Preparation and application of Michael receptor main protease inhibitor targeting novel coronavirus

A technology of protease inhibitors and Michael receptors, which is applied in the field of preparation and application of Michael receptor-type main protease inhibitors targeting the new coronavirus, can solve the problem that virus replication and transcription cannot continue normally

Pending Publication Date: 2021-12-17
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Among the non-structural proteins, the main protease (also known as 3CL protease) is a key protein in the replication process of SARS-CoV-2, and its hydrolytic processing of polyproteins into non-structural proteins includes RNA-dependent RNA polymerase, gyrase, etc. Once the function of this protein is lost, the further replication and transcription of the virus cannot continue normally

Method used

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  • Preparation and application of Michael receptor main protease inhibitor targeting novel coronavirus
  • Preparation and application of Michael receptor main protease inhibitor targeting novel coronavirus
  • Preparation and application of Michael receptor main protease inhibitor targeting novel coronavirus

Examples

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[0083] 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.

[0084] 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...

Embodiment 1

[0087] Implementation Example 1: Preparation of Compound 4-1

[0088]

[0089] At 0°C, slowly add acetyl chloride (5 mL) dropwise into methanol (100 mL), stir for 5 minutes, then add glutamic acid (10 g, 67.9 mmol), continue stirring and heat to reflux, and keep the reflux temperature for 2 hours . After the reaction was complete, the solvent was distilled off under reduced pressure and recrystallized with diethyl ether. The obtained oil was dissolved in THF (150mL), TEA (28.5mL, 203.7mmol) was added dropwise at 0°C, kept stirring at 0°C for 5 minutes, and dicarbonate dicarbonate dissolved in THF (30mL) was continued to be added dropwise. Tert-butyl ester (17.8g, 81.5mmol), raised to room temperature and stirred for 2.5 hours. After the reaction, the solvent was distilled off under reduced pressure, water (200 mL) was added to the residue, and the aqueous phase was extracted with DCM (2×200 mL), the combined organic phases were dried over anhydrous sodium sulfate, and the...

Embodiment 2

[0090] Implementation Example 2: Preparation of Compound 4-2

[0091]

[0092] At -78°C, under the condition of nitrogen protection, lithium bis(trimethylsilyl)amide (78.5mL, 1.0M solution in THF, 78.5mmol) was slowly added dropwise to 4-1 (10g, 36.4mmol) without A solution of THF (200 mL) in water was 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 phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash chromatography (PE:EA =2:1), 4-2 was obtained as pale yellow oily liqu...

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Abstract

The invention relates to a novel double-activation Michael receptor novel coronavirus (SARS-CoV-2) main protease inhibitor. The compounds can effectively inhibit or block the replication of SARS-CoV-2. The invention relates to discovery and application of a compound containing a structural general formula as well as various optical isomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates and prodrugs of the compound in preparation of antiviral drugs for treating novel coronavirus pneumonia (COVID-19). The invention also relates to an intermediate for preparing the compound with the structural general formula and a synthesis method. Each variable in the structure is defined in the specification, and the structural general formula skeleton of the compound is shown in the drawings.

Description

technical field [0001] The present invention relates to a compound containing the skeleton of this general formula, a pharmaceutical composition for the treatment of novel coronavirus (SARS-CoV-2) infection, as well as a synthesis method of such compounds, a preparation method and a compound 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 SARS-CoV-2 infections with such compounds. This is the general formula skeleton of the compound: [0002] [0003] Background of the invention [0004] Novel coronavirus pneumonia (COVID-19) is caused by a novel coronavirus (SARS-CoV-2) infection. The spread of the new coronavirus is fast, the scope of infection is wide, and the prevention and control is difficult. The mode of transmission of the novel coronavirus includes droplet transmission and aerosol transmission. The clinical symptoms a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02A61K38/06A61P31/14
CPCC07K5/0205A61P31/14A61K38/00
Inventor 尚鲁庆何帅王昊
Owner NANKAI UNIV
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