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Glycyrrhetinic acid cyclic phosphonate ester derivative and preparation method thereof

A technology of glycyrrhetinic acid and its products, which is applied in the field of glycyrrhetinic acid cyclic phosphate derivatives and its preparation, can solve problems such as difficulty in maintaining stable blood drug concentration and tissue drug concentration, affecting drug efficacy, and short half-life, achieving significant relief. release performance, improve drug efficacy, and facilitate synthesis

Inactive Publication Date: 2012-06-27
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, a common disadvantage of glycyrrhetinic acid compounds is that the metabolism in the body is too fast, the half-life is very short, and it is difficult to maintain a stable blood and tissue drug concentration, which affects the efficacy of this type of drug
In addition, the distribution of glycyrrhetinic acid in various organs in the body is highest in the lungs, while the concentration in the liver is relatively low, which also limits the application of such drugs in the treatment of liver diseases

Method used

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  • Glycyrrhetinic acid cyclic phosphonate ester derivative and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0013] Cis-3-O-[4-(R)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid methyl of the present invention Esters (i.e. R 1 is methyl, R 2 It is 3-chlorophenyl, and the 4-position of the phosphorus heterocyclic ring is a glycyrrhetinic acid cyclic phosphate derivative of R type) and cis-3-O-[4-(S)-(3-chlorophenyl)-2-oxo Generation-1,3,2-dioxaphosphorinyl]-18β-methyl glycyrrhetinate (ie R 1 is methyl, R 2 It is 3-chlorophenyl, and the 4-position of phosphorus heterocycle is the preparation of the glycyrrhetinic acid cyclic phosphate derivative of S type):

[0014] cis-3-O-[4-(R)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid methyl ester

[0015] Weigh 0.44g (0.906mmol) of methyl glycyrrhetinate, put it in a 25mL eggplant-shaped bottle, add 5mL of anhydrous tetrahydrofuran to dissolve, add 2mol / L of N,N-diisopropylamide lithium in tetrahydrofuran solution 2.3mL (4.6mmol), stirred at room temperature for 1h. Weigh the known trans...

Embodiment 2

[0024] Cis-3-O-[4-(R)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid ( i.e. R 1 for hydrogen, R 2 It is 3-chlorophenyl, and the 4-position of the phosphorus heterocyclic ring is a glycyrrhetinic acid cyclic phosphate derivative of R type) and cis-3-O-[4-(S)-(3-chlorophenyl)-2-oxo Generation-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid (i.e. R 1 for hydrogen, R 2 It is 3-chlorophenyl, and the 4-position of phosphorus heterocycle is the preparation of the glycyrrhetinic acid cyclic phosphate derivative of S type):

[0025] cis-3-O-[4-(R)-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid

[0026] Weigh 1.26g (2.68mmol) of glycyrrhetinic acid, put it in a 100mL eggplant-shaped bottle, add 30mL of anhydrous tetrahydrofuran to dissolve, add 2mol / L of N, N-diisopropylamide lithium tetrahydrofuran solution 6.7mL (13.4 mmol), stirred at room temperature for 2h. Weigh the known trans-4-(R)-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo...

Embodiment 3

[0039] The preparation of the glycyrrhetinic acid substituted by different substituents of the present invention:

[0040] cis-3-O-[4-(R)-phenyl-2-oxo-1,3,2-dioxaphosphorinyl]-18β-glycyrrhetinic acid

[0041] Starting from the known trans-4-(R)-phenyl-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane, instead of Trans-4-(R)-(3-chlorophenyl)-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorane in Example 2 Hexane was reacted, and other reaction reagents and experimental operations were the same as in Example 2 to obtain 0.82 g of a light yellow powder product, with a yield of 43.0%, a melting point greater than 200 ° C, and a specific rotation of +93.0 ° (c 1.000, CHCl 3 ). MS (ES + ): m / z=667.6[M+H + ].

[0042] The proton nuclear magnetic resonance spectrum, carbon spectrum and phosphorus spectrum data of the compound obtained are respectively: 1 H NMR (600MHz, CDCl 3 , only list the chemical shift value of characteristic hydrogen) δ: 7.41-7.34 (m, 5H), 5.71 (s, 1H), 5.41 (...

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Abstract

The invention discloses a glycyrrhetinic acid cyclic phosphonate ester derivative and a preparation method thereof. During preparation, 4-substituted product of trans-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane of phosphorous heterocyclic, which is substituted by different substituent groups, respectively generates an ester exchange reaction with glycyrrhetinic acid or glycyrrhetinic acid methyl ester under the catalysis of N,N-diisopropyl amino lithium to generate a phosphorous heterocyclic 4-position glycyrrhetinic acid cyclic phosphonate ester derivative substituted by different substituent groups. The glycyrrhetinic acid cyclic phosphonate ester derivative is convenient to synthesize. The in-vivo experiments of animals prove that the invention has obvious slow-release performance and liver targeting performance and antiviral and anti-tumor effects and has extensive application prospect in the aspects of prolonging the acting time of the glycyrrhetinic acid, enhancing the medicine effect and preventing or treating tumors and liver diseases.

Description

technical field [0001] The invention relates to a glycyrrhetinic acid cyclic phosphate derivative with sustained release effect, liver targeting effect and antitumor effect and a preparation method thereof. Background technique [0002] Glycyrrhetinic acid is widely distributed in nature, also known as glycyrrhetinic acid, which is the aglycon of glycyrrhizin, the active ingredient of licorice. Modern medical research shows that glycyrrhetinic acid has anti-inflammatory, anti-ulcer, anti-viral (hepatitis virus, HIV, SARS Viruses, etc.), anti-tumor, anti-allergic and many other effects, it has been used as an anti-inflammatory drug to treat various inflammations and skin diseases. However, a common disadvantage of glycyrrhetinic acid compounds is that the metabolism in the body is too fast, and the half-life is very short, which makes it difficult to maintain stable blood and tissue drug concentrations, which affects the efficacy of such drugs. In addition, the distribution ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/665A61P1/16A61P35/00
Inventor 江涛孙伟之李国强彭维兵
Owner OCEAN UNIV OF CHINA