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3CL protease inhibitor of non-peptide SARS coronavirus and use thereof

A use, R13 technology, applied in the field of compounds for the prevention and treatment of anti-SARS coronavirus and other viral infections, achieving good reproducibility and high accuracy

Inactive Publication Date: 2009-06-24
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, so far there is no recommended drug for SARS

Method used

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  • 3CL protease inhibitor of non-peptide SARS coronavirus and use thereof
  • 3CL protease inhibitor of non-peptide SARS coronavirus and use thereof
  • 3CL protease inhibitor of non-peptide SARS coronavirus and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1. The synthesis of oxamide

[0029] [References: Liu Xiang, Liu Tinghui, Liu Baili. Journal of Shenyang Pharmaceutical University, 2001, 18(5), 327-328. ]

[0030] 1. Synthetic route:

[0031]

[0032] 2. Experimental steps:

[0033] Preparation of A, 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (2)

[0034] In a reaction flask equipped with a water separator, add 54g (0.5mol) of o-phenylenediamine and 220ml of xylene, and after heating and stirring to reflux, slowly add a mixture of 71.5g (0.55mol) of ethyl acetoacetate and 20ml of xylene , After dropping, stir and reflux, azeotropic dehydration until no water drops appear, continue to stir and reflux for 2h. After the reaction is complete, cool and precipitate crystals, filter and dry to obtain 56.2 g of white granular crystals (3) (64.6% yield), mp 121-122°C

[0035] B, the preparation of 1-(3-chloropropyl)-1,3-dihydro-2HH-benzimidazol-2-one (3)

[0036] In the reaction flask, add (2) 5.042g ...

Embodiment 2

[0044] The synthesis of embodiment 2.1-benzhydryl-4-benzylpiperazine (pkumdl_cvs_1006)

[0045] According to the operating conditions of step E in Example 1, (3) was replaced by benzyl chloride to obtain 1-benzhydryl-4-benzylpiperazine, which was recrystallized from acetone to obtain colorless crystals with a yield of 81.2%.

[0046] 1 HNMR (CDCl 3 )δ: 2.46(s, 8H, hydrogen on the piperazine ring), 3.51(s, 2H, CH 2 Ph), 4.23 (s, 1H, ArCH), 7.14-7.42 (m, 15H, hydrogen on the benzene ring)

Embodiment 3

[0047] The synthesis of embodiment 3.1-benzhydryl-4-[(pyridin-3-yl) methyl] piperazine (pkumdl_cvs_1007)

[0048] According to the operating conditions of step E in Example 1, replace (3) with 3-chloromethylpyridine hydrochloride to obtain 1-benzhydryl-4-[(pyridin-3-yl)methyl]piperazine , recrystallized from acetone to obtain colorless crystals with a yield of 61.8%.

[0049] 1 HNMR (CDCl 3 )δ: 2.41 (s, 8H, hydrogen on the piperazine ring), 3.49 (s, 2H, CH 2 -), 4.27 (s, 1H, CH-), 7.12-7.42, 7.65-7.69, 8.43-8.45 (m, d, d, 14H, hydrogen on benzene ring and pyridine ring).

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Abstract

The invention relates to a class of inhibitors of non-peptidic SARS coronavirus 3CL protease and uses thereof. The inhibitor is a benzhydryl piperazine derivative, and its inhibition mechanism lies in the volume occupation and the hydrophobic interaction with 3CL protease. Utilize reversed-phase high-pressure liquid chromatography method and substrate pNA-labeled enzyme activity system to test the influence of the inhibitor on SARS coronavirus 3CL protease activity, confirm that it has inhibitory effect on 3CL protease, and cell experiments also confirm its effect on cell culture SARS coronavirus has inhibitory effect and can be used for treating and preventing SARS virus infection.

Description

technical field [0001] The present invention relates to a class of compounds for preventing and treating SARS coronavirus and other viral infections, in particular to a class of non-peptidic SARS coronavirus 3CL protease inhibitor benzhydryl piperazine derivatives. Background technique [0002] In the spring of 2003, SARS (Severe Acute Respiratory Syndrome) broke out in Hong Kong, Guangzhou, Beijing and other regions, causing great harm to people's physical and mental health. The SARS epidemic, which has no precedent for prevention or treatment, has aroused people's great attention. The research and development of drugs for SARS once became the focus of research by Chinese scientists. However, so far there is no recommended drug for SARS. [0003] Studies have shown that the variant coronavirus is the main culprit that causes SARS. The main protease or 3CL protease of coronavirus is a key protein in virus replication, and its main function is to hydrolyze two polyproteins...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/495A61P31/14A61P11/00
Inventor 来鲁华刘莹刘振明范可强黄常康魏平裴剑锋刘士勇陈浩
Owner PEKING UNIV
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