A water-soluble triazole compound

A triazole compound, water-soluble technology, applied in the field of water-soluble triazole compound and its preparation, can solve the problems of difficult synthesis of water-soluble compounds, poor drug stability, etc., achieve excellent water solubility, improve solubility and stability , good stability

Active Publication Date: 2019-08-13
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the problems of water solubility, poor drug stability and difficulty in synthesizing water-soluble compounds in existing triazole antifungal drugs, the purpose of the present invention is to provide a kind of triazole antifungal drug with good solubility in water, stability, low toxicity and good drug efficacy. Water-soluble triazole compounds and pharmaceutically acceptable salts thereof

Method used

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  • A water-soluble triazole compound
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  • A water-soluble triazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Synthesis of Compound 3

[0040] Chemical reaction formula:

[0041]

[0042] Steps:

[0043] In a 500 mL reaction flask, add 20 g of compound a and 200 mL of dichloromethane, stir, and then add 12.8 g of pyridine. Then 17.7 g of chloromethyl chloroformate was added dropwise at 10-20°C, after the dripping was completed, the temperature was raised to 20-25°C for 24 hours. Add 100 mL of water to the reaction solution, stir and separate the layers, and then wash the organic layer with 80 mL×2 with water. Collect the organic layer, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 27.4 g of oil, which is compound 1. The yield was 87%.

[0044] In a 1L reaction flask, add 27.4g of compound 1, 23.4g of potassium iodide and 410mL of acetonitrile, stir, and then add 37.8g of compound X (voriconazole), and heat to reflux for 15h. Stop the reaction, cool to 20-25°C, filter to remove insoluble materials, and concentrate the filtrat...

Embodiment 2

[0050] Example 2 Synthesis of Compound 6

[0051] Chemical reaction formula:

[0052]

[0053] Steps:

[0054] In a 250 mL reaction flask, add 10 g of compound b and 100 mL of dichloromethane, stir, and then add 13.7 g of pyridine. Then 18.9 g of chloromethyl chloroformate was added dropwise at 10-20°C, and after the dripping was completed, the temperature was raised to 20-25°C for 24 hours. Add 50 mL of water to the reaction solution, stir and separate the layers, and then wash the organic layer with 30 mL×2 of water. Collect the organic layer, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 18.9 g of oil, which is compound 4. The yield was 84%.

[0055] In a 500 mL reaction flask, add 18.9 compound 4, 24.3 g potassium iodide and 285 mL acetonitrile, stir, then add 39.3 g compound X (voriconazole), and heat to reflux for 15 hours. Stop the reaction, cool to 20-25°C, filter to remove insoluble materials, and concentrate the filtrate to...

Embodiment 3

[0059] Example 3 Synthesis of Compound 9

[0060] Chemical reaction formula:

[0061]

[0062] Steps:

[0063] In a 500 mL reaction flask, add 20 g of compound c and 200 mL of dichloromethane, stir, and then add 14.7 g of pyridine. Then 17.6g of chloromethyl chloroformate was added dropwise at 10-20°C, after the dripping was completed, the temperature was raised to 20-25°C for 24h reaction. Add 100 mL of water to the reaction solution, stir and separate the layers, and then wash the organic layer with 80 mL×2 with water. Collect the organic layer, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 26.8 g of oil, which is compound 7. The yield was 85%.

[0064] In a 1 L reaction flask, add 26.8 g of compound 7, 22.8 g of potassium iodide and 400 mL of acetonitrile, stir, and then add 36.8 g of compound X (voriconazole), and heat to reflux for 15 hours. Stop the reaction, cool to 20-25°C, filter to remove insoluble materials, and concentrat...

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Abstract

The present invention belongs to the pharmaceutical chemistry field, and particularly relates to a water-soluble triazole compound represented by a formula (I), a pharmaceutically acceptable hydrate and an isomer thereof, wherein the substituents are defined in the specification. According to the present invention, the new group is introduced on the basis of the compound voriconazole widely used in the clinic and having the high-efficiency and broad-spectrum antibacterial effect to form the stable compound having the amphipathic property, such that the solubility and the stability of the compound in the water are improved; and the compound has characteristics of safety, low toxicity and good antibacterial effect, the synthesis of the compound is simple and easy to operate, the purity of the synthesized product is high, and the method is suitable for industrial production. The general I is defined in the specification.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a water-soluble triazole compound and a preparation method thereof. Background technique [0002] In recent years, due to the extensive use of broad-spectrum antibiotics in the clinic, the normal flora symbiosis relationship between human bacteria and fungi has been destroyed, making the flora imbalance; in addition, the extensive use of cancer radiotherapy, chemotherapy drugs, corticosteroids and immunosuppressants, and The spread of AIDS has sharply increased the rate of deep fungal infections. Deep fungal infection is increasingly becoming a common and frequently-occurring disease, and has become one of the main causes of death in patients with cancer and immunodeficiency diseases. Therefore, the development and clinical application of antifungal drugs have received increasing attention. Among them, triazole antifungal drugs are currently the largest in the market, w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06A61K31/506A61P31/10
CPCC07D403/06
Inventor 张孝清黄辉包金远蒋玉伟江振兴
Owner NANJING HUAWE MEDICINE TECH DEV
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