Nucleoside compound for antiviral therapy and application thereof

A nucleoside and anti-virus technology, which is applied in anti-viral agents, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., can solve problems such as discounting of immune effects, loss of aquaculture, and impact on the immune protection effect of vaccines , to achieve the effect of novel structure, excellent effect and good safety

Pending Publication Date: 2022-03-15
NANJING NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since 2010, mutant PEDV strains with higher pathogenicity and lethality have been widely prevalent in my country. The existing prevention and control methods are difficult to cope with the threat posed by PEDV, which has brought huge losses to my country's aquaculture industry.
[0013] At present, there is no specific drug for porcine epidemic diarrhea, and vaccine immunization is the most important prevention and control measure. However, for newborn piglets, there are some problems in vaccine immunization
Newborn piglets absorbing sow milk containing PEDV antibody will affect the immune protection effect induced by the vaccine. In addition, PEDV vaccine mainly exerts its effect through mucosal immunity, and the mucosal immune system of piglets is not yet fully developed, resulting in a greatly reduced immune effect
In addition to vaccine immunization, antibiotics, hormones, and traditional Chinese medicine compounds are also used to relieve diarrhea symptoms in piglets, but there are no reports of nucleotide analogues. Therefore, the study of corresponding drugs has important clinical significance for the treatment of porcine epidemic diarrhea

Method used

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  • Nucleoside compound for antiviral therapy and application thereof
  • Nucleoside compound for antiviral therapy and application thereof
  • Nucleoside compound for antiviral therapy and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] step 1

[0039] Weighed NaOH (985mg, 24.63mmol), added 13mL of water to prepare a solution and placed it in an ice bath with stirring and cooling for 5 minutes, then added bis(N,N-dimethylamino)phosphonyl chloride (2g, 11.73mmol), then raised to room temperature and stirred until the reaction was complete. Then spin the solvent to dry, add ethanol to dissolve, and concentrate the filtrate after suction filtration to obtain compound 1.

[0040] step 2

[0041] Weigh compound 2 (100mg, 0.34mmol) and compound 1 (60mg, 0.34mmol), dimethyl tin dichloride (8mg, 0.034mmol) and place in an eggplant-shaped bottle, add 3mL of N-methylpyrrolidone to dissolve it Dissolved and placed in an oil bath at 80° C. to react overnight until complete. After concentrating the solvent, compound I (96 mg, yield 80%) was prepared by high pressure.

[0042] 1 H NMR (400MHz, DMSO-d 6 )δ8.01(d, J=52.0Hz, 3H), 6.93(d, J=7.6Hz, 2H), 5.24(s, 1H), 4.88-4.61(m, 2H), 4.61-4.43(m, 1H ), ...

Embodiment 2

[0045]

[0046] step 1

[0047] Weigh NaOH (247mg, 6.16mmol), add 3.5mL of water to prepare a solution and place it in an ice bath with stirring and cooling for 5 minutes, then add bis(N,N-dimethylamino)phosphonyl chloride (500mg , 2.93mmol), then raised to room temperature and stirred until the reaction was complete. Then spin the solvent to dry, add ethanol to dissolve, and concentrate the filtrate after suction filtration to obtain compound 1.

[0048] step 2

[0049] Weigh compound 3 (200mg, 0.33mmol) and compound 1 (116mg, 0.66mmol), dimethyl tin dichloride (8mg, 0.033mmol) and place in an eggplant-shaped bottle, add 4mL of N-methylpyrrolidone to dissolve it Dissolved and placed in an oil bath at 80° C. to react overnight until complete. After concentrating the solvent, compound II (171 mg, yield 78%) was prepared by high pressure.

[0050] 1 H NMR (400MHz, DMSO-d 6 )δ8.19(s, 2H), 7.97(d, J=7.1Hz, 1H), 7.32(t, J=8.1Hz, 2H), 7.17(t, J=7.4Hz, 3H), 7.05-6.79( m, 2H)...

Embodiment 3

[0053]

[0054] step 1

[0055] Weigh compound I (2057mg, 5.81mmol) and place it in an eggplant-shaped bottle, then add 24mL triethylamine to dissolve the substrate completely, then add 4-dimethylaminopyridine (36mg, 0.29mmol) and place the reaction system in Stir for 5-10 minutes under ice bath. Isobutyric anhydride (1011 mg, 6.39 mmol) was then added slowly. Warmed to room temperature, the reaction mixture was stirred until the reaction was complete. Concentrate the reaction mixture by distilling off the solvent under reduced pressure, add the residue to water, extract with ethyl acetate and saturated sodium bicarbonate, wash the organic layer with saturated brine, dry with anhydrous sodium sulfate, and distill off the solvent under reduced pressure . The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain compound III (1536 mg, yield 62.5%).

[0056] 1 H NMR (400MHz, DMSO-d 6 )δ8.01(d, J=52.0Hz, 3H), 6.93(d, J=7.6...

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PUM

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Abstract

The invention discloses a nucleoside compound for antiviral treatment and application, the structure of the antiviral nucleoside analogue is shown in formula I. The compound can inhibit coronavirus, porcine epidemic diarrhea virus and avian influenza virus, and can inhibit the virus resistance of the compound. The pharmaceutical composition can be used for treating and preventing human and animal diseases caused by various viruses, such as acute pneumonia caused by new coronavirus and epidemic diarrhea caused by porcine epidemic diarrhea virus, and has the advantages of remarkable and better effect and better safety.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to nucleoside compounds used for antiviral therapy and their application. Background technique [0002] Human coronaviruses were first isolated by British scientists in the 1960s, and a total of 7 species have been discovered so far. The 2019 novel coronavirus (2019-nCoV, which causes COVID-19) is the seventh known species that can infect humans. The remaining six are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome) and MERS-CoV (causing Middle East respiratory syndrome). Four of them cause only common cold symptoms, and the remaining three are highly pathogenic pneumonia-associated coronaviruses, namely severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the new Coronavirus (SARS-CoV-2). Coronaviruses are enveloped RNA viruses and are divided into four genera: α, β,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574A61K31/685A61K31/675A61P31/12A61P31/14A61P31/16
CPCC07F9/65744A61P31/12A61P31/14A61P31/16
Inventor 朱永强刘运龙王雪源庄义庆李彬雷萌范宝超李基棕
Owner NANJING NORMAL UNIVERSITY
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