Silybin esters derivatives and preparation and use thereof

A technology of silibinin and derivatives, which is applied in the field of preparation of silibinin ester derivatives, and can solve the problems of limited drug market, insufficient water solubility and bioavailability, etc.

Inactive Publication Date: 2007-07-04
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Silybin compounds have definite curative effect, but the market of this drug is limited due to some shortcomings in water solubility and bioavailability

Method used

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  • Silybin esters derivatives and preparation and use thereof
  • Silybin esters derivatives and preparation and use thereof
  • Silybin esters derivatives and preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Compound I-1, p-methoxybenzoic acid [3-(hydroxyl-3-methoxyphenyl)-6-(2,3-dihydro-3,5,7-trihydroxyl-4 Preparation of -oxo-benzopyran-2-)-2,3-dihydro-1,4-benzodioxane-2-]-methyl ester:

[0040]

[0041] Add 1 gram of compound I-a (silibinin), 0.6 gram of p-methoxybenzoic acid and 1.6 gram of triphenylphosphine into a dry reaction flask, dissolve with 20 milliliters of anhydrous tetrahydrofuran, add 1 gram of azodicarboxylate Ethyl ester was stirred at room temperature for 10 hours after the addition, the solvent was distilled off under reduced pressure, 5 ml of chloroform was added, the white solid was removed by filtration, and the mother liquor was subjected to column chromatography to obtain 0.7 g of a light yellow powder with a yield of 47%.

[0042] Compound I-1: Rf (chloroform:methanol=50:1)=0.33; 1 H NMR (400MHz, deuterated chloroform) δ: 3.80(s, 3H, OCH 3 ), 3.86(s, 3H, OCH 3 ), 4.20(m, 1H, H-9′a), 4.34(m, 1H, H-8′), 4.48(m, 1H, H-9′b), 4.53(m, 1H...

Embodiment 15

[0062] Example 15: Compound I-15 (p-methoxybenzoic acid [3-hydroxy-3-methoxyphenyl)-8-methoxy-6-(2,3-dihydro-3,5,7 - Preparation of trihydroxy-4-oxo-benzopyran-2-)-2,3-dihydro-1,4-benzodioxane-2-]-methyl ester):

[0063] According to the method of Example 1, with 2-[2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-8-methoxy-1,4- Benzodioxane-6-]-2,3-dihydro-3,5,7-trihydroxy-4H-1-benzopyran-4-one instead of silybin can give compound I-15 : Rf (chloroform: methanol = 50: 1) = 0.28; 1 H NMR (400MHz, deuterated chloroform) δ: 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.22 (m, 1H, H-9'a) , 4.33.(m, 1H, H-8'), 4.50(m, 1H, H-9'b), 4.51(m, 1H, H-3), 4.98(d, J=12.0Hz, 1H, H -2), 5.02(d, J=8.0Hz, 1H, H-7'), 6.00(s, 1H, H-6), 6.03(s, 1H, H-8), 6.95(d, J=8.8 Hz, 1H, H-3, 5), 6.86-7.15(m, 5H, Ar-H), 7.95(d, J=8.8Hz, 1H, H-2, 6) 11.24(s, 1H , 5-OH); ESI-MS: 645[M-1] + .

Embodiment 16

[0064] Example 16: p-nitrobenzoic acid [3-(4-hydroxy-3-methoxyphenyl)-8-methoxy-6-(2,3-dihydro-3,5,7-trihydroxy - Preparation of 4-oxo-benzopyran-2-)-2,3-dihydro-1,4-benzodioxane-2-]-methyl ester:

[0065] According to the same method as in Example 15, compound I-16 can be obtained: Rf (chloroform: ethyl acetate: formic acid = 50: 1: 0.25) = 0.15; 1 H NMR (400MHz, deuterated chloroform) δ: 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.35 (m, 1H, H-9'a), 4.50 (m, 1H, H- 8'), 4.57(m, 2H, H-3, H-9'b), 4.96(d, J=6.8Hz, 1H, H-7'), 5.01(d, J=12.0Hz, 1H, H -2), 6.01(s, 1H, H-6), 6.13(s, 1H, H-8), 7.59(d, J=8.8Hz, 2H, 2, 6), 6.93-8.16(m, 5H, Ar-H), 8.33(d, J=8.8Hz, 2H, 3, 5), 11.20(s, 1H, 5-OH); ESI-MS: 660[M-1]+ .

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Abstract

The invention relates to a silibinin monoester derivative and its medicine salt or solvates. The invention also relates to its preparation method and its drug combination and medical application. The compound can inhibit activity of hepatitis b virus, so it is expected to be used as drug to treat hepatitis b virus and relevant virus diseases. The compound can protect liver and is expected to be used as drug preventing liver damage. The compound possesses effect anti free radical and is expected to be used as drug treating diseases caused by free radical.

Description

field of invention [0001] The invention belongs to the field of organic chemistry and medicinal chemistry, in particular, the invention relates to the preparation method and application of silybin ester derivatives. Such compounds are obtained through total synthesis and semi-synthesis methods. This type of compound has the activity of inhibiting human hepatitis B virus deoxyribonucleic acid (HBVDNA) and reducing hepatitis B virus surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), so it can be expected to be used as a drug for treating viral hepatitis B and related viral diseases . In addition, the present invention screens the hepatocyte injury protection activity of the series of compounds on the hydrogen peroxide-induced primary liver cell injury model of rat suckling rats. This type of compound has been found to protect liver cells and promote the repair of liver cells. Secondly, the liver injury protection activity test was carried out on the animal liver injur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/02A61P31/12A61P1/16A61P39/06A61P35/00A61P9/00A61K31/357A61K9/00
Inventor 赵昱龚景旭伍义行白骅
Owner ZHEJIANG HISUN PHARMA CO LTD
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