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Itraconazole isomer and medical application thereof

A technology of itraconazole and isomers, which is applied in the field of medical application of 2’S itraconazole isomer combinations, can solve the problem that itraconazole liver cell damage cannot be confirmed by the liver cytotoxicity model

Inactive Publication Date: 2013-08-28
广州安赛莱生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Conventional drug hepatotoxicity models cannot confirm the liver cell damage that is often observed in clinical applications of itraconazole. Using a fresh human primary liver cell model that is closer to the human environment, we have obtained unexpected findings. and

Method used

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  • Itraconazole isomer and medical application thereof
  • Itraconazole isomer and medical application thereof
  • Itraconazole isomer and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the synthesis of itraconazole 2'S isomer

[0032] step 1:

[0033]

[0034] K 2 CO 3 (0.26g, 1.92mmol), crown ether 18-C-6 (0.34g, 1.28mmol) and tosylate (0.44g, 1.92mmol). The resulting mixture was stirred overnight at room temperature, diluted with water and washed with CH 2 Cl 2 of extraction. The organic layers were combined and dried (Na 2 SO 4 ), filtered, concentrated to obtain crude product, and purified: column chromatography (dichloromethane: acetone = 10: 1) to obtain white solid 2 (0.27g, 51%).

[0035] Step 2:

[0036]

[0037] A solution of triazolone 2 (0.50 g, 1.2 mmol) was added to HBr (48%, 5 mL). The reaction mixture was heated to 110°C and refluxed overnight. The reaction mixture was cooled to room temperature and a pink solid precipitated. The solid was collected by filtration, dissolved in methanol-water (1:1, 40 mL) and saturated NaHCO 3 aqueous solution (20 mL) and extracted with chloroform (3 x 20 mL). The organi...

Embodiment 2

[0042] Example 2: Synthesis of 2'R isomers

[0043]

[0044] K 2 CO 3 (0.26g, 1.92mmol), crown ether 18-C-6 (0.17g, 0.6mmol) and tosylate (0.22g, 1.0mmol). The resulting mixture was stirred overnight at room temperature, diluted with water and washed with CH 2 Cl 2 of extraction. The organic layers were combined and dried (Na 2 SO 4 ), filtered, concentrated to obtain the crude product, and purified: column chromatography (dichloromethane: acetone = 10: 1) to obtain white solid 4 (0.12 g, 51%).

[0045]

[0046] A solution of triazolone 2 (0.50 g, 1.2 mmol) was added to HBr (48%, 5 mL). The reaction mixture was heated to 110°C and refluxed overnight. The reaction mixture was cooled to room temperature and a pink solid precipitated. The solid was collected by filtration, dissolved in methanol-water (1:1, 40 mL) and saturated NaHCO 3 aqueous solution (20 mL) and extracted with chloroform (3 x 20 mL). The organic layer was washed with brine and washed with MgSO ...

Embodiment 3

[0050] Example 3: Antifungal Activity

[0051] Take a sterile 96-well plate, and add 100ul of RPMI1640 culture solution in the first space of each row as a blank control, add 100ul of freshly prepared bacterial solution in each of the 3-12 wells, and add 180ul of the bacterial solution and itraconazole or Isomer solution 20ul, 2-11 wells were diluted 10 times, the drug concentration in each well was 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125mg / L. The content of dimethyl sulfoxide in each well was lower than 1%. Candida, Cryptococcus neoformans, and filamentous bacteria were cultured at 35°C for 24 hours, 72 hours, and 7 days respectively, and the dimethyl sulfoxide content in each well was measured at 630nm with an enzyme label analyzer. OD value, compared with the positive control well, the lowest concentration at which the OD value decreases by more than 80% is MIC80 (representing that 80% of the fungal growth is inhibited).

[0052] Antibacterial test results in vitro (mg / L)...

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Abstract

The invention provides a novel itraconazole isomer composition and a method for increasing the therapeutic index of the novel itraconazole isomer composition. The itraconazole isomer composition can be used for improving the selectivity to fungi and endothelial cells and also lowering the toxicity of liver cells. The itraconazole isomer composition provided by the invention is a drug with potential for treating fungi and angiogenesis related diseases, and meanwhile, the side effects caused by taking itraconazole are avoided.

Description

technical field [0001] The invention relates to a medicine composed of optical isomers and its medical application, specifically a medical application of a combination of 2'S itraconazole isomers. Background technique [0002] The present invention relates to a new combination of optical isomers, consisting of 2'S isomers substantially free of 2'R itraconazole. The composition of this isomer has potential antifungal and anti-vascular endothelial cell proliferation activities, and can treat or prevent fungal infections (including local, systemic fungi, yeast, skin fungal infections) and vascular endothelial cell proliferation-related diseases (including but Not limited to tumors, senile fundus macular degeneration, etc.). [0003] Itraconazole is a lipophilic triazole broad-spectrum antifungal drug, and its mechanism of action is highly selective inhibition of cytochrome enzymes in fungal cells. Inhibition of dependent enzyme activity leads to fungal cell membrane damage, r...

Claims

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Application Information

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IPC IPC(8): A61K31/496C07D405/14A61P31/10A61P35/00A61P27/02
Inventor 傅和亮谢永立沈小宁吴蓉蓉何凤英
Owner 广州安赛莱生物科技有限公司
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