applied in the field of hepatitis B core protein regulator, can solve the problems of poor tolerance of interferon alpha side effects and the like

Inactive Publication Date: 2018-07-31
ASSEMBLY BIOSCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interferon alfa has severe side effects and is poorly tolerated in patients and is only successful in a small percentage of patients due to limited treatment strategies

Method used

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  • Hepatitis b core protein modulators
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  • Hepatitis b core protein modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Synthesis of 7-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8- Formic acid (7): a common intermediate

[0109]

[0110] Synthesis of 4-fluoro-2-methyl-5-nitrobenzoic acid (3):

[0111]

[0112] To a stirred solution of 4-fluoro-2-methylbenzoic acid 2 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) at 0 °C under an inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol); warmed to room temperature and stirred for 6 hours. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), and the precipitated solid was filtered and dried in vacuo to obtain a crude product. The crude product was chromatographed on a silica gel column using 5% MeOH / CH 2 Cl 2 Purification afforded compound 3 (300 mg, 60%) as a brown syrup. TLC: 10% MeOH / CH 2 Cl 2 (R f :0.3); 1 H-NMR (DMSO-d 6 , 500MHz): δ13.56 (br s, 1H), 8.52 (d, J=8.0Hz, 1H), 7.61 (d, J=12.5Hz, 1H), 2.63 (...

Embodiment 2

[0125] Example 2: Synthesis of 2-chloro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-methan Acid (16): a common intermediate

[0126]

[0127] Synthesis of 5-chloro-2-((4-methoxybenzyl)thio)benzonitrile (10):

[0128]

[0129] To a stirred solution of 5-chloro-2-fluorobenzonitrile 8 (1.0 g, 6.41 mmol) in DMF (10 mL) under an inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at room temperature; heated to 40 °C And (4-methoxyphenyl)methanol 9 (1.08 g, 7.05 mmol) was added thereto; heated to 60° C. and stirred for 2 hours. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using 3-5% EtOAc / hexanes to afford compound 10 (1 g, 54%) as a white solid. TLC: 10% E...

Embodiment 3

[0145] Example 3: Synthesis of 3-chloro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-methan Acid (23): a common intermediate

[0146]

[0147] Synthesis of 4-chloro-2-((4-methoxybenzyl)thio)benzonitrile (18):

[0148]

[0149] To a stirred solution of 4-chloro-2-fluorobenzonitrile 17 (1 g, 6.41 mmol) in DMF (25 mL) under an inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at room temperature; heated to 40 °C and To this was added (4-methoxyphenyl)methanethiol 9 (1.08 g, 7.05 mmol); heated to 60° C. and stirred for 2 hours. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give crude product. The crude product was purified by silica gel column chromatography using 4% EtOAc / hexanes to afford compound 18 (900 mg, 48%) as a white solid. TLC: 1...

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PUM

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Abstract

The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitisB, comprising administering to a patient in need thereof a disclosed compound.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 62 / 218,815, filed September 15, 2015, the entire contents of which are incorporated herein by reference. Background technique [0003] Hepatitis B (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, approximately 2 billion people have been infected with HBV, approximately 360 million are chronically infected, and HBV infection causes more than 500,000 deaths per year (2009; WHO, 2009). HBV can be transmitted through bodily fluids: from mother to child, sexually and through blood products. Children born to HBV-positive mothers can also become infected unless vaccinated at birth. [0004] The virion consists of a lipid outer membrane covered with surface proteins (HBsAg) surrounding the viral core. The core consists of a protein shell (or caps...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/554C07D281/16C07D417/12
CPCC07D417/12C07D417/14A61K45/06A61P31/20C07D403/12C07D401/12C07D413/12C07D453/02C07D471/04C07D243/38C07D267/20C07D281/16A61P31/22A61K31/554A61P31/00A61K31/553
Inventor W.特纳L.D.阿诺德H.马格M.布雷斯
Owner ASSEMBLY BIOSCI
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