Pyridazinone compound, preparation method thereof, pharmaceutical composition and application thereof

A technology for compounds and solvates, applied in the fields of phthalazinone compounds, their preparation, pharmaceutical compositions and uses, can solve the problems of no marketed drugs, strong variability, dependence on antibody enhancement, etc.

Pending Publication Date: 2019-02-26
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

There are four subtypes of dengue virus with strong variability. Currently, there is no vaccine that can prevent all four subtypes at the same time, and preventing one subtype alone may lead to antibody-dependent enhancement
[0004] At present, Celgosivir, a potential α-glucosidase inhibitor for the treatment of dengue, is in the second phase of clinical research. In addition, UV-4B, 60-P-004, and Modipafant have entered the first phase of clinical trials, and there are no marketed drugs yet.

Method used

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  • Pyridazinone compound, preparation method thereof, pharmaceutical composition and application thereof
  • Pyridazinone compound, preparation method thereof, pharmaceutical composition and application thereof
  • Pyridazinone compound, preparation method thereof, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Embodiment 1: the preparation of compound I-1

[0093]

[0094] Step 1: Add 10g of 1,4-dichlorophthalazine (compound 1) into 200mL of acetic acid, stir at 120°C for 5h, cool to room temperature, concentrate, wash with water, and filter with suction to obtain 8.5g of white crystals (compound 2) (yield rate of 94%). 1 H NMR (400MHz, CDCl 3 )δ 9.94–9.87 (m, 1H), 8.48 (d, J=8.0Hz, 1H), 8.07 (d, J=8.0Hz, 1H), 8.00–7.87 (m, 2H).

[0095] Step 2: Dissolve 8.5g of compound 2 in 200ml of dioxane and 40ml of water, add 7.21g of p-fluorophenylboronic acid, 1.71g of ferrocene palladium dichloride, 30g of cesium carbonate, nitrogen replacement 3 times, 100 The reaction was overnight at ℃, TLC showed that the substrate disappeared completely, the reaction was stopped and cooled to room temperature, the reaction was extracted with ethyl acetate, the organic layer was washed 3 times, dried over anhydrous sodium sulfate, concentrated, and column chromatography gave 3.6g yellow crys...

Embodiment 2

[0108] Embodiment 2: the preparation of compound II-1

[0109]

[0110] Step 1: Prepare intermediate compound 5 by the same method as in Example 1;

[0111] Step 2: Dissolve 70mg of N,N-dimethylbutyric acid in 20ml of anhydrous dichloromethane, then add 0.15ml of oxalyl chloride and a drop of DMF, react the reaction solution at 0°C for 5-6 hours, stop the reaction and concentrate, and The reaction solution was dissolved in anhydrous THF, and was dropped into 143 mg of the intermediate compound 5 prepared in Example 1 and 0.118 ml of triethylamine THF solution. The reaction solution was reacted overnight at 0° C., TLC monitored the completion of the reaction, and concentrated column chromatography 90 mg of yellow crystals (II-1) were obtained (yield 47%). 1 H NMR (400MHz, CDCl 3 )δ9.86(s,1H),8.51(dd,J=6.8,2.5Hz,1H),7.76(ddt,J=9.8,7.1,3.4Hz,2H),7.69(dt,J=6.5,3.2Hz ,1H),7.56(ddd,J=17.4,8.7,5.3Hz,4H),7.47(d,J=8.5Hz,2H),7.26–7.19(m,2H),5.42(s,2H),2.51( dd,J=14.2,7.3Hz,4H),2....

Embodiment 3

[0116] Embodiment 3: the preparation of compound III-48

[0117]

[0118] Step 1: Dissolve 220mg of chlorophthalazinone in 20ml of N,N-dimethylformamide (DMF), then add 252mg of methyl bromomethylbenzoate and 359mg of cesium carbonate, and react the reaction solution at 50°C for 5 -6 hours, TLC showed that the substrate disappeared completely, stopped the reaction and cooled the reaction solution to room temperature, the reaction solution was extracted with ethyl acetate, the organic layer was washed 3 times, dried with anhydrous sodium sulfate, concentrated, and column chromatography gave 300 mg of yellow Crystal (compound 9) (yield 84.2%)

[0119] Step 2: Dissolve 300mg of intermediate compound 9 in 30ml THF / H2O (5:1), then add 97mg of lithium hydroxide hydrate, and react the reaction solution overnight at room temperature. TLC shows that the substrate completely disappears, and the reaction solution is concentrated. Column chromatography gave 150 mg of yellow crystals (...

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Abstract

The invention relates to a pyridazinone compound shown as a formula I or an isomer thereof, or a pharmaceutically acceptable salt, ester, a prodrug or a solvate thereof, a preparation method thereof,a pharmaceutical composition and an application of the pharmaceutical composition for preparing a dengue virus inhibitor. The pyridazinone compound has a structure shown in the formula I. The compoundor the pharmaceutical composition thereof has anti-dengue virus activity and better selectivity, and can be used for preventing and / or treating dengue virus infection.

Description

technical field [0001] The present invention relates to a phthalazinone compound or its isomer or its pharmaceutically acceptable salt, ester, prodrug or solvate, its preparation method, pharmaceutical composition and application. Background technique [0002] Dengue fever has become a major public health problem in tropical and subtropical regions. Studies report that 390 million people are infected with the dengue virus each year, and 96 million people show symptoms of the disease. About 1 / 2 of the world's population is at risk from the dengue virus. In China, Guangdong, Guangxi, Fujian, and Yunnan are the main dengue fever-endemic areas. [0003] Dengue virus (Dengue virus, DV) belongs to one of the main members of the Flaviviridae. The disease it infects humans is called dengue virus disease. It is clinically divided into dengue fever (dengue fever) and dengue hemorrhagic fever according to the severity of the disease. (dengue hemorrhagic fever) and dengue shock syndr...

Claims

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Application Information

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IPC IPC(8): C07D237/32C07D401/04C07D471/04C07D405/14C07D401/14C07D487/04C07D403/04A61K31/502A61K31/5377A61K31/519A61P31/14
CPCC07D237/32C07D401/04C07D401/14C07D403/04C07D405/14C07D471/04C07D487/04Y02A50/30
Inventor 胡有洪左建平陆栋童贤崑张韫喆唐炜任文明何佩岚陈五红杨晓倩曾丽敏杨莉刘佳楠
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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