Application of nucleoside analogue or combined preparation containing nucleoside analogue in virus resistance

A compound and solvate technology, which is applied in the field of antiviral application of combined preparations, can solve the problems of vaccines and antiviral drugs without specific effects for severe pneumonia

Pending Publication Date: 2021-05-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently, there is no effective vaccine or antiviral drug for severe pneumonia caused by SARS-CoV-2 coronavirus

Method used

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  • Application of nucleoside analogue or combined preparation containing nucleoside analogue in virus resistance
  • Application of nucleoside analogue or combined preparation containing nucleoside analogue in virus resistance
  • Application of nucleoside analogue or combined preparation containing nucleoside analogue in virus resistance

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0292] Preparation Example 1: Synthesis of Compound A1

[0293]

[0294] Compound 1-1 was synthesized by the method reported in the literature (Nature.2016, 531, 381-385). Compound 1-1 (1.5 g, 2.67 mmol) was added to acetonitrile (30 mL), followed by the addition of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetra Fluoboric acid) salt (Selectfluor, 1.13g, 3.2mmol, 1.2eq) and sodium bicarbonate (0.67g, 8.0mmol, 3eq) were added and reacted at room temperature for 3-4 hours. TLC showed that the reaction was complete. The reaction solution was added to water (120 mL), extracted with ethyl acetate, the organic layer was separated, dried, concentrated, and separated by silica gel column chromatography to obtain compound 1-2, 0.43 g of off-white solid, with a yield of 28%. 1 H NMR (500MHz, DMSO-d 6)δ8.12(brs,1H),7.87(s,1H),7.50–7.20(m,16H),6.59(s,1H),4.92(d,J=11.7Hz,1H),4.85–4.78(m ,2H),4.57–4.46(m,4H),4.42–4.35(m,1H),4.12(t,J=5.7Hz,1H),3.73(dd,J=11.2,3.2Hz,1H),3....

preparation Embodiment 2

[0296] Preparation Example 2: Synthesis of Compound A2

[0297]

[0298] Compound 2-1 was synthesized according to the method reported in the literature (Nature.2016, 531, 381-385). Compound 2-1 (291mg, 1.0mmol) was added to N,N-dimethylformamide (5mL), N-chlorosuccinimide (245mg, 1.1mmol, 1.1eq) and trifluoroacetic acid ( 24mg, 0.2mmol, 0.2eq), reacted at 50°C for 1 hour, TLC showed that the reaction was complete. The reaction solution was added into a mixed solution of sodium sulfite and sodium carbonate, and compound A2 was obtained by filtration, 185 mg of white solid, with a yield of 57%. 1 H NMR (500MHz, DMSO-d 6 )δ8.26(brs,1H),7.95(s,1H),7.09(brs,1H),6.98(s,1H),6.23(d,J=5.7Hz,1H),5.18(d,J=5.6 Hz,1H),4.92(t,J=5.6Hz,1H),4.52(t,J=5.0Hz,1H),4.06–4.00(m,1H),3.96–3.88(m,1H),3.69–3.61 (m,1H),3.54–3.45(m,1H). MS m / z=326.0[M+1] + .

preparation Embodiment 3

[0299] Preparation Example 3: Synthesis of Compound A3

[0300]

[0301] Compound 2-1 (291mg, 1.0mmol) was added to N,N-dimethylformamide (5mL), N-iodosuccinimide (245mg, 1.1mmol, 1.1eq) and trifluoroacetic acid ( 24mg, 0.2mmol), reacted at 50°C for 1 hour, TLC showed that the reaction was complete. The reaction liquid was added into a mixed solution of sodium sulfite and sodium carbonate, and compound A3 was obtained by filtration, 200 mg of white solid, with a yield of 48%. 1 H NMR (500MHz, DMSO-d 6 )δ7.98(s,1H),7.12(s,1H),6.21(brs,1H),5.20(brs,1H),4.91(s,1H),4.52(d,J=4.6Hz,1H), 4.11–3.99 (m, 1H), 3.97–3.85 (m, 1H), 3.64 (d, J=11.3Hz, 1H), 3.49 (d, J=10.9Hz, 1H). MS m / z=418.0[M+1] + .

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Abstract

The invention relates to an application of nucleoside analogs in virus resistance. Specifically, the invention relates to the use of nucleoside analogs and pharmaceutical compositions thereof as (a) inhibitors for inhibiting the replication of coronavirus, influenza virus, respiratory syncytial virus, flaviviridae virus, filoviridae virus and/or porcine epidemic diarrhea virus (PEDV); and/or (b) medicines for treating and/or preventing and relieving related diseases caused by infection of coronavirus, influenza virus, respiratory syncytial virus, flaviviridae virus, filoviridae virus and/or porcine epidemic diarrhea virus (PEDV). The nucleoside analogue disclosed by the invention can be used for treating and/or preventing and relieving related diseases such as respiratory tract infection, pneumonia (COVID-19) and the like caused by 2019 novel coronavirus infection.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of nucleoside analogs or combined preparations containing nucleoside analogs in antiviral. Background technique [0002] Among the acute infectious diseases, most of them are viral infectious diseases, and the incidence rate of viral infectious diseases is high, and the mortality rate is also high. Viruses are pathogenic microorganisms that are extremely small, lack independent metabolic capabilities, and exist in a parasitic manner. There are many kinds of viruses. At present, many viruses with high infectivity and pathogenicity to humans have been discovered. These viruses often cause outbreaks of local or even global infectious diseases and are extremely harmful to human society, such as influenza virus , respiratory syncytial virus (RSV), parainfluenza virus, atypical pneumonia (SARS) virus, Middle East respiratory syndrome (MERS) virus, Ebola virus, etc. Some viruse...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07F9/6561A61P31/14A61P31/16A61K31/53A61K31/685A61K31/675
CPCC07D487/04C07F9/6561A61P31/14A61P31/16Y02A50/30A61K31/53A61K31/675A61P31/12C07B2200/05C07H7/06
Inventor 谢元超肖庚富何洋张磊砢蒋华良沈敬山
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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