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Nitrogen-heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application

A technology of glycyrrhetinic acid and its derivatives, applied in the field of medicine, can solve the problems of poor water solubility, large gap in anticancer activity, and low bioavailability

Active Publication Date: 2022-03-01
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 18β-glycyrrhetinic acid has poor water solubility and low bioavailability, and its anticancer activity is far behind the current clinically used anticancer drugs.

Method used

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  • Nitrogen-heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application
  • Nitrogen-heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application
  • Nitrogen-heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: Preparation of N-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-acyl)-4-piperidinylpiperidine

[0122] Step A: Preparation of 3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid

[0123]

[0124] Weigh 3.5g (7.48mmol) GA and dissolve it in 150mL DMSO, add 8.37g (30mmol) IBX, and stir at reflux at 85°C for 4h. Cool to room temperature, pour 300mL 5% NaHCO 3 In solution, a white solid precipitated out. Extracted with ether (150mL×3), combined organic layers, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 2.65g of white solid, yield: 76%. 1 H NMR (600MHz, DMSO-d 6 )δ12.21(1H,s),7.64(1H,d,J=10.2Hz),5.72(1H,d,J=10.8Hz),5.52(1H,s),2.73(1H,s),2.17~ 2.06(2H,m), 1.83~1.65(5H,m), 1.60~1.53(3H,m), 1.44~1.39(2H,m), 1.38(3H,s), 1.37~1.34(1H,m), 1.31(3H,s),1.29~1.25(1H,m),1.21~1.16(1H,m),1.11(3H,s),1.10(3H,s),1.07(3H,s),1.02(3H, s), 1.00~0.96(1H,m), 0.78(3H,s).

[0125]...

Embodiment 2

[0131] Example 2: Preparation of N-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-acyl)-piperazine

[0132] According to the preparation method of Example 1, the raw material anhydrous piperazine was used instead of the raw material 4-piperidinylpiperidine in Example 1 to prepare the title compound. Mp: 150-153℃. IR(KBr): 3424.4, 2951.7, 2867.5, 1655.9, 1628.6, 1457.8, 1412.5, 1384.9, 1319.7, 1212.6, 1099.8, 1024.2, 975.8. 1 H NMR (600MHz, DMSO-d 6 )δ8.43(1H,s),5.61(1H,s),3.52~3.41(4H,m),2.87(1H,s),2.69~2.59(4H,m),2.31~2.23(1H,m) ,2.17~2.09(1H,m),1.99~1.93(1H,m),1.88~1.82(1H,m),1.82~1.61(4H,m),1.59~1.50(2H,m),1.46~1.39( 2H,m),1.38(3H,s),1.37~1.33(2H,m),1.32(3H,s),1.26~1.22(1H,m),1.20~1.17(1H,m),1.16(3H, s), 1.11(3H, s), 1.08(3H, s), 1.07(3H, s), 1.01~0.96(1H, m), 0.75(3H, s). 13 C NMR (150MHz, DMSO-d 6 )δ198.7, 197.8, 173.3, 172.7, 170.7, 127.4, 100.5, 60.2, 54.7, 51.5, 48.4, 46.4, 45.5, 45.4, 43.9, 43.8, 43.4, 40.5, 37.9, 32.5, 31.9, 31.5, 26.6, 2.8, 2 ,23.0,22.4,20.5,19...

Embodiment 3

[0133] Example 3: Preparation of N-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)-morpholine

[0134] According to the preparation method of Example 1, the raw material morpholine was used instead of the raw material 4-piperidinylpiperidine in Example 1 to prepare the title compound. Mp: 302-304℃. IR(KBr): 3424.2, 2959.8, 2872.7, 1681.3, 1648.1, 1631.9, 1385.7, 1268.6, 1210.7, 1173.5, 1117.3, 1024.4, 975.5. 1 H NMR (600MHz, DMSO-d 6 )δ8.43(1H,s),5.62(1H,s),3.62~3.48(8H,m),2.86(1H,s),2.30~2.24(1H,m),2.18~2.09(1H,m) ,1.99~1.93(1H,m),1.88~1.82(1H,m),1.82~1.63(4H,m),1.59~1.40(4H,m),1.38(3H,s),1.37~1.33(2H, m), 1.32(3H,s), 1.28~1.23(1H,m), 1.17(3H,s), 1.11(3H,s), 1.08(3H,s), 1.07(3H,s), 1.02~0.96 (1H,m),0.76(3H,s). 13 C NMR (150MHz, DMSO-d 6 )δ 198.8, 197.8, 173.7, 172.6, 170.7, 127.4, 100.5, 66.8, 54.8, 51.5, 48.4, 45.5, 45.4, 43.9, 43.8, 43.6, 43.4, 37.8, 32.3, 31.9, 31.5, 28.8, 28.8, 2 ,23.0,22.4,20.4,19.0,18.3. HRMS m / z calcd for C 34 h 49 INO 4 + [M+H] + 662.2701...

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Abstract

The invention belongs to the technical field of medicine, and specifically relates to nitrogen-heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application, and also relates to nitrogen-heterocyclic-substituted 18β-glycyrrhetinic acid derivatives and their optical isomers and pharmaceutically acceptable Pharmaceutical compositions of the accepted salts, and their use in the manufacture of medicaments for the treatment and / or prevention of various cancers. The derivatives represented by the general formula I involved in the present invention, and their optical isomers and pharmaceutically acceptable salts have the following structure: wherein, X, Y, Z, m are as described in the claims and description.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and specifically relates to nitrogen heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their preparation and application, and also relates to nitrogen heterocyclic substituted 18β-glycyrrhetinic acid derivatives and their optical isomers and pharmaceutically acceptable Pharmaceutical compositions of the accepted salts, and their use in the manufacture of medicaments for the treatment and / or prevention of various cancers. Background technique: [0002] 18β-Glycyrrhetinic acid is the product of the hydrolysis of glycyrrhizic acid, the main component of licorice, to remove two molecules of glucuronic acid. It belongs to the oleanane-type pentacyclic triterpenoids and has a wide range of pharmacological activities. Among them, the antitumor effect of 18β-glycyrrhetinic acid has attracted much attention. However, 18β-glycyrrhetinic acid has poor water solubility and low bioavailabili...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61P35/00A61P35/02A61K31/58
CPCC07J63/008A61P35/00A61P35/02
Inventor 赵临襄刘丹黄敏唐煜龚萍王悦桐景永奎
Owner SHENYANG PHARMA UNIVERSITY