Berberine derivative as well as preparation method and application thereof

A technology of compounds and mixtures, applied in the field of derivatives of natural product berberine, can solve problems such as limited anticancer activity

Active Publication Date: 2021-04-20
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the research on the 9-position modification of BBR to improve its

Method used

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  • Berberine derivative as well as preparation method and application thereof
  • Berberine derivative as well as preparation method and application thereof
  • Berberine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0061] The preparation of intermediates 1-4 has been reported and can be prepared by a relatively simple method.

[0062]

[0063] Specifically, the following steps are included:

[0064] (1) Commercial or self-made substituted pentadecyl acid 1 generates the corresponding acid chloride under the condition of oxalyl chloride;

[0065] (2) The intermediate acid chloride 6 is condensed with berbererythine to generate differently substituted compounds I-I;

[0066] (3) intermediate acid chloride 6 and intermediate 4 are condensed to generate amides compound I-II;

[0067] (4) condensation of different substituted pentadecyl halides and berberine to generate ether compounds I-III;

[0068] in,

[0069] In the step (1), the solvent used for the reaction with oxalyl chloride is selected from solvents such as dichloromethane; the reaction temperature is 0°C;

[0070] The solvent used for the condensation reaction described in step (2) is selected from acetonitrile; the reactio...

Embodiment 1

[0091]

[0092] Synthesis of Intermediate 5: The starting material ETC-1002 (1eq, 0.96mmol) was dissolved in dichloromethane, and Dess-Martin oxidant (2eq, 1.92mmol) was added at 0°C, stirred at room temperature for 1 hour, and the reaction was monitored by TLC completely. Quenched by saturated sodium thiosulfate solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=25:1) to obtain the product intermediate 5 (0.82 mmol, 86%): 1 H NMR (300MHz, CDCl 3 )δ2.36 (t, J=6.0Hz, 4H), 1.61-1.44 (m, 8H), 1.27-1.23 (m, 8H), 1.16 (s, 12H). ESI-MS (m / z): [ M+Na] + ,365.2.

[0093] Synthesis of Intermediate 6: At 0°C, oxalyl chloride (2.46mmol, 3eq) was added dropwise to anhydrous dichloromethane solution of Intermediate 5 (0.82mmol, 1eq), and then a catalytic amount of DMF was added. The mixed solution was raised to room temperature and stirred fo...

Embodiment 2

[0101] The synthesis of embodiment 2 compound B3

[0102]

[0103] Reagent 13 (0.83mmol, 1eq) was dissolved in anhydrous dichloromethane, oxalyl chloride (1.65mmol, 2eq) and a catalytic amount of DMF were added dropwise at 0°C, and stirred at room temperature for 2h. The reaction solution was concentrated under reduced pressure, and the anhydrous acetonitrile solution of the crude product was added dropwise to the anhydrous acetonitrile solution of intermediate 1 (0.83 mmol, 1 eq), and the temperature was raised to reflux and stirred overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH=15:1) to obtain compound B3 (0.50 mmol, 60%): 1 H NMR (400MHz, CD3OD) δ9.71(s, 1H), 8.82(s, 1H), 8.22(dd, J=13.6, 9.6Hz, 2H), 7.69(s, 1H), 6.97(s, 1H) ,6.12(s,2H),4.94(t,J=6.4Hz,2H),4.08(s,3H),3.27(d,J=6.4Hz,2H),2.86(t,J=7.2Hz,2H) ,1.88-1.80(m,2H),1.53(s,2H),1.33-1.30(m,20H),0.90(t,J=6.0Hz,3H). 13 C ...

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Abstract

The invention discloses a berberine derivative as well as a preparation method and application thereof. The structure of the berberine derivative is shown as a formula I, and definitions of substituent groups are shown in the specification and claims. The berberine derivative disclosed by the invention has antitumor activity and can be used for treating cancers such as lung cancer and the like.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and relates to a series of derivatives having the structure of natural product berberine and their preparation methods and applications. More specifically, the present invention relates to derivatives of natural product berberine, their preparation methods and Use of tumor compounds in the treatment of cancer such as lung cancer. Background technique [0002] Berberine (BBR) is an isoquinoline class IV alkaloid isolated from Coptis chinensis. It has been used as an over-the-counter drug to treat diarrhea in my country for decades, with good safety. It has been reported in many studies that BBR has various pharmacological effects, including antidiarrheal, antibacterial, anti-inflammatory, antidiabetic, and antihyperlipidemic effects. In particular, some recent studies have shown that BBR has inhibitory effects on a variety of tumors, including lymphoma, breast cancer, colon cancer, live...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P35/00
Inventor 南发俊李静雅刘艺朱可欣陈林海谢治富
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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