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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 directions of antiviral agents, medical preparations containing active ingredients, and pharmaceutical formulations, can solve the problems that new uses have not been effectively developed, and achieves It is beneficial to large-scale production, the preparation method is simple and feasible, and the source of raw materials is easy to obtain.

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 flavonoid lignans represented by silibinin have the above-mentioned antioxidant effects, there are relatively few literatures on antiviral treatment. Flavonoids are especially effective in treating DNA virus infections 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 all 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 S...

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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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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