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4-pyridine substituted phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof

A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as many adverse reactions, poor interferon tolerance, and high cost

Active Publication Date: 2020-12-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, interferon has disadvantages such as poor tolerance, many adverse reactions, and high cost; and 6 nucleoside drugs (lamivudine, adefovir dipivoxil, entecaine, telbivudine, Tenofovir and Clavudine) both act on the reverse transcriptase of hepatitis B virus
Since the existing treatment methods are far from meeting the clinical needs of hepatitis B treatment, it is increasingly urgent to research and develop more non-nucleoside small molecule anti-HBV drugs that act on new targets, new mechanisms and new structural cores. At present, it is a research hotspot in the field of medicinal chemistry, and has very important theoretical, economic and social significance.

Method used

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  • 4-pyridine substituted phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof
  • 4-pyridine substituted phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof
  • 4-pyridine substituted phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Embodiment 1: The synthetic route of compound 1 is as follows:

[0099]

[0100] Step (i):

[0101] 3,6-Dichlorophthalazine i-1 (10g, 50.3mmol) was added to acetic acid (150mL), and refluxed at 120°C for 6 hours. After the reaction was complete as monitored by TLC, the reaction was stopped and the reaction solution was cooled to room temperature and decompressed. Acetic acid was removed by rotary evaporation to obtain compound i-2 as a white solid.

[0102] Step (ii):

[0103] Compound i-2 (1.0g, 5.5mmol) was dissolved in DMF (70mL), and 4-cyanobenzyl chloride (1.26g, 6.6mmol) and Cs were added successively 2 CO 3 (2.1 g, 6.6 mmol). After the reaction system was stirred at 50° C. for 5 hours, the reaction was complete as monitored by TLC. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, the organic layer was separated, and the organic layer was washed successively with water (100 mL x 4) and saturated brine (100 mL). The organic ph...

Embodiment 2

[0131]

[0132] Step a:

[0133] Compound I-1 (85mg, 0.13mmol) was dissolved in dry tetrahydrofuran (5mL), added dropwise to 60% NaH (25mg, 64mmol) at 0°C, and stirred for 30 minutes. Add a solution of iodomethane (9.58uL, 0.15mmol) in tetrahydrofuran (2mL). After the addition is complete, the reaction solution is gradually raised to room temperature and stirred overnight. The reaction solution is poured into ice water, extracted with ethyl acetate (20mL×3), and the organic phase is anhydrous. It was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain compound I-33' (47mg, 55%) as a white powdery solid.

[0134] Step b:

[0135] Dissolve I-33' (40mg 0.059mmol) in 5mL of dichloromethane, add 0.5mL of trifluoroacetic acid, react in an oil bath at 40°C for 3h, add saturated sodium bicarbonate solution to adjust the pH value to neutral, extract with dichloromethane ...

Embodiment 3

[0139]

[0140]Step: Dissolve compound 1 (300mg, 0.65mmol) in tetrahydrofuran, under nitrogen protection, at -5°C, add a solution of tert-butylmagnesium bromide in tetrahydrofuran (1.35mmol, 1.35mL, c 1mol / L) successively, N -[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester B (351mg, 0.775mmol) in tetrahydrofuran, react The temperature of the solution was gradually raised to 5°C, and the reaction was carried out for 17 hours. TLC monitors that there is no raw material, add water to quench the reaction, spin dry the solvent, add 100mL water, extract with ethyl acetate 3 times (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry the solvent to obtain the crude product . The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 90 / 10-50 / 50) to obtain white solid compound I-36 (280 mg, 52%).

[0141]

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PUM

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Abstract

The invention relates to a 4-pyridine substituted phthalazinone compound, a preparation method, a pharmaceutical composition and an application thereof, the structure of the 4-pyridine substituted phthalazinone compound is shown as a formula I, the compound of the formula I has improved pharmaceutical physicochemical properties and in-vivo pharmacokinetic properties, oral bioavailability is high,druggability is good, The compound is a non-nucleoside small-molecule HBV virus inhibitor which is novel in structure and can be orally taken.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to 4-pyridine substituted phthalazinone compounds, a preparation method, a pharmaceutical composition and uses thereof. Background technique [0002] About 750,000 people worldwide die from hepatitis B and its complications every year, including hepatocellular carcinoma, cirrhosis, and liver failure. Therefore, hepatitis B virus infection is still a worldwide disease that seriously endangers public health. [0003] At present, interferon and nucleoside anti-HBV drugs are the two main methods for treating HBV infection. However, interferon has disadvantages such as poor tolerance, many adverse reactions, and high cost; and 6 nucleoside drugs (lamivudine, adefovir dipivoxil, entecaine, telbivudine, Tenofovir and Clavudine) both act on the reverse transcriptase of hepatitis B virus. Since the existing treatment methods are far from meeting the clinical needs of hepatitis B treatment,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07F9/6558C07F9/6574A61K31/502A61K31/5377A61K31/685A61K31/675A61P31/20A61P31/14A61P31/16A61P31/18A61P31/22
CPCC07D401/04C07D401/14C07F9/65583C07F9/65744C07F9/65742A61K31/502A61K31/5377A61K31/685A61K31/675A61P31/20A61P31/14A61P31/16A61P31/18A61P31/22C07F9/6558C07F9/6574A61K31/5025Y02P20/55Y02A50/30
Inventor 胡有洪左建平陈五红杨莉赵琪良刘菲菲曾艳萍童贤崑曾丽敏魏爱环
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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