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Hydrophilic berberine type derivative connected with R10 and R11 and application of hydrophilic berberine type derivative to preparation of drugs

A technology of R11 and dihalomethyl berberine, 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 the pharmacological action, the strength of the chemical structure, and the absence of 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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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] 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 connected with R10 and R11 and application of hydrophilic berberine type derivative to preparation of drugs
  • Hydrophilic berberine type derivative connected with R10 and R11 and application of hydrophilic berberine type derivative to preparation of drugs
  • Hydrophilic berberine type derivative connected with R10 and R11 and application of hydrophilic berberine type derivative to preparation of drugs

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preparation example Construction

[0101] 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.

[0102] One, the preparation experiment example of compound of the present invention

experiment example (1

[0103] Experimental example (1) Preparation process and structure identification data of compound 2

[0104] Dissolve isotropine hydrochloride (1.0g, 2.81mmol) in 80ml of chloroform in a reaction flask, add NaH (450mg, 18.75mmol) under ice, slowly warm up to room temperature and stir for 24h, then concentrate the reaction solution under reduced pressure to Obtain a residue; first add ethyl acetate to the residue, then add an appropriate amount of pure water, extract 3 times with ethyl acetate, combine the ethyl acetate extracts, and use anhydrous MgSO 4 Dry, filter, and evaporate the filtrate to dryness. The resulting crude product is purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3 / 1, v / v), and the eluted part is concentrated to obtain 8-trichloromethyldihydro 995 mg of isotropine yellow solid, yield 80.7%. 1 HNMR (500MHz, CDCl 3 )δ: 2.68 (d, J = 15.5 Hz, 1H, NCH 2 C H 2 ),3.35-3.40(m,1H,NCH 2 C H 2 ), 3.70(t, J=8.5Hz, 1H, NC...

experiment example (2

[0105] Experimental example (2) Preparation process and structure identification data of compound 4

[0106] Take palmatine hydrochloride (5.0g, 12.9mmol) and dissolve in 200ml chloroform in the reaction flask, further add concentrated ammonia water 30ml; Stir and react at room temperature after 24h, separate the chloroform layer, wash the chloroform solution with water for 2 times, with anhydrous MgSO 4 Dry and filter; the crude product after the filtrate was evaporated to dryness was purified by silica gel column chromatography, eluted with dichloromethane, and the eluate was evaporated to dryness to give 4.545 g of 8-trichloromethyldihydropalmatine as a pale yellow solid, the yield 74.9%. 1 H NMR (500MHz, CDCl 3 )δ: 2.76 (d, J=15.5Hz, 1H, NCH 2 C H 2 ),3.42(m,1H,NCH 2 C H 2 ), 3.77(m,1H,NC H 2 CH 2 ), 3.88 (br ov, 4H, NC H2 CH 2 ,ArOCH 3 ),3.90(s,3H, ArOCH 3 ),3.948(s,3H,ArOCH 3 ),3.953(s,3H,ArOCH 3 ),5.66(s,1H, CH-CCl 3 ),6.12(s,1H,C=CH),6.65(s,1H,ArH),6....

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Abstract

The invention discloses a 8-dihalogenated methyl berberine type quaternary ammonium salt compound and a synthesis method thereof and application of the 8-dihalogenated methyl berberine type quaternaryammonium salt compound to drug preparation. Compared with a substrate, the 8-dihalogenated methyl berberine type compound shows the more obvious hydrophilicity without containing conventional hydrophilic groups, the 8-dihalogenated methyl berberine type compound has the significant anti-microbial activity, the anti-inflammatory activity and the anti-ulcerative colitis activity, the clear and significant regulatory effect on target molecules related to tumorigenesis in tumor cells of colon cancer, liver cancer, lung cancer, breast cancer, osteosarcoma and glioma, and the anti-tumor activity isachieved; and the pharmacological action intensity of the compound is higher than that of a contrast drug, and the compound has the characteristics of non-toxicity or low toxicity, and can be used for preparing drugs of preventing, relieving and / or treating microbial infection, inflammation, ulcerative colitis and tumors.

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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