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Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses

A technology of glycyrrhetic acid and derivatives, applied in the field of medicine, can solve the problems of low anti-tumor activity of glycyrrhetic acid

Inactive Publication Date: 2011-11-23
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the antitumor activity of glycyrrhetinic acid is relatively low (Huang Wei, Huang Jiqun, Zhang Dongfang, et al. Journal of Integrated Traditional Chinese and Western Medicine Hepatology, 2003, 13(3): 148-150; Huang Wei, Huang Jiqun, Zhang Dongfang, etc. Chinese Journal of Lung Cancer, 2003, 6(4): 254-257), for which people have carried out structural modification and transformation of glycyrrhetinic acid

Method used

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  • Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses
  • Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses
  • Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Preparation of 3β-hydroxy-18β-oleanane-12-en-30-acid (II)

[0103]

[0104] Mercury chloride (3.60g, 13.3mmol) was dissolved in 50mL of 5% hydrochloric acid solution, zinc powder (18g, 0.28mol) was added, stirred at room temperature for 30min, the water layer was decanted, and zinc amalgam (10mL× 3). Add glycyrrhetinic acid (4.0g, 8.51mmol) in dioxane solution (60mL) to the freshly prepared zinc amalgam, slowly add 15mL of concentrated hydrochloric acid dropwise, finish dropping within 30 minutes, react at room temperature for 3h, evaporate under reduced pressure Add most of the solvent, add 200 mL of water, stir thoroughly for 30 minutes, filter with suction, recrystallize with glacial acetic acid, and dry to obtain 3.32 g of white needle-like powder, yield 75%, mp>300°C.

[0105] Preparation of 3-oxo-18β-oleanane-1,12-diene-30-oic acid (III)

[0106]

[0107] II (4.56g, 10mmol) was dissolved in 60mL DMSO, added IBX (11.2g, 40mmol), slowly heated to 85°C under ...

Embodiment 2

[0115] 2-cyano-3-oxo-18β-oleanane-1,12-diene-30-oic acid (I b ) preparation

[0116]

[0117] I a (0.35g, 0.61mmol) was dissolved in 20mL N-methylpyrrolidone (NMP), added CuCN (110mg, 1.21mmol), kept the internal temperature at 140°C for 2h, cooled to room temperature, added 50mL 10% FeCl 3 Aqueous solution, a gray solid precipitated, suction filtered, dried, and column chromatography (ethyl acetate:petroleum ether=1:8 (V:V)) gave 220 mg of a white solid, yield 76%, mp>300°C.

[0118] ESI-MS 476.4[M-H] - ;

[0119] IR (KBr, cm -1 )v: 3428, 2955, 2933, 2868, 2236, 1695, 1460, 1385, 1231, 1180, 972, 817, 617; 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 0.879 (s, 3H, CH 3 ), 1.065 (s, 3H, CH 3 ), 1.073 (s, 3H, CH 3 ), 1.155(s, 6H, 2×CH 3 ), 1.163 (s, 3H, CH 3 ), 1.224 (s, 3H, CH 3 ), 1.228 (s, 3H, CH 3 ), 5.375 (brs, 1H, C 12 -H), 7.752(s, 1H, C 1 -H).

Embodiment 3

[0121] Preparation of 1,2-epoxy-3-oxo-18β-oleanane-12-ene-30-acid (IV)

[0122]

[0123] III (0.90g, 2.0mmol) was dissolved in 30mL THF, 8mL of 2M sodium hydroxide solution was added, 15mL of methanol solution of hydrogen peroxide (6mL, 30%) was added dropwise, and the addition was completed within 10 minutes, stirred at room temperature for 12h, evaporated under reduced pressure Most of the solvent was removed, 50mL of 5% hydrochloric acid aqueous solution was added, a solid was precipitated, suction filtered, dried, and column chromatography (petroleum ether: ethyl acetate = 10:1 (V:V)) gave a white solid 0.78g, yield 84 %, mp 206-208°C.

[0124] ESI-MS 486.3[M+NH 4 ] + ;503.6[M+Cl] - ;

[0125] IR (KBr, cm -1 )v: 3426, 2941, 2870, 1701, 1458, 1384, 1333, 1317, 1261, 1231, 1167, 1030, 928, 880, 827, 816, 671;

[0126] 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 0.791 (s, 3H, CH 3 ), 1.021 (s, 3H, CH 3 ), 1.065(s, 3H, 2×CH 3 ), 1.110 (s, 3H, CH 3 ), 1.135 (s, 3H, CH 3...

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Abstract

Relating to the medicine field, the invention specifically relates to a glycyrrhetic acid derivative with a 1, 12-diene-3-ketone skeleton or a pharmaceutically acceptable salt thereof, their preparation method and medicinal uses, in particular their application in preparing antitumor drugs. Pharmacological experiment results show that these compounds have good antitumor activity and can be used for preparing antitumor drugs clinically.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a glycyrrhetinic acid derivative with a 1,12-dien-3-one skeleton or a pharmaceutically acceptable salt thereof, their preparation method, and a pharmaceutical combination containing these derivatives Drugs and their medical use, especially in the preparation of antineoplastic drugs. Background technique [0002] Licorice is one of the commonly used Chinese herbal medicines in my country, and it is listed as the best medicine in "Shen Nong's Materia Medica". The theory of traditional Chinese medicine believes that licorice is flat in nature and sweet in taste, and has the functions of harmonizing urgency, nourishing the lungs, detoxifying, eliminating phlegm, relieving cough, dredging meridians, benefiting qi and blood, and harmonizing various medicines. Glycyrrhizic acid and its aglycon glycyrrhetinic acid are the main active ingredients of licorice. Studies have shown that glyc...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61K31/56A61P35/00A61P1/16A61P1/00A61P1/18A61P13/08
Inventor 赖宜生沙磊缪泽鸿张奕华宦霞娟丁健
Owner CHINA PHARM UNIV
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