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Vancomycin derivative as well as preparation method and pharmaceutical use thereof

A technology of derivatives and antibiotics, applied in the field of medicine, can solve problems such as high toxicity

Inactive Publication Date: 2014-06-25
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Especially in the last decade, the emergence of highly virulent vancomycin-resistant Staphylococcus aureus (VRSA) has brought new major challenges to the treatment of infectious diseases caused by drug-resistant bacteria.

Method used

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  • Vancomycin derivative as well as preparation method and pharmaceutical use thereof
  • Vancomycin derivative as well as preparation method and pharmaceutical use thereof
  • Vancomycin derivative as well as preparation method and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of N-Heterocyclic Amino Substituted Vancomycin

[0058]

[0059] As shown in Scheme2, take a 10ml reaction tube, add vancomycin hydrochloride (80mg, 0.054mmol), dissolve it with 0.8ml dry DMF, add (2) (R 4 =nC 10 H 21 , n=2) 26mg (0.108mmol). DIEA (37μl, 28mg, 0.216mmol) was added dropwise, protected by Ar, and reacted at room temperature for 31h. Then add 320mg (0.324mmol) of NaCNBH, add 0.8ml of methanol to dissolve, add 25μl of TFA (37mg, 0.324mmol) dropwise, and react at room temperature for 15h. The methanol in the reaction solution was distilled off under reduced pressure. 50ml of ether was added to precipitate a white solid. The supernatant was removed. The residue was washed with ether for 30ml*2. After drying, the sample was dissolved with methanol: water=1:4, RP- 18 silica gel column layer, CH3OH:H2O=1:4→1:1 eluted to obtain powdery solid (3)a19mg with a yield of 20%. 1H NMR(DMSO-d6)δ7.53-7.39(m,7H),7.32-7.08(m,9H), 3.82(s,1H), 1.28(s,3H), 1.05(d,J=6....

Embodiment 2

[0064] The final product (3) ah tested for in vitro antibacterial activity against Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, Methicillin-resistant Staphylococcus aureus 09-250, and Vancomycin-resistant Enterococcus 193,186,435. . Methods: According to the agar double dilution method recommended by CLSI (Clinical Laboratory Standardization Association) in 2006, the minimum inhibitory concentration of antibacterial drugs (Minimal Inhibitory concentration MIC) was determined. Experimental design: Pour 1ml of antibacterial drugs of different types and different concentrations into a 9cm sterile empty plate, and then pour 19ml of sterile MH agar cooled to about 55℃ on the plate immediately, mix well with the drug solution, and cultivate The final concentration of base antibacterial drugs is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 μg / ml; meanwhile, MH plates without antibacterial drugs are prepared as a control. Bacteria inoculation: Add the bacte...

Embodiment 3

[0067] Example 3 In vivo antibacterial protection test

[0068] 1) Test strain

[0069] Clinical isolate: methicillin-resistant Staphylococcus aureus 11002.

[0070] 2) Laboratory animal system:

[0071] Animal grade: clean grade.

[0072] Gender and number: There are 300 KM mice in total, with half male and half female, 150 each.

[0073] Animal weight: 18-22g in weight.

[0074] Source of experimental animals: Shanghai Slack Laboratory Animal Center, Chinese Academy of Sciences, license number SCXK (Shanghai) 2011-0005.

[0075] Animal feeding and management: SPF environmental animal room, laboratory animal use license number: SYXK (Shanghai) 2009-0068.

[0076] Animal feeding: All animals are fed standard sterilized full-price rat feed. Animal drinking water is supplied from drinking bottles. Animals drink freely. Animal feeding: 10 animals per cage before modeling, 5 animals per cage after modeling. The animal is set at room temperature of 20℃~22℃, humidity of 40%~70%, light and dark ...

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Abstract

The invention discloses a vancomycin derivative as well as a preparation method and a pharmaceutical use thereof. The invention belongs to the technical field of medicines and relates to a glycopeptide antibiotics derivative substituted by heterocyclic nitrogen with a general formula (1) as shown in the specification, a pharmaceutically acceptable salt of glycopeptide antibiotics derivative, an isomer of the glycopeptide antibiotics derivative, a preparation method of the compounds and uses of the compounds in preparation of medicines for treating or preventing bacterial infectious diseases. An extraneous bacteriostasis experiment shows that the antimicrobial activity of the compounds is 60 times the antimicrobial activity of vancomycin or norvancomycin, particularly the bacteriostatic activity of the compounds to various gram-positive bacteria is obviously higher than that of vancomycin or norvancomycin. Thus, by adopting the preparation method, medicines containing the derivative as an active ingredient can be prepared, particularly medicines resisting to bacterial infection. The structure formula is as shown in the specification.

Description

Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to glycopeptide antibiotic derivatives substituted with nitrogen heterocycles, pharmaceutically acceptable salts, and isomers thereof, and preparation methods of these compounds, and the use of these compounds in the preparation of therapeutics Or use in medicines to prevent bacterial infectious diseases. Background technique [0002] According to reports, glycopeptide antibiotics are a class of antibiotics with a very complex structure that are effective against gram-positive resistant bacteria. Such antibiotics that are frequently used in clinical practice include vancomycin, norvancomycin and teicolar Ning wait. They all have similar heptapeptide oxygen-linked cup-shaped rigid backbone system and special amino sugar substituents. Among them, vancomycin, as the representative and most widely used natural glycopeptide antibiotic, was isolated from the fermentation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00A61K38/14A61P31/04
Inventor 孙逊徐亮金潇昌军江永伟
Owner FUDAN UNIV
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