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Hydrophilic berberine-type derivative with R<9> connected with R<10> and application of hydrophilic berberine-type derivative to medicine preparation

A technology of dihalomethyl berberine and R11, which is applied in the field of 8-dihalomethyl berberine type quaternary ammonium salt compounds, can solve the problems of poor solubility and toxicity, the stability of pharmacological action strength, chemical structure, and no Significantly improve druggability and other issues

Active Publication Date: 2019-10-25
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In summary, poor solubility is one of the main obstacles in the clinical application of imine-quaternized berberine-type quaternary ammonium compounds
The improvement of fat solubility helps to improve its pharmacological effects, but due to the problems of toxicity, strength of pharmacological effects, stability of chemical structure, etc., it has not significantly improved its druggability

Method used

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  • Hydrophilic berberine-type derivative with R&lt;9&gt; connected with R&lt;10&gt; and application of hydrophilic berberine-type derivative to medicine preparation
  • Hydrophilic berberine-type derivative with R&lt;9&gt; connected with R&lt;10&gt; and application of hydrophilic berberine-type derivative to medicine preparation
  • Hydrophilic berberine-type derivative with R&lt;9&gt; connected with R&lt;10&gt; and application of hydrophilic berberine-type derivative to medicine preparation

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preparation example Construction

[0107] The preparation process and structural identification data of the active compounds of the present invention, wherein the compound number corresponds to the specific compound number in the content of the present invention.

[0108] One, the preparation experiment example of compound of the present invention

experiment example (1

[0109] Experimental example (1) Preparation process and structure identification data of compound 1

[0110] Coptisine hydrochloride (2.0g, 5.62mmol) was dissolved in 200mL of chloroform-methanol (3:1) mixed solvent in the reaction flask, 24ml of concentrated ammonia was added, stirred and reacted at room temperature for 24h, then the chloroform layer was separated, and The chloroform layer was washed twice with water and washed with anhydrous MgSO 4 After drying, it was filtered; the filtrate was evaporated to dryness, and the resulting crude product was purified by silica gel column chromatography, eluting with dichloromethane, and the eluate was concentrated to obtain 617 mg of 8-trichloromethyldihydrocoptisine as a light yellow solid, with a yield of 25.0%. 1 H NMR (500MHz, CDCl 3 )δ:2.63–2.78(m,1H,NCH 2 C H 2 ),3.35(m,1H,NCH 2 C H 2 ),3.71(m,1H,NC H 2 CH 2 ),3.78-3.90(m,1H,NC H 2 CH 2 ),5.42(s,1H,CH-CCl 3 ),5.91(br,1H,OCH 2 O),5.95(br,2H,OCH 2 O),6.02(br,2...

experiment example (2

[0111] Experimental example (2) Preparation process and structure identification data of compound 3

[0112] Dissolve berberine hydrochloride (2.0g, 5.38mmol) in 60ml chloroform in a reaction flask, add 24ml of concentrated ammonia water, stir and react at room temperature for 24h, then separate the chloroform layer, wash the chloroform solution with water twice, and wash with Anhydrous MgSO 4 After drying the chloroform solution, filter it, and evaporate the filtrate to dryness to obtain a residue; the residue is separated and purified by silica gel column chromatography, eluted with dichloromethane, and the eluent is evaporated to dryness to obtain 8-trichloromethyldihydroberberis The base is 1.775 g of light yellow solid, the yield is 78.9%. 1 H NMR (500MHz, CDCl 3 )δ: 2.73 (d, J=15.5Hz, 1H, NCH 2 C H 2 ),3.33(m,1H,NCH 2 C H 2 ),3.71(m,1H,NC H 2 CH 2 ),3.87(ov,4H,ArOCH 3 ,NC H 2 CH 2 ),3.94(s,3H,ArOCH 3 ),5.65(s,1H,CH-CCl 3 ),5.94(s,2H,OCH 2 O),6.08(br s,1...

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Abstract

The invention discloses a 8-dihalomethyl berberine-type quaternary ammonium salt compound as shown in formulas I and II and a synthesis method and application to medicine preparation thereof. The 8-dihalomethyl berberine-type compound shows more pronounced hydrophilicity in the absence of a conventional hydrophilic group compared with a substrate; the 8-dihalomethyl berberine-type compound has significant antimicrobial activity, anti-inflammatory activity, anti-ulcerative colitis activity and anti-tumor activity; and clear and significant regulatory effects are shown in tumorigenesis related target molecules in tumor cells of colon cancer, liver cancer, lung cancer, breast cancer, osteosarcoma and glioma, and the significant anti-tumor activity is achieved. The 8-dihalomethyl berberine-type quaternary ammonium salt compound has higher pharmacological action intensity than control drugs, has the characteristic of no toxicity or low toxicity, and can be used for preparing medicine for preventing, alleviating and / or treating microbial infection, inflammation, the ulcerative colitis and the tumors. (Please see the specification for the formulas)

Description

technical field [0001] The present invention relates to the 8-dihalomethyl berberine type with low toxicity or non-toxic hydrophilic imine type quaternized ammonium salt synthesized from naturally occurring berberine type alkaloid quaternary ammonium salt substrates Quaternary ammonium salt compound, preparation method of the compound of the present invention, anti-tumor, anti-microbial infection, anti-inflammatory and anti-ulcerative colitis pharmacological activities of the compound of the present invention. Compared with the natural berberine type alkaloid quaternary ammonium salt substrate, the compound of the present invention has obvious hydrophilicity. The pharmacological activity screening experiment carried out to the compound of the present invention proves that the 8-dihalomethyl berberine type quaternary ammonium salt compound of the imine type quaternary ammonium salt of the present invention has significant antitumor, antimicrobial infection, anti-inflammatory an...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P31/04A61P31/10A61P29/00A61P1/00A61P35/00A61K8/49A61Q19/00A23L33/00
CPCC07D455/03A61P31/04A61P31/10A61P29/00A61P1/00A61P35/00A61K8/4926A61Q19/00A23L33/00A23V2002/00A23V2200/308A23V2200/30A23L33/10A61P1/04C07D493/14C07D493/22
Inventor 秦海林吴练秋李想张海婧宋利宋华琛邓安珺唐晓楠张志辉李志宏
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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