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Berberine azole compound and preparation method and application thereof

An azole compound, berberine azole technology, applied in the field of preparation of the compound, can solve the problems of low solubility of berberine, low bioavailability, many times of medication, etc. strong effect

Active Publication Date: 2012-06-27
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low solubility of berberine in water, direct clinical application has disadvantages such as poor absorption, low bioavailability, many times of medication, poor tolerance, and poor curative effect. Therefore, scientific researchers focus on structural modification of berberine. On the one hand, it enhances its water solubility and bioavailability; on the other hand, it strives to develop berberine derivatives with wider antimicrobial spectrum, stronger activity and less toxic side effects

Method used

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  • Berberine azole compound and preparation method and application thereof
  • Berberine azole compound and preparation method and application thereof
  • Berberine azole compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1, the preparation of berberine azole compound and hydrochloride thereof shown in general formula as I

[0047]

[0048] 1. Preparation of Intermediate VII

[0049] Method 1: In a 100mL round bottom flask, add azole compound (HIm), anhydrous potassium carbonate and acetonitrile (10mL), stir and heat up to 60°C for 1 hour, then add raw material VI under ice-water bath cooling condition, and react at room temperature , monitor the progress of the reaction with thin-layer chromatography (TLC); after the reaction is completed, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and purify by column chromatography (with a volume ratio of 1 to 3:5 Ethyl acetate-petroleum ether mixture is the eluent) to obtain intermediates VII-1~VII-20. The specific experimental conditions and results are shown in Table 1.

[0050] Table 1 Preparation conditions and results of intermediate VII

[0051]

[0052]

...

Embodiment 2

[0120] Embodiment 2, the preparation of berberine azole compound II-1

[0121]

[0122] 1. Preparation of Intermediate VIII-1

[0123] Consistent with the preparation method 1 of intermediate VII, in a 100mL round bottom flask, add 1H-2-mercaptobenzimidazole (1.58g, 10mmol), anhydrous potassium carbonate (2.76g, 20mmol) and acetonitrile (10mL), stir Raise the temperature to 60°C and react for 1 hour, then add raw material VI (4.37g, 12mmol) under ice-water bath cooling condition, react at room temperature, and monitor the reaction progress with TLC; after the reaction is completed, extract with ethyl acetate and wash with saturated sodium chloride solution , dried over anhydrous sodium sulfate, and purified by column chromatography (using ethyl acetate-petroleum ether mixture with a volume ratio of 1 to 3:5 as the eluent) to obtain Intermediate VIII-12.73g with a yield of 61%; White solid; m.p.: 138-140°C; 1 H NMR (300MHz, CDCl 3 ): δ7.59 (m, J=9.0Hz, 2H, Benim-Ph 3, 6-H...

Embodiment 3

[0126] Embodiment 3, the preparation of berberine azole compound III-1

[0127]

[0128] 1. Preparation of Intermediate X-1

[0129] According to the literature (Yan Ma, et al. Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands. Bioorganic & Medicinal Chemistry Letters, 2009, 19: 34714-3 ) method, using acetonitrile as a solvent, reacting raw material V with 1,6-dibromohexane at 75°C.

[0130] 2. Preparation of compound III-1

[0131] In a 100mL round bottom flask, add 1H-1,2,4-triazole (45mg, 0.65mmol), anhydrous potassium carbonate (150mg, 1.09mmol) and acetonitrile (10mL), stir and heat up to 60°C for 1 hour, Then cool to room temperature with an ice-water bath, add intermediate X-1 (240 mg, 0.46 mmol), react at 50 ° C, and monitor the progress of the reaction with TLC; after the reaction is completed, extract with chloroform, wash with saturated sodium ...

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Abstract

The invention discloses a berberine azole compound shown in general formulas such as I-IV, and a pharmaceutically acceptable salt thereof, and also discloses a preparation method of the compound, which comprises the following steps that: a compound VI and an azole compound HIm or 1H-2-mercaptobenzimidazole are reacted to obtain an intermediate VII or VIII, and then the obtained intermediate is reacted with a compound V to obtain the berberine azole compound shown in general formulas such as I or II; and the compound V and a compound IX or XI are reacted to obtain an intermediate X or XII, and then the obtained intermediate is reacted with the azole compound Him to obtain the berberine azole compound shown in general formulas such as III or IV. The berberine azole compound has a certain inhibitory activity on Gram-positive bacteria, Gram-negative bacteria and fungi, the anti-bacterial activity of part of the compounds is equal to or even stronger than that of chloramphenicol or norfloxacin, the antifungal activity of part of the compounds is equal to or even stronger than that of fluconazole, and the berberine azole compound can be used for preparing anti-microbial drugs.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to a new organic compound, a preparation method of the compound and its medical application. Background technique [0002] Berberine is a natural isoquinoline alkaloid extracted from Chinese medicinal materials such as Coptis chinensis and Cortex Phellodendri. It has significant antibacterial effect and is often used to treat digestive tract diseases such as bacterial gastroenteritis and dysentery. Due to the low solubility of berberine in water, direct clinical application has disadvantages such as poor absorption, low bioavailability, many times of medication, poor tolerance, and poor curative effect. Therefore, scientific researchers focus on structural modification of berberine. On the one hand, it enhances its water solubility and improves its bioavailability; on the other hand, it strives to develop berberine derivatives with wider antimicrobial spectrum, stronger activity, and l...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P31/04A61P31/10
CPCY02A50/30
Inventor 周成合常娟娟张奕奕
Owner SOUTHWEST UNIVERSITY
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