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Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof

An erythromycin and substituent technology, which is applied in the field of erythromycin A ketolide antibiotic derivatives, can solve the problems of inability to improve antibacterial activity, inability to enhance macrolide and ribosomal subunits, etc., and achieve efficient synthesis and the effects of industrial production

Active Publication Date: 2016-04-27
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And at 4, the introduction of hydrophobic groups such as alkyl and aryl at the position cannot improve the antibacterial activity (such as 25 and 29) due to the inability to enhance the effect of macrolides and ribosomal subunits

Method used

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  • Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof
  • Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof
  • Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0084] Preparation part

[0085] The structure of the compound was obtained by H NMR spectroscopy ( 1 HNMR), carbon nuclear magnetic resonance ( 13 CNMR) and mass spectrometry (MS) to determine. Proton and Carbon NMR shifts (δ) are given in parts per million (ppm). Proton nuclear magnetic resonance spectrum is measured with Mercury-300, Mercury-300 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.

[0086] High-resolution mass spectrometry was determined by Agilent1100seriesLC / MSDtrapmassspectrometer or ThermoExactiveorbitrapplusLC / MSDmassspectrometer.

[0087] Column chromatography generally uses 160-200 mesh silica gel as the carrier.

[0088] Anhydrous solvents were all worked up by standard methods. Other reagents were commercially available analytically pure.

[0089] in,

[0090] Acacetyl

[00...

preparation example 1

[0125] Synthetic route of Scheme1 intermediate 5a

[0126]

[0127] Scheme 1 Reagents and conditions: a.CH 3 COSK, DIEA, Pd 2 (dba) 3 , Xantphos, 1,4-dioxane, macrowave; b.1), KOH, EtOH, 2), H + , r.t; c.K 2 CO 3 ,DMF,90℃; d.NH 2 NH 2 ·H 2 O, EtOH, reflux.

[0128] Synthesis of compound (2a)

[0129] 3-bromopyridine (1a) (250mg, 1.2mmol), potassium thioacetate (275mg, 2.4mmol), Pd 2 (dba) 3 (27.5mg, 0.03mmol), Xantphos (35mg, 0.06mmol) were added to a 10ml microwave tube, sealed with a three-way ventilation valve, vacuumed by a decompression pump, and the gas in the microwave tube was replaced three times with argon, and weighed with a syringe Inject the calculated amount of diisopropylethylamine (0.42ml, 2.4mmol) and 1,4-dioxane into the microwave tube, quickly remove the tee and quickly cover the mouth of the bottle with the microwave tube cap , placed in a microwave reactor, set the microwave reactor according to the following parameters (Power: 150W, Ramp: 1...

preparation example 2

[0144] Synthetic route of Scheme2 intermediate 3b

[0145]

[0146] Scheme 2 Reagents and conditions: a.N-(3-Bromopropyl)phthalimide, K 2 CO 3 ,DMF,90℃; b.NH 2 NH 2 ·H 2 O, EtOH, reflux, 80°C.

[0147] Synthesis of compound (2b)

[0148] 3-hydroxyquinoline (1b) (2.0g, 13.78mmol), N-(3-bromopropyl) phthalimide (3.7g, 13.78mmol), potassium carbonate (2.1g, 15.156mmol) They were added to N,N-dimethylformamide (40ml), heated to 90°C, and reacted for 10h. TLC (ethyl acetate / petroleum ether 1:3) showed complete reaction. Stop the reaction, cool the reaction solution to room temperature, filter to remove solids, concentrate the filtrate, dissolve the residue in dichloromethane, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and perform silica gel column chromatography (ethyl acetate / petroleum ether 1 :15) to obtain light yellow compound 2b (4.186g, yield 91.6%).

[0149]1 HNMR (400MHz, CDCl 3 ):δ8.457(s,1H),7.956(d,J=8Hz,1H),7.824~...

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PUM

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Abstract

The invention discloses a series of erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, represented by a formula I. The invention also provides preparation methods and applications of the derivatives, and side-chain intermediates of the compounds and synthesis methods thereof. The key point of the invention is that the compounds represented by the formula I have the efficacy of broad-spectrum antibiotics, and have outstanding antibacterial activity and anti-resistance activity in inhibiting Gram-positive bacteria and Gram-negative bacteria. The compounds provided by the invention can be used as broad-spectrum antibiotics, and also have antibacterial and antiviral activities in 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 erythromycin A ketolide antibiotic derivatives containing quinoline substituents and their synthesis methods, synthesis methods of related intermediates, and the biological activity of these compounds as well as the role of broad-spectrum antibiotics in inhibiting genetic Lambert-positive bacteria and negative bacteria, anti-virus applications. Background technique [0002] Bacterial drug resistance has become a serious problem in the field of anti-infection therapy in the world. Bacterial drug resistance and drug-resistant bacterial infection are great challenges in the field of anti-infection in the 21st century. With the increasing use of antibiotics, the problem of drug resistance is becoming more and more serious, which makes anti-infection treatment fail, leading to an increase in morbidity and mortality and medical expenses. And in recent ye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00A61K31/706A61P31/04A61P31/12
CPCY02A50/30
Inventor 靳龙龙雷平生赵哲辉
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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