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Pyrazindione derivative and application thereof

A compound and hydrate technology, applied in the field of anti-influenza drugs, pyrazine diketone derivatives, can solve the problems of low immunity, low efficacy in children, etc., to achieve inhibition of influenza virus, low cytotoxicity, and excellent pharmacodynamic properties in vivo Effect

Pending Publication Date: 2022-01-04
GUANGZHOU NUCIEN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Influenza vaccination is the main preventive method and is highly effective, but it has the major disadvantages of having to be given annually and being less effective for immunocompromised and at-risk adults and young children
Since the currently circulating influenza viruses are all resistant to amantadine drugs (the virus NS gene has a S31N mutation), amantadine drugs are no longer the first choice for the prevention and treatment of influenza recommended by WHO.

Method used

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  • Pyrazindione derivative and application thereof
  • Pyrazindione derivative and application thereof
  • Pyrazindione derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1: 4-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-9-hydroxyl-2-isopropyl-1H-pyrido[ Preparation of 1,2-a]pyrazine-1,3,8(2H,4H)-trione (Compound 1)

[0158] Obtained by the following reaction formula:

[0159]

[0160] experiment procedure:

[0161] Dissolve compound 1a (100g, 480mmol, 1.00eq) into the reaction flask with methanol (1L), cool down to 0-5°C, and add NaBH to the reaction system 4 (36.3g, 960mmol, 2.00eq), after adding the materials, the system was stirred at 0-5°C for 2 hours. TLC (petroleum ether: ethyl acetate=10:1, R f (R1)=0.4) spot plate to monitor the complete reaction of compound 1. The reaction solution was poured into 800mL water, filtered, and the filter cake was concentrated to obtain compound 1b (100g, 476mmol, white solid, structure confirmed by NMR). The crude product was directly used in the next step. 1 H NMR: (400MHz, CDCl 3 )δ7.54 -7.43(m,2H),7.26-7.14(m,6H),5.97(d,J=2.8Hz,1H),3.52-3.37(m,2H),3.21-3.06(m,2H) ,2.36-2.23 ...

Embodiment 2

[0172] Example 2: In vitro anti-influenza virus activity screening experiment of compounds

[0173] In the following examples, the inventors took part of the compounds of the present invention as an example, did experiments using cytopathic effect (CPE), and detected the antiviral activity of the compound against influenza virus A / WSN / 33 (H1N1) and the antiviral activity against MDCK Cell toxicity.

[0174] The following abbreviations are used throughout this example

[0175] English abbreviations English full name Chinese full name ATCC American Tissue Culture Collection American Type Culture Collection CC 50

Concentration for 50% Cytotoxicity 50% cytotoxic concentration CCK8 Cell Counting Kit 8 Cell Counting Kit 8 CPE Cytopathic Effect cytopathic effect DMSO Dimethyl Sulfoxide Dimethyl sulfoxide EC 50

Concentration for 50% of Maximal Effect 50% effective concentration ml Millilitre ml mM ...

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Abstract

The invention belongs to the field of medicines, and particularly relates to a pyrazindione derivative and application thereof, a compound of the pyrazindione derivative and pharmaceutically acceptable salts and solvates of the pyrazindione derivative. The solvates comprise hydrates, polycrystals, prodrugs, co-crystals, tautomers and stereoisomers. More specifically, the compound can be used as an anti-influenza medicine with a CEN inhibition effect.

Description

[0001] field of invention [0002] The invention belongs to the field of medicines, and in particular relates to a pyrazinedione derivative and its application. More specifically, the compounds described in the present invention can be used as anti-influenza drugs with CEN inhibitory effect. Background technique [0003] Unusually for viruses, the genome is not a single segment of nucleic acid; instead, the genome contains seven or eight segments of negative-sense RNA. The influenza A genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP), PA, PB1, PB1-F2, and PB2 . H and N are macromolecular glycoproteins outside the virus particle. HA is the lectin that mediates viral binding to target cells and entry of the viral genome into target cells, while NA is involved in the release of progeny virus from infected cells by cleaving sugars bound to mature virus particles. Therefore, these proteins have become targets of ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4985A61K45/06A61P31/12A61P31/16
CPCC07D471/04A61K31/4985A61K45/06A61P31/12A61P31/16A61K2300/00
Inventor 胡双华林寨伟崔柏成
Owner GUANGZHOU NUCIEN PHARM CO LTD