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Coumarin phenyl isoxazole derivatives and applications thereof

A technology of phenylisoxazole and isoxazole, which can be applied in drug combinations, skin diseases, and vector-borne diseases, etc., can solve the constraints of secondary development, weak material basis research, and inconsistencies in the mechanism of action and metabolic processes in vivo and in vitro. Clarity and other issues

Active Publication Date: 2017-05-31
XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although Uyghur medicine has a remarkable effect and advantages in treating vitiligo, its material basis research is weak, and its mechanism of action and metabolic process in vivo and in vitro are not clear, which seriously restricts its secondary development

Method used

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  • Coumarin phenyl isoxazole derivatives and applications thereof
  • Coumarin phenyl isoxazole derivatives and applications thereof
  • Coumarin phenyl isoxazole derivatives and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Preparation of 3-substituted phenyl-5-bromomethylisoxazoles (4a-4o):

[0064] 1.1 Synthesis of substituted benzaldoxime (2a-2o):

[0065] Dissolve 10.0 mmol of benzaldehyde containing different R substitutions in 30 mL of 30% aqueous methanol, and add 695 mg (10.0 mmol) of NH 2 OH·HCl, slowly add 530mg (5.0mmol) Na after dissolving 2 CO3 , react at room temperature for 2h, then add 30mL distilled water and 30mL dichloromethane to extract 3 times, combine the organic phases, and use anhydrous Na 2 SO 4 Dry, filter, and evaporate the solvent under reduced pressure to obtain the corresponding substituted benzaldoxime 2a-2o, which is directly carried out to the next step without separation and purification;

[0066] 1.2 Synthesis of 3-substituted phenyl-5-hydroxymethylisoxazole (3a-3o):

[0067] Dissolve 10.0 mmol of benzaldoxime (2a-2o) containing different R substitutions in 30 mL of dichloromethane, add 1.60 g (12.0 mmol) of N-chlorosuccinimide (NCS) in batches under...

Embodiment 2

[0071] The preparation of 4-methylumbelliferone (compound 5):

[0072] Under ice-bath conditions, 2.0 g (18.2 mmol) of resorcinol was dissolved in dioxane solution, and 0.5 ml of concentrated sulfuric acid was slowly added dropwise, and the temperature of the reaction solution did not exceed 20°C. After the dropwise addition is complete, continue to add 2.8 g (21.8 mmol) of ethyl acetoacetate to the reaction solution, and heat to 60°C. After TLC detects that all the raw materials disappear, the reaction solution is poured into ice water, and a large amount of solid is precipitated, filtered, and dried. The crude product was obtained, and 2.87 g of 4-methylumbelliferone (compound 5) was obtained after methanol recrystallization.

Embodiment 3

[0074] Preparation of 7-((3-(4-fluorophenyl)isoxazol-5-yl)methoxy)-4-methyl-2H-benzopyran-2-one (compound 6a):

[0075] At room temperature, 0.176g (1mmol) 4-methylumbelliferone, 0.307g (1.2mmol) 3-(4-fluoro)phenyl-5-bromomethylisoxazole and 0.414g (3.0mmol) Dissolve dry potassium carbonate in 50ml of dry acetone, heat it to a temperature of 56°C, and allow it to reflux for 4 hours. After the reaction is complete by TLC, stop the reaction and filter, and the filtrate is vacuum-desolvated. : 1 petroleum ether: ethyl acetate column chromatography with gradient elution to obtain 0.284 g of compound 6a.

[0076] NMR data of 7-((3-(4-fluorophenyl)isoxazol-5-yl)methoxy)-4-methyl-2H-benzopyran-2-one (compound 6a):

[0077] 1 H NMR (400MHz, CDCl 3 )δ7.83-7.76(m,2H),7.55(d,J=8.6Hz,1H),7.15(t,J=8.6Hz,2H),6.98-6.91(m,2H),6.66(s,1H ),6.18(s,1H),5.27(s,2H),2.41(s,3H).

[0078] 13 C NMR (101MHz, CDCl 3 )δ 167.37, 165.19, 162.70, 160.46, 155.12, 152.31, 130.91, 128.82, 125.92, 116.15,...

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Abstract

The invention relates to coumarin phenyl isoxazole derivatives and applications thereof. 4'-hydroxyl chalcone is taken as the raw materials. 4'-hydroxyl chalcone reacts with bromomethyl isoxazole with different substituent groups in the presence of potassium carbonate to generate 15 coumarin phenyl isoxazole derivatives. At the same time, the influence on generation of melanin in B16 cells of mice and inhibition effect on three bacteria (candida albicans, escherichia coli, and staphylococcus aureus) of 15 coumarin phenyl isoxazole derivatives are also observed. The results of leukoderma resistant experiments show that compared with a negative control, 15 compounds (6a-6o) can all promote the generation of melanin in B16 cells; and compared with a positive control, the compounds (6b-6f and 6j-6o) has a better effect on promoting the generation of melanin. The antibacterial results show that compounds (6d-6f, 6i, and 6l-6n) has an inhibiting effect on candida albicans; and the coumarin phenyl isoxazole derivatives (6d-6f, 6i, and 6l-6n) can be used to prepare drugs for treating leukoderma or candida albicans infection in clinic.

Description

technical field [0001] The invention relates to a coumarin phenylisoxazole derivative and its application. The compound has been screened for anti-vitiligo and antibacterial activity, and compounds 6a-6o are used for clinically preparing medicine for treating vitiligo. Compounds 6d-6f, 6i, 6l-6n are used in the clinical preparation of medicaments for treating Candida albicans (Candida albicans) infection. Background technique [0002] Vitiligo is a common spontaneous or idiopathic depigmentation skin disease, known as one of the three chronic skin diseases in the world, afflicting more than 50 million patients worldwide. The incidence rate varies from 0.1% to 8% in different regions and different races in the world. The prevalence rate of the general population in my country is about 0.56%. About half of the patients develop the disease before the age of 20, and the prevalence rate of males and females is equal. Vitiligo mainly manifests as white spots on the skin and mucou...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14A61P17/00A61P31/04
CPCC07D413/12C07D413/14Y02A50/30
Inventor 阿吉艾克拜尔·艾萨庞广宪牛超
Owner XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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