Preparation and uses of novel Michael receptor-based enterovirus 71 type inhibitor

An enterovirus and protease inhibitor technology, applied in the field of compounds of general formula (M), can solve problems such as restricting development

Inactive Publication Date: 2019-08-09
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, in vitro instability in plasma and liver microsomes, as well as potential t

Method used

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  • Preparation and uses of novel Michael receptor-based enterovirus 71 type inhibitor
  • Preparation and uses of novel Michael receptor-based enterovirus 71 type inhibitor
  • Preparation and uses of novel Michael receptor-based enterovirus 71 type inhibitor

Examples

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example

[0091] The present invention is illustrated in more detail by the following non-limiting examples, but the present invention is not limited to the following examples. Temperatures are provided in degrees Celsius in the following examples. Unless otherwise stated, solution percentages express a weight-to-volume relationship, and solution ratios express a volume-to-volume relationship. The structures of the compounds in the examples were determined by one or more of the following methods: nuclear magnetic resonance spectrometer, high-resolution mass spectrometry, and thin-layer chromatography.

[0092] NMR spectrum ( 1 H NMR and 13 C NMR) were measured with a Bruker 400 spectrometer at a field strength of 400 MHz. Chemical shifts are expressed in parts per million (ppm, δ) relative to the internal standard tetramethylsilane. 1 The multiplicity of peaks in H-NMR is indicated as follows: s=singlet; d=doublet; t=triplet; m=multiplet. Coupling constants are expressed in Hertz. ...

Embodiment 1

[0095] Implementation Example 1: Preparation of Compound 1-2

[0096]

[0097] Add acetyl chloride (5 mL) slowly to methanol (100 mL) dropwise at 0 °C, stir for 5 minutes, then add glutamic acid (10 g, 67.9 mmol), continue stirring and heat to reflux, keep reflux Temperature reaction for 2 hours. After the reaction was complete, the solvent was distilled off under reduced pressure and recrystallized with ether. Dissolve the obtained oil in THF (150 mL), add TEA (28.5 mL, 203.7 mmol) dropwise at 0 °C, keep stirring at 0 °C for 5 minutes, continue to add dropwise to dissolve in THF (30 mL) di-tert-butyl dicarbonate (17.8 g, 81.5 mmol), raised to room temperature and stirred for 2.5 hours. After the reaction was over, the solvent was distilled off under reduced pressure, water (200 mL) was added to the residue, extracted from the aqueous phase with DCM (2×200 mL), the combined organic phases were dried over anhydrous sodium sulfate, and then concentrated to obtain The crude...

Embodiment 2

[0098] Implementation Example 2: Preparation of Compound 1-3

[0099]

[0100] At -78 °C, under the condition of nitrogen protection, lithium bis(trimethylsilyl)amide (78.5 mL, 1.0 M solution in THF, 78.5 mmol) was slowly added dropwise to 1-2 (10 g, 36.4 mmol) in anhydrous THF (200 mL) and stirred at this temperature for 30 minutes. Then, keeping the temperature constant, bromopropionitrile (3.4 mL) was slowly added dropwise, and the reaction mixture was stirred at -78°C for 2 hours. After the reaction was complete, glacial acetic acid (5 mL) was added to quench the reaction, and stirred to room temperature. The solvent was distilled off under reduced pressure, then water (200 mL) was added, the aqueous phase was extracted with DCM (2×200 mL), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash chromatography (PE :EA=2:1), 1-3 was obtained as light yellow oily liquid (7.1 g...

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PUM

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Abstract

The present invention relates to a class of novel Michael receptor-based virus 71 (EV71) 3C protease inhibitors, wherein various variables of the structure general formula (M) are defined in the specification, and the compounds effectively inhibit or block the replication of enterovirus 71. The present invention relates to discovery and applications of the compound containing the structure generalformula (M), various optical isomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates and prodrugs thereof in preparation of antiviral drugs for the treatment of hand-foot-mouth virus infection diseases. The invention relates to an intermediate and a synthesis method for preparing the compound having the structure general formula (M). The formula (M) is defined inthe specification.

Description

technical field [0001] The present invention relates to compounds of general formula (M) for treating enterovirus 71 (EV71) infection, pharmaceutical compositions, synthesis methods, preparation methods of such compounds and compounds used in these synthesis. Specifically, the present invention provides a class of novel Michael receptor compounds, pharmaceutical compositions containing such compounds and methods for treating EV71 infection with such compounds. Background technique [0002] Hand-foot-mouth disease (Hand-Foot-Mouth disease, HFMD) is a common infectious disease caused by enterovirus. Thousands of infant deaths have been caused, bringing huge economic and spiritual damage to the families of children. And in recent years, due to the influence of various factors such as personnel flow and virus mutation, the number of cases in the Western Pacific such as China, Japan, Malaysia and Singapore has shown an increasing trend year by year. The disease is mainly transm...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14A61K31/4439A61K31/444A61P31/14
CPCC07D413/12C07D413/14A61K31/4439A61K31/444A61P31/14Y02A50/30
Inventor 尚鲁庆马玉莹何帅尚成友
Owner NANKAI UNIV
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