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Dihydroisoquinoline compound

A technology of compounds and hydrates, applied in the fields of organic chemistry, organic active ingredients, antiviral agents, etc., can solve the problem that the activity of compounds is not very high

Active Publication Date: 2020-07-14
SUZHOU ARK BIOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The applicant of the present invention reported a dihydroisoquinoline compound in WO2018 / 130152A1, which can be used to treat and prevent hepatitis B virus infection. Large doses can achieve better effect of prevention and treatment of hepatitis B

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0339] 6-tert-butyl-9-[2-(4-hydroxypiperidin-1-yl)thiazol-5-yl]-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine And[2,1-a]isoquinoline-3-carboxylic acid

[0340]

[0341] Step 1a: Preparation of 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester

[0342]

[0343]Under nitrogen protection, to 9-bromo-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine[2,1-a]isoquinoline-3-carboxylic acid Add double pinacol borate (3.5g, 13.81mmol) to ethyl ester (see Example 8 in WO 2018130152 for the preparation method) (3.0g, 6.91mmol) in 1,4-dioxane (50mL) solution , potassium acetate (1.4 g, 13.81 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (505 mg, 0.69 mmol). The mixture was stirred at 100° C. for 1 hour. The mixture was diluted with dichloromethane (100 mL), then washed with water (100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate, ...

Embodiment 2

[0354] 6-tert-butyl-9-{2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl}-10-methoxy-2-oxo-6,7-dihydro -2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid

[0355]

[0356] Step 2a: Preparation of [1-(5-bromothiazol-2-yl)piperidin-4-yl]methanol

[0357]

[0358] 2,5-dibromothiazole (100mg, 0.41mmol) and piperidin-4-ylmethanol (57mg, 0.49mmol) were prepared according to a method similar to Example 1 step 1b to obtain a white solid [1-(5-bromothiazole -2-yl)piperidin-4-yl]methanol (51 mg).

[0359] Step 2b: Preparation of 6-tert-butyl-9-{2-[4-(hydroxymethyl)piperidin-1-yl]thiazol-5-yl}-10-methoxy-2-oxo-6, 7-Dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester

[0360]

[0361] 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100mg, 0.21mmol) and [1-(5-bromothiazol-2-yl)piper Pyridin-4-yl]methanol (58mg, 0.21mmol) was prepared according to a method similar t...

Embodiment 3

[0366] 9-[2-(azetidin-1-yl)thiazol-5-yl]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyridine And[2,1-a]isoquinoline-3-carboxylic acid

[0367]

[0368] Step 3a: Preparation of 2-(azetidin-1-yl)-5-bromothiazole

[0369]

[0370] 2,5-dibromothiazole (300mg, 1.23mmol) and azetidine (85mg, 1.48mmol) were prepared according to a method similar to Example 1 step 1b to obtain white solid 2-(azetidine-1 -yl)-5-bromothiazole (55mg).

[0371] Step 3b: Preparation of 9-[2-(azetidin-1-yl)thiazol-5-yl]-6-tert-butyl-10-methoxy-2-oxo-6,7-dihydro -2H-Pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester

[0372]

[0373] 6-tert-butyl-10-methoxy-2-oxo-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (100mg, 0.21mmol) and 2-(azetidin-1-yl)- 5-Bromothiazole (50mg, 0.23mmol) was prepared according to a method similar to Example 1 step 1c to obtain a yellow solid 9-[2-(azetidin-1-yl)thiazol-5-yl]-6-tert Butyl...

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Abstract

The invention provides a dihydroisoquinoline compound or a pharmaceutically acceptable salt, ester, isomer, solvate, hydrate, prodrug or isotope marker thereof. The compound has a structure shown as ageneral formula I. The compound has extremely strong activity of inhibiting hepatitis B surface antigen, also has extremely strong activity of inhibiting hepatitis B DNA, has relatively high bioavailability, can play a drug effect at a relatively low dosage, and reduces the potential toxicity of the compound.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a dihydroisoquinoline compound substituted with a thiazole ring, and a mixture or composition containing a dihydroisoquinoline compound, especially a compound for preventing and treating hepatitis B A thiazole ring-substituted dihydroisoquinoline compound for virus infection and a mixture or composition containing the dihydroisoquinoline compound. Background technique [0002] Hepatitis B virus (HBV) is one of the most common pathogens in the world. Hepatitis B virus is caused by hepatitis B virus (HBV), spreads through blood and body fluids, and is an infectious disease mainly caused by liver damage. Serious public health problem, the disease is a great threat to human health. According to statistics, about one-third of the world's population has been infected with hepatitis B, of which 350 to 500 million people are chronic hepatitis B virus (HBV) carriers. Hepat...

Claims

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Application Information

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IPC IPC(8): C07D455/06A61P31/20A61K31/4745A61K31/5377
CPCC07D455/06A61P31/20A61K31/4745A61K31/5377A61P31/12A61K45/06Y02P20/55A61K2300/00A61K31/4375C07D417/10
Inventor 彭程张绍云赖小刚龚超骏韩健徐宝林邹罡李丹彬袁海卿邬征
Owner SUZHOU ARK BIOPHARM CO LTD
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