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New fosfomycin derivatives and medicinal use thereof

The technology of a derivative, fosfomycin, is applied in the field of new fosfomycin derivatives and their medical applications, which can solve the problems of high water solubility of fosfomycin, short half-life of fosfomycin, and high concentration of kidney distribution

Inactive Publication Date: 2014-10-29
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, fosfomycin has a short half-life and needs to be administered 3-4 times a day, which is not conducive to wartime and emergency needs; in addition, fosfomycin has high water solubility and poor tissue permeability; it is excreted through the kidneys, and its distribution concentration in the kidneys is high. Mainly used to treat urinary tract infections

Method used

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  • New fosfomycin derivatives and medicinal use thereof
  • New fosfomycin derivatives and medicinal use thereof
  • New fosfomycin derivatives and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 P, P-bis((S)-alanine propyl ester)-N-fosfomycin (I 1 )Synthesis

[0019]

[0020] In 100ml anhydrous pyridine, add 1.16g (6.4mmol) fosfomycin, 6.4g (38.4mmol) (S)-alanine-O-propyl ester hydrochloride, 10.6ml triethylamine, pass N 2 , Stir at 60°C. Then add 11.8 g of 2,2’-dithiodipyridine and 9.8 g of triphenylphosphine dissolved in 50 ml of anhydrous pyridine, in N 2 The reaction was stirred at 60°C for 16h under protection. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in 100ml of dichloromethane, and 10% Na 2 CO 3 Wash with 1N hydrochloric acid and saturated brine, dry the organic layer with anhydrous sodium sulfate, filter off the desiccant, and separate the residue with silica gel column chromatography, eluting with dichloromethane: petroleum ether (5:5), and collect The required components are evaporated to dryness under reduced pressure to obtain I 1 0.58 grams. Elemental analysis (%), theoretical val...

Embodiment 2

[0021] Example 2 P, P-bis((S)-alanine methyl ester)-N-fosfomycin (I 2 )Synthesis

[0022]

[0023] Refer to the method of Example 1, replace (S)-alanine-O-propyl ester hydrochloride with (S)-alanine-O-methyl ester hydrochloride, and react with fosfomycin sodium to obtain I 2 , The yield is 24%. Elemental analysis (%), theoretical value: C42.86 H6.87 N9.09; experimental value: C42.76 H6.92 N8.97.

Embodiment 3

[0024] Example 3 P, P-bis((S)-alanine ethyl ester)-N-fosfomycin (I 3 )Synthesis

[0025]

[0026] Refer to the method of Example 1, replace (S)-alanine-O-propyl ester hydrochloride with (S)-alanine-O-ethyl ester hydrochloride, and react with fosfomycin sodium to obtain I 3 , The yield is 30%. Elemental analysis (%), theoretical value: C46.43 H7.49 N8.33; experimental value: C46.60 H7.28 N8.39.

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PUM

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Abstract

The invention relates to fosfomycin derivatives represented by formula I, and nontoxic pharmaceutically acceptable salts and hydrates thereof. In the formula I, R1 is H or a C1-6 alkyl group, and R2 is H or a C1-6 alkyl or cycloalkyl group.

Description

Technical field [0001] The present invention relates to fosfomycin derivatives represented by formula I and non-toxic pharmaceutically acceptable salts and hydrates thereof: [0002] [0003] Where R 1 Is H or an alkyl group with 1-6 carbon atoms, R 2 It is H or an alkyl or cycloalkyl group having 1 to 6 carbon atoms. Background technique [0004] Bacterial resistance and drug-resistant bacterial infections are huge challenges facing the global anti-infection field. Fosfomycin is an antibacterial drug with a unique mechanism of action. It can inhibit the synthesis of bacterial cell walls by irreversibly combining with pyruvate-uracil diphosphate-acetylglucosamine transferase and exert a bactericidal effect. Fosfomycin is a broad-spectrum antibacterial drug and has high antibacterial activity against most Gram-positive and Gram-negative bacteria. Due to its unique antibacterial mechanism, fosfomycin has no cross-resistance to other types of antibacterial drugs currently in clinica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/655A61K31/665A61P31/04
Inventor 仲伯华樊士勇苏卓然孙宇史卫国姚宜山
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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