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Triazole compounds, preparation method and application of triazole compounds in antifungal drugs

An antifungal drug, triazole technology, applied in the direction of antifungal agents, chemical instruments and methods, compounds of elements of Group 5/15 of the periodic table, etc. To achieve the effect of strong druggability, overcoming drug resistance problems and improving activity

Active Publication Date: 2020-09-11
QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the long-term and extensive use or even abuse of triazole drugs, more and more drug-resistant bacteria have emerged, which has become one of the main reasons for the failure of clinical antifungal treatment

Method used

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  • Triazole compounds, preparation method and application of triazole compounds in antifungal drugs
  • Triazole compounds, preparation method and application of triazole compounds in antifungal drugs
  • Triazole compounds, preparation method and application of triazole compounds in antifungal drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the preparation of compound I-1

[0032] Step 1: Preparation of Amphiphilic Cationic Compounds

[0033] Weighed triphenylphosphine (5g) and dissolved it in toluene (30ml), added 8-bromooctanoic acid (3g), and refluxed at 110°C for 12h. After the reaction, the liquid in the reaction bottle was directly poured out, the solid in the bottle was washed 3 times with ethyl acetate, and after the ethyl acetate was evaporated to dryness, a light yellow oily substance 1 was obtained.

[0034]

[0035] Weighed triphenylphosphine (5g) and dissolved it in toluene (30ml), added 3-bromopropionic acid (2g), and refluxed at 110°C for 12h. After the reaction, the reaction liquid was directly poured out, washed 3 times with ethyl acetate, and after the ethyl acetate was evaporated to dryness, a light yellow oily substance 2 was obtained.

[0036]

[0037] Step 2: Preparation of Compound 4

[0038] Weigh 2,4-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone (5g) into a ...

Embodiment 2

[0046] Embodiment 2: the preparation of compound 1-2

[0047] Step 1: Preparation of compound 5-2

[0048] To a DMF solution of compound 1 (50 mg), add 1,4-dibromobutane (122.6 μL) and K 2 CO 3 (28.55 mg) and the reaction was monitored by TLC. The reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane and washed with water, the organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was spin-dried in vacuo to obtain the crude product, which was purified by flash chromatography to obtain White solid compound 5-2. 1 H NMR (500MHz, Methanol-d 4 )δ7.92–7.87(m,3H),7.81(t,J=6.2Hz,4H),7.81–7.73(m,9H),4.10(t,J=6.3Hz,2H),3.44–3.37(m ,2H),2.30(t,J=7.3Hz,2H),1.77(dt,J=12.9,6.5Hz,2H),1.68(dq,J=16.0,8.2Hz,2H),1.57(dp,J= 14.9,7.3Hz,4H),1.41–1.25(m,6H).

[0049]

[0050] Step 2: Preparation of Compound I-2

[0051] In the DMF solution of compound 4 (25mg), add compound 5-...

Embodiment 3

[0053] Embodiment 3: the preparation of compound 1-3

[0054] Step 1: Preparation of compound 5-3

[0055] To a DMF solution of compound 1 (50 mg), add 1,5-dibromopentane (143 μL) and K 2 CO 3 (28.55 mg) and the reaction was monitored by TLC. The reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane and washed with water, the organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was spin-dried in vacuo to obtain the crude product, which was purified by flash chromatography to obtain White solid compound 5-3. 1 H NMR (500MHz, Chloroform-d) δ7.87 (dd, J = 12.4, 7.7Hz, 6H), 7.78 (t, J = 7.1Hz, 3H), 7.70 (dt, J = 10.5, 5.2Hz, 6H) ,4.04(t,J=6.5Hz,2H),3.92–3.83(m,2H),2.24(t,J=7.4Hz,2H),1.64(dt,J=13.3,7.3Hz,8H),1.54( dd,J=12.6,5.9Hz,2H),1.52–1.45(m,2H),1.34–1.20(m,6H).

[0056]

[0057] Step 2: Preparation of Compound I-3

[0058] In the DMF solution of compound...

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Abstract

The invention discloses a series of novel triazole compounds obtained by coupling a triazole drug skeleton and diversified lipophilic cations through different chains, and also discloses a preparationmethod of the compounds and application of the compounds in antifungal aspects. The research found that the triazole drug skeleton is coupled with lipophilic cations, so that the efflux effect of anefflux pump on azole drugs can be overcome, and the drug resistance problem of the azole drugs is solved.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a series of triazole derivatives with novel structures, their preparation methods and the application of these compounds in antifungal drugs. [0002] technical background [0003] Triazole drugs have the characteristics of high bioavailability, few adverse reactions, and moderate price. They have significant curative effects on deep fungal infections. They are the most important drugs for the treatment of systemic fungal infections and are widely used in clinical practice. The representative drugs are fluconazole, itraconazole, voriconazole, posaconazole and so on. The mechanism of action of this type of drug is to competitively block the biosynthesis of fungal ergosterol by binding to CYP51, resulting in the accumulation of lanosterol, thereby destroying the fungal cell membrane and exerting an antibacterial effect. Since there is no ergosterol synthesis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558C07F9/6518A61P31/10
CPCC07F9/65583C07F9/6518A61P31/10
Inventor 娄红祥王鑫刘军
Owner QINGDAO UNIV
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