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r 10 with r 11 Linked hydrophilic berberine derivatives and their application in the preparation of medicines

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

Active Publication Date: 2021-03-30
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, poor solubility is one of the main obstacles to 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, the strength of pharmacological effects, and the stability of chemical structures, etc., it does not significantly improve its druggability

Method used

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  • r <sub>10</sub> with r <sub>11</sub> Linked hydrophilic berberine derivatives and their application in the preparation of medicines
  • r <sub>10</sub> with r <sub>11</sub> Linked hydrophilic berberine derivatives and their application in the preparation of medicines
  • r <sub>10</sub> with r <sub>11</sub> Linked hydrophilic berberine derivatives and their application in the preparation of medicines

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preparation example Construction

[0101]The preparation process and structure identification data of the active compound of the present invention, wherein the compound number corresponds to a particular compound number in the content of the present invention.

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

experiment example (1

[0103]Experimental example (1) Preparation process and structural identification data of Compound 2

[0104]Isorgectate hydrochloride (1.0 g, 2.81 mmol) is dissolved in the reaction bottle of 80 ml of chloroform, and the ice wants to add NaH (450 mg, 18.75 mmol), and the temperature is stirred up to room temperature and stirred after 24 h after 2. Concentrate reaction liquid. The residue was obtained; ethyl acetate was added before the residue was added, and then the amount of pure water was added, extracted 3 times with ethyl acetate, combined with ethyl acetate extract, with anhydrous MgSO4Dry, filtration, evaporation of the filtrate, the resulting crude product was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3 / 1, v / v), eluent moiety was concentrated to be 8-trichloromethyl dihydrogen The isoaline alkaline yellow solid 995 mg, yield 80.7%.1H NMR (500MHz, CDCL3) δ: 2.68 (D, J = 15.5 Hz, 1H, NCH2CH2), 3.35-3.40 (m, 1H, NCH2CH2), 3.70 (t...

experiment example (2

[0105]Experimental Example (2) Preparation Process and Structural Identification Data of Compound 4

[0106]The Bamatine hydrochloride (5.0 g, 12.9 mmol) was referred to, 200 ml of chloroform in the reaction flask, 30 ml of concentrated ammonia water was further added; after stirring at room temperature, the chloroform layer was purified, and the chloroform solution was washed 2 times with water. Anhydrous MGSO4Dry, filtration; purified the crude film after the filtrate was purified by silica gel column chromatography, eluting with dichloromethane, evaporated. 74.9%.1H NMR (500MHz, CDCL3) δ: 2.76 (d, j = 15.5 Hz, 1H, NCH2CH2), 3.42 (m, 1H, NCH2CH2), 3.77 (m, 1H, NCH2CH2), 3.88 (Br OV, 4H, NCH2CH2Aroch3), 3.90 (s, 3h, aroch3), 3.948 (s, 3h, aroch3), 3.953 (s, 3h, aroch3), 5.66 (S, 1H, CH-CCL3), 6.12 (S, 1H, C = CH), 6.65 (S, 1H, ARH), 6.92 (D, J = 8.5 Hz, 1H, ARH), 6.99 (D, J = 8.5 Hz, 1H, ARH), 7.22 (S, 1H, ARH). 8-trichloromethyl dihydrohydrotamine (1.0 g, 2.12 mmol) is dissolved in a...

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Abstract

The invention discloses 8-dihalomethyl berberine type quaternary ammonium salt compounds represented by general formulas I and II, its synthesis method and its application in the preparation of medicines. Compared with the substrate, the 8-dihalomethyl berberine type compound shows more obvious hydrophilicity without conventional hydrophilic groups; the 8-dihalomethyl berberine-type compound is small Berine-type compounds have significant antimicrobial activity, anti-inflammatory activity and anti-ulcerative colitis activity; target molecules related to tumorigenesis in colon cancer, liver cancer, lung cancer, breast cancer, osteosarcoma and glioma tumor cells It shows a clear and significant regulatory effect and has anti-tumor activity. The pharmacological action intensity of the compound of the invention is higher than that of the control drug, and has the characteristics of no toxicity or low toxicity, and can be used to prepare drugs for preventing, alleviating and / or treating microbial infection, inflammation, ulcerative colitis and tumors.

Description

Technical field[0001]The present invention relates to low toxicity or non-toxic hydrophilic imine-type quaternary ammonium salt-based 8-dihydrogen-based berberine-based samples synthesized in naturally occurring berberine alkaline alkaline quaternary ammonium salt substrates. Quaternary ammonium salt compound, preparation method of the compound of the present invention, anti-tumor, antimicrobial infection, anti-inflammatory and anti-ulcer colitis of the compounds of the invention. Pharmacological activity of anti-ulcer colitis. The compounds of the invention have significant hydrophilicity compared to natural berberine alkaline quaternary ammonium salt substrates. The pharmacological active screening of the compounds of the invention demonstrates the amine-type quaternary ammonium salt-type quaternary ammonium salt compound of the present invention with significant anti-tumor, anti-microbial infection, anti-inflammatory and anti-inflammatory Ulcerative colitis activity, and also hav...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 CHINESE ACAD OF MEDICAL SCI
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