Novel isoquinoline compound and medical application thereof

A technology of compounds and medicinal salts, which is applied in the field of new isoquinoline compounds and their medical applications, can solve the problem of not being able to reduce hepatitis B surface antigen

Inactive Publication Date: 2018-11-02
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, nucleoside drugs cannot reduce HBsAg, and it is necessary to design a drug with a new mechanism of action, which can be used in combination with powerful nucleosi...

Method used

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  • Novel isoquinoline compound and medical application thereof
  • Novel isoquinoline compound and medical application thereof
  • Novel isoquinoline compound and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1: 6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-N-(cyclopropylsulfonyl)-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxamide (10)

[0098]

[0099] Step 1: Synthesis of 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (2)

[0100]

[0101] 1-Bromo-3-methoxypropane (49.8g, 325.4mmol) was added dropwise to a solution of 5-bromo-2-methoxyphenol (22.0g, 108.4mmol) and anhydrous potassium carbonate (45g, 325.6mmol) in DMF (30mL) suspension, stirred overnight at room temperature, poured into water, extracted three times with ethyl acetate, combined organic phase, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid, 26g, 87.2% . ESI-MS: [M+H]+: 275.2.

[0102] Step 2: 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-2-one (3)

[0103]

[0104] In the reaction flask of THF (180mL), add compound 2 (20.6g, 75.1mmol), Pd2(dba)3(1.38g, 1.5mmol), xantphos (1.74g, 3.0mmol), sodium tert...

Embodiment 2

[0126] Example 2: 6-isopropyl-10-methoxy-9-(3-methoxypropoxy)-3-(1H-tetrazol-5-yl)-6,7-dihydro-2H -pyrido[2,1-a]isoquinolin-2-one (12)

[0127]

[0128] Reaction process 2:

[0129]

[0130] Step 1: 6-Isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a ] Synthesis of isoquinoline-3-carboxamide (11)

[0131]

[0132]Compound 9 (1g, 2.49mmol) was added to a reaction flask of thionyl chloride (10mL), dripped into 1d DMF, refluxed for 3 hours, concentrated, and the residual thionyl chloride was removed with toluene, then diluted with THF (10mL), Cool to 0°C, add ammonia water (5 mL) dropwise, raise to room temperature, stir overnight, evaporate THF under reduced pressure, filter the obtained solid, wash with ice water to obtain compound 11, 0.86 g, 87%. Proceed directly to the next reaction. ESI-MS: [M+H]+: 401.2.

[0133] Step 2: 6-Isopropyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1-a ] Synthesis of isoquinoline-3-carbo...

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PUM

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Abstract

The invention relates to an isoquinoline compound shown as a formula (A) or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, a medicinal composition thereof and application thereof as antiviral medicines. The isoquinoline compound inhibits hepatitis B DNA activity and hepatitis B surface antigen activity at the same time. The invention particularly relates to application thereof to preparation of medicines for treating and/or preventing hepatitis B, hepatitis B viruses (HBV) thereof and other viral infectious diseases, in particular to treatment and/or prevention of the hepatitis B and the hepatitis B viruses as HBV Surface antigen inhibitor medicines and HBV DNA production inhibitor medicines.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry antiviral, in particular to a class of novel isoquinoline compounds or their stereoisomers and the use of pharmaceutical compositions containing isoquinoline compounds or their stereoisomers as antiviral drugs, in particular It is used as a medicine for treating and / or preventing hepatitis B virus infection as a hepatitis B surface antigen inhibitor (HBV Surface antigen inhibitors) and a hepatitis B DNA inhibitor (HBVDNA production inhibitors), especially referring to such compounds and nucleoside drugs and Use of other medicines as a medicinal composition for curing hepatitis B. Background technique [0002] There are about 350 million chronic hepatitis B infections in the world, and 780,000 people died of hepatitis B in 2011. Among them, hepatitis B patients in China account for one-third of the global total. China currently spends more than 100 million people on hepatitis B treatment each yea...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D491/22C07D495/14C07D471/04C07D491/147C07D498/04C07D498/10C07D513/04C07D498/20C07F9/6561C07F5/02A61K31/4375A61K31/519A61K31/4745A61K31/537A61K31/5377A61K31/675A61K31/69A61K45/06A61P31/20
CPCC07D471/14C07D471/04C07D491/147C07D491/22C07D495/14C07D498/04C07D498/20C07D513/04C07F5/025C07F9/6561
Inventor 陈力翟培斌
Owner GINKGO PHARMA
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