Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof

A technology of glycyrrhetinic acid and derivatives, applied in the field of medicine

Inactive Publication Date: 2010-07-14
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention discloses a new class of furazan nitrogen oxide NO-donor glycyrrhetinic acid deri

Method used

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  • Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof
  • Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof
  • Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Preparation of methyl 3-O-succinic acid monoacylglycyrrhetinate (1)

[0132] Add 0.48g (1.00mmol) methyl glycyrrhetinate, 0.60g (6.00mmol) succinic anhydride, 0.16g (1.30mmol) DMAP into 20mL anhydrous CH 2 Cl 2 refluxed for 15 hours, the reaction solution was washed three times with water, concentrated, and recrystallized from methanol / water to obtain 0.57 g of white powder (1), yield 98%, mp: 260-262°C.

[0133] Preparation of 2-[(4-benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]ethanol (2a)

[0134] Dissolve 3 mL (50 mmol) of ethylene glycol and 1.85 g (5 mmol) of 2-oxo-3,4-diphenylsulfonyl-1,2,5-oxadiazole in 20 mL of THF, cool in an ice bath, and drop in 2.5 mol / L NaOH Solution 2mL, react at room temperature for 0.5h, add 1mL of 2.5mol / L NaOH solution, continue to stir until the reaction of the raw materials is complete, pour 80mL of water, extract with ethyl acetate (3×20mL), wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate and recrys...

Embodiment 3

[0143] Preparation of 1-methyl-3-[(4-benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]propanol (2c)

[0144] Referring to the preparation method of 2a, a white solid was prepared from 1,3-butanediol with a yield of 88%, mp: 101-103°C.

[0145] 3-{4-[1-methyl-3-[(4-benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]propoxy]-1,4-di Oxobutoxy}glycyrrhetinic acid methyl ester (I 3 ) preparation

[0146] Refer to I 1 The preparation method is prepared by reacting 3-O-succinic acid monoacylglycyrrhetinic acid methyl ester (1) with 2c, white solid, yield 65%, mp: 66~68°C. ESI-MS(m / z): 881.5[M+H] + ; IR(KBr, cm -1 )ν: 2950, ​​2871, 1730, 1658, 1616, 1552, 1454, 1380, 1164; 1H-NMR (300MHz, CDCl 3 )δ: 0.80~1.56(m, 21H, 7CH 3 ), 2.35(s, 1H, C 9 -H), 2.68(m, 4H, CO(CH 2 ) 2 ), 3.69 (s, 3H, OCH 3 ), 4.50~4.53 (m, 3H, C 3 -H,OCH 2 ), 4.61~4.64 (m, 1H, OCH), 5.66 (s, 1H, C 12 -H), 7.60~7.65(m, 2H, ArH), 7.76(m, 1H, ArH), 8.06~8.08(m, 2H, ArH).

Embodiment 4

[0148] Preparation of 4-[(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazol-3-)oxy]butanol (2d)

[0149] Referring to the preparation method of 2a, a white solid was obtained from 1,4-butanediol with a yield of 89%, mp: 70-72°C.

[0150] 3-{4-[4-[(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]butoxy]-1,4-dioxobutoxy }Methyl glycyrrhetinate (I 4 ) preparation

[0151] Refer to I 1 The preparation method is prepared by reacting 3-O-succinic acid monoacylglycyrrhetinic acid methyl ester (1) with 2d, white solid, yield 68%, mp: 78~80℃. ESI-MS(m / z): 881.3[M+H] + ; IR(KBr, cm -1 )ν: 2954, 2869, 1731, 1660, 1616, 1552, 1452, 1373, 1163; 1 H-NMR (300MHz, CDCl 3 )δ: 0.80~1.45(m, 21H, 7CH 3 ), 2.35(s, 1H, C 9 -H), 2.64(m, 4H, CO(CH 2 ) 2 ), 3.69 (s, 3H, OCH 3 ), 4.17~4.21(t, 2H, OCH 2 , J=6.0Hz), 4.43~4.47(t, 2H, OCH 2 , J=6.0Hz), 4.52(m, 1H, C 3 -H), 5.66(s, 1H, C 12 -H), 7.62~7.65(m, 2H, ArH), 7.76(m, 1H, ArH), 8.05~8.07(m, 2H, ArH).

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Abstract

The invention discloses a novel glycyrrhetinic acid derivative, and a preparation method and medicinal uses thereof. The glycyrrhetinic acid derivative is a compound prepared by coupling nitric oxide donor of furazan nitrogen oxides and glycyrrhetinic acid through ester bonds or amide bonds. As proved by pharmacological experiments, the glycyrrhetinic acid derivative has superior antitumor effectand can be used for the preparation of antitumor medicines.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a class of nitric oxide donor type glycyrrhetinic acid derivatives and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their medical applications, especially The invention is an application in the preparation of medicines for treating tumor diseases. Background technique [0002] Licorice belongs to leguminous plants, mainly distributed in western my country and Russia and other countries and regions, it is one of the commonly used Chinese herbal medicine varieties in my country. Glycyrrhizic acid and its aglycon glycyrrhetinic acid (glycyrrhetic acid, GA for short) are the main pharmacological active substances of licorice. Glycyrrhetinic acid, also known as glycyrrhetinic acid, is a pentacyclic triterpenoid compound obtained by hydrolysis of glycyrrhizic acid, of which 18β-glycyrrhetinic acid is ...

Claims

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Application Information

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IPC IPC(8): C07J63/00C07J75/00A61K31/58A61P35/00A61P35/02
Inventor 赖宜生王振国申利红张奕华季晖叶小磊李月珍
Owner CHINA PHARM UNIV
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