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Synthesizing method of Ursolic Acid (UA) derivative and application thereof in pharmacy

A compound and representative technology, applied in the application field of preparing drugs for inducing liver tumor cell apoptosis, can solve the problems of affecting clinical efficacy, low bioavailability, poor solubility, etc.

Inactive Publication Date: 2009-12-30
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its poor solubility and low bioavailability affect its clinical efficacy

Method used

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  • Synthesizing method of Ursolic Acid (UA) derivative and application thereof in pharmacy
  • Synthesizing method of Ursolic Acid (UA) derivative and application thereof in pharmacy
  • Synthesizing method of Ursolic Acid (UA) derivative and application thereof in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Ursolic acid-3-nitrooxypropyl ester (I 2 )

[0048] UA (500mg, 1.05mmol) was suspended in 15ml of acetone, and triethylamine (2ml) was added to dissolve it completely, and 1,3-dibromopropane (0.5ml, 6mmol) was added under stirring at room temperature, and stirred and refluxed for 12 hours to obtain intermediate Ursolic acid-3-bromopropyl ester, then reflux with silver nitrate in the dark for 6h to filter out insoluble matter, concentrate the filtrate, and perform silica gel column chromatography [ethyl acetate:petroleum ether (60~90°C)=1:4(V : V)], 150mg of white solid was obtained, yield 65%, m.p.76~78℃.

[0049] ESI-MS: 568[M+Na] +

[0050] IR (KBr, cm -1 ): 3474 (OH), 1720 (C=O), 1637 (ONO 2 )

[0051] 1 H NMR (300MHz, CDCl 3 ), δ: 0.71 (s, 3H, CH 3 ), 0.78(s, 3H, CH 3 ), 0.88(s, 6H, 2×CH 3 ), 0.90 (d, 3H, CH 3 ), 0.97 (d, 3H, CH 3 ), 1.00 (s, 3H, CH 3 ), 3.20(m, 1H, 3α-H), 4.13(t, 2H, OCH 2 , J=6Hz), 4.54(t, 2H, OCH 2 , J=6Hz), 5.25~5.27(m, 1H, C 12...

Embodiment 2

[0056] (1) 4-hydroxyl-3-methoxyphenyl acrylate-2-bromoethyl ester (2a 1 )

[0057] Ferulic acid (5g, 25.8mmol) was dissolved in 50ml of acetone, 1,2-dibromoethane (22.26g, 100mmol) and 10ml of triethylamine were added, heated at an external temperature of 50°C for 4 hours, cooled to room temperature, A large amount of white solid was precipitated, filtered, the filtrate was concentrated, column chromatography [ethyl acetate:petroleum ether (60-90°C)=1:4 (V:V)], 7.8g of needle-like solid was obtained, yield 67% , m.p.102-104°C.

[0058] 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.

[0059] (2) 3-O-trifluoroacetyl-ursolic acid-2-methoxy-4-[2-(2-bromo-ethoxycarbonyl)-vinyl]-phenyl ester (2b 1 )

[0060] UA (456mg, 1mmol) was suspended in toluene, trifluoroacetic anhydride (1ml, 7.42mmol) was added under stirring, the reaction solution was c...

Embodiment 3

[0069] (1) 4-hydroxyl-3-methoxyphenyl acrylate-2-bromopropyl ester (2a 2 )

[0070] Refer to 2a 1 The preparation method is prepared from ferulic acid and 1,3-dibromopropane, with a yield of 68%, m.p.100-102°C.

[0071] (2) 3-O-trifluoroacetyl-ursolic acid-2-methoxy-4-[2-(3-bromo-propoxycarbonyl)-vinyl]-phenyl ester (2b 2 )

[0072] Refer to 2b 1The preparation method of UA and 8b, column chromatography [ethyl acetate: petroleum ether (60 ~ 90 ° C) = 1: 4 (V: V)] to obtain a yellow oil, yield 74%.

[0073] (3) 3-O-trifluoroacetyl-ursolic acid-2-methoxy-4-[2-(3-nitrooxy-propoxycarbonyl)-vinyl]-phenyl ester (II 3 )

[0074] Reference II 1 The preparation method, by 2b 1 Prepared by reacting with AgNO3 in the dark, column chromatography [ethyl acetate:petroleum ether (60-90°C)=1:4 (V:V)] gave a white solid with a yield of 71.8%, m.p.100-102°C.

[0075] ESI-MS: 849[M+NH 4 ] +

[0076] IR (KBr, cm -1 ): 1778 (C=O), 1754 (C=O), 1720 (C=O), 1634 (ONO 2 )

[0077] 1 H ...

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Abstract

The invention relates to an Ursolic Acid (UA) derivative. The Ursolic Acid (UA) derivative is a NO-donating UA derivative formed by coupling ester bonds or amido bonds of Ursolic Acid (UA) which has anti-tumor activity with NO donators in different types by connecting groups; and external primary screening result shows that the toxic effect of a plurality of compounds on HepG2 is evidently stronger than UA, therefore, the Ursolic Acid (UA) derivative has the prospect of anti-tumor application.

Description

technical field [0001] The present invention relates to ursolic acid coupling derivatives and their medicinal uses, specifically, different types of nitric oxide (abbreviated as NO, the same below) donors are coupled with ursolic acid having hepatoprotective effects through ester bonds or amide bonds compound, and its application in the preparation of drugs for inducing liver tumor cell apoptosis. Background technique [0002] Ursolic acid (UA), also known as ursolic acid, belongs to pentacyclic triterpenoids, widely distributed in the plant kingdom, showing a variety of biological activities. UA has a more obvious anti-tumor effect, and its anti-tumor spectrum is broad. Studies have shown that UA mainly exerts anti-tumor effects through various mechanisms such as inducing tumor cell apoptosis, differentiation, anti-initiative mutation, cytotoxicity, anti-angiogenesis, anti-carcinogenesis, and anti-oxidation. However, its poor solubility and low bioavailability affect its ...

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 陈莉仇文汤佳王志凤汤伟彬张蕾
Owner CHINA PHARM UNIV
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