A new 18α-glycyrrhetinic acid derivative and its medical application

A technology of glycyrrhetinic acid and its derivatives, which is applied in the field of medicine and can solve problems such as limitations in clinical application

Active Publication Date: 2019-11-29
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the side effects of 18α-glycyrrhetinic acid are less than those of 18β-glycyrrhetinic acid, its clinical application is still very limited

Method used

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  • A new 18α-glycyrrhetinic acid derivative and its medical application
  • A new 18α-glycyrrhetinic acid derivative and its medical application
  • A new 18α-glycyrrhetinic acid derivative and its medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 8

[0044] Example 1 Synthesis and Crystal Form Preparation of 18α-Glycyrrhetinic Acid Choline Salt

[0045] Synthesis of 18α-ethyl glycyrrhetinate, the structure of which is shown in formula (II)

[0046] Add 2kg of 18α-diamine glycyrrhizinate into 11L of absolute ethanol, add dropwise 1L of acetyl chloride, after the dropwise addition is complete, heat and reflux for 2 hours. TLC detects that the reaction is complete. Evaporate to dryness, add 4L of dichloromethane to dissolve, wash with water, take the dichloromethane layer, evaporate to dryness, and refine with ethanol / water, yield: 70%.

[0047] Structural Confirmation:

[0048] (1)MS m / z[M+H] + : 499 quasi-molecular ion peaks and [M++H-H 2 O] + : The fragment ion peak of 481, so the molecular weight of this product is 482.

[0049] (2) NMR:

[0050] Testing unit: China Pharmaceutical University Analysis and Testing Center

[0051] Instrument: BRUKER AV-500 Nuclear Magnetic Resonance Apparatus

[0052] Solvent: CDCl ...

Embodiment 2 8

[0069] Example 2 Synthesis of 18α-sodium glycyrrhetinate

[0070] Synthesis of 18α-Ethyl Glycyrrhetinate

[0071] Add 2kg of 18α-diamine glycyrrhizinate into 11L of absolute ethanol, add dropwise 1L of acetyl chloride, after the dropwise addition is complete, heat and reflux for 2 hours. TLC detects that the reaction is complete. Evaporate to dryness, add 4L of dichloromethane to dissolve, wash with water, take the dichloromethane layer, evaporate to dryness, and refine with ethanol / water, yield: 70%.

[0072] Synthesis of 18α-glycyrrhetinic acid

[0073] Take 50g of ethyl 18α-glycyrrhetinate and add it into 450ml of ethanol, add 16g of sodium hydroxide, heat to reflux, and react for about 2 hours. Evaporate to dryness under reduced pressure, add 400ml of water, slowly add hydrochloric acid under stirring to adjust pH = 1-2, a white solid precipitates, and is filtered. Dry at 50°C for 5 hours and then at 80°C to obtain 44.3g. Yield 96.7%.

[0074] Synthesis of 18α-sodium...

Embodiment 3 8

[0076] Example 3 Synthesis of 18α-glycyrrhetinic acid arginine salt

[0077] Synthesis of 18α-Ethyl Glycyrrhetinate

[0078] Add 2kg of 18α-diamine glycyrrhizinate into 11L of absolute ethanol, add dropwise 1L of acetyl chloride, after the dropwise addition is complete, heat and reflux for 2 hours. TLC detects that the reaction is complete. Evaporate to dryness, add 4L of dichloromethane to dissolve, wash with water, take the dichloromethane layer, evaporate to dryness, and refine with ethanol / water, yield: 70%.

[0079] Synthesis of 18α-glycyrrhetinic acid

[0080] Take 50g of ethyl 18α-glycyrrhetinate and add it into 450ml of ethanol, add 16g of sodium hydroxide, heat to reflux, and react for about 2 hours. Evaporate to dryness under reduced pressure, add 400ml of water, slowly add hydrochloric acid under stirring to adjust pH = 1-2, a white solid precipitates, and is filtered. Dry at 50°C for 5 hours and then at 80°C to obtain 44.3g. Yield 96.7%.

[0081] Synthesis of...

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Abstract

The invention relates to a new 18α-glycyrrhetinic acid derivative and its medical application. The compound has weak inhibition on 11β-hydroxysteroid dehydrogenase, can effectively improve the adrenal cortex hormone-like adverse reactions of glycyrrhetinic acid drugs, and reduce the risk of water and sodium retention.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new 18α-glycyrrhetinic acid derivative and its medical application. Background technique [0002] Glycyrrhizin (GL) is an effective active ingredient extracted from licorice, which has various pharmacological effects such as anti-inflammatory, anti-allergic, and anti-biological oxidation. After research, glycyrrhizic acid is hydrolyzed by gastric acid or decomposed into glycyrrhetinic acid by β-glucuronidase in the liver, and then generates 3-epi-glycyrrhetinic acid and a small amount of 3-dehydroglycyrrhetinic acid in the enterohepatic circulation to produce pharmaceutical activity , so the effect of glycyrrhizic acid drugs is essentially the effect of glycyrrhetinic acid (Hao Fei, research progress of glycyrrhizic acid abroad, Chinese Pharmacy, 2001, 12 (8): 500-501). [0003] Glycyrrhizic acid is a pentacyclic triterpene saponin. Due to the difference in the co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61P1/16A61P31/14
CPCA61P1/16A61P31/14C07J63/008
Inventor 张喜全张爱明徐宏江董平周浩田心
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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