Curcumenol derivatives resisting influenza A(H1N1) virus

Abstract

The invention belongs to the technical field of medical technology, and relates to novel compounds, which are shown in a general formula (I) and have the activity of resisting influenza A(H1N1) virus, wherein R1 and R2 are defined as in the specification. The invention also relates to application and a preparation method of the compounds, and clinically acceptable medicines for treating infectious diseases of influenza A(H1N1) virus, which are prepared by combining the compounds with pharmaceutically acceptable carriers. The structure of formula (I) is shown in the specification.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular to a curcumol derivative against influenza A (H1N1) virus. Background technique

[0002] Influenza (influenza) is a highly contagious and fast-spreading acute viral respiratory infectious disease caused by influenza virus that seriously endangers the health of people, livestock and poultry. It is a typical zoonotic disease. It is generally accepted by the medical profession that the harm of influenza is no less than that of AIDS and war. Complications and death from influenza can be severe. According to the announcement issued by the World Health Organization (WHO), there are 600 million to 1.2 billion cases of influenza in the world every year, and 500,000 to 1 million deaths, including 3 million to 5 million cases of severe influenza, and the fatality rate of severe influenza is 8%. -10%. Influenza not only causes morbidity and death of a large number of people, but also cause...

Examples

Embodiment 1

[0041] Example 1 : Compound of the present invention ( 1 ) preparation

[0042] Preparation of intermediates:

[0043] Will m- CPBA (17.2g, 1mol) was dissolved in dichloromethane (100ml), added to a solution of curcumol (11.8g, 0.05mol) in dichloromethane (100ml) at 0°C, and kept stirring at 0°C for 2 hours. After the reaction, the reaction liquid was extracted three times with NaOH (2 mol / l) solution, the organic phases were combined, extracted with water until neutral, and dried over anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness, and the crude product was purified by silica gel column chromatography (cyclohexane:ethyl acetate=50:1~10:1) to obtain 11.95 g of white waxy solid 10,14-epoxycurcumol, yield 95% .

[0044] 10,14-epoxycurcumol (10.08g, 0.04mol) was dissolved in acetonitrile (600ml), and lithium perchlorate trihydrate (6.4g, 0.04mol) and diethylamine (20ml) were added at room temperature. The resulting mixture was heated t...

Embodiment 2

[0049] Example 2 : Compound of the present invention ( 2 ) preparation

[0050] The preparation of intermediate: the same Example 1 The preparation method of intermediates.

[0051] target compound ( 2 ) preparation:

[0052] Dissolve (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-ene-14-chloroguaiacol (27mg, 0.1mmol) in DMF (2ml), add acetic acid Sodium (12.3 mg, 0.15 mmol). The resulting mixture was reacted at 70°C for 3.5 hours. The reaction solution was concentrated and evaporated to dryness, and the resulting crude product was purified by PTLC (cyclohexane:ethyl acetate=3:1, eluted with ethyl acetate) to obtain colorless oily compounds (1S, 4S, 5S, 7S, 8R)-5, 8 -Epoxy-9,10-ene-8-hydroxy-14-guaiacol acetate ( 2 ) 21.2mg, yield 72%. The spectral data of the compound are as follows: MS(ESI) m / z : 317.0 [M+Na] + ; 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 1.96 (1H, dd, J =8.8, 16.4Hz, H-1), 1.87 (1H, m, H-2a), 1.56 (1H, m, H-2b), 1.87 (1H, m, H-3a), 1.56 (1H, m, H-3b), 1.8...

Embodiment 3

[0054] Example 3 : Compound of the present invention ( 3 ) preparation

[0055] The preparation of intermediate: the same Example 1The preparation method of intermediate (1S, 4S, 5S, 7S, 8R)-5, 8-epoxy-9, 10-ene-8, 14-guaiacol.

[0056] target compound ( 3 ) preparation:

[0057] Dissolve (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-ene-8,14-guaiarediol (25.2mg, 0.1mmol) in dry pyridine (4ml) , succinic anhydride (15mg, 0.15mmol), DMAP (2.5mg, 0.02mmol) were added. The resulting mixture was reacted at 70°C for 2 hours. The reaction solution was concentrated and evaporated to dryness, and the resulting crude product was purified by PTLC (cyclohexane:ethyl acetate=2:1, eluted with ethyl acetate) to obtain colorless oily compounds (1S, 4S, 5S, 7S, 8R)-5, 8 -Epoxy-9,10-ene-8-hydroxy-14-guaiacol succinate ( 3 ) 24.6mg, yield 71%. The spectral data of the compound are as follows: MS(ESI) m / z : 361.2 [M+Na] + ; 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 1.95 (1H, dd, J =8.8, 16.3H...

technical field

[0001] The invention relates to the technical field of medicine, in particular to a curcumol derivative against influenza A (H1N1) virus. Background technique

[0002] Influenza (influenza) is a highly contagious and fast-spreading acute viral respiratory infectious disease caused by influenza virus that seriously endangers the health of people, livestock and poultry. It is a typical zoonotic disease. It is generally accepted by the medical profession that the harm of influenza is no less than that of AIDS and war. Complications and death from influenza can be severe. According to the announcement issued by the World Health Organization (WHO), there are 600 million to 1.2 billion cases of influenza in the world every year, and 500,000 to 1 million deaths, including 3 million to 5 million cases of severe influenza, and the fatality rate of severe influenza is 8%. -10%. Influenza not only causes morbidity and death of a large number of people, but also cause...

Examples

Embodiment 1

[0041] Example 1 : Compound of the present invention ( 1 ) preparation

[0042] Preparation of intermediates:

[0043] Will m- CPBA (17.2g, 1mol) was dissolved in dichloromethane (100ml), added to a solution of curcumol (11.8g, 0.05mol) in dichloromethane (100ml) at 0°C, and kept stirring at 0°C for 2 hours. After the reaction, the reaction liquid was extracted three times with NaOH (2 mol / l) solution, the organic phases were combined, extracted with water until neutral, and dried over anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness, and the crude product was purified by silica gel column chromatography (cyclohexane:ethyl acetate=50:1~10:1) to obtain 11.95 g of white waxy solid 10,14-epoxycurcumol, yield 95% .

[0044] 10,14-epoxycurcumol (10.08g, 0.04mol) was dissolved in acetonitrile (600ml), and lithium perchlorate trihydrate (6.4g, 0.04mol) and diethylamine (20ml) were added at room temperature. The resulting mixture was heated t...

Embodiment 2

[0049] Example 2 : Compound of the present invention ( 2 ) preparation

[0050] The preparation of intermediate: the same Example 1 The preparation method of intermediates.

[0051] target compound ( 2 ) preparation:

[0052] Dissolve (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-ene-14-chloroguaiacol (27mg, 0.1mmol) in DMF (2ml), add acetic acid Sodium (12.3 mg, 0.15 mmol). The resulting mixture was reacted at 70°C for 3.5 hours. The reaction solution was concentrated and evaporated to dryness, and the resulting crude product was purified by PTLC (cyclohexane:ethyl acetate=3:1, eluted with ethyl acetate) to obtain colorless oily compounds (1S, 4S, 5S, 7S, 8R)-5, 8 -Epoxy-9,10-ene-8-hydroxy-14-guaiacol acetate ( 2 ) 21.2mg, yield 72%. The spectral data of the compound are as follows: MS(ESI) m / z : 317.0 [M+Na] + ; 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 1.96 (1H, dd, J =8.8, 16.4Hz, H-1), 1.87 (1H, m, H-2a), 1.56 (1H, m, H-2b), 1.87 (1H, m, H-3a), 1.56 (1H, m, H-3b), 1.8...

Embodiment 3

[0054] Example 3 : Compound of the present invention ( 3 ) preparation

[0055] The preparation of intermediate: the same Example 1The preparation method of intermediate (1S, 4S, 5S, 7S, 8R)-5, 8-epoxy-9, 10-ene-8, 14-guaiacol.

[0056] target compound ( 3 ) preparation:

[0057] Dissolve (1S, 4S, 5S, 7S, 8R)-5,8-epoxy-9,10-ene-8,14-guaiarediol (25.2mg, 0.1mmol) in dry pyridine (4ml) , succinic anhydride (15mg, 0.15mmol), DMAP (2.5mg, 0.02mmol) were added. The resulting mixture was reacted at 70°C for 2 hours. The reaction solution was concentrated and evaporated to dryness, and the resulting crude product was purified by PTLC (cyclohexane:ethyl acetate=2:1, eluted with ethyl acetate) to obtain colorless oily compounds (1S, 4S, 5S, 7S, 8R)-5, 8 -Epoxy-9,10-ene-8-hydroxy-14-guaiacol succinate ( 3 ) 24.6mg, yield 71%. The spectral data of the compound are as follows: MS(ESI) m / z : 361.2 [M+Na] + ; 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 1.95 (1H, dd, J =8.8, 16.3H...

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