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Amine compound, preparation method thereof and application of amine compound in preparation of anti-influenza virus medicine

An amine compound and anti-influenza virus technology, applied in the field of medicine and biology, can solve problems such as obvious side effects, gastrointestinal adverse reactions, drug cross-resistance, etc.

Inactive Publication Date: 2014-03-26
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this type of drug has obvious defects (Schnell JR, Chou JJ. Nature. 2008, 451(7178): 591-595.): (1) It is ineffective against influenza B virus; (2) There are obvious side effects, causing obvious Gastrointestinal adverse reactions; central nervous system side effects, mainly manifested as insomnia, distraction and nervousness; (3) About one-third of the patients developed drug resistance; the two drugs have a single structure, and there are already two drug cross-resistance

Method used

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  • Amine compound, preparation method thereof and application of amine compound in preparation of anti-influenza virus medicine
  • Amine compound, preparation method thereof and application of amine compound in preparation of anti-influenza virus medicine
  • Amine compound, preparation method thereof and application of amine compound in preparation of anti-influenza virus medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: General synthetic steps for compounds 1 and 2:

[0022] Compound 1:

[0023]

[0024] A synthetic route: This compound is a known compound and commercial compound, which can be purchased from related reagent companies, so no synthetic route is required. Purchase URL: http: / / www.sigmaaldrich.com / catalog / product / aldrich / 179604?lang=zh®ion=CN. CAS#: 7242-92-4.

[0025] B Chemical Characterization: Not required.

[0026] Compound 2:

[0027]

[0028] A synthetic route:

[0029]

[0030] B Raw material and abbreviation explanation

[0031]

[0032]

[0033] C chemical characterization

[0034] 1. Intermediate products

[0035]

[0036] Add hydroxylamine hydrochloride (5g, 65.7mmol), pyridine 20ml in a 100ml eggplant-shaped flask, stir in an oil bath at 80°C for 5min until hydroxylamine hydrochloride is completely dissolved and clear. Add fenchone (2g, 13.14mmol), heat to reflux, and stir overnight. After overnight, the reaction was st...

Embodiment 2

[0040] Embodiment 2: Influenza virus suppression experiment

[0041]Experimental materials: MDCK dog kidney cells; H1N1 influenza virus A / PR / 8 / 34 (M2 wild type); culture medium DMEM+10%FBS, maintenance solution DMEM+2%FBS (DMEM, Hyclone; FBS, Gibco); Hanks buffer; CCK-8 (Donjindo, Japan); Amantadine (Sigma Aldrich).

[0042] experimental method

[0043] 1. Determination of virus virulence (TCID50 of virus virulence is 10 -5.5 )

[0044] MDCK cells were divided into 5×10 4 Inoculate each well in a 96-well plate to form a confluent monolayer of cells, add 100 μl of 10-fold serially diluted virus solution of 6 concentrations (the virus stock solution is derived from chicken embryo proliferation, diluted in DMEM) after adsorption for 1-2 hours, pour out the virus , rinsed twice with Hanks solution, added maintenance solution, observed cytopathic changes (CPE) every day with an inverted microscope, measured hemagglutination titer, observed cell survival status and virus amplifi...

Embodiment 3

[0049] Example 3: Detection of Compounds for Inhibition of H1N1-M2 Ion Channel Activity

[0050] 1. Construction of HEK293T-rex cell line stably expressing wild-type H1N1-M2 ion channel (Sun J, Li C, Xu W, Li Z, Liu J, Chen L. Chin J Biotech.2008,24(11):1902- 1906.).

[0051] 2. Patch clamp technique to detect the blocking effect of compounds on H1N1-M2 ion channels

[0052] HEK293T-rex cells expressing H1N1-M2 ion channels were induced by 1 μg / ml tetracycline for 24-48 hours, and the current changes before and after drug addition were recorded by patch clamp at room temperature (Hu W, Zeng S, Li C, Jie Y, Li Z, Chen L. J Med Chem. 2010, 53(9): 3831-3834.).

[0053] Results: 100 μmol / L compound 1 blocked the H1N1-M2 ion channel current by 76.8%, 100 μmol / L compound 2 blocked the current by 70.7%, and 100 μmol / L amantadine (Amantadine) could completely block the current ( figure 2 ), it can be seen that compound 1 and compound 2 have M2 ion channel inhibitory activity.

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PUM

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Abstract

The invention discloses an amine compound, a preparation method thereof and application of the amine compound in preparation of anti-influenza virus medicine. The structure of the amine compound is shown in formula (I) (referring to the Specification). According to the invention, two novel framework M2 ion channel inhibitors are identified for the first time, have completely different structures compared with the existing amantadine and rimantadine, may restrain and interdict influenza viruses through a novel mechanism of action, and overcome the defects of amantadine and rimantadine such as ineffective to B-type influenza virus, obvious side effect and cross resistance, so as to provide more medicine choices for clinical anti-influenza.

Description

Technical field: [0001] The invention belongs to the field of medicine and biology, and in particular relates to an amine compound, a preparation method thereof and an application in preparation of an anti-influenza virus drug. Background technique: [0002] Influenza, referred to as influenza, is an acute respiratory infectious disease caused by influenza virus. It is highly contagious and has a high incidence rate, which can easily cause outbreaks or pandemics. According to the data released by the World Health Organization, influenza will cause 600-120 million people to be infected every year in the world, and 3-5 million patients will develop complications such as pneumonia, myocarditis, and respiratory failure, and 250,000-500,000 patients will even die as a result, especially in infants. Young children, the elderly, and patients with underlying cardiopulmonary diseases are prone to severe complications such as pneumonia and death. [0003] Currently, the flu shot is s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/38C07C209/40A61K31/13A61P31/16
Inventor 李志远揭艳玲徐慧娟梁欣
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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