Ketene-bridged berberine azole derivatives and preparation method and application thereof

A technology of azole derivatives and enone bridging, which is applied in the chemical field, can solve the problems of poor tolerance and curative effect, many times of medication for patients, and low bioavailability, so as to achieve easy availability of raw materials, solve drug resistance, The effect of simple preparation method

Active Publication Date: 2017-05-31
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, berberine has a large conjugated group, and its solubility in water is small, so it has disadvantages such as poor absorption, low bioavailability, many times of medication, poor tolerance and curative effect when it is directly used in clinical practice.

Method used

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  • Ketene-bridged berberine azole derivatives and preparation method and application thereof
  • Ketene-bridged berberine azole derivatives and preparation method and application thereof
  • Ketene-bridged berberine azole derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1, the preparation of intermediate X

[0055]

[0056] In a 100mL round bottom flask, dissolve compound IX (2.0g, 6.1mmol) and hexamethylenetetramine (1.0g, 7.4mmol) in an appropriate amount of trifluoroacetic acid, stir at reflux for 5 hours, and then add 10% sulfuric acid solution 40mL, keep stirring at 90°C, track the reaction by thin-layer chromatography until the end of the reaction, cool to room temperature, neutralize with sodium bicarbonate, add ethyl acetate for extraction, then concentrate and dry to obtain 1.77g of intermediate X, the yield is 82.1% .

[0057] Intermediate X: brown powder; melting point 242–244°C; 1 H NMR (600MHz, DMSO-d 6 )δ: 10.12(s,1H,CHO),9.93(s,1H,OH),7.33(s,1H,berberrubine-11-H),6.99(s,1H,berberrubine-1-H),6.68(s ,1H,berberrubine-4-H),5.96(d,J=8.7Hz,2H,OCH 2 O), 4.06–4.01 (m, 1H, berberrubine-8-H), 3.96 (dd, J=16.8, 3.1Hz, 1H, berberrubine-13-H), 3.86 (s, 3H, OCH 3 ), 3.39 (d, J = 11.1Hz, 1H, chiral-H), 3.30 (d, J = 1...

Embodiment 2

[0058] Embodiment 2, the preparation of azole compounds XV and XVI

[0059]

[0060] Reference "Yin B T, Yan C Y, Peng X M, Zhang S L, Rasheed S, Geng R X, Zhou CHe. Synthesis and biological evaluation of α-triazolyl chalcones as a new type of potential antimicrobial agents and their interaction with calf thymus DNA and human serum albumin. Eur.J.Med.Chem., 2014,71,148-159 "method described in preparation. Obtain 0.69g azole compound XV (X 1 with X 3 Both are F, X 2 for H, R 6 for CH 3 ), yield 23.0%. Obtain 0.69g azole compound XVI (X 1 with X 3 Both are F, X 2 for H, R 6 for CH 3 ), yield 23.0%.

[0061] Azole compound XV: yellow powder; melting point 101–102°C; 1 H NMR (600MHz, DMSO-d 6 )δ: 8.05 (dd, J = 15.3, 8.5Hz, 1H, Ph-3-H), 7.54 (dd, J = 15.1, 5.6Hz, 1H, Ph-5-H), 7.34–7.30 (m, 1H , Ph-6-H), 6.33 (d, J=2.4Hz, 2H, CH 2 ),2.50(s,3H,CH 3 )ppm.

[0062] Azole compound XVI: yellow powder; melting point 76–77°C; 1 H NMR (600MHz, DMSO-d 6 )δ: 8.07(dd, J=...

Embodiment 3

[0063] Embodiment 3, preparation of berberine azole derivatives I-1 of enone bridge

[0064]

[0065] In a 100mL round bottom flask, add intermediate X (1.9g, 5.4mmol), the azole compound (X 1 with X 3 Both are F, X 2 , R 1 with R 2 Both are H) (1g, 4.5mmol), glacial acetic acid (1.0mL) and an appropriate amount of 1,4-dioxane, the temperature is controlled at 100°C and the reaction is stirred, followed by TLC until the end of the reaction, cooled to room temperature, and then concentrated , extraction, separation by column chromatography, and drying to obtain 0.69 g of compound I-1, with a yield of 23.3%.

[0066] Compound I-1: yellow powder; melting point 220–221°C; 1 H NMR (600MHz, DMSO-d 6 )δ: 9.64(s,1H,OH),7.87(dd,J=14.9,8.2Hz,1H,Ph-3-H),7.73(s,1H,enone-H),7.63(s,1H,imidazole -2-H), 7.38(td, J=9.9, 2.2Hz, 1H, Ph-5-H), 7.23–7.20(m, 2H, Ph-6-H, imidazole-5-H), 7.11(s ,1H,imidazole-4-H),6.87(s,1H,berberrubine-1-H),6.68(s,1H,berberrubine-4-H),6.01(s,1H,OCHO),5.97(s...

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Abstract

The invention discloses ketene-bridged berberine azole derivatives with structures in general formulas I-VII and medicinal salts thereof. The compounds have certain inhibitory activity on gram positive bacteria, gram negative bacteria and fungi, can be used for preparing antibacterial/antifungal drugs, and can also be used for preparing DNA- cleavage agents and intercalators. The preparation raw materials are high in commercial degree and are cheap and available, the preparation route is short, and the method is simple and convenient. The general formulas are as shown in the specification.

Description

technical field [0001] The invention belongs to the field of chemistry, relates to a new class of organic compound, and also relates to the preparation method and application of the compound. Background technique [0002] Natural berberine is a kind of quaternary ammonium isoquinoline alkaloid with condensed ring aromatic hydrocarbon structure, and its unique fused ring aromatic hydrocarbon structure and positive and negative ion centers are easy to pass through static electricity, hydrogen bonds, π-π stacking, hydrophobic interactions, etc. This kind of non-covalent bond interacts with many enzymes, proteins and other active sites in organisms, thus exhibiting a variety of biological activities. In recent years, berberine compounds have attracted much attention because of their long antibacterial history and the outstanding ability of no drug-resistant bacteria, showing great development value. However, berberine has a large conjugated group and low solubility in water. It...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61K31/4375A61P31/04A61P31/10
CPCC07D455/03Y02A50/30
Inventor 周成合玛尼·杰克库玛高巍伟程宇张国彪坦咖丹初·维加库玛·瑞迪
Owner SOUTHWEST UNIVERSITY
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