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PROTAC molecule targeting SARS-CoV-2 3C protease and application of PROTAC molecule

A protease inhibitor, chymotrypsin technology, applied in the field of medicine, can solve the problems such as the inability to completely inhibit the virus infection process, the inability to enter the 3C protease active protein binding domain, and the loss of the binding ability of GC376 to 3C protease.

Pending Publication Date: 2022-08-09
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, GC376 is difficult to completely block the replication of the virus and cannot completely inhibit the infection process of the virus
Moreover, the existing structural modification methods of GC376 usually cannot give GC376 the ability to completely block virus replication. On the contrary, these modification methods may also cause GC376 to be unable to enter the active protein binding domain of 3C protease, unable to interact with its active protein binding domain, and / or change the mechanism of action between GC376 and 3C protease, resulting in the loss of the binding ability of GC376 and 3C protease, unable to achieve effective inhibition of 3C protease, and even more difficult to achieve the goal of completely blocking virus replication

Method used

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  • PROTAC molecule targeting SARS-CoV-2 3C protease and application of PROTAC molecule
  • PROTAC molecule targeting SARS-CoV-2 3C protease and application of PROTAC molecule
  • PROTAC molecule targeting SARS-CoV-2 3C protease and application of PROTAC molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1: Preparation of Compounds A, B and C

[0103] Compounds A1, B1 and C1 were synthesized by the following route 1, wherein compound 4 was purchased from Shanghai Shaoyuan Reagent Co., Ltd., and compound 1 and 4-O-propynyl benzyl alcohol were purchased from Aladdin Reagent Co., Ltd.

[0104]

preparation example 1-1

[0105] Preparation Example 1-1: Synthesis of Compounds A1, B1 and C1

[0106] Synthesis of intermediate 2 in step 1: Compound 1 (1.3 g, 7.60 mmol) and 4-O-propynyl benzyl alcohol (0.9 g, 5.55 mmol) were dissolved in dry acetonitrile (30 mL), and 1.5 mL of triethylamine was added, and the reaction was carried out at room temperature. , After 2 hours, the solution was concentrated, and the silica gel column was separated. Mobile phase: petroleum ether / ethyl acetate=4 / 1 to obtain 1.75 g of white solid with a yield of 95%.

[0107] Synthesis of Intermediate 3 in Step 2: Compound 2 (2.47 g, 7.73 mmol) was dissolved in 30 mL of tetrahydrofuran, 15 mL of 1M LiOH aqueous solution was added, stirred at room temperature, and after 2 hours, the system was neutralized with an acidic resin, the resin was filtered off, and concentrated , the white solid was directly used in the next reaction.

[0108] Synthesis of intermediate 5 in step 3: Compound 3 (2.1 g, 6.6 mmol) and compound 4 (1.23 ...

preparation example 1-2

[0112] Preparation Example 1-2: Synthesis of Compounds A2, B2 and C2

[0113] As shown in Scheme 1, except that 4-O-propynyl benzyl alcohol was replaced by (The compound was purchased from Jiangsu Aikang Biomedical R&D Co., Ltd.), using the same steps as the synthesis of compounds A1, B1 and C1, respectively, with the yields of 47%, 34% and 29% to obtain compound A2 as a white solid , B2 and C2.

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Abstract

The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt or solvent compound thereof wherein M1 represents a 3-chymotrypsin-like protease inhibitor moiety; m2 represents an E3 ubiquitin ligase ligand part; l represents a linking group having a-(CH2CH2O) q (CH2) e (NH) f (O) g (CH2) hCO (CH2) i (CO) j-structure. The invention also relates to a preparation method of the compound and application of the compound in preparation of 3-chymotrypsin-like protease inhibitors and anti-coronavirus drugs.

Description

Technical field [0001] This application belongs to the field of medicine. Specifically, it relates to a class of PROTAC (proteolysis targeting chimeras, protein degradation targeting chimeras) compounds that target the 3C protease of the new coronavirus (SARS-CoV-2), or pharmaceutically acceptable compounds thereof. Salts, or solvates, and also relate to preparation methods of the above compounds and their use in preparing 3-chymotrypsin-like protease inhibitors, especially anti-coronavirus drugs. Background technique [0002] The pathogenic virus SARS-CoV-2 mainly attacks the human lower respiratory system and causes viral pneumonia; it may also affect the gastrointestinal system, heart, kidneys, liver and central nervous system, seriously threatening human life, health and safety, and bringing consequences to the entire society. had a huge negative impact. As of the submission of this application, the global number of cases and deaths is still rising sharply. [0003] Ju...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D401/14A61P31/14A61K31/454A61K31/427
CPCC07D417/14C07D401/14A61P31/14
Inventor 李学兵程水红毕玉海冯永武斌杰施文文李晨宁
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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