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Application of diamine formyl dehydrogenated silybin serving as medicament for curing viral hepatitis B

A technology of dehydrosilibinin and biscarbamoylmethoxy, which is applied in the direction of antiviral agents, can solve the problems that new uses have not been effectively developed, and achieve large-scale production, energy saving and emission reduction. , Synthetic convenient effect

Inactive Publication Date: 2012-10-17
DALI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0015] Although the flavonoid lignans represented by silibinin have the above-mentioned antioxidant effects, there are relatively few literatures on their antiviral treatment. The flavonoid lignans treat DNA virus infection especially Its new application for anti-hepatitis B virus (including inhibition of HBsAg or HBeAg, inhibition of HBV DNA replication) has not been effectively developed, so the active compound in the field of anti-hepatitis B virus is found from flavonoid lignans, that is, the structure of flavonoid lignans Engineering to have anti-DNA viroid activity is a new field

Method used

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  • Application of diamine formyl dehydrogenated silybin serving as medicament for curing viral hepatitis B
  • Application of diamine formyl dehydrogenated silybin serving as medicament for curing viral hepatitis B
  • Application of diamine formyl dehydrogenated silybin serving as medicament for curing viral hepatitis B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Formula (1) compound N, N-diethyl-2-{2-[3-(4-diethylcarbamoylmethoxy-3-methoxyphenyl)-2-hydroxymethyl-2 ,3-Dihydro-benzo[1,4]dioxan-6-yl]-3,5-dihydroxy-4-oxo-4H-benzopyran-7-yloxy}-acetamide preparation of

[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 Pharmacia Biotech AB Company of Swede...

Embodiment 2

[0034] Example 2: Inhibitory Effect of Compound (1) on Hepatitis B Surface Antigen (HBsAg) Secreted by HepG2.2.15 Cells

[0035] 2.1 Cell culture:

[0036] 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.

[0037] 2.2 The inhibitory effect of the compound of formula (1) on HepG2.2.15 cell growth was measured by MTT method:

[0038] 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

[0047] Example 3: Inhibitory Effect of Compound (1) on Hepatitis B e Antigen (HBeAg) Secreted by HepG2.2.15 Cells

[0048] 3.1 Cell culture: the method is the same as in Example 2.

[0049] 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.

[0050] 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 20 μg / ml, 4 μg / ml and 0.8 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 diamine formyl dehydrogenated silybin serving as a medicament for curing viral hepatitis B, in particular to application of a flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents or pharmaceutically acceptable salts thereof in preparation of a medicament for clearing HBsAg and HBeAg and a medicament for inhibiting HBV DNA replication. The flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents has extremely high HBsAg and HBeAg inhibiting activities; when the flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents is at a concentration of 20 mu g / ml, the inhibition rates of the HBsAg and the HBeAg are respectively 94.4 percent and 95.7 percent which exceed 5.9 times and 5.7 times those of a positive control alpha-interferon; and simultaneously the inhibition rate of the HBV DNA is 99.7 percent when the flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents is at the same concentration, and the inhibition activity of the flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents is higher than that of lamivudine and the alpha-interferon. In summary, the flavonolignan of dehydrogenated silibinin esters of which the ring A and the ring E have diamine formyl-methoxyl substituents or the pharmaceutically acceptable salts thereof can be expected for preparing non-nucleoside medicaments for clearing the HBsAg and the HBeAg, inhibiting the HBV DNA replication, and curing the hepatitis B virus infection diseases.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular, the present invention relates to a kind of dehydrosilibinin ester flavonoid lignans or pharmaceutically acceptable salts thereof substituted by dicarbamoyl methoxy on ring A and ring E. The invention 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 94.4% and 95.7% at a concentration of 20 micrograms / milliliter, respectively surpassing the positive control drug (10000 units / milliliter of α- Interferon) 5.9 times and 5.7 times; Simultaneously, it shows 99.7% inhibitory rate to HBV DNA at this concentration, 23% higher than lamivudine, and higher than alpha-interferon 2.6 times. T...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/357A61P31/20
Inventor 丁跃明林文艳甘平汪峰罗尔夫·希尔根菲尔德巫秀美赵昱戴志明
Owner DALI UNIV
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