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Penem derivative containing sulfhydryl pyrrolidine formamido triazine

A technology of compounds and hydrates, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, antibacterial drugs, etc., can solve the problems of low clinical utilization and short half-life

Active Publication Date: 2009-02-04
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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. The half-life of penem is relatively short, which can no longer meet the clinical needs

Method used

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  • Penem derivative containing sulfhydryl pyrrolidine formamido triazine
  • Penem derivative containing sulfhydryl pyrrolidine formamido triazine
  • Penem derivative containing sulfhydryl pyrrolidine formamido triazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1 (2S, 4S)-4-mercapto-2-formyl[[4-thiomethyl-6-(pyridin-2-yl)-1,3,5-triazin-2-yl]amino] -1-(tert-D Oxycarbonyl) pyrrolidine preparation

[0089] Add 8.7 g (30 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 100 ml of anhydrous tetrahydrofuran into the dry reaction flask. Under nitrogen protection, 6.5g (40mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 0.5h, and 4.8g (50mmol) of 2-amino-4-thiomethyl-6-(pyridine- 100ml of a tetrahydrofuran solution of 2-yl)-1,3,5-triazine, and continue the reaction for 0.5h. Then 40ml of 1mol / l hydrochloric acid was added dropwise, extracted with ethyl acetate (50ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added with 100ml of 3mol / l hydrochloric acid, stirred for 2h, and The dilute alkaline solution was adjusted to be alkaline, and a solid was precipitated, w...

Embodiment 2

[0090] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[[4-thiomethyl-6-(pyridin-2-yl)-1,3,5-triazine -2-yl]amine Base]-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

[0091] In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrogen Heterobicyclo-[3,2,0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 35.8g (60mmol) in 400ml of acetonitrile solution was cooled to below -20°C, added diisopropylethylamine 16ml and (2S,4S)-4-Mercapto-2-formyl[[4-thiomethyl-6-(pyridin-2-yl)-1,3,5-triazin-2-yl]amino]-1- A solution of 29.1 g (65 mmol) of (tert-butoxycarbonyl)pyrrolidine in 200 ml of acetonitrile was stirred at 0°C for 24 h. After the reaction was completed, it was diluted with 600 ml of ethyl acetate, washed with water and saturated brine successively, the organic layer was dried and concentrated to ...

Embodiment 3

[0092] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[[4-thiomethyl-6-(pyridin-2-yl)-1,3,5-triazine -2-yl]amino]- Pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]hept-2- Preparation of ene-2-carboxylic acids

[0093](4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[[4-thiomethyl-6-(pyridin-2-yl)-1,3,5-triazine-2 -yl]amino]-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrogen Heterobicyclo-[3,2,0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester 23.8g (30mmol) was dissolved in 100ml of dichloromethane, added anisole 30ml and nitromethane 30ml, in Add 200ml of nitromethane solution of 1mol / L aluminum chloride dropwise at -50°C, stir at -30°C for 4h, add 300ml of water, precipitate a solid, filter, dissolve the filter cake in a mixture of 600mlTHF and 50ml of water, add 10% palladium-carbon 5g, stirred at room temperature under 5MPa hydrogen pressure for 2h, filtered palladium-carbon, added THF 200ml to the filtrate, sep...

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Abstract

The invention belongs to the medicine technology field, which more particularly relates to an ertapenem compound containing hydrosulphonyl pyrrolidine formamide triazine, the salt acceptable in pharmacy thereof, the ester which is easy to be hydrolyzed, the isomer thereof, the hydrate thereof and the hydrate of ester or salt thereof shown in the formula (I) and a preparing method of the compound shown in the formula (I); wherein, the definitions of R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are elaborately described in an introduction. The invention also relates to preparing methods of compounds and the drug combination containing the compounds and the applications of the compounds in preparing the medicine for curing or preventing infectious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to penem compounds containing mercaptopyrrolidine carboxamidotriazine, their pharmaceutically acceptable salts, their easily hydrolyzed esters, their isomers, their hydrates, and their esters or Hydrates of salts, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and uses of these compounds in the preparation of medicaments for treating and / or preventing infectious diseases. 2. Background technology [0002] Carbapenem antibiotics are a class of β-lactam antibiotics developed in the 1970s. It has attracted much attention because of its broad antibacterial spectrum, strong antibacterial activity, and stability to β-lactamase. Its structural feature is that the sulfur at the 1-position of the penicillane core is replaced by carbon, and the 2-position has a double bond, which combines the five-membered ring of penicillin an...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/53A61P31/04
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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