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Novel tetraterpene derivatives and pharmaceutical use thereof

A compound, the technology of trifluoroacetyl group, applied in the application field of anti-liver tumor, can solve the problems of unsatisfactory curative effect, low bioavailability and the like

Inactive Publication Date: 2010-01-27
王志凤
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Oleanolic acid (abbreviated as OA, the same below) or ursolic acid (abbreviated as UA, the same below) widely exists in the plant kingdom, and is clinically used to treat chronic hepatitis, liver cirrhosis and malignant tumors, etc. Low, unsatisfactory curative effect and other issues (see: Xiong Xiaojuan, Chen Wu, Xiao Xiaohua, etc. Comparison of protective effects of ursolic acid and oleanolic acid on experimental liver injury in mice [J]. Journal of Jiangxi Normal University (Natural Science Edition), 2004, 28(6): 540~543. Wang Lixin, Han Guangxuan, Liu Wenyong, etc. Chemical and pharmacological research on oleanolic acid [J]. Journal of Pharmaceutical Practice, 2001, 19(2): 104-107; Chen Wu, Xiong Xiaojuan, Li Kaiquan, et al. Clinical research on the treatment of acute viral hepatitis with ursolic acid [J]. 2001, 13(1): 1~3.

Method used

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  • Novel tetraterpene derivatives and pharmaceutical use thereof
  • Novel tetraterpene derivatives and pharmaceutical use thereof
  • Novel tetraterpene derivatives and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1) ursolic acid-2-bromoethyl ester (1a 1 )

[0043] Suspend UA (1.0g, 2.19mmol) in 15ml of acetone, add triethylamine (2ml) to dissolve completely, add 1,2-dibromoethane (1.0ml, 11.5mmol) under stirring at room temperature, stir and reflux for 6 hours , filtered off the insoluble matter, concentrated the filtrate, and column chromatography [ethyl acetate:petroleum ether (60~90°C)=1:4(V:V)] gave a white solid 0.80g, yield 65%, mp: 150 ~152°C.

[0044] 2) ursolic acid-2-nitroxyethyl ester (I 1 )

[0045] 1a 1 (0.4g, 0.71mmol) was dissolved in a mixed solvent of acetonitrile and tetrahydrofuran, silver nitrate (177mg, 1.06mmol) was added, and the light was refluxed for 6 hours, the yellow silver bromide precipitate was filtered off, and the filtrate was concentrated to obtain a light yellow oil The product was subjected to column chromatography [ethyl acetate:petroleum ether (60-90°C)=1:4 (V:V)] to obtain 0.3g of pure product, yield 77.6%, mp: 178-180°C.

[0046] ESI...

Embodiment 2

[0052] Ursolic acid-3-(3-benzenesulfonyl-2-oxo-furazan-4-oxo)-1-methylpropyl ester (II 1 )

[0053] UA (456mg, 1mmol) was suspended in toluene, trifluoroacetic anhydride (0.82ml, 5.87mmol) was added, stirred at room temperature, and intermediate 2-(3-benzenesulfonyl-1,2,5-oxadiol) was added after 10 minutes Azole-2-oxide-4-)oxy-3-butanol (305mg, 1mmol) (refer to literature Li Ruiwen, Zhang Yihua, Ji Hui, etc. benzenesulfonyl furazan nitrogen oxide and diclofenac coupling compound Synthesis and anti-inflammatory activity [J]. Acta Pharmaceutica Sinica, 2001, 36 (11): 821-826), stirred and refluxed reaction, finished reaction after 6 hours, cooled, and the reaction solution was washed to neutrality with 10% NaOH, and the organic layer was Washed with water, saturated brine, anhydrous Na 2 SO 4 Drying, column chromatography [ethyl acetate: petroleum ether (60 ~ 90 ° C) = 1: 4 (V: V)], to obtain 523 mg of milky white solid, which was suspended in methanol, and sodium bicarbonat...

Embodiment 3

[0060] 1) 3-O-carboxypropionyl-ursolic acid (3a 1 )

[0061] UA (2.50g, 5.48mmol), succinic anhydride (2.19g, 21.9mmol), DMAP (0.668g, 5.48mmol), anhydrous CH 2 Cl 2 (60ml) was added in the reaction flask successively, and heated to reflux for 48 hours. The reaction solution was washed 3 times with water, and the organic layer was anhydrous Na 2 SO 4 Drying; filtration, concentration of the filtrate, and column chromatography of the concentrate [ethyl acetate:petroleum ether (60-90° C.)=1:4 (V:V)] yielded 1.696 g of the product, with a yield of 53%.

[0062] 2) 3-O-{4-[2-(2-nitrooxy-ethoxycarbonyl)-vinyl]-phenoxy}-succinyl-ursolic acid (III 1 )

[0063] Will 3a 1 (556mg, 1mmol), 2-bromoethyl 4-hydroxyphenylacrylate (260mg, 1mmol), DCC (206mg, 1mmol), and a catalytic amount of DMAP were added to the reaction flask, anhydrous CH 2 Cl 2 10ml, stirred at room temperature, filtered, the filtrate was concentrated under reduced pressure, and column chromatography [ethyl acet...

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Abstract

The invention relates to nitric oxide donor OA or UA derivatives formed by coupling various types of NO donors and oleanolic acid (OA) or uraolic acid (UA) which is a medicament for treating liver diseases through ester bonds or amido bonds of link groups respectively. Bioactivity researches show that some compounds have the effects of killing liver tumor cells and have an application prospect in liver cancer treatment.

Description

technical field [0001] The present invention relates to oleanolic acid or ursolic acid derivatives and their medicinal uses, specifically, different types of nitric oxide (abbreviated as NO, the same below) donors are combined with olean fruit which has the effect of treating liver diseases through an ester bond or an amide bond. Acid or ursolic acid-coupled compound, and its application in anti-hepatic tumor. Background technique [0002] Oleanolic acid (abbreviated as OA, the same below) or ursolic acid (abbreviated as UA, the same below) widely exists in the plant kingdom, and is clinically used to treat chronic hepatitis, liver cirrhosis and malignant tumors, etc. Low, unsatisfactory curative effect and other issues (see: Xiong Xiaojuan, Chen Wu, Xiao Xiaohua, etc. Comparison of protective effects of ursolic acid and oleanolic acid on experimental liver injury in mice [J]. Journal of Jiangxi Normal University (Natural Science Edition), 2004, 28(6): 540~543. Wang Lixin, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P35/00A61P1/16
Inventor 王志凤
Owner 王志凤
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