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New derivatives of berberine coupled with cholic acid at ninth position through ester bond and preparation methods thereof

A derivative, berberine technology, applied in the field of preparation of berberine derivatives, can solve the problems of low bioavailability, poor targeting, poor fat solubility, etc., achieve good fat solubility, maintain pharmacological activity, increase biological The effect of utilization

Inactive Publication Date: 2011-11-02
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a class of berberine derivatives that fully maintain the antitumor pharmacological activity of berberine, improve drug targeting, and solve the problems of poor fat solubility, poor targeting, and low bioavailability

Method used

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  • New derivatives of berberine coupled with cholic acid at ninth position through ester bond and preparation methods thereof
  • New derivatives of berberine coupled with cholic acid at ninth position through ester bond and preparation methods thereof
  • New derivatives of berberine coupled with cholic acid at ninth position through ester bond and preparation methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the synthesis of cholic acid-9-propoxy-berberine:

[0033] (1) Synthesis of Berberine

[0034] Add 744mg (2mmol) of berberine into a 250mL round bottom flask, heat at 195-210°C for 30min at a vacuum of 20-30mmHg, the yellow solid gradually turns dark red, cool to room temperature in a vacuum desiccator, and perform silica gel column chromatography Purified to obtain a dark red powder with a yield of 73%, molecular weight: 322, and the structure as follows:

[0035]

[0036] (2) Cholic acid-3-bromopropyl ester

[0037] Add 204 mg (0.5 mmol) of cholic acid into a 25 mL round bottom flask, add 1 mL of DMF to dissolve, add 200 μL of 1,3-dibromopropane, add K 2 CO 3 276mg (2mmol), TLC followed the reaction, after the reaction was complete, vacuum filtration, 50mL of chloroform was added to the filtrate, followed by 50mL of distilled water, 50mL of saturated NaHCO 3 Solution extraction 3 times, anhydrous MgSO 4 Dry, filter under reduced pressure to remo...

Embodiment 2

[0042] Embodiment 2: the synthesis of dehydrocholic acid-9-propoxyberberine: (B2)

[0043] (1) Synthesis of Berberine

[0044] Same as (1) in Example 1.

[0045] (2) Dehydrocholic acid-3-bromopropyl ester

[0046] Add 201 mg (0.5 mmol) of dehydrocholic acid into a 25 mL round bottom flask, add 1 mL of DMF to dissolve, add 200 μL of 1,3-dibromopropane, add K 2 CO 3 276mg (2mmol), TLC followed the reaction, after the reaction was complete, vacuum filtration, 50mL of chloroform was added to the filtrate, followed by 50mL of distilled water, 50mL of saturated NaHCO 3 Solution extraction 3 times, anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrated under reduced pressure, separated and purified by silica gel column chromatography to obtain a white powder with a yield of 95%; molecular weight: 522, and the structure is as follows:

[0047]

[0048] (3) Synthesis of dehydrocholic acid-9-propoxyberberine: (B2)

[0049] Add 161mg (0.5mmol) of berb...

Embodiment 3

[0051] Embodiment 3: the synthesis of deoxycholic acid-9-propoxyberberine: (B3)

[0052] (1) Synthesis of Berberine

[0053] Same as (1) in Example 1.

[0054] (2) Deoxycholic acid-3-bromopropyl ester

[0055] Add 201 mg (0.5 mmol) of dehydrocholic acid into a 25 mL round bottom flask, add 1 mL of DMF to dissolve, add 200 μL of 1,3-dibromopropane, add K 2 CO 3 276mg (2mmol), TLC followed the reaction, after the reaction was complete, vacuum filtration, 50mL of chloroform was added to the filtrate, followed by 50mL of distilled water, 50mL of saturated NaHCO 3 Solution extraction 3 times, anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrated under reduced pressure, separated and purified by silica gel column chromatography to obtain a white powder with a yield of 85%; molecular weight: 512, and the structure is as follows:

[0056]

[0057] (3) Synthesis of deoxycholic acid-9-propoxyberberine: (B3)

[0058] Add 161mg (0.5mmol) of berberine in...

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Abstract

The invention relates to new derivatives of berberine coupled with cholic acid at the ninth position through an ester bond with a general formula (I) and preparation methods thereof. The invention also relates to the preparation methods of compounds of the present invention, and an application of the compounds as drugs especially as the drugs for tumor treatment. R1 in the formula (I) is hydroxy and / or carbonyl; and R2 / R3 is hydrogen, hydroxy and / or carbonyl.

Description

technical field [0001] The invention relates to a preparation method of a class of berberine derivatives and their application in antitumor therapy. Background technique [0002] Since M.-E. Chavalier and G. Peltin first extracted berberine from the bark of Xanthoxylonclava in 1826, pharmacologists have found that berberine has a wide antibacterial spectrum and has the functions of lowering blood fat, blood sugar, Anti-peptic ulcer and other pharmacological effects. Coptis chinensis, Cortex Phellodendron, Sangezhen, etc. are commonly used in traditional Chinese medicine as heat-clearing and detoxifying drugs, the main ingredient of which is berberine. In 1966, the Japanese Pharmacopoeia collected berberine hydrochloride and berberine tannic acid for the treatment of intestinal infections. With in-depth research, Japanese scholars in the 1970s proposed that berberine and its derivatives have anti-tumor effects. In recent years, many researchers have actively invested in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/00
Inventor 李庆勇祖元刚何乌娜邱伟张宝友赵腾飞高文轻邓晓秋
Owner NORTHEAST FORESTRY UNIVERSITY
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