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Triazole alcohol antifungal compound with piperidine oxadiazole side chain, preparation method and application thereof

A technology of oxadiazoles and compounds, which is applied in the field of triazole antifungal compounds and their preparation, can solve the problems of narrow antibacterial spectrum, large side effects, and easy drug resistance

Active Publication Date: 2018-07-17
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as far as its clinical application is concerned, the existing antifungal drugs have problems such as large side effects, narrow antibacterial spectrum, and easy drug resistance, which are far from meeting the needs of clinical treatment.

Method used

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  • Triazole alcohol antifungal compound with piperidine oxadiazole side chain, preparation method and application thereof
  • Triazole alcohol antifungal compound with piperidine oxadiazole side chain, preparation method and application thereof
  • Triazole alcohol antifungal compound with piperidine oxadiazole side chain, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1: Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole mesylate (Ⅱ)

[0101] Take 2-(1H-1,2,4-triazol-1-yl)-2',4'-difluoroacetophenone (Ⅰ) 29.8g (0.115mol), trimethyl iodine oxysulfide 25.3g ( 0.115mol), 1.6g of trimethylhexadecylammonium bromide, put into a 500ml three-necked flask, add 180ml of toluene and 225ml of 20% sodium hydroxide solution (w / w), heat at 60°C for 3 hours, and the reaction ends Finally, separate the toluene layer, extract the water layer with ethyl acetate (100mlX2), combine the organic layers, wash with water until neutral, evaporate the solvent to dryness, add 120ml of ethyl acetate to the residual solution and dilute with 8.3g of formazan at 0°C. 2ml of ethyl acetate of sulfonic acid precipitated a pale yellow solid, which was filtered and recrystallized from methanol to obtain 21.71g of compound IV with a yield of 56.7% and a melting point of 128-129°C.

Embodiment 2

[0102] Embodiment 2: Preparation of N-Boc-4-hydrazinecarbonylpiperidine (III)

[0103] 2 g (7.77 mmol) of methyl N-tert-butoxycarbonyl-4-piperidinecarboxylate was dissolved in a (1:1) mixed solvent (30 mL) of hydrazine hydrate and ethanol, and stirred overnight at room temperature. Ethanol was concentrated to dryness, added to water (50 mL), dried with dichloromethane (50 mL×3), anhydrous sodium sulfate, filtered, and concentrated to obtain 1.8 g of white solid with a yield of 95%.

Embodiment 3

[0104] Embodiment 3: Preparation of N-Boc-4-hydrazide carbonyl piperidine compound (IV class compound)

[0105] Take 0.2g (0.82mmol) of N-Boc-4-hydrazinecarbonylpiperidine, 0.12g (1.23mmol) of triethylamine and dissolve it in dichloromethane (20mL), and slowly add 0.22g (1.23mmol) of nicotinyl chloride under ice bath ), and stirred at room temperature for 2 hours. Add dichloromethane (30mL) to dilute, wash with saturated brine (20mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and obtain crude product by silica gel column chromatography (ethyl acetate:methanol=50:1-30: 1), 0.2 g of white solid was obtained, and the yield was 70%.

[0106] Other IV compounds are prepared by using III as a raw material, reacting with different aryl formyl chlorides as raw materials, and repeating the steps in Example 3.

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Abstract

The invention relates to the technical field of medicine, and provides a class of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-((piperidine oxadiazole side chain substituted))-2-propanol compound, which comprises cis-trans-isomers of the compound and any mixture of these forms or medical salts thereof. The chemical structure of the compound is as shown in a formula (I) in the Specification. The invention further provides a preparation method of the compound, and an application in the preparation of an antifungal drug. Antifungal experiments show that the compound has excellent antifungal effect for various shallow and deep funguses; compared with an existing antifungal drug such as fluconazole in clinical application, the compound has the advantages of high efficiency, low toxicity and wide antifungal spectrum, and can be used for preparing new antifungal drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of triazole alcohol antifungal compounds with piperidine oxadiazole side chains, a preparation method and application thereof, and an application in medicine. Background technique [0002] In recent years, with the extensive application of broad-spectrum antibiotics, antineoplastic drugs, and immunosuppressants, the widespread implementation of radiotherapy and organ transplantation, the widespread development of catheters and intubations, and the rapid increase in immunocompromised patients, especially AIDS patients, have resulted in Fungal infections, especially deep fungal infections, have risen sharply, and deep fungal infections have become the main cause of death from major diseases such as AIDS and tumors. Existing antifungal drugs mainly include amphotericin B that acts on fungal cell membrane lipids, nitrogen azoles that act on lanosterol 14-demethylase (flucona...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14A61P31/10
CPCC07D211/62C07D405/06C07D413/04C07D413/14
Inventor 张万年盛春泉贺潇蒙王胜正董国强缪震元姚建忠刘娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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