Small molecular inhibiting agent for coronavirus main proteinase, its preparation method and uses

A compound, free technology, applied in the direction of antiviral agents, peptide/protein components, medical preparations containing active ingredients, etc., to achieve the effect of good application prospects

Inactive Publication Date: 2006-04-26
TSINGHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

SARS is a severe infectious disease that poses a huge threat to human beings. Currently, there is no specific drug or vaccine on the market

Method used

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  • Small molecular inhibiting agent for coronavirus main proteinase, its preparation method and uses
  • Small molecular inhibiting agent for coronavirus main proteinase, its preparation method and uses
  • Small molecular inhibiting agent for coronavirus main proteinase, its preparation method and uses

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preparation example Construction

[0067] The preparation method of the compound of the present invention

[0068] The preparation method of the compound of formula (I) provided by the present invention comprises the following steps:

[0069] The protecting group R of the amino group in the formula (II) compound 6 removed, where the R 6 selected from the group consisting of the following groups: tert-butoxycarbonyl, trifluoroacetyl, benzyloxycarbonyl;

[0070] In the presence of a condensation reagent, the product of the previous step is condensed with a compound of formula (III) to obtain a compound of formula (I),

[0071]

[0072]

[0073]

[0074] Wherein, R in formula (II) and formula (III) 1 , R 2 , R 4 , the definition of U is the same as that in formula (I).

[0075] The synthesis of the compound of formula (II) can refer to: Qingping Tian, ​​Naresh K.Nayyar, Srinivasan Babu, Lijian Chen, Junhua Tao, Steven Lee, Anthony Tibbetts, Terence Moran, Jason Liou, Ming Guo and Timothy P.Kennedy...

Embodiment 1

[0082] 42mg of Dissolve in 2 ml of CH 2 Cl 2 , add 0.5ml of TFA to react at room temperature for 1 hour, and drain the solvent. The resulting de-Boc substrate was dissolved in 2 ml of CH 2 Cl 2 In, add 40mg of Then add 71 μl of i PR 2 NEt, then add 63mg of HATU. React at room temperature for 12 hours, successively wash with 1M HCl, saturated NaHCO 3 aqueous solution, saturated brine washing, Na 2 SO 4 dry. Filtration, evaporation of the solvent under reduced pressure, and flash column chromatography gave 52 mg of the product Yield 80%.

[0083] The spectrogram data is as follows:

[0084] H NMR: δ (500MHz, CDCl 3)0.76(d, 3H, J=6.9Hz), 0.98(d, 3H, J=5.7Hz), 1.30(t, 3H, J=7.3Hz), 1.42(s, 9H), 1.74-1.94(m, 4H), 2.10-2.40(m, 2H), 2.49-2.52(m, 1H), 2.67-2.71(m, 1H), 2.85-3.00(m, 1H), 3.05-3.17(m, 1H), 3.23- 3.39(m, 3H), 4.18(q, 2H, J=7.1Hz), 4.41-4.51(m, 1H), 4.58-4.65(m, 1H), 5.03-5.10(m, 1H), 5.49(t, 1H, J=14.7Hz), 5.98(dd, 1H, J=15.8Hz, 4.4Hz), 6.70-7.00(m, 3...

Embodiment 2

[0088] 45mg Dissolve in 2 ml of CH 2 Cl 2 , add 0.5ml of TFA to react at room temperature for 1 hour, and drain the solvent. The resulting de-Boc substrate was dissolved in 2 ml of CH 2 Cl 2 , add 12mg of Then add 48 μl of i PR 2 NEt, then add 44mg of HATU. React at room temperature for 12 hours, successively wash with 1M HCl, saturated NaHCO 3 aqueous solution, saturated brine washing, Na 2 SO 4 dry. Filtration, evaporation of the solvent under reduced pressure, and flash column chromatography gave 34 mg of the product Yield 73%.

[0089] The spectrogram data is as follows:

[0090] H NMR: δ (300MHz, CDCl 3 )0.85(d, 3H, J=6.6Hz), 1.03(d, 3H, J=6.9Hz), 1.30(t, 3H, J=7.2Hz), 1.52-1.61(m, 1H), 1.71-1.90( m, 2H), 2.26-2.42(m, 2H), 2.48(s, 3H), 2.53-2.73(m, 3H), 2.84-2.98(m, 2H), 3.13-3.23(m, 1H), 3.30- 3.42(m, 2H), 4.18(q, 2H, J=7.2Hz), 4.41-4.56(m, 1H), 4.66-4.76(m, 1H), 5.50(d, 1H, J=15.6Hz), 5.91 (s, 1H), 6.39 (s, 1H), 6.63 (dd, 1H, J = 15.3Hz, 4.8Hz), 6.94...

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Abstract

The present invention is serial small molecular inhibitor designed based on the crystal structure of main proteinase of SARS coronavirus and in the structural general expression as shown. The present invention also provides the preparation process of the small molecular inhibitor and its use in preparing medicine for preventing and treating various kinds of coronavirus infection.

Description

technical field [0001] The present invention provides a series of small molecule inhibitors designed based on the crystal structure of SARS coronavirus main protease, a preparation method and its application in the preparation of medicines for treating or preventing various coronavirus infections. Background technique [0002] A new type of coronavirus has been identified as the culprit of severe acute respiratory syndrome (Severe Acute Respiratory Sydrome, referred to as SARS), and was named SARS coronavirus (referred to as SARS-CoV). SARS coronavirus belongs to "Nidovirales" order, "Coronaviridae" family, and "Coronavirus" genus in terms of species classification. It is a new variant in the coronavirus family, with a full length of 29,736bp (Urbani Strain). SARS is a severe infectious disease that poses a huge threat to human beings. Currently, there is no specific drug or vaccine on the market. [0003] According to serological classification, the coronavirus family (Co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/26A61K31/40A61K31/42A61P11/00A61P31/14C07D413/12
CPCA61K38/00A61P11/00A61P31/12A61P31/14C07D207/27C07D413/12C07K5/0205
Inventor 饶子和杨海涛薛晓宇杨楷林马克·巴特拉姆马大为谢卫青
Owner TSINGHUA UNIV
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