Vancomycin or demethyl vancomycin analogue and medicinal uses thereof

A technology of norvancomycin and vancomycin, applied in antibacterial drugs, drug combinations, anti-infective drugs, etc., can solve the problems of severe patients and increased mortality

Inactive Publication Date: 2012-12-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, recent reports have shown that the emergence of highly virulent Clostridium difficile has led to frequent

Method used

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  • Vancomycin or demethyl vancomycin analogue and medicinal uses thereof
  • Vancomycin or demethyl vancomycin analogue and medicinal uses thereof
  • Vancomycin or demethyl vancomycin analogue and medicinal uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of new vancomycin or norvancomycin analogs,

[0027] The compound is prepared according to the preparation methods known in the art 2a-d .

[0028] Add vancomycin hydrochloride (90mg, 0.061mmol) in 5ml reaction tube, mix solvent (Py:H 2 O=1:1) After 2ml is dissolved, add ethyl isocyanate (7.1 l, 0.091mmol), reacted at 30°C for 4h. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography with CH 3 OH:H2 O=1:1 elution gave carboyl vancomycin (2a) 62 mg with a yield of 53%.

[0029] According to the same method, the compounds represented by 2b-d were prepared in high yield.

[0030]

[0031] Table 1 Compounds 2a-d Mass spectral data (ESI-MS)

[0032] Numbering measured value Calculated value (M+Na + ) 2a 1541.5 1541.5 (C 69 h 80 Cl 2 N 10 o 25 Na) 2b 1603.1 1603.5 (C 74 h 82 Cl 2 N 10 o 25 Na) 2c 1589...

Embodiment 2

[0033] Example 2 Preparation of new vancomycin or norvancomycin analogs,

[0034] The compound is prepared according to the preparation methods known in the art 3a-d .

[0035] Take the compound N-Fmoc norvancomycin (100mg, 0.06mmol) and dissolve it in 2ml of mixed solvent (Py:DMF =1:1), add ethyl isocyanate (6.4ul, 0.09mmol) dropwise, react at room temperature for 5h, and reduce pressure Evaporate most of the solvent, add 20ml of diethyl ether to precipitate a white solid, filter off the diethyl ether, and wash the solid with 2*20ml of diethyl ether. The solid was dried to obtain 98.8 mg of the compound with a yield of 94.8%. Add the above solid (90mg, 0.061mmol) into a 5ml reaction tube, dissolve it with 1ml DMF, add dropwise 0.2ml of piperidine, and react at 10°C for 12h. The reaction solution was subjected to silica gel column chromatography, and CHCl 3 :CH 3 OH:H 2 O=4:4:0.7 eluted compound ( 3a) 72 mg, the yield was 91.8%.

[0036] According to the same method,...

Embodiment 3

[0040] Example 3 In vitro antibacterial activity test

[0041] The antibacterial activity of vancomycin analogues against Clostridium difficile IQCC23903, ATCC700057 and ATCC43255 was tested in vitro. Methods The minimum inhibitory concentration of antibacterial drugs (Minimal Inhibitory concentration MIC) was determined according to the agar double dilution method recommended by CLSI (Clinical Laboratory Standards Institute) in 2006. Experimental design: Take 1ml of antibacterial drugs of different types and different concentrations and pour them into a 9cm sterile empty plate, then pour 19ml of sterile M-H agar cooled to about 55°C on the plate immediately, mix well with the drug solution, and make the culture The final concentrations of base antibacterial drugs were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 μg / ml; at the same time, M-H plates without antibacterial drugs were prepared as a control . Bacterial inoculation Add the bacteria that have been incubated ...

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Abstract

The invention, belonging to the technical field of pharmaceutical chemistry and medicine, particularly relates to a novel vancomycin or demethyl vancomycin analogue of formula (1) and medicinal uses thereof. By carrying out tests of in vivo inhibition of clostridium difficile on the compound of formula (1), the results show that the compound has significantly higher antibacterial activity on clostridium difficile than vancomycin or demethyl vancomycin in the prior art, and the compound disclosed herein can be prepared into safe, effective and novel vancomycin or demethyl vancomycin analogues, pharmaceutical compositions of a medicinal carrier and various preparations. The novel vancomycin or demethyl vancomycin analogue disclosed herein can be used for preparing anti-infection medicines, especially medicines for resisting the infection of clostridium difficile.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and medicine, and specifically relates to novel vancomycin or norvancomycin analogues and their medicinal application. Background technique [0002] Clostridium difficile (Clostridium difficile) is a Gram-positive anaerobic bacillus. With the widespread use of broad-spectrum antibiotics, Clostridium difficile mainly causes fever, abdominal pain, watery diarrhea and pseudomembranous colitis. Symptomatic Clostridium difficile-associated diarrhea (Clostridium difficile-associated diarrhea, CDAD) has gradually become a new challenge in clinical treatment. It is generally believed that Clostridium difficile infection accounts for 15%-20% of antibiotic-associated diarrhea and is the main cause of severe pseudomembranous colitis. Studies have shown that the above-mentioned diarrhea is not only caused by the widespread use of antibacterial drugs, but also other factors that affect the normal ...

Claims

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Application Information

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IPC IPC(8): C07K9/00A61K38/14A61P31/00A61P31/04
Inventor 孙逊徐亮章思及昌军
Owner FUDAN UNIV
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