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Beta-lactam twin antibiotic compound, preparation method thereof and use thereof

A technology of lactams and compounds, applied in the field of medicine, can solve the problems of bacterial resistance and cross-resistance, and achieve significant antibacterial activity and the effect of overcoming drug resistance.

Inactive Publication Date: 2010-06-09
刘超美
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The widespread clinical use of these structurally similar antibiotics has created a problem of bacterial resistance and there is cross-resistance

Method used

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  • Beta-lactam twin antibiotic compound, preparation method thereof and use thereof
  • Beta-lactam twin antibiotic compound, preparation method thereof and use thereof
  • Beta-lactam twin antibiotic compound, preparation method thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Preparation of N,N'-bis-[(2S,5R,6R)-3,3-dimethyl-7-oxo-4-thio-1-azabicyclo[3,2,0]heptane-2 -Carboxylic acid-6-yl]-1,6-hexanediamide

[0069] In a dry 250ml three-neck flask, add 0.73g (5.0mmol) of adipic acid and 50ml of tetrahydrofuran, cool to -5°C in an ice-salt bath, and then add 2.4g of N,N-dicyclohexylcarbodiimide (DCC) (12.0mmol) and N-hydroxysuccinimide (NHS) 1.4g (10.0mmol), naturally heated and stirred for 6h, filtered to remove solid N,N-dicyclohexyl urea, the filtrate was decompressed to recover the solvent, washed with a small amount of tetrahydrofuran The N-hydroxysuccinimide ester of 1,6-adipic acid is obtained. Add 15ml of N,N-dimethylformamide to another reaction flask, cool down to 5-10°C in an ice bath, add 2.16g (10.0mmol) of 6-APA and 1.5ml of triethylamine, and stir for 15 minutes. The above ester was then dissolved in a small amount of N,N-dimethylformamide and added to the reaction flask, and stirred overnight. Add 50 ml of ice water, adjust t...

Embodiment 2

[0072] Preparation of N,N'-bis-[(6R,7R)-3-(acetoxymethyl)-8-oxo-5-thio-1-azabicyclo[4,2,0]oct-2-ene -2-Carboxylic acid-7-yl]-1,6-hexanediamide

[0073] In a dry 100ml three-necked flask, add 0.73g (5.0mmol) of adipic acid, 15ml of benzene and 5 drops of N,N-dimethylformamide, heat to 60-70°C, add dropwise 1.2g (4.0mmol) The benzene solution of triphosgene (bistrichloromethanol carbonate) was dropped in about 30 minutes. Continue to stir for 4 hours after the addition, transfer to a 100ml round bottom bottle, recover the solvent, and obtain a light yellow adipoyl chloride liquid, which is stored at low temperature until use.

[0074] In a 250ml three-necked flask, add 2.72g (10.0mmol) of 7-ACA, 20ml of water, 0.5g of disodium hydrogen phosphate and 1.5ml of triethylamine, and slowly add 5% sodium hydroxide solution dropwise until the solution is clear. Then add 15ml of water, 15ml of acetone, a little tetrabutylammonium bromide, adjust the pH to 8-9 with saturated sodium bica...

Embodiment 3

[0077] Preparation of N,N'-bis-[(6R,7R)-8-oxo-5-thio-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid-7-yl ]-1,6-Hipamide

[0078] In a dry 250ml three-necked flask, add 0.73g (5.0mmol) of adipic acid and 50ml of tetrahydrofuran, cool to about -5°C in an ice-salt bath, and then add 2.4g (12.0 mmol) and N-hydroxysuccinimide (NHS) 1.4g (10.0mmol), naturally heated and stirred for 6h, filtered to remove solid N, N-dicyclohexyl urea, the filtrate recovered solvent, washed with a small amount of tetrahydrofuran to obtain 1,6 -N-Hydroxysuccinimide ester of adipic acid. Add 15ml of N,N-dimethylformamide to another reaction flask, cool down to 0-5°C in an ice bath, add 2.0g (10.0mmol) of 7-ANCA and 1.5ml of triethylamine, stir for 15 minutes, and use A small amount of N,N-dimethylformamide was added to the reaction flask after dissolving the above-mentioned N-hydroxysuccinimide ester of 1,6-adipic acid, and stirred overnight. Add 50ml of ice water, adjust the pH to 1-2 with 1N hydroc...

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Abstract

The invention relates to the technical field of medicines, in particular to a twin antibiotic compound formed by bonding each two parent nucleuses with the same structure of a beta-lactam antibiotic compound or of a derivative of the beta-lactam antibiotic compound with a dicarboxylic acid by two amido bonds, preparation method thereof and use thereof. The chemical structural general formula of the twin antibiotic compound is represented by a formula III. In the formula, R3 is a parent nucleus structure of a molecule of a penicillin compound or a derivative of the penicillin compound or a molecule of a cephalosporin compound or a derivative of the cephalosporin compound; and R may be alkyl and aryl or heteroaryl or substituted alkyl and substituted aryl or heteroaryl. In-vitro antibacterial experiments show that the beta-lactam twin antibiotic compound of the invention has remarkable antibacterial activity and is a novel antibacterial compound. The beta-lactam twin antibiotic compound of the invention can be used in the preparation of bacteriostats or bacteriacides as well as anti-infection medicaments. According to the general knowledge of pharmacy, the compound of the invention can be made into pharmaceutically acceptable salts or hydrates.

Description

technical field [0001] The invention relates to the technical field of medicine, which is a double antibiotic compound formed by connecting the mother cores of two β-lactam antibiotic compounds or their derivatives with the same structure and a dibasic carboxylic acid through two amide bonds and the preparation thereof Methods and uses. Background technique [0002] Antibiotics are a large class of antibacterial drugs used clinically, including penicillins, cephalosporins, penems, carbapenems, monocyclic β-lactams and tricyclic β-lactams. Among them, penicillins and cephalosporins are collectively referred to as β-lactam antibiotics, and their compound molecules all contain a β-lactam structure, and the nucleus structure in the penicillin compound molecule is 6-aminopenicillanic acid (6-APA) Or its derivative, see general structural formula I, the core structure of cephalosporin compound is 7-aminocephalosporanic acid (7-ACA) or its derivative, see general structural formul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06A61K31/431A61P31/04A61K31/546
CPCY02P20/55
Inventor 刘超美刘珏莹权振华张月莉刘涛张鲁榕
Owner 刘超美
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