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Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle

A carbamoyl and alkyl technology, which is applied in the field of penem derivatives containing mercaptopyrrolidine carboxamide phenyl alkyl heterocycles, can solve the problems of inability to meet clinical needs, low clinical availability, weak MRSA antibacterial activity and the like

Active Publication Date: 2008-12-31
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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  • Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle
  • Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle
  • Penem derivates with mercapto pyrrolidine formamide benzene alkyl heterocycle

Examples

Experimental program
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Effect test

Embodiment 1

[0104] Example 1 (2S, 4S)-4-mercapto-2-formyl [4-(pyridin-4-yl)methyl-phenylamino]-1-(tert-butoxycarbonyl)pyrrolidine preparation

[0105] Add (2S, 4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine 5.8g (20mmol) and 100ml of anhydrous tetrahydrofuran to the dry reaction flask, under nitrogen protection, in Add 4.9g (30mmol) of 1,1-carbonyldiimidazole at room temperature, react for 1h, add 4-(pyridin-4-yl)methyl-aniline 7.4g (40mmol) in 100ml of tetrahydrofuran solution below 0°C, and continue the reaction for 0.5h , then dropwise added 40ml of 1mol / L hydrochloric acid, extracted with ethyl acetate (50ml×2), washed the organic phase with water and saturated sodium chloride solution successively, concentrated under reduced pressure, added 100ml of 5mol / L hydrochloric acid to the residue, stirred for 2h, Adjust to basicity with dilute alkali solution, precipitate solid, and recrystallize solid with ethyl acetate-cyclohexane mixture to obtain 6.9 g of solid, yield:...

Embodiment 2

[0106] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(pyridin-4-yl)methyl-phenylamino]-1-(tert-butoxycarbonyl) Pyril Rolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2- p-nitrobenzyl alkene-2-carboxylate preparation of

[0107]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[4-(pyridin-4-yl)methyl-phenylamino]-1-(tert-butoxycarbonyl)pyrrolidine 9.1g (22mmol) Acetonitrile solution 80ml, 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 11.7 g of solid, yield: 77.1%.

Embodiment 3

[0108] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(pyridin-4-yl)methyl-phenylamino]-pyrrolidin-4-yl]sulfur base - Preparation of 6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2-ene-2-carboxylic acid

[0109] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[4-(pyridin-4-yl)methyl-phenylamino]-1-(tert-butoxycarbonyl)pyrrolidine -4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2-ene- 7.6g (10mmol) of p-nitrobenzyl 2-carboxylate was dissolved in 50ml of dichloromethane, 10ml of anisole and 20ml of nitromethane were added, and 1mol / L of nitromethane of aluminum trichloride was added dropwise at -50°C. 100ml of methane solution, stirred at -40°C for 2h, added 200ml of water, precipitated solid, filtered, dissolved the filter cake in a mixture of 400ml of THF and 30ml of water, added 2g of 10% palladium-carbon, stirred at room temperature for 2h under hydrogen pressure of 5MPa , filter off palladium carbon, add THF 150ml to the filtrate, separate...

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Abstract

The invention relates to a penem derivative containing sulfhydryl pyrrolidine formamide heterocyclic alkyl benzene as shown in general formula (I), and also relates to the easy hydrolysis esters of the derivative, the pharmaceutical acceptable non-toxic salts of the derivative, the isomers of the derivative, the hydrates of the derivative, as well as the hydrates of the esters or salts of the derivative; wherein, the detailed definitions of R1, R2, R3, R4, R5, R6, R7 and n are shown in the instruction book. The invention also relates to the preparation methods for the compounds in formula (I), the drug combinations containing the compounds in formula (I), as well as the purposes of the compounds in formula (1) as medicinal active substances, especially the applications of the compounds in the preparation of drugs for curing and / or preventing infectious diseases.

Description

1. Technical field [0001] The present invention relates to penem derivatives containing mercaptopyrrolidinecarboxamide phenylalkyl heterocycles, their easily hydrolyzed esters, their pharmaceutically acceptable non-toxic salts, their isomers, their hydrates, and their esters or salts Hydrates of these compounds, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds for preparing medicines for treating and / or preventing infectious diseases belong to the field of medical technology. 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 derivatives. At present, such drugs that have been ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/4439A61K31/541A61K31/407A61P31/04
CPCY02P20/55
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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