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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: 2019-06-25
ASSEMBLY BIOSCI
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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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0365] Example 1: Synthesis of 11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid 5,5- Dioxide(9)

[0366]

[0367] Synthesis of methyl 4-((2-(methoxycarbonyl)phenyl)thio)-3-nitrobenzoate (3):

[0368]

[0369] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) at room temperature under an inert atmosphere 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 hours. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain a 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),...

Embodiment 2

[0388] Example 2: Synthesis of tert-butyl 4-(5-(aminomethyl)thiazol-2-yl)piperidine-1-carboxylate (18)

[0389]

[0390] Synthesis of tert-butyl 4-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (12):

[0391] To a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole 10 (5 g, 21.83 mmol) in anhydrous THF (100 mL) at -78 °C under an inert atmosphere n-BuLi (1.6M, hexane solution, 22.0 mL, 1.2 mmol) was added dropwise to the solution over 15 minutes, and stirred for 2 h. At -78°C, tert-butyl 4-oxopiperidine-1-carboxylate 11 (4.8 g, 24.01 mmol) was added thereto and stirred at the same temperature for 2 h. The reaction was monitored by TLC; upon completion, the reaction mixture was quenched by saturated ammonium chloride (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude product. The crude product was purifie...

Embodiment 3

[0404] Example 3: Synthesis of (2-(3,3-dimethylcyclopentyl)thiazol-5-yl)methanamine hydrochloride (27)

[0405]

[0406] Synthesis of 3,3-Dimethylcyclopent-1-one(20)

[0407] To a stirred solution of cuprous iodide (12 g, 62.5 mmol) in diethyl ether (200 mL) was added methyllithium (65 mL, 104.1 mmol) dropwise over 1 h at 0 °C under an inert atmosphere. The reaction mixture was stirred at 0 °C for 2 h.

[0408] To a stirred solution of 3-methylcyclopent-2-en-1-one 19 (5 g, 52 mmol) in ether (50 mL) was added dropwise the above reaction mixture at 0 °C under an inert atmosphere. The reaction mixture was stirred at 0 °C for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into sodium sulfate hydrate (50 mL) and stirred for 30 min. The reaction mixture was filtered through celite. The filtrate was dried over sodium sulfate and concentrated in vacuo to obtain crude product. The crude product was purified by column ...

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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 of formula:

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit and priority of U.S. Application Serial No. 62 / 395126, filed September 15, 2016, U.S. Application Serial No. 62 / 395114, filed September 15, 2016, filed September 15, 2016 U.S. Application Serial No. 62 / 395132, filed September 15, 2016, and U.S. Application Serial No. 62 / 395118, filed September 15, 2016, each of which is hereby incorporated by reference in its entirety. 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 H...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D513/04C07D487/04
CPCC07D417/12C07D487/04C07D513/04A61P31/20A61K31/426A61K31/427A61K31/454A61K31/554C07D277/28C07D281/14C07D417/04
Inventor W.特纳L.D.阿诺德L.李M.布雷斯S.海达尔H.马格L.班宁
Owner ASSEMBLY BIOSCI
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