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Pyridopyrimidinone compounds and their preparation methods and applications

A compound, pyrimidone technology, applied in the field of medicine

Active Publication Date: 2021-11-09
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The invention discloses a class of pyridopyrimidinone HBV RNase H inhibitors, which have not been reported in the prior art

Method used

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  • Pyridopyrimidinone compounds and their preparation methods and applications
  • Pyridopyrimidinone compounds and their preparation methods and applications
  • Pyridopyrimidinone compounds and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of 2-((Benzyloxy)amino)-5-bromonicotinic acid methyl ester (intermediate IIB-2)

[0045] 2-Chloro-5-bromonicotinic acid methyl ester IIB-1 (1.0g, 4.0mmol), O-benzyl hydroxylamine (465μL, 4.0mmol) and diisopropylethylamine (2.8mL, 16.0mmol) were weighed together in In a round bottom flask, heat and stir at 60° C. for 6 h (TLC detects the reaction). After the reaction is over, add an appropriate amount of ethyl acetate to the reaction solution for dilution, add dilute hydrochloric acid (20mL*3) to wash, and dry the organic phase over anhydrous sodium sulfate. Column chromatography (eluent is petroleum ether: ethyl acetate = 20 : 1) isolated yellow oil, yield 13%.

Embodiment 2

[0047] Preparation of 1-benzyloxy-6-bromopyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (intermediate IIB-3)

[0048] Weigh intermediate IIB-2 (0.1g, 0.3mmol) into a 50mL flask, add an appropriate amount of 1,2-dichloroethane, slowly add trichloroacetyl isocyanate (74μL , 0.6mmol) in 1,2-dichloroethane solution, after reacting for half an hour, slowly add triethylamine (86μL, 0.6mmol) in 1,2-dichloroethane solution to the above reaction system, and continue to stir 40min. After the reaction, most of the solvent was evaporated, and the residue was dissolved with an appropriate amount of methanol. Under stirring conditions, 30% w / w methanol solution of sodium methoxide (276 μL, 1.5 mmol) was slowly added to continue stirring for 6 h. After the reaction, most of the solvent was evaporated, redissolved in an appropriate amount of ethyl acetate, the pH of the reaction mixture was adjusted to 3 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL*3), and the organic ph...

Embodiment 3

[0050] Weigh compound IIB-3 (1eq) into a round-bottomed flask, add diisopropylethylamine (5eq) and phosphorus oxychloride (5eq) in sequence, heat and stir at 100°C for 45min, then evaporate most of the solvent under reduced pressure to obtain a black Oil (Intermediate IIB-4). Add 10 mL of anhydrous N,N-dimethylformamide to the crude product of IIB-4 above, and then add 1-tert-butoxycarbonylpiperazine (1.5eq) dropwise with anhydrous N,N-dimethylformamide under stirring condition. Base formamide solution, stirred at room temperature for 2h. After the reaction was completed, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic phase was successively washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain a crude product, which was mixed with ethyl acetate / dichloro Recrystalliza...

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Abstract

The invention discloses a pyridinium pyrimidinone compound and a preparation method and application thereof. The compound has the structure shown in formula I. The present invention also relates to a preparation method and a pharmaceutical composition containing the compound of formula I and the application of the above compound in the preparation of anti-HBV drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a pyridopyrimidinone compound, a preparation method thereof and a pharmaceutical use thereof. Background technique [0002] Viral Hepatitis Type B (Hepatitis B) is a major infectious disease caused by Hepatitis B Virus (HBV). Long-term development can lead to acute and chronic viral hepatitis, liver A series of complications such as cirrhosis and primary hepatocellular carcinoma (Hepatocellular Carcinoma, HCC). According to the World Health Organization (WHO) statistics, nearly 2 billion people in the world have been infected with HBV, of which about 260 million people are chronic HBV-infected, and an average of about 600,000 people die each year from related diseases caused by HBV infection. As of 2019, the drugs approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of Chronic Hepatitis B (CHB) are mainly divided into interferon a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P31/20A61K31/519
CPCA61P31/20C07D471/04
Inventor 刘新泳高萍展鹏宋淑约翰·塔维斯李其岚
Owner SHANDONG UNIV
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