Oleanolic acid couple derivatives and their pharmaceutical use

A compound and a representative technology used in the preparation of drugs that inhibit apoptosis or selectively induce apoptosis of liver tumor cells can solve the problems of low bioavailability and unsatisfactory curative effect.

Inactive Publication Date: 2005-03-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Oleanolic acid (abbreviated OLA, the same below) widely exists in the plant kingdom, and is clinically used to treat chronic hepatitis, liver cirrhosis and malignant tumors, etc., but there are still problems such as low bioavailability and unsatisfactory curative effect (see: Wang Lixin, Han Guangxuan, Liu Wenyong, et al. Chemical and Pharmacological Research of Oleanolic Acid [J]. Journal of Pharmaceutical Practice, 2001, 19(2): 104-107; Research on the Effect of Oleanolic Acid on Prevention and Treatment of Experimental Liver Injury[J] ]. Acta Pharmaceutica Sinica, 1982, 17(2): 93-97)

Method used

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  • Oleanolic acid couple derivatives and their pharmaceutical use
  • Oleanolic acid couple derivatives and their pharmaceutical use
  • Oleanolic acid couple derivatives and their pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] 1) oleanolic acid-2-bromoethyl ester (1a 1 )

[0082] Suspend OLA (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.

[0083] In the same way, other intermediates such as 1a can be prepared from OLA and other dibromoalkanes, dibromoalkenes, and dibromoalkynes.

[0084] 2) oleanolic acid-2-nitrooxyethyl ester (I 1 )

[0085] 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...

Embodiment 2

[0092] 1) 4-bromomethylphenyl 3-trifluoroacetoxy oleanolic acid ester (1b 1 )

[0093] OLA (456mg, 1mmol) was suspended in toluene, added trifluoroacetic anhydride (0.8ml, 4mmol), stirred at room temperature for 10 minutes, then added p-hydroxybenzyl bromide (238mg, 1.4mmol), stirred and refluxed for 6 hours, cooled to room temperature, 10 % sodium bicarbonate was washed to neutrality, the organic layer was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and column chromatography [ethyl acetate: petroleum ether (60-90° C.) = 1: 4 (V: V )] to obtain light yellow oil, yield 67.9%.

[0094] 2) 3-trifluoroacetoxy oleanolic acid 4-nitrooxymethylphenyl ester (I 8 )

[0095] 1b 1 (310mg, 0.51mmol) was dissolved in a mixed solvent of acetonitrile and tetrahydrofuran, silver nitrate (127mg, 0.76mmol) was added, and the reaction was stirred under reflux in the dark for 4 hours, and the silver bromide precipitate was filtered off, an...

Embodiment 3

[0102] 1) 4-Hydroxy-3-methoxyphenylacrylate-3-bromopropyl ester (2a 1 )

[0103] Ferulic acid (5g, 25.8mmol) was dissolved in 50ml of acetone, 1,3-dibromopropane (20.2g, 100mmol), 10ml of triethylamine were added, and the reaction was heated at an external temperature of 50°C for 4 hours, cooled to room temperature, and A large amount of white solid precipitated, filtered, the filtrate was concentrated, and column chromatography [ethyl acetate:petroleum ether (60-90°C)=1:4 (V:V)] gave 5.53 g of needle-like solid. Yield: 68%, mp: 100-102°C.

[0104] In the same way, other intermediates such as 2a can be prepared from ferulic acid, vanillic acid, p-hydroxycinnamic acid and other dibromoalkanes, dibromoalkenes, and dibromoalkynes.

[0105] 2) 3-O-trifluoroacetyl-oleanolic acid-2-methoxy-4-[2-(3-bromo-propoxycarbonyl)-vinyl]-phenyl ester (2b 1 ) OLA (1.14g, 2.5mmol) was suspended in toluene, trifluoroacetic anhydride (2ml, 14.85mmol) was added under stirring, the reaction solut...

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Abstract

The invention discloses an oleanolic acid couple, which is a nitric oxide donator type OLA derivative coupled by dissimilar NO donators with hepatic disease treating medicament oleanolic acid (OLA) through binding groups with ester bonds or amido bonds, wherein the suppressor cell apoptosis action of some of the compounds is stronger than that of the NCX-10000 that are undergone US stage I clinical research, thus may possibly be used for the treatment of hepatitis and cirrhosis.

Description

technical field [0001] The present invention relates to oleanolic acid coupling derivatives and their medicinal uses, specifically, different types of nitric oxide (abbreviated as NO, the same below) donors are combined with olean fruit with hepatoprotective effects through ester bonds or amide bonds. An acid-coupled compound and its application in the preparation of drugs for inhibiting cell apoptosis or selectively inducing liver tumor cell apoptosis. Background technique [0002] Oleanolic acid (abbreviated OLA, the same below) widely exists in the plant kingdom, and is clinically used to treat chronic hepatitis, liver cirrhosis and malignant tumors, etc., but there are still problems such as low bioavailability and unsatisfactory curative effect (see: Wang Lixin, Han Guangxuan, Liu Wenyong, et al. Chemical and Pharmacological Research of Oleanolic Acid [J]. Journal of Pharmaceutical Practice, 2001, 19(2): 104-107; Research on the Effect of Oleanolic Acid on Prevention an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/56A61P1/16A61P31/12A61P35/00C07J53/00
Inventor 张奕华陈莉田季徳郭青龙
Owner CHINA PHARM UNIV
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