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Novel azole antifungal compound and preparation method thereof

A technology for antifungal drugs and compounds, applied in the field of medicine, to achieve the effects of high yield, good antifungal effect and broad antifungal spectrum

Inactive Publication Date: 2009-12-16
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But so far no azole compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[N- Alkyl-N-(1H-1,2,3-triazol-4-yl-1-substituted benzyl)methylamino]-2-ol or its salts

Method used

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  • Novel azole antifungal compound and preparation method thereof
  • Novel azole antifungal compound and preparation method thereof
  • Novel azole antifungal compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Preparation of intermediate 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-alkylamino-2- alcohol

[0048] (1) Preparation of 2-chloro-2', 4'-difluoroacetophenone

[0049] Put 200g (1.494mol) of anhydrous aluminum trichloride and 150g (1.30mol) of m-difluorobenzene into a 1000mL three-necked flask, stir at room temperature, and slowly add 150g (1.30mol) of chloroacetyl chloride dropwise. Continue to stir at room temperature for 30 minutes, slowly raise the temperature to 45°C, continue to stir at this temperature for 4.5 hours, pour the reaction solution into ice water as usual, precipitate a solid, and filter; the filtrate is extracted twice with 800 mL of dichloromethane, The dichloromethane extracts were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered to obtain a solid, which was combined twice and recrystallized with ethanol to obtain 2-chloro 2',4'-difluorophenethyl Ketone 21...

Embodiment 2

[0061] Example 2: Preparation of intermediate 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-alkyl-N-yne Propylamino)-2-ol

[0062] (1) Preparation of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-isopropyl-N-propargyl) Amino)-2-ol

[0063] Add 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-isopropylamino)- 1.7g (5mmol) of 2-alcohol, 1.2g (10mmol) of propyne bromide, 2.76g (20mmol) of anhydrous sodium carbonate, 20mL of acetonitrile, heated to reflux in an oil bath for 8 hours, then evaporated to dryness, extracted with 30mL of ethyl acetate, and filtered , ethyl acetate column chromatography [developing agent chloroform:methanol (V / V, the same below) 60:1], finally get 1-(1H-1,2,4-triazol-1-yl)-2-( 1.30 g of 2,4-difluorophenyl)-3-(N-isopropyl-N-propargylamino)-2-ol, yield 62.2%.

[0064] (2) Preparation of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-n-propyl-N-propargyl) Amino)-2-ol

[0065] Add 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoroph...

Embodiment 3

[0070] Example 3: Preparation of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{N-isopropyl-N-[1H -1,2,3-triazol-4-yl-1-(2-fluorobenzyl)methylamino]}-2-alcohol (compound 1 in Table 1)

[0071] Add 100mg (1.4mmol) of sodium azide, 200mg (1.2mmol) of o-fluorobenzyl bromide, and 15mL of dimethyl sulfoxide into a 25mL eggplant-shaped flask, and react with magnetic stirring at room temperature for 6h. Then add 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(N-isopropyl-N-propargylamino) -2-ol 200mg (0.6mmol), sodium ascorbate 20mg, CuSO 4 ·5H 2 O 25mg, water 1mL, stirred and reacted at room temperature for 10min, poured the reaction solution into dilute ammonia water, extracted with ethyl acetate (20mL×2), acidified the ethyl acetate layer with dilute hydrochloric acid (20mL×2), separated the water layer and the water layer use Na 2 CO 3 Adjust the pH to about 7, extract with ethyl acetate (20mL×2), dry the ethyl acetate layer with anhydrous sodium sulfate for 4h, fil...

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Abstract

The invention relates to the technical field of medicament, and provides a novel azole antifungal compound and salts thereof, a preparation method and application thereof. The compound has a chemical structure formula as the right, wherein, X is hydroxide radical; Ar is 2,4-difluorophenyl; R1 is hydrogen or a linear chain with 1 to 6 carbon atoms or low alkyl group with unsaturated or saturated branched chain; and R2 is selected from hydrogen, alkyl, halogen, cyano-group, nitryl and alkoxyl, can be positioned on ortho, meta, para positions of a benzene ring, and can be mono-substituted or multi-substituted. Salts of the compound can be hydrochloride, nitrate, hydrobromide or methane sulfonate. Pharmacological tests prove that the compound has strong antifungal activity, has the advantages of high efficiency, low toxicity, wide antifungal spectrum and the like compared with the prior antifungal medicines applied in clinic, and can be used for preparing antifungal medicines.

Description

technical field [0001] The invention relates to the field of medical technology, and is a novel azole antifungal compound-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3- [N-Alkyl-N-(1H-1,2,3-triazol-4-yl-1-substituted benzyl)methylamino]-2-alcohol compounds and their salts, and their preparation methods and uses. Background technique [0002] In recent years, with the widespread application of broad-spectrum antibiotics, antineoplastic drugs, and immunosuppressants, the widespread development of peritoneal dialysis, organ transplantation, and radiotherapy, and the rapid spread of immunodeficiency diseases, especially AIDS, Candida albicans, Cryptography neoformans The incidence of opportunistic deep fungal infections such as coccus and Aspergillus fumigatus has increased dramatically. Deep fungal infection has risen to the third largest infectious disease clinically, seriously threatening human life and health. Most of the antifungal drugs currently in clinical use ha...

Claims

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Application Information

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IPC IPC(8): C07D249/08A61K31/4196A61P31/10
Inventor 吴秋业俞世冲柴晓云胡宏岗王保刚邹燕孙青龑管忠俊邹敏辉薛云云姜远英
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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