Antiviral compounds, pharmaceutically acceptable salts or optical isomers thereof, methods for producing them, and pharmaceutical compositions for preventing or treating viral diseases comprising them as active ingredients

A compound, pharmaceutical technology applied to antiviral compounds, pharmaceutically acceptable salts or optical isomers thereof, pharmaceutical compositions for preventing or treating viral diseases for preparing them and containing them as active ingredients In the field, it can solve the problems of side effects, unapproved antiviral drugs, and low treatment success rate, and achieve the effect of low cytotoxicity

Active Publication Date: 2018-01-23
KOREA RES INST OF CHEM TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the proven efficacy is not enough to make praconnelli registered in the United States (Picovir, Viropharma, USA) as a preparation for the treatment of rhinovirus infection
In March 2002, the corresponding application was rejected by the Food and Drug Administration (FDA) because of its low treatment success rate and observed side effects
[0012] However, antiviral drugs that have been developed for the treatment of enteroviruses or rhinoviruses have not yet been approved

Method used

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  • Antiviral compounds, pharmaceutically acceptable salts or optical isomers thereof, methods for producing them, and pharmaceutical compositions for preventing or treating viral diseases comprising them as active ingredients
  • Antiviral compounds, pharmaceutically acceptable salts or optical isomers thereof, methods for producing them, and pharmaceutical compositions for preventing or treating viral diseases comprising them as active ingredients
  • Antiviral compounds, pharmaceutically acceptable salts or optical isomers thereof, methods for producing them, and pharmaceutical compositions for preventing or treating viral diseases comprising them as active ingredients

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0191] N-(4b-hydroxy-7-isopropyl-10-oxo-9b, 10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b- Preparation of -2-(1H-indol-3-yl)-2-oxoacetamide

[0192] 2-(1H-indol-3-yl)-2-oxoacetic acid (352mg, 1.86mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (355mg, 1.86mmol) and HOBt (hydroxybenzotriazole) (251mg, 1.86mmol) were dissolved in dichloromethane (MC) (10ml), then added 9b-amino-4b-hydroxy-7-isopropyl- 4bH-Benzo[d]indeno[1,2-b]furan-10(9bH)-one (500 mg, 1.69 mmol) and the mixture was stirred at room temperature for one day. The reaction mixture was extracted with dichloromethane to collect the organic layer, which was dissolved in MgSO 4 Dry under low temperature and concentrate under reduced pressure. The concentrated compound was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to obtain N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo [d] Indeno[1,2-b]furan-9b-yl)-2-(1H-indol-3-yl)-2-oxoacetamide (199 mg, 25%).

[0193] 1 H-NM...

Embodiment 2

[0195] N-(4b-hydroxy-7-isopropyl-10-oxo-9b, 10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)- Preparation of 2-oxo-2-(thiophen-2-yl)acetamide

[0196] After dissolving 2-oxo-2-(thiophen-2-yl)acetic acid (107mg, 1.07mmol) in DMF (3ml), the temperature was lowered to 0°C, and the solution was stirred. After 10 minutes, triethylamine (TEA) (213mg, 1.07mmol) and HATU (407mg, 1.07mmol) were added, stirred for 10 minutes before the temperature dropped to 0°C, and 9b-amino-4b-hydroxy-7-isopropyl yl-4bH-indeno[1,2-b]benzofuran-10(9bH)-one (300 mg, 1.02 mmol). Then, the temperature was raised to normal temperature, and the solution was stirred overnight. After washing with water, Na 2 SO 4 Remove moisture. After filtration and concentration, it was purified by column chromatography (EA:Hex=3:7) to obtain the title compound (52mg, 28%).

[0197] 1 H-NMR (300MHz, DMS0-d6) δ1.12 (d, 6H, J = 6.0Hz), 4.13 (q, 1H, J = 6.0Hz), 4.72 (s, 1H), 6.88 (d, 1H, J =6.0Hz),7.32(d,2H,J=6.0Hz),7.63...

Embodiment 3

[0199] N-(4b-hydroxyl-7-isopropyl-10-oxo-9b, 10-dihydro-4bH-indeno[1,2-b]benzofuran-9b-yl)- Preparation of 3-(2-nitrophenyl)-2-oxopropionamide

[0200] 2-Nitrophenylpyruvate (390mg, 1.86mmol) was placed in DMF:DCM (1:2, 15ml), and EDCI (487mg, 2.54mmol) was added at 0°C. Then, after adding 1-hydroxybenzotriazole (343 mg, 2.54 mmol), the mixture was stirred at room temperature for 15-30 minutes. Then, after adding 9b-amino-4b-hydroxyl-7-isopropyl-4bH-indeno[1,2-b]benzofuran-10(9bH)-one (500mg, 1.69mmol), TEA was added ( 0.709ml, 5.09mmol). After stirring at 60°C for 2 days, water (100ml) was added. The separated organic layer was collected and ethyl acetate (70ml x 3), washed with water (50ml) and brine (50ml), and the water was removed with sodium sulfate. After concentration, it was purified by silica gel column chromatography (25% ethyl acetate: hexane) to obtain 100 mg (24%) of the title compound.

[0201] 1 H-NMR (300MHz, CDC1 3 )δ1.18(dd, J=2.7Hz, J=6.9Hz, 6H, CH3...

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Abstract

The present invention relates to a novel compound, a pharmaceutically acceptable salt or an optical isomer thereof, a method for preparing them, and a pharmaceutical composition for preventing or treating viral diseases containing them as active ingredients. The novel compounds according to the present invention not only have low cytotoxicity, but also have excellent antiviral activity against picornaviruses including coxsackieviruses, enteroviruses, echoviruses, polioviruses and rhinoviruses, therefore It can be used as a pharmaceutical composition for the prevention or treatment of viral diseases such as poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, blister disease, hepatitis A, myositis, Myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, common cold, herpetic angina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutically acceptable salts or optical isomers thereof, methods for preparing them, and pharmaceutical compositions for preventing or treating viral diseases comprising them as active ingredients. Background technique [0002] Picornaviruses are non-enveloped positive single-stranded RNA viruses with RNA genomes 7.2-8.5 Kb in length. These viruses are very small, spherical, about 22-30nm in size, and were first identified a long time ago. Viruses belonging to the picornaviridae family are the genus Enterovirus and include rhinovirus, poliovirus, coxsackievirus A, coxsackievirus B, echovirus, and hepatitis A virus. [0003] Diseases caused by picornaviruses and RNA viruses range from respiratory to digestive, circulatory, to skin, examples include poliomyelitis, acute hemorrhagic conjunctivitis, viral meninges Inflammation, hand, foot and mouth disease, blistering disease, hepatitis A, myositis, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07D409/12A61K31/4025A61P31/12
CPCC07D405/12C07D409/12C07D413/12C07D407/12C07D307/93C07D417/12A61P1/02A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P17/00A61P21/00A61P25/00A61P27/02A61P27/16A61P31/12A61P31/14A61P31/16A61P9/00A61P3/10Y02A50/30A61K31/404C07D307/79
Inventor 郑永植韩水逢李钟娇金海洙申珍洙约翰·奈茨亨德里克·杨·蒂博马尔帕尼·亚什沃德汉·拉德哈莫汉
Owner KOREA RES INST OF CHEM TECH
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