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Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof

A technology of small molecule inhibitors and proteases, applied in the fields of antiviral agents, bulk chemical production, organic chemistry, etc., can solve the problems of long clinical trials, poor specificity, no specific drugs, etc., and achieve good application prospects, good The effect of inhibiting activity

Inactive Publication Date: 2016-08-10
TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Long before SARS, people began to study coronaviruses and their inhibitors. Some laboratories found that PMSF, TLCK and PefalocS have a strong inhibitory effect on the activity of the main protease of human coronavirus 229E, because of their poor specificity. , Toxic and side effects are large and not used in treatment
During the SARS period, scientists tried to develop inhibitors for important components of the virus such as RNA polymerase, S protein, and N protein to block virus invasion, replication, and transcription. However, the development of new drugs is risky and takes a long time for clinical trials. Specific drugs without corresponding targets

Method used

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  • Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof
  • Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof
  • Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof

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preparation example Construction

[0085] The preparation method of MERS-CoV main protease small molecule inhibitor of the present invention comprises the following steps:

[0086] A, the amino protecting group R in the corresponding compound of general formula (II) 6 removed, where the R 6 Selected from the group consisting of the following groups: tert-butoxycarbonyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl;

[0087] B, in the presence of a condensing agent, the product of step A is condensed with the corresponding compound of general formula (III) to obtain general formula (I),

[0088]

[0089] Wherein, R in general formula (II) and general formula (III) 1 , R 2 , R 3 , the definitions of U are the same as R in the general formula (I) 1 , R 2 , R 3 , U have the same definition.

[0090] In the preparation method of the small molecule inhibitor of MERS-CoV main protease, the following steps are also included: in an organic solvent, the compound corresponding to the ge...

Embodiment 1

[0103] 300mg of Dissolve in 3mL

[0104] Dry CH 2 Cl 2 , add 0.49g sodium bicarbonate, then add 1.23g Dess Martin reagent, react at room temperature for 8-12 hours, quench the reaction with sodium thiosulfate solution, wash with saturated saline and spin dry to obtain Dissolve with dry THF5ml and set aside. 0.52g Dissolve in 5ml of dry THF, cool and stir at -78°C, then add 60% NaH 0.078g and stir for 1h, then slowly add the ready-to-use Solution, turn off the refrigeration, react for 12h, quench the reaction with saturated ammonium chloride, spin dry the THF in the system, and extract the product with EA. Flash silica gel column chromatography, obtain 82mg product Dissolve the resulting product in 1 mL CH 2 Cl 2 , add 58 μL TFA, stir at room temperature for 2 hours, drain the solvent to obtain the product deprotected by Boc, and then dissolve it in 5ml of CH 2 Cl 2 , add 158mg

[0105] and 257uL DIEA, followed by 220mg HATU. The system was reacted at room te...

Embodiment 2

[0111] 200mg Dissolve in 3ml CH 2 Cl 2 In, add 220μl DIEA and 140mg Stir at room temperature for 12h, and obtain 100mg by silica gel column chromatography

[0112] Dissolve the resulting product in 1 mL CH 2 Cl 2 , add 58 μL TFA, stir at room temperature for 2 hours, drain the solvent to obtain the product deprotected by Boc, and then dissolve it in 3ml of CH 2 Cl 2 , add 192mg

[0113] And 320ul DIEA, followed by 380mg HATU. The system was reacted at room temperature for 12 hours, followed by 1M HCl, saturated NaHCO 3 aqueous solution, saturated brine, and then collected the organic phase, anhydrous Na 2 SO 4 dry, the Na 2 SO 4 Filtered out, the organic phase was evaporated under reduced pressure to remove the solvent, followed by flash silica gel column chromatography to obtain 80 mg of product M18

[0114] Product hydrogen spectrum and mass spectrum data are as follows:

[0115] 1 H NMR (400MHz, DMSO-d6): δ8.59 (d, J=7.5Hz, 1H, NH), 8.18-8.28 (m, 1H, ...

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Abstract

A small molecule inhibitor of MERS-CoV main protease, designed based on the crystal structure of the new coronavirus MERS-CoV main protease, the present invention also provides a synthesis method of the small molecule inhibitor, and its preparation for treatment and prevention Use in medicine for MERS‑CoV infection. The MERS-CoV main protease small molecule inhibitor of the present invention can significantly inhibit the activity of the MERS coronavirus main protease, and at the same time, it also has good inhibitory activity on the coronavirus main proteases such as SARS and MHV, and is used in the preparation for treating or preventing coronavirus infection. It has a good application prospect in medicine.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, specifically a small molecule inhibitor of MERS-CoV main protease and its preparation method and application. Background technique [0002] Coronavirus (CoV) is a single-stranded positive-sense RNA virus with a membrane, "Nidovirales" order, "Coronaviridae" family, "Coronavirinae" subfamily, and is currently the most known large RNA virus. According to serological characteristics and genetic differences, the Coronaviridae subfamily is divided into 4 genera α, β, γ, and δ, and the genus β is further divided into four subgroups (A-D). Since September 2012, a novel coronavirus MERS-CoV (Middle East Respiratory SyndromeCoronavirus, Middle East Respiratory Syndrome), a β genus C subgroup, has posed a major threat to global public health security. As of May 25, 2015, according to the data released by the World Health Organization (WHO), a total of 1139 cases of MERS-CoV infection have been ...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07D413/12C07D403/12A61K31/4025A61K31/422A61K31/5377A61K31/497A61P31/14
CPCY02P20/55C07D207/16C07D403/12C07D413/12
Inventor 饶子和傅晟杨海涛杨诚蔡岩王喆刘贺李爽徐杨
Owner TIANJIN INT JOINT ACADEMY OF BIOTECH & MEDICINE
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