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Nitroimidazole azole derivative, preparation method and application thereof

A compound and amino acid technology, applied in chemical instruments and methods, drug combinations, pharmaceutical formulations, etc., can solve problems such as unsafety, increased degree of degradation, and unknown toxicity of degraded impurities, and achieve good solubility, extended validity period, and superior stability Effect

Pending Publication Date: 2021-05-11
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Levo-ornidazole is the left-handed isomer of ornidazole. Chinese patents CN200510068478.9 and CN200510083517.2 describe its poor water solubility and low melting point. It requires strong acidity when made into infusion preparations, and patients are prone to phlebitis when taking medicine. ; and the toxic degradation product 2-methyl-5-nitroimidazole is higher during high-temperature sterilization of infusion, which brings great unsafeness to clinical medication
[0004] The prior art discloses levonidazole phosphate and its pharmaceutical salts, which greatly increase water solubility, but impurities will be produced during the placement process, and the degree of degradation will increase as the temperature increases, and the toxicity of the degraded impurities is unknown. Great impact on clinical use

Method used

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  • Nitroimidazole azole derivative, preparation method and application thereof
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  • Nitroimidazole azole derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of levonidazole phosphate

[0049] Weigh 10 g of left-ornidazole and place it in a dry 250 mL three-necked flask. Under nitrogen protection, add 100 mL of dichloromethane, cool down to 0-5°C, slowly add 6.56 g of phosphorus oxychloride, and finish adding in about 1 min. In-process HPLC was used to determine whether the reaction was complete.

[0050] Chromatographic conditions:

[0051] Mobile phase A: Potassium dihydrogen phosphate 6.8g / L, sodium heptanesulfonate 0.3g / L, adjust the pH value to 6.5 with triethylamine.

[0052] Mobile Phase B: Methanol

[0053] Detection wavelength: 321nm; Flow rate: l.0ml / min; Column temperature: 25°C; Sample concentration: 2mg / ml

[0054] Dilution medium: 0.1mol / L potassium dihydrogen phosphate

[0055] time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 5 85 15 10 75 25 20 75 25 25 55 45 45 55 45 50 85 15 60 85 15

[0056]Add the ...

Embodiment 2

[0057] Embodiment 2: the preparation of nitroimidazole compound 1

[0058] Take 10.0 g of levonidazole phosphate and place it in a dry 250 mL three-necked flask, add 100 ml of acetonitrile and stir evenly, add 10.5 g of 1-methylimidazole, 14.1 g of 2,2'-dithiodipyridine, triphenyl Base phosphorus 19.3g, react at room temperature for 1 hour, slowly add triethylamine phosphate 3.0g, during the reaction process, HPLC judges whether the reaction is complete.

[0059] Chromatographic conditions:

[0060] Mobile phase A: Potassium dihydrogen phosphate 6.8g / L, sodium heptanesulfonate 0.3g / L, adjust the pH value to 6.5 with triethylamine.

[0061] Mobile Phase B: Methanol

[0062] Detection wavelength: 321nm; Flow rate: l.0ml / min; Column temperature: 25°C; Sample concentration: 2mg / ml

[0063] Dilution medium: 0.1mol / L potassium dihydrogen phosphate

[0064] time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 5 85 15 10 75 25 20 75 25 ...

Embodiment 3

[0068] Embodiment 3: the preparation of nitroimidazole compound 1

[0069] Take 10.0g of levonidazole phosphate and 1.0g of triethylamine in a dry 100mL three-necked flask, add 50ml of dichloromethane and stir evenly, add N,N-carbonyldiimidazole at room temperature and stir for 2 hours, slowly add Triethylamine phosphate 3.0g, manganese chloride 2.4g and magnesium sulfate 3.0g, in the reaction process, HPLC judges whether the reaction is complete.

[0070] Chromatographic conditions:

[0071] Mobile phase A: Potassium dihydrogen phosphate 6.8g / L, sodium heptanesulfonate 0.3g / L, adjust the pH value to 6.5 with triethylamine.

[0072] Mobile Phase B: Methanol

[0073] Detection wavelength: 321nm; Flow rate: l.0ml / min; Column temperature: 25°C; Sample concentration: 2mg / ml

[0074] Dilution medium: 0.1mol / L potassium dihydrogen phosphate

[0075] time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 5 85 15 10 75 25 20 75 25 25 55...

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Abstract

The invention provides a nitroimidazole derivative as shown in a general formula I or a pharmaceutically acceptable salt, a solvent compound, a hydrate, a polymorphic substance, a deuterated substance and an isomer thereof. The invention also provides a pharmaceutical composition containing the compound and application of the pharmaceutical composition. The nitroimidazole derivative provided by the invention has excellent pharmacokinetic properties, and also has excellent antibacterial activity.

Description

technical field [0001] The invention relates to a nitroimidazole derivative and its preparation method and application, and further relates to a nitroimidazole derivative for resisting anaerobic bacteria and antiprotozoal infection, its preparation method and application. Background technique [0002] Ornidazole is a nitroimidazole derivative, which is a powerful drug against anaerobic bacteria and antiprotozoal infection. Broader third-generation nitroimidazole derivatives. The antimicrobial effect of ornidazole is through the reduction of the nitro group in its molecular formula to an amino group in an oxygen-free environment or through the interaction with cell components in the form of free radicals, resulting in the death of microorganisms. [0003] Levo-ornidazole is the left-handed isomer of ornidazole. Chinese patents CN200510068478.9 and CN200510083517.2 describe its poor water solubility and low melting point. It requires strong acidity when made into infusion pre...

Claims

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Application Information

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IPC IPC(8): C07F9/6506A61K31/675A61P33/02A61P31/04
CPCC07F9/6506A61P33/02A61P31/04Y02A50/30
Inventor 杨成刘晓鹏张起愿
Owner HC SYNTHETIC PHARMA CO LTD
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