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8-dihalo methylene dihydroberberine compound and anti-infection and anti-inflammatory application thereof

A technology of dihalomethylene dihydroberberine and compound is applied in the application field of preparing anti-microbial infection and anti-inflammatory products, and can solve the problems of structural change, chemical structure instability, influence on pharmacological action and the like

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

AI Technical Summary

Problems solved by technology

[0006] Published data show that derivatives of various parent unsubstituted dihydroberberine structures and derivatives of dihydroberberine structures substituted with an acetonyl group at the 8-position have clear and significant anti-ulcerative colitis activity , but there is an unstable chemical structure, and structural changes are likely to occur in a variety of solvents, thus affecting pharmacological effects

Method used

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  • 8-dihalo methylene dihydroberberine compound and anti-infection and anti-inflammatory application thereof
  • 8-dihalo methylene dihydroberberine compound and anti-infection and anti-inflammatory application thereof
  • 8-dihalo methylene dihydroberberine compound and anti-infection and anti-inflammatory application thereof

Examples

Experimental program
Comparison scheme
Effect test

experiment example (1

[0046] Experimental example (1) Preparation process and structure identification data of compound 1

[0047] 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

[0048] Experimental example (2) Preparation process and structural identification data of compound 2

[0049] 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 the reaction 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=15.5Hz, 1H, NCH 2 C H 2 ),3.35-3.40(m,1H,NCH 2 C H 2 ), 3.70 (t, J=8...

experiment example (3

[0050] Experimental example (3) Preparation process and structure identification data of compound 3

[0051] 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 an 8-dihalo methylene dihydroberberine compound and anti-infection and anti-inflammatory application thereof, and specifically relates to the 8-dihalo methylene dihydroberberine compound shown as the general formula I and physiologically acceptable salt, a synthetic method and application in preparation of a product to prevent, relieve and / or treat microbial infections andinflammation of the 8-dihalo methylene dihydroberberine compound. Compared with a berberine alkaloid quaternary ammonium salt substrate, the 8-dihalo methylene dihydroberberine compound shows significantly enhanced antibacterial activity to gram-positive bacteria and fungus; and pharmacological activity intensity of the 8-dihalo methylene dihydroberberine compound is obviously higher than that ofa control drug, and the 8-dihalo methylene dihydroberberine compound has the advantages of non-toxicity or low toxicity at the same time and can be used for preparing the product to prevent, relieve and / or treat the microbial infections and inflammation.

Description

technical field [0001] The present invention relates to a class of 8-dihalogenomethylene dihydroberberine derivatives obtained through derivatization reaction using various naturally occurring berberine quaternary ammonium salt compounds as substrates or physiologically acceptable The salt of , its preparation method and its application in the preparation of antimicrobial infection and anti-inflammatory products. It belongs to the field of medical technology. Background technique [0002] Antimicrobial (or called antibacterial) infection drugs are the first large class of drugs used clinically. There are many antibacterial drugs commonly used clinically, including β-lactams, aminoglycosides, macrolides, quinolones, and tetracyclines. However, due to the well-known overuse of antibacterial drugs, bacterial resistance has increased year by year, resulting in such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), vanc...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61K8/49A61Q19/00A61P31/04A61P31/10A61P29/00A23L33/10
CPCA23V2002/00A61K8/4926A61Q19/00A23L33/10A61P29/00A61P31/04A61P31/10C07D455/03A23V2200/30A23V2250/30
Inventor 秦海林吴练秋李想张海婧宋利宋华琛张志辉唐晓楠邓安珺李志宏
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI