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Glycyrrhetinic acid derivatives and preparation method, medicinal composition and application thereof to preparation of antitumor drug

A technology of glycyrrhetinic acid and glycyrrhetinic acid ester, which is applied in the field of compounds and can solve the problems of weak anti-tumor activity of glycyrrhetinic acid

Inactive Publication Date: 2012-04-04
JIANGSU INST OF NUCLEAR MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the antitumor activity of glycyrrhetinic acid is relatively weak. In order to further improve the antitumor activity of glycyrrhetinic acid, it is necessary to modify and transform the chemical structure of glycyrrhetinic acid to obtain GA derivatives with better activity.

Method used

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  • Glycyrrhetinic acid derivatives and preparation method, medicinal composition and application thereof to preparation of antitumor drug
  • Glycyrrhetinic acid derivatives and preparation method, medicinal composition and application thereof to preparation of antitumor drug
  • Glycyrrhetinic acid derivatives and preparation method, medicinal composition and application thereof to preparation of antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0028] Preparation of 3-{[(5-methylthio-1,3,4-thiadiazole-2)amino]-1,4-dioxobutoxy}glycyrrhetinic acid methyl ester.

[0029] a), Preparation of 2-amino-5-methylmercapto-1,3,4-thiadiazole.

[0030] Weigh 2.0g (14mmoL) of 2-mercapto-5-amino-1,3,4-thiadiazole, add 20 mL of anhydrous dimethylformamide (DMF), then add 2.76g of anhydrous K 2 CO 3 , stirred at room temperature for 10 min, finally added 2.82g (20mmoL) methyl iodide, continued the reaction for 4h, stopped the reaction, poured the reaction solution into 50ml of ice water, and left it overnight, a white solid precipitated, suction filtered, and the filter cake was weighed with absolute ethanol Crystallized to obtain 1.91g of white crystals, yield 93%, mp: 158-160°C.

[0031] b) Preparation of methyl 3-O-succinic acid monoacylglycyrrhetinate.

[0032] Add 0.96g (2.00mmol) methyl glycyrrhetinate, 0.40g (4.00mmol) succinic anhydride, 0.048g (4.00mmol) 2-aminopyridine (DMAP) into 50ml of anhydrous dichloromethane, stir a...

preparation Embodiment 2

[0036] Preparation of 3-{[(5-ethylthio-1,3,4-thiadiazole-2)amino]-1,4-dioxobutoxy}glycyrrhetinic acid methyl ester.

[0037] a), Preparation of 2-amino-5-ethylmercapto-1,3,4-thiadiazole.

[0038] Referring to the preparation method of step a in Preparation Example 1, it is prepared by reacting bromoethane with 2-mercapto-5-amino-1,3,4-thiadiazole, white solid, yield 88%, mp: 152~ 154°C.

[0039] b), Preparation of 3-O-succinic acid monoacyl glycyrrhetinate methyl ester.

[0040] The difference between the preparation method of this step and the preparation method of step b in Preparation Example 1 is that the reaction solution is concentrated under reduced pressure and then recrystallized with water, and the rest are the same.

[0041] c), Preparation of 3-{[(5-ethylthio-1,3,4-thiadiazole-2)amino]-1,4-dioxobutoxy}glycyrrhetinic acid methyl ester

[0042] Referring to the preparation method of step c in Preparation Example 1, the 2-amino-5-ethylmercapto-1,3,4 prepared fro...

preparation Embodiment 3

[0044] 3-{[(5-(tert-butoxy-carbonyl-methylthio)-1,3,4-thiadiazole-2)amino]-1,4-dioxobutoxy}glycyrrhetinic acid A Esters (I 3 ) preparation.

[0045] a), Preparation of 2-amino-5-(tert-butoxycarbonylmethylthio)-1,3,4-thiadiazole.

[0046] Referring to the preparation method of step a in Preparation Example 1, it was prepared by reacting tert-butyl bromoacetate with 2-mercapto-5-amino-1,3,4-thiadiazole, white solid, yield 45%, mp: 105-107°C.

[0047] b), Preparation of 3-O-succinic acid monoacyl glycyrrhetinate methyl ester.

[0048] The preparation method of this step is the same as the preparation method of step b in Preparation Example 1.

[0049] c), 3-{[(5-(tert-butoxy-carbonyl-methylthio)-1,3,4-thiadiazole-2)amino]-1,4-dioxobutoxy}licorice Methyl hypochlorite (I 3 ) preparation.

[0050] Referring to the preparation method of step c in Preparation Example 1, the 2-amino-5-(tert-butoxycarbonylmethylthio) prepared in step a of 3-O-succinic acid monoacyl glycyrrhetinat...

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Abstract

The invention provides glycyrrhetinic acid derivatives and medically acceptable salt thereof in a general formula (I) and a general formula (II). In the general formulas (I) and (II), R1 represents H, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, alcyl alkyl, heterocycle alkyl, aryl, ceteroary, monosaccharide or polysaccharide, amino acid and polypeptide residue; R2 represents H, CH3, CH2CH3 or CH(CH3)2; R3 represents H, CH3CO, C2H5CO, C3H7CO, CF3CO and C6H5CO; and the salt comprises hydrochloride, hydrobromide, phosphate, lactate, tartrate, salicylate, sulfate, oxalate, acetate, succinate, maleate, malate, gluconate, toluenesulfonate, citrate, fumarate, formate and phenpropionate. The invention also provides a preparation method, a medicinal composition and application of the glycyrrhetinic acid derivatives. The glycyrrhetinic acid derivatives have a good anticancer effect.

Description

technical field [0001] The invention belongs to the field of compounds, and in particular relates to a glycyrrhetinic acid derivative, its preparation method, its pharmaceutical composition and its application in the preparation of antitumor drugs. Background technique [0002] Glycyrrhetinic acid (GA) is an important active ingredient in traditional Chinese herbal medicine licorice to exert its pharmacological effects. GA can inhibit the proliferation of leukemia, liver cancer, colon cancer, gastric cancer, breast cancer, cervical cancer and other tumor cells in vitro. Studies have shown that GA can inhibit cell mitosis, make it stagnate in G1 phase, and induce tumor cell apoptosis, which can be used as an effective antitumor drug against various tumor lines (Nabekura T, Yamaki T, Uenok, et al Cancer Chemother Pharmacol, 2008, 62(5): 254-257). However, the antitumor activity of glycyrrhetinic acid is relatively weak. In order to further improve the antitumor activity of ...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P35/00A61P35/02
Inventor 王涛李倩倩
Owner JIANGSU INST OF NUCLEAR MEDICINE
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