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Erythromycin A ketolide antibiotic derivative, its preparation method and application

A technology of antibiotics and derivatives, applied in the field of medicine, can solve the problems of increasing and affecting the clinical application of telithromycin, and achieve the effects of high total yield, novel structure and simple synthesis

Active Publication Date: 2022-01-11
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the clinical application of telithromycin, more and more reports of hepatotoxicity have been reported. Several studies have shown that although the incidence of serious liver adverse events of telithromycin is low, there have been reports of acute liver failure and severe liver damage.
For safety considerations, the US FDA has restricted the indications of telithromycin, which has affected the clinical application of telithromycin

Method used

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  • Erythromycin A ketolide antibiotic derivative, its preparation method and application
  • Erythromycin A ketolide antibiotic derivative, its preparation method and application
  • Erythromycin A ketolide antibiotic derivative, its preparation method and application

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Experimental program
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Effect test

preparation example

[0074] Preparation part

[0075] The structure of the compound was obtained by H NMR spectroscopy ( 1 H NMR), carbon nuclear magnetic resonance ( 13 C NMR) and mass spectrometry (MS). Proton and Carbon NMR shifts (δ) are given in parts per million (ppm). Proton NMR spectrum is measured with Mercury-300, Mercury-400, Bruke-400 or Mercury-600 type nuclear magnetic resonance instrument, deuterated chloroform (CDCl 3 ) or heavy water (D 2 O) or deuterated dimethylsulfoxide (DMSO-d 6 ) as solvent and tetramethylsilane (TMS) as internal standard.

[0076] High-resolution mass spectrometry was determined by Agilent 1100series LC / MSD trap mass spectrometer or Theromo Exactive orbitrap plus LC / MSD mass spectrometer.

[0077] Column chromatography generally uses 160-200 mesh silica gel as the carrier.

[0078] Anhydrous solvents were all worked up by standard methods. Other reagents were commercially available analytically pure.

[0079] in,

[0080] Acetyl

[0081] Bn benzyl...

preparation example 1

[0113] The preparation of preparation example 1 raw material compound 8

[0114] The macrocyclic ketolide compound of the present invention starts from clarithromycin, adopts known literature reports or a feasible reaction method known to the public in synthetic chemistry, and obtains appropriate derivatives as raw materials of the present invention.

[0115]

[0116]Add 2.0 g, 2.675 mmol of clarithromycin to 20 ml of 1N hydrochloric acid under cooling in an ice-water bath and stir. When the reaction starts, the reaction solution becomes viscous. Continue stirring for 4 hours, and the reaction solution gradually becomes clear. TLC (CH 2 Cl 2 :CH 3 OH=10:1) to monitor the completion of the reaction, that is, to stop the reaction. Cool the reaction system in an ice-water bath, add 20% sodium hydroxide solution dropwise to the reaction solution while stirring, adjust the pH to alkaline, a large amount of white solid precipitates, filter, and the filter cake is washed with w...

preparation example 2

[0153] The synthetic route of preparation example 2 intermediate side chain a4

[0154]

[0155] Scheme 1 reagents and reaction conditions: a. Di-tert-butyl dicarbonate, sodium bis(trimethylsilyl)amide, tetrahydrofuran, room temperature, 2 hours, 92.8%; b. Nitrogen-3-bromopropyl-phthalamide Formimide, potassium carbonate, N,N-dimethylformamide, 90°C, 8 hours, 85.2%; c. Trifluoroacetic acid, dichloromethane, 0°C, 8 hours, 97.3%; d. Hydrazine hydrate, Ethanol, 4 hours, 80°C, 82.7%;

[0156] Dissolve 10.02g, 69.50mmol of 3-aminoquinoline in 150ml of dry tetrahydrofuran, place the reaction system in an ice-water bath for cooling, and slowly add 69ml of bis(trimethylsilyl) to the reaction system under the protection of argon. Base) sodium amide (THF solution of 2mol / L), then add 16.68g, 76.45mmol of di-tert-butyl dicarbonate, the reaction solution is gradually returned to room temperature, TLC (petroleum ether: ethyl acetate=1:1) monitoring When the reaction is complete, stop ...

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Abstract

The invention discloses a series of erythromycin A ketolide antibiotics containing an aminoquinoline ring as shown in formula I, a preparation method and application thereof, side chain intermediates of each compound and a synthesis method. The key points of the present invention are: the compound shown in formula I has broad-spectrum antibiotic efficacy, and has outstanding antibacterial activity to sensitive and drug-resistant Gram-positive bacteria and negative bacteria, especially to vancomycin The antimicrobial activities of antibiotic-resistant Enterococcus faecalis, Enterococcus faecium, erythromycin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, Klebsiella pneumoniae, and Shigella flexneri were significantly better than those of the control drug Telithromycin white. The compound proposed by the invention can be used as a broad-spectrum antibiotic, and has the antibacterial and antiviral activities of inhibiting Gram-positive bacteria and Gram-negative bacteria.

Description

technical field [0001] The invention belongs to the technical field of medicine. The present invention relates to a series of highly antibacterially active erythromycin A ketolide antibiotic derivatives containing amino-quinoline substitutions and their synthetic methods, related intermediate synthetic methods, and the biological activity of such compounds and as a broad-spectrum The use of antibacterial antibiotics in inhibiting sensitive and drug-resistant Gram-positive bacteria and negative bacteria, and anti-virus. Background technique [0002] Erythromycin A is the first clinical application of macrolide antibiotics. It has definite curative effect, low toxicity and good safety. It is widely used for Gram-positive bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, The treatment of infections caused by Streptococcus pneumoniae and Streptococcus pyogenes also has good antibacterial effects on atypical pathogenic bacteria such as Chlamydia, Mycoplasma,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/00A61K31/706A61P31/04
CPCC07H17/08C07H1/00A61P31/04Y02A50/30
Inventor 赵哲辉雷平生张晓曦杨爽
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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