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Tetracyclic pyridone compounds as antivirals

A compound and heterocyclic technology, applied in antiviral agents, drug combinations, organic chemistry, etc., can solve the problems of unapproved therapeutic drugs, inability to eradicate transcribed HBsAg, viral recurrence, etc., to reduce viral load and viral replication , reduced sodium ion channel inhibition, reduced interaction effects

Active Publication Date: 2018-12-21
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More importantly, these therapies cannot eradicate the intrahepatic HBV cccDNA pool in patients with chronic hepatitis B or limit the transcription of HBsAg from pre-existing cccDNA, nor affect the secretion of synthetic HBsAg into the patient's blood to counteract the host innate immune response
Therefore, these HBV treatments are lifelong in most cases, and discontinuation often leads to viral relapse
Some compounds have been reported to reduce serum HBsAg levels, but no new approved treatments have been produced to date

Method used

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  • Tetracyclic pyridone compounds as antivirals
  • Tetracyclic pyridone compounds as antivirals
  • Tetracyclic pyridone compounds as antivirals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0327] Example 1: Synthesis of racemic 10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7, 12b-Hexahydrocyclopentadiene[c]pyrido[2,1-a]isoquinoline-6-carboxylic acid[rac-1]

[0328]

[0329] Step 1: 5-(4-Methoxy-3-(3-methoxypropoxy)phenyl)-2,2-dimethylcyclopentanone [1.1a]

[0330]

[0331] Pd(OAc) 2 (8.16mg, 0.036mmol), sodium tert-butoxide (0.454g, 4.72mmol), dicyclohexyl (2'-methyl-[1,1'-biphenyl]-2-yl)phosphine (32mg), 2 , 2-dimethylcyclopentanone (0.547ml, 4.36mmol) and 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (1g, 3.63mmol) in toluene (4.0 mL) solution was heated in a sealed vial at 50°C for 18 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the remaining oil was purified by silica gel column chromatography, EtOAc / heptane 5 to 50% to give the product (500 mg, 45% yield). LC-MS(m / z):307.2[M+H] + . 1 H NMR (400MHz, CDCl 3 ):7.72–7.28(m,1H),6.94–6.61(m,2H),4.10(m,2H),3.91–3.77(m,4H),3.65–3.49(m,2H),3.4...

Embodiment 2

[0358] Example 2: Synthesis of racemic 10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7, 12b-Hexahydrocyclopentadiene[c]pyrido[2,1-a]isoquinoline-6-carboxylic acid[rac-2]

[0359]

[0360] Using the trans-fused isomer in Step 4 of Example 1, the title compound was prepared by the same method as in Preparation Example 1. LCMS(m / z):428.2[M+H] + .1H NMR (400MHz, CD 3 CN): δ8.72(s,1H),7.34(s,1H),7.23(s,1H),6.84(s,1H),4.17(q,J=6.4Hz,2H),3.90(s,3H ),3.74(d,J=13.5Hz,1H),3.60-3.42(m,4H),3.32(s,4H),2.31(dq,J=17.6,7.9,6.3Hz,2H),2.10-2.00( m,3H),1.52(s,4H),1.29(s,4H)

Embodiment 31

[0361] Example 3.1: Synthesis of (3aS,12bR)-8-fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2 ,3,3a,7,12b-Hexahydrocyclopentadiene[c]pyrido[2,1-a]isoquinoline-6-carboxylic acid.

[0362] Step 1: (Z)-Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-((trimethylsilyl)oxy)but-3-enoate [3.1a]

[0363]

[0364] A mixture of Mg (3.69 g, 152 mmol) and TMSCl (19.43 mL, 152 mmol) was treated with ultrasonic radiation for 15 minutes under an argon atmosphere. Under an argon atmosphere, DMF (30 mL)) and ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate were added dropwise to the mixture at 50 °C Ester (4.56 g, 19 mmol). The reaction mixture was stirred for an additional 3 minutes at 50 °C. After excess TMSCl was removed in vacuo, the crude mixture was filtered and the filtrate (containing 3.1a and DMF) was used in the next step without further purification.

[0365]Step 2: 8-Fluoro-10-methoxy-11-(3-methoxypropoxy)-3,3-dimethyl-7-oxo-1,2,3,3a,7,12b -Ethyl hexahydro...

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Abstract

The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by hepatitis B virus, and reducing the occurrence of serious conditions associated with HBV.

Description

technical field [0001] The present invention relates to novel tetracyclopyridone compounds which are inhibitors of hepatitis virus replication and are therefore useful in the treatment of viral infections, especially hepatitis B virus (HBV). The present invention provides novel tetracyclic pyridone compounds disclosed herein, pharmaceutical compositions containing these compounds, and methods for treating and preventing HBV infection using these compounds and compositions. technical background [0002] Globally, more than 240 million people are chronically infected with the hepatitis B virus (HBV), including more than 2 million in the United States alone. Of those chronically infected, up to 40% eventually develop complications that progress from cirrhosis or hepatocellular carcinoma (HCC) to liver failure. Hepatitis B virus (HBV) belongs to the Hepadnaviridae family and is a group of small hepadnaviridae viruses that replicate through reverse transcription of RNA intermedi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/08C07D491/14A61K31/4745A61P31/12
CPCC07D217/08C07D491/14A61K31/4375C07D471/14C07D491/147A61P1/16A61P31/12A61P31/20A61P43/00C07D471/04C07D519/00
Inventor 傅继平金仙明P·李路培超J·M·杨
Owner NOVARTIS AG
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