Hepatitis B core protein allosteric modulators

A compound, selected technology, applied in the directions of plant growth regulators, biocides, antiviral agents, etc., can solve problems such as poor tolerance to side effects of interferon alpha

Active Publication Date: 2017-02-15
INDIANA UNIV RES & TECH CORP +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 allosteric modulators
  • Hepatitis B core protein allosteric modulators
  • Hepatitis B core protein allosteric modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1: 11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine -8-Formic acid (6)-common Synthesis of Intermediates

[0184]

[0185] Synthesis of methyl 4-((2-(methoxycarbonyl)phenyl)thio)-3-nitrobenzoate (3):

[0186]

[0187] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) was added cesium carbonate (58.76 g, 180.8 mmol) and 2- Methyl mercaptobenzoate 1 (22.6 mL, 165.47 mmol); heated to 55-60° C. and stirred for 2 h. The reaction was monitored by TLC; after the reaction was complete, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to give the crude product. The crude product was washed with water (500 mL), hexane (200 mL) and dried in vacuo to give compound 3 (48.8 g, 93%) as a yellow solid. TLC: 20% EtOAc / hexane (R f :0.4); 1 H NMR (CDCl 3 , 400MHz): δ8.85(s, 1H), 7.99-7.92(m, 2H), 7.66-7.56(m, 3H), 6.93(d, J=8.6Hz, 1H), 3.94(s, 3H), 3.79 (s, 3H).

[0188] S...

Embodiment 2

[0197] Example 2: 2-Chloro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine -8-Formic acid (14)- Synthesis of common intermediates

[0198]

[0199] Synthesis of 5-chloro-2-((4-methoxybenzyl)thio)benzonitrile (9):

[0200]

[0201] To a stirred solution of 5-chloro-2-fluorobenzonitrile 7 (1 g, 6.41 mmol) in DMF (10 mL) was added cesium carbonate (2.30 g, 7.05 mmol) at room temperature under an inert atmosphere; heated to 40 °C and To this was added (4-methoxyphenyl)methanethiol 8 (1.08 g, 7.05 mmol); heated to 60° C. and stirred for 2 h. The reaction was monitored by TLC; after the reaction was complete, 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, eluting with 3-5% EtOAc / hexanes, to afford compound 9 (1 g, 54%) as a white solid. TL...

Embodiment 3

[0217] Example 3: 3-Chloro-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine -8-Formic acid (21)- Synthesis of Common Intermediates

[0218]

[0219] Synthesis of 4-chloro-2-((4-methoxybenzyl)thio)benzonitrile (16):

[0220]

[0221] To a stirred solution of 4-chloro-2-fluorobenzonitrile 15 (1 g, 6.41 mmol) in DMF (25 mL) was added cesium carbonate (2.30 g, 7.05 mmol) at room temperature under an inert atmosphere at room temperature; heated to 40 °C and (4-methoxyphenyl)methanol 8 (1.08 g, 7.05 mmol) was added thereto; heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after the reaction was complete, 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 16 (900 mg, 48%) as a white ...

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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 hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

Description

[0001] Statement of Government Support [0002] This invention was made with Government support under AI067417 issued by the National Institutes of Health. The US Government has certain rights in this invention. [0003] related application [0004] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 61 / 952,467, filed March 13, 2014, and U.S. Provisional Patent Application Serial No. 62 / 010,025, filed June 10, 2014, the contents of each This article is incorporated by reference. Background technique [0005] 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 mothe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/00A61K31/55C07D498/00
CPCC07D403/12C07D223/20C07D401/12C07D413/12C07D243/38C07D281/14A61K31/55A61K31/5513A61K31/553A61K31/554C07D281/16C07D417/12A61P1/16A61P31/20A61P43/00A61K45/06A61P31/12
Inventor W.W.特纳L.D.阿诺德H.马格A.兹洛特尼克
Owner INDIANA UNIV RES & TECH CORP
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