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Carbapenem compound containing formyl hydrazino

A compound, carbamoyl technology, applied in the field of carbapenem compounds containing carboxyl hydrazide group, can solve the problems of inability to meet clinical needs, weak antibacterial activity of MRSA, low clinical availability, etc.

Active Publication Date: 2011-03-23
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Due to the continuous increase of bacterial resistance due to the abuse of antibiotics and the limitation of digestive tract absorption, the currently marketed carbapenems can only be administered as injections in clinical practice, and the clinical utilization is not high, and the antibacterial activity against MRSA Weak, can no longer meet clinical needs

Method used

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  • Carbapenem compound containing formyl hydrazino
  • Carbapenem compound containing formyl hydrazino
  • Carbapenem compound containing formyl hydrazino

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1 Preparation of (2S, 4S)-4-mercapto-2-formyl (1-methyl-1H-imidazolyl-5-formyl)hydrazine-1-(tert-butoxycarbonyl)pyrrolidine

[0106] 14.5 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 150 ml of anhydrous tetrahydrofuran were added to a dry reaction flask. Under the protection of nitrogen, 13g (80mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 0.5h, and 8.4g (60mmol) of 1-methyl-1H-imidazolyl-5-formylhydrazine was added below 0°C. Tetrahydrofuran solution was 100ml, and the reaction was continued for 0.5h. Then 60ml of 1mol / L hydrochloric acid was added dropwise, extracted with ethyl acetate (100ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added with 150ml of 3mol / L hydrochloric acid, stirred for 2h, and The dilute alkaline solution was adjusted to be basic, and a solid was precipitated, ...

Embodiment 2

[0107] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl (1-methyl-1H-imidazolyl-5-formyl)hydrazine-1-(tert-butoxycarbonyl )pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2 Preparation of -ene-2-carboxylic acid p-nitrobenzyl ester

[0108]In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo-[3,2,0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 11.9g (20mmol) in 120ml of acetonitrile solution, cooled to below -10°C, add diisopropylethylamine 5ml and (2S,4S)-4-mercapto-2-formyl (1-methyl-1H-imidazolyl-5-formyl)hydrazino-1-(tert-butoxycarbonyl)pyrrolidine 8.1g (22mmol) 80ml of acetonitrile solution, stirred at 0°C for 15h. After the reaction was completed, 300 ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 10.1 g of solid, yield: 71.2%.

Embodiment 3

[0109] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl (1-methyl-1H-imidazolyl-5-formyl)hydrazine Base-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]heptyl- Preparation of 2-ene-2-carboxylic acid (compound A)

[0110] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl(1-methyl-1H-imidazolyl-5-formyl)hydrazino-1-(tert-butoxycarbonyl)pyrrole Alk-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2-ene 7.1 g (10 mmol) of p-nitrobenzyl 2-carboxylate was dissolved in 50 ml of dichloromethane, 10 ml of anisole and 20 ml of nitromethane were added, and 1 mol / L of aluminum trichloride was added dropwise at -50°C Nitromethane solution 100ml, stir at -40°C for 2h, add 200ml of water, precipitate solid, filter, dissolve the filter cake in a mixture of 400ml of THF and 30ml of water, add 2g of 10% palladium-carbon, stir at room temperature under 5MPa hydrogen pressure After reacting for 2 hours, palladium carbon was filtered off, 150 ml of THF was...

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Abstract

The invention relates to a method for preparing a carbapenem compound shown in general formula (I) which contains formyl hydrazino, the ester which is easy to be hydrolyzed, pharmaceutically acceptable salt, isomer, hydrate, ester or salt hydrate thereof and the compound shown in the formula (I); the compounds are used for producing medical active materials, particularly preparing medicines for treating and / or preventing infectious diseases and pharmaceutical combination of the compounds shown in the formula (I). Definitions of R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and n in the general formula (I) can be seen in the specification.

Description

1. Technical field [0001] The present invention relates to a new carbapenem compound containing a hydrazide group, its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate, and the hydrate of its ester or salt , the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the application of these compounds for the preparation of medicines for treating and / or preventing infectious diseases belong to the technical field of medicine. 2. Background technology [0002] Carbapenems are new broad-spectrum, enzyme-resistant and highly effective β-lactam antibiotics developed in the 1970s. In 1976, Thiamycin, the first carbapenem antibiotic, was discovered, but it was not used clinically due to its poor chemical stability. Later, the chemical structure modification of thiamycin produced a series of carbapenem antibiotics. At present, such drugs that have been marketed include imipenem, panipene...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/06A61P31/04C07D477/20A61K31/407
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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