Isoquinoline compound, medicinal composition thereof and application of isoquinoline compound as antiviral drug

A technology of isoquinoline and compound, applied in the field of hepatitis B surface antigen inhibitor and hepatitis B DNA inhibitor, in the field of treatment and/or prevention of infection with hepatitis B virus, and can solve the problem of inability to reduce hepatitis B surface antigen and the like

Inactive Publication Date: 2018-03-06
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 nucleoside drugs, and at the same time effectively remove HBsAg and viral DNA in the blood, activate and restore its own Immune function, and thus an eventual possible cure for hepatitis B

Method used

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  • Isoquinoline compound, medicinal composition thereof and application of isoquinoline compound as antiviral drug
  • Isoquinoline compound, medicinal composition thereof and application of isoquinoline compound as antiviral drug
  • Isoquinoline compound, medicinal composition thereof and application of isoquinoline compound as antiviral drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: 10 Chloro-1-fluoro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1 -α]isoquinoline-3-carboxylic acid (9)

[0062]

[0063] Modified Step 1: Synthesis of 4-bromo-1-chloro-2-(2-methoxypropoxy)benzene (2)

[0064]

[0065] 1-bromo-2-methoxypropane (49.8g, 325.4mmol) was added dropwise to 5-bromo-2-chlorophenol (22.5g, 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 phases, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid, 27g, 89%. ESI-MS: [M+H]+: 278.9.

[0066] Modified Step 2: 1-(4-Chloro-3-(2-methoxypropoxy)phenyl)-3-methylbutan-2-one (3)

[0067]

[0068] To THF (180 mL) was added compound 2 (21.0 g, 75.1 mmol), Pd2(dba)3 (1.38 g, 1.5 mmol), xantphos (1.74 g, 3.0 mmol), sodium tert-butoxide (13.0 g, 135....

Embodiment 2

[0089] Example 2: 10-chloro-6-isopropyl-9-(2-methoxypropoxy)-1-methyl-2-oxo-6,7-dihydro-2H-pyrido[2 , 1-α]isoquinoline-3-carboxylic acid (12)

[0090]

[0091] Step 1: 10-Chloro-6-isopropyl-9-(2-methoxypropoxy)-1-methyl-2-oxo-1,6,7,11b tetrahydro-2H-pyrido Synthesis of ethyl [2,1-α]isoquinoline-3-carboxylate (10)

[0092]

[0093] Compound 6 (5g, 16.9mmol), ethyl (E)-2-(ethoxymethylene)-3-oxopentanoate (10.6g, 52.9mmol) in ethanol (50mL) was heated at 100°C, Reacted overnight, concentrated, and simply purified to obtain compound 10, 3.7 g, 48%. Proceed directly to the next reaction. ESI-MS: [M+H]+: 450.2.

[0094] Step 2: 10-Chloro-6-isopropyl-9-(2-methoxypropoxy)-1-methyl-2-oxo-6,7-dihydro-2H-pyrido[2, Synthesis of ethyl 1-α]isoquinoline-3-carboxylate (11)

[0095]

[0096] Compound 10 (3g, 6.6mmol) and p-chlorobenzoquinone (1.63g, 6.6mmol) were dissolved in DME (20mL), heated to 70°C, reacted under nitrogen for 3 hours, poured into water, extracted with dichlo...

Embodiment 3

[0102] Example 3: 10-chloro-1-cyano-6-isopropyl-9-(2-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2 , 1-α]isoquinoline-3-carboxylic acid (17)

[0103]

[0104] Step 1: 10-Chloro-6-isopropyl-9-(2-methoxypropoxy)-2-oxo1,6,7,11b tetrahydro-2H-pyrido[2,1-α ] Synthesis of ethyl isoquinoline-3-carboxylate (13)

[0105]

[0106] Compound 6 (3g, 10.1mmol), ethyl (E)-2-(ethoxymethylene)-3-oxobutanoate (5.94g, 31.9mmol) in ethanol (30mL) was heated at 100°C, Reacted overnight, concentrated, and simply purified to obtain compound 13, 2.23g, 50.4%. Proceed directly to the next reaction. ESI-MS: [M+H]+: 436.1.

[0107] Step 2: 10-Chloro-6-isopropyl-9-(2-methoxypropoxy)-2-oxo-6,7-dihydro-2H-pyrido[2,1-α]iso Synthesis of ethyl quinoline-3-carboxylate (14)

[0108]

[0109] Compound 13 (2.0g, 4.5mmol) and chlorbenzoquinone (1.16g, 4.7mmol) were dissolved in DME (15mL), heated to 70°C, reacted under nitrogen for 3 hours, poured into water, extracted with dichloromethane, water an...

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Abstract

The invention relates to an isoquinoline compound, a medicinal composition thereof and application of the isoquinoline compound as an antiviral drug, and particularly relates to application of an isoquinoline compound as shown in the general formula I or a stereoisomer, medicinal salt, hydrate, solvate or crystal thereof and a medicinal composition containing them in preparing drugs for treating and / or preventing hepatitis B, hepatitis B viruses (HBV) and other viral infectious diseases, in particular to application in treating and / or preventing hepatitis B and hepatitis B viruses as HBV surface antigen inhibitors and HBV DNA production inhibitors.

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 The invention is used as the medicine of hepatitis B surface antigen inhibitors (HBV Surface antigen inhibitors) and hepatitis B DNA inhibitors (HBVDNA production inhibitors) for treating and / or preventing hepatitis B virus infection. 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 year 100 billion, is the world's largest hepatitis B drug market. Although the hepatitis B vaccine has been widely used, the numb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/06C07D471/04C07D491/048C07D491/056C07D498/04C07D513/04A61K31/4375A61K31/55A61K31/5365A61K31/542A61K31/519A61K31/5025A61K45/06A61P31/20A61P31/12
CPCA61K31/4375A61K31/5025A61K31/519A61K31/5365A61K31/542A61K31/55C07D455/06C07D471/04C07D491/048C07D491/056C07D498/04C07D513/04C07D455/03C07D491/147C07D497/14A61K2300/00A61P31/20
Inventor 陈力翟培彬张红利杨光
Owner GINKGO PHARMA
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