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Peptidomimetic compound as well as derivative, preparation method, pharmaceutical composition and application thereof

A technology of compounds and derivatives, which is applied in the field of peptidomimetic compounds and their derivatives, can solve the problems of inability to respond to late treatment of patients with viral infections in a timely and effective manner, threaten the lives of patients, and have toxic and side effects, and achieve easy operation and applicability Broad and efficient inhibitory activity

Pending Publication Date: 2022-03-08
YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing antiviral drugs are aimed at specific virus strains for early and mid-term treatment, and cannot respond to sudden outbreaks and late treatment of virus-infected patients in a timely and effective manner, and severe drug resistance will occur when such antiviral drugs are used for a long time and serious side effects
In addition, the cytokine storm caused by the failure to effectively clear the virus also greatly threatens the life safety of patients

Method used

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  • Peptidomimetic compound as well as derivative, preparation method, pharmaceutical composition and application thereof
  • Peptidomimetic compound as well as derivative, preparation method, pharmaceutical composition and application thereof
  • Peptidomimetic compound as well as derivative, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Embodiment 1: synthetic compound S1

[0154] (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutyryl)-N-((S)-1-cyano Base-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (S1 )

[0155]

[0156]

[0157] Step 1: Synthesis of compound 2

[0158] Weigh raw material 1 (2g, 10mmol), dissolve N-Boc-L-tert-leucine (2.3g, 10mmol) in N,N-dimethylformamide (20mL), add N,N, N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (3.7 g, 12 mmol) and N-methylmorpholine (3.3 mL, 30 mmol), Maintain 0 ℃ reaction 3h. Add saturated ammonium chloride solution (20mL) to quench, extract with ethyl acetate (30mL×3), wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, concentrate, make sand, and purify by column chromatography (PE : EA=10:1) to obtain white foamy solid compound 2 (2.8 g, 75%). 1 H NMR (400MHz, Chloroform-d) δ5.11(d, J=10.2Hz, 1H), 4.46(s, 1H), 4.20(d, J=10.3Hz, 1H), 3.99(d, J=10....

Embodiment 2

[0219] Embodiment 2: synthetic compound S39

[0220]

[0221] Step 1: Synthesis of Compound 13

[0222] Weighed triphosgene (930mg, 3.1mmol) and dissolved it in anhydrous dichloromethane (5mL), added raw material 3 (1g, 3.1mmol) at 0°C under nitrogen protection, stirred for 5min, and slowly added triethylamine ( 0.9mL, 6.2mmol), stirred at room temperature for 2h, moved to 0°C and slowly added isobutanol (0.6mL, 6.2mmol), and reacted overnight at room temperature. Stop the reaction, add saturated ammonium chloride solution (10 mL) to quench, diatomaceous earth filter, remove the solvent under reduced pressure, extract with dichloromethane (10 mL), wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, Concentrate, make sand, and purify by column chromatography (DCM:MeOH=20:1) to obtain compound 13 (734 mg, 62%) as a colorless liquid. 1 H NMR (300 MHz, Chloroform-d) δ4.68–4.62(m,1H),4.24(d,J=4.8Hz,1H),4.17(d,J=8.1Hz,1H), 3.87(s,3H ),3.54(dd,J=12.6,4...

Embodiment 3

[0243] Embodiment 3: synthetic compound S173

[0244]

[0245] Step 1: Synthesis of compound 15

[0246] Compound 8 (2.0 g, 7.0 mmol) was weighed and dissolved in dioxane solution, and a solution of hydrogen chloride in dioxane (17.6 mL, 70 mmol) was slowly added dropwise at 0° C., and stirred at room temperature for 6 h. The reaction was stopped, and the solvent was removed under reduced pressure to obtain a white solid, which was directly used in the next reaction.

[0247] Step 2: Synthesis of compound 16

[0248] Dissolve compound 5 (1.7g, 4.5mmol), compound 15 (1.0g, 4.5mmol) in N,N-dimethylformamide (20mL), add N,N,N',N'- Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (2.1 g, 5.4 mmol) and N-methylmorpholine (1.5 mL, 13.5 mmol), maintained at 0°C 3h. Add saturated ammonium chloride solution (20mL) to quench, extract with ethyl acetate (30mL×3), wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, concentrate, make sand, and ...

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Abstract

The invention discloses a peptidomimetic compound and a derivative thereof, the chemical structural formula of the compound is as shown in formula (I), and the derivative is a tautomer, a stereoisomer, a solvate, a salt of the solvate, a metabolite, a metabolic precursor or a prodrug, a pharmaceutically acceptable salt or a mixture of the tautomer, the stereoisomer, the solvate, the salt of the solvate, the metabolite, the metabolic precursor or the prodrug and the pharmaceutically acceptable salt of the compound. The peptidomimetic compound and the derivative of the peptidomimetic compound can effectively inhibit 3C-like cysteine protease, and can be prepared into drugs for treating and / or preventing SARS-CoV, HBV, HCV, H1N1, Ebola or SARS-CoV-2 virus infection diseases.

Description

technical field [0001] The present invention relates to a peptidomimetic compound and its derivative, preparation method, pharmaceutical composition and application, in particular to a peptidomimetic compound capable of inhibiting 3C-like cysteine ​​protease and its derivative, preparation method and application . Background technique [0002] Symptoms of SARS-CoV-2 infection range from asymptomatic illness to moderate and severe pneumonia, and life-threatening complications, including hypoxic respiratory failure, acute respiratory distress syndrome, multisystem organ failure, and eventually death. What's more, the virus is not only highly contagious, but can be transmitted by asymptomatic infections and those in symptomatic and pre-symptomatic stages. [0003] Like other coronaviruses, SARS-Cov-2 will be decomposed to release the nucleocapsid and viral genome after entering the host cell. The host cell ribosome translates the open reading frame (ORF) 1a and ORF1b of the v...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D403/14C07D405/14A61K31/403A61P31/12A61P31/16A61P31/14
CPCC07D403/12C07D403/14C07D405/14A61P31/12A61P31/16A61P31/14
Inventor 蒋晟肖易倍郝海平谢幼华倪勇张阔军廖金标武倩倩王天雨邱亚涛章翔宇
Owner YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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