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Anti-influenza virus compound as well as preparation method and application thereof

An anti-influenza virus and compound technology, applied in antiviral agents, steroids, organic chemistry, etc., can solve problems such as restrictions on promotion

Active Publication Date: 2020-06-19
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its high hydrophilicity, the clinical use of this drug can only be given by inhalation. Therefore, zanamivir is too water-soluble, and it is quickly metabolized after entering the human body and excreted in the form of urine. Therefore, only It can be made into nasal spray, which greatly limits its clinical promotion

Method used

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  • Anti-influenza virus compound as well as preparation method and application thereof
  • Anti-influenza virus compound as well as preparation method and application thereof
  • Anti-influenza virus compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0079] Experimental example 1, the specific synthetic operation of the anti-influenza virus compound of the present invention

[0080]

[0081] When R of compound I is Ts, the reaction conditions a include: compound I (R=Ts, 1mol) and compound II (1.2mol) are dissolved in 1,4-dioxane (100mL), 125°C Under reflux reaction overnight. After the solution is concentrated (when Y 1 =SAc, the concentrate needs to be treated with 1N sodium methoxide / methanol solution to remove the acetyl group on SAc) and separated by silica gel column chromatography to obtain compound III as a white solid with a yield of 78-86%.

[0082] When R of compound I is ClCO, the reaction condition a includes: compound I (R=ClCO, 1 mol) and compound II (1.2 mol) are dissolved in pyridine (100 mL), and stirred at room temperature overnight. Methanol (2 mL) was added to the reaction solution, concentrated and dissolved in dichloromethane, and successively washed with 1M HCl solution and 1M NaHCO 3 The solu...

experiment example 2

[0087] Experimental example 2, the activity evaluation of anti-influenza virus compound of the present invention:

[0088] NA enzyme activity inhibition test: the purified NA protein (N1, N5, etc.) was diluted 5×, 25×, 125×, 625×, 3125×, 15625× with 20 / 150 Tris / NaCl with a pH value of 8.0 Afterwards, 10 μL of NA solutions of different concentrations and 10 μL of PBS were added to the black 96-well ELISA plate, and incubated in a constant temperature incubator at 37°C for 30 min, and then 30 μL of 167 μM 4-MUNANA (4-methylumbelliferyl-N -acetylneuraminic acid) fluorescent substrate. The fluorescence value per minute (excitation wavelengths 355nm, emission wavelengths 460nm) was measured with a microplate reader for a total of 30 minutes. From the results, the concentration of NA whose fluorescence value increased linearly within 30 minutes and did not exceed 5000RU was selected as the concentration of the enzyme activity inhibition experiment. Inhibitor (VI) was diluted with ...

experiment example 3

[0105] Experimental example 3, the determination of the lipid-water partition coefficient of the anti-influenza virus compound of the present invention

[0106] Shake n-octanol and double-distilled water with a constant temperature (37±1)°C shaker at room temperature for 24h to make them mutually saturated. After standing overnight for stratification, the two phases were separated and stored for future use. Accurately weigh an appropriate amount of the compound to be tested in a 10 mL volumetric flask, dissolve in n-octanol saturated with water, oscillate ultrasonically for 30 min, and constant volume to obtain a mother solution with a concentration of 1 mmol / L. Precisely measure a certain amount of the total solution with a pipette gun into a 10mL volumetric flask, dilute with n-octanol saturated with water and set the volume to a series concentration of 10-100 μmol / L, the concentration increase gradient is 10 μmol / L, respectively at 200-400nm Scan within the wavelength rang...

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Abstract

The invention discloses an anti-influenza virus compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The anti-influenza virus compound has a structural general formula shown in the specification, wherein m is any natural number selected from 2-11, n is any natural number selected from 3-12, X is selected from OCOO or O, and the expression of Y is described in the specification. The anti-influenza virus compound provided by the invention has obvious inhibition activity on various influenza viruses, especially on zanamivir-resistant influenza viruses (H3N2, E119V), the water solubility of the original medicine is remarkably improved, the lipid-water distribution coefficient is tens of times higher than that of the original medicine, and the compound can be prepared into an oral preparation and has a great breakthrough in medicine dosage forms.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to an anti-influenza virus compound and its preparation method and application. Background technique [0002] Influenza (Infuenza) full name influenza, is the acute respiratory infectious disease that is caused by influenza virus. In recent years, seasonal influenza and highly pathogenic influenza viruses (such as H1N1, H5N1, and H7N9) that have emerged from time to time have always warned of the potential threat of a new round of influenza outbreaks in humans. The prevention and control of influenza is important and urgent . At present, oseltamivir (Tamiflu) and zanamivir (Relenza), represented by influenza virus neuraminidase (NA) inhibitors, are still the main means of preventing and treating influenza. However, with the widespread use of these drugs, drug-resistant strains of influenza viruses continue to emerge, and it is imminent to find new anti-influenza drugs. ...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61P31/16A61K31/58
CPCA61P31/16C07J43/00
Inventor 李学兵吕迅陈建忠王鹏飞
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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