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Application of aromatic carbamoyl dehydro-silibinin as medicament for treating viral hepatitis B

A technology of dehydrosilibinin and arylcarbamoyl methoxy is applied in the directions of antiviral agents, drug combinations, medical preparations containing active ingredients, etc., and can solve the problems of lack of literature and no effective development, and the like, To achieve the effect of convenient source, convenient source of raw materials and clear industrialization prospects

Inactive Publication Date: 2010-09-15
DALI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although the flavonoid lignan compounds represented by silibinin have the above-mentioned antioxidant effects, there are relatively few literatures on their antiviral treatment
Flavonoid lignans have not been effectively developed for the treatment of DNA-like virus infection, especially its use in anti-hepatitis B virus (including inhibiting hepatitis B surface antigen HBsAg or HBeAg, inhibiting HBV DNA replication), so from flavonoid lignans Looking for active compounds in the field of anti-hepatitis B virus, that is, modifying the structure of flavonoid lignans so that they have anti-DNA virus activity is a new field, and it is even more unprecedented to find lead compounds that clear HBsAg or HBeAg and inhibit HBV DNA replication. untried challenge

Method used

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  • Application of aromatic carbamoyl dehydro-silibinin as medicament for treating viral hepatitis B
  • Application of aromatic carbamoyl dehydro-silibinin as medicament for treating viral hepatitis B
  • Application of aromatic carbamoyl dehydro-silibinin as medicament for treating viral hepatitis B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Formula (1) compound N-(2,4-dichloro-phenyl)-2-[2-(3-{4-[(2,4-dichloro-phenylcarbamoyl)-methoxy] -3-methoxy-phenyl}-2-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxane-6-yl)-3,5-dihydroxy-4- Preparation of Oxy-4H-benzopyran-7-yloxy]-acetamide

[0028] 1.1 Instruments and reagents:

[0029] The ultraviolet spectrum was measured with a Shimadzu UV-240 ultraviolet spectrophotometer; the hydrogen nuclear magnetic resonance spectrum 1 H-NMR is measured by INOVA type superconducting nuclear magnetic resonance spectrometer (VARIAN INOVA-400MHz) (tetramethylsilyl ether TMS is the internal standard); (100-200, 200-300 and 300-400 mesh) and silica gel GF254 (10-40 mesh) for thin-layer chromatography are produced by Qingdao Ocean Chemical Factory; all reagents used are analytically pure, thin-layer preparative chromatography (PTLC ) uses the aluminum foil silica gel plate of Merck Company; Sephadex LH-20 used for column chromatography adopts the product of Amersham Pharma...

Embodiment 2

[0033] Example 2: Inhibitory Effect of Compound (1) on Hepatitis B Surface Antigen (HBsAg) Secreted by HepG2.2.15 Cells

[0034] 2.1 Cell culture:

[0035] HepG2.2.15 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum, 100 U / ml penicillin and 100 U / ml streptomycin, 100 μg / ml G418 at 37°C, 5% CO 2 , cultured in an incubator with 100% relative humidity.

[0036] 2.2 The inhibitory effect of the compound of formula (1) on HepG2.2.15 cell growth was measured by MTT method:

[0037] Take the HepG2.2.15 cells in the logarithmic growth phase, and dilute the cells to 1×10 with medium 5 cells / ml, seeded in 96-well cell culture plate, 100 μl per well, at 37°C, 5% CO 2 After 24 hours in an incubator with 100% relative humidity, add compound (1) diluted with medium, the concentration is 1000 μg / ml, 200 μg / ml, 40 μg / ml and 8 μg / ml, 200 μg / ml in each well microliter, each concentration was set up in triplicate, placed at 37°C, 5% CO 2 , cultivated in an ...

Embodiment 3

[0046] Example 3: Inhibitory Effect of Compound (1) on Hepatitis B e Antigen (HBeAg) Secreted by HepG2.2.15 Cells

[0047] 3.1 Cell culture: the method is the same as in Example 2.

[0048] 3.2 Determination of the inhibitory effect of the compound of formula (1) on the growth of HepG2.2.15 cells by MTT method: the method is the same as in Example 2.

[0049] 3.3 Determination of the inhibitory effect of the compound on hepatitis B e antigen (HBeAg): take the HepG2.2.15 cells in the logarithmic growth phase, and dilute the cells to 1 × 10 with the medium 5 / ml, seeded in 96-well cell culture plate, 100ml per well, at 37°C, 5% CO 2 After culturing in an incubator with 100% relative humidity for 24 hours, add samples diluted with culture medium at concentrations of 100 μg / ml, 20 μg / ml and 4 μg / ml, 200 μl per well, and set three concentrations for each Multiple wells were placed at 37°C, 5% CO 2 , cultivated in an incubator with 100% relative humidity, change the culture med...

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Abstract

The invention relates to application of aromatic carbamoyl dehydro-silibinin as a medicament for treating viral hepatitis B, in particular to application of todehydro-silibinin flavonolignans with a ring A and a ring E which are substituted by double base aromatic carbamoyl methoxyl and pharmaceutically acceptable salt thereof for preparing medicaments for removing HBsAg and HBeAg and medicaments for inhibiting HBV DNA. The todehydro-silibinin flavonolignans has extremely obvious activity on inhibiting the HBsAG and the HBeAg, has the intensity of 46.2 percent and 68.9 percent for respectively removing the HBsAG and the HBeAg in the presence of the concentration of 100 microgram / milliliter, which is 2.9 times and 4.1 times higher than that of positive control medicament alpha-interferon, and has the inhibition ratio of 96 percent on HBV DNA in the presence of the concentration of 100 microgram / milliliter, which is higher than that of lamivudine and the alpha-interferon. Accordingly, the flavonolignans and the pharmaceutically acceptable salt thereof can be expected to be used for preparing non-nucleoside medicaments applied for removing HBsAg and HBeAg, inhibiting HBV DNA replication and treating hepatitis B virus infection diseases.

Description

technical field [0001] The invention relates to the field of medical technology, in particular, the invention relates to a dehydrosilibinin ester flavonoid lignan or a pharmaceutically acceptable salt thereof substituted by bisarylcarbamoylmethoxy on ring A and ring E It is used for preparing medicines for reducing hepatitis B virus surface antigen HBsAg and hepatitis B e antigen HBeAg, inhibiting HBV DNA replication, and treating hepatitis B virus infection diseases. This flavonoid lignan has extremely significant inhibition of HBsAg and HBeAg activity, and its intensity of removing HBsAg and HBeAg is respectively 46.2% and 68.9% at the concentration of 100 micrograms per milliliter, surpassing the positive control drug (10000 units / ml of α- Interferon) 2.9 times and 4.1 times; Simultaneously, it shows about 96% inhibitory rate to HBV DNA at this concentration, is higher than lamivudine, and is higher than alpha-interferon 2.5 times. The above pharmacodynamic results show th...

Claims

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Application Information

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IPC IPC(8): A61K31/357A61P31/20A61P1/16
Inventor 刘光明王丽薇胡艳芬汪峰付红波巫秀美赵昱曾苏
Owner DALI UNIV
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