Carbapenem compound

A compound and hydrate technology, applied in the field of medicine, can solve the problems of not meeting clinical needs, weak antibacterial activity of MRSA, and low clinical utilization

Inactive Publication Date: 2009-06-17
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 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
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1 (2S, 4S)-4-acetylthio-2-formyl [(2-tert-butylamino-acetyl-1-yl)amino]-1-(tert-butoxycarbonyl)pyridine Preparation of rolidine

[0095] Add (2S, 4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine 8.7g (30mmol) and 100ml of anhydrous tetrahydrofuran to the dry reaction flask, under nitrogen protection, in Add 6.5g (40mmol) of 1,1-carbonyldiimidazole at room temperature, react for 0.5h, add (2-tert-butylamino)acetamide 7.8g (60mmol) in 100ml of tetrahydrofuran solution below 0°C, continue the reaction for 0.5h, then Add 40ml of 1mol / L hydrochloric acid dropwise, extract with ethyl acetate (50ml×2), wash the organic phase with water and saturated sodium chloride solution successively, concentrate under reduced pressure, and recrystallize the solid from a mixed solution of acetonitrile and ethyl acetate to obtain 10.4g , Yield: 86.5%.

Embodiment 2

[0096] Example 2 (2S, 4S)-4-mercapto-2-formyl [(2-(N-tert-butoxycarbonyl-tert-butylamino)-acetyl-1-yl)amino]-1-(tert Preparation of butoxycarbonyl)pyrrolidine

[0097] Add (2S,4S)-4-acetylthio-2-formyl[(2-tert-butylamino-acetyl-1-yl)amino]-1-(tert-butoxycarbonyl)pyrrolidine 10g into the reaction flask (25mmol) of dichloromethane solution in 80ml, cooled in an ice bath to 5°C, added 10ml of triethylamine, stirred for 5min, then added dropwise 10g of (Boc) 2 100ml of dichloromethane solution of O, stirred for 1h, added 100ml of water under ice-water cooling, separated the water layer, and extracted the water layer with 50ml×3 dichloromethane, combined the organic layers, dried over anhydrous sodium sulfate, and concentrated to dryness. Add 100ml of 2mol / L hydrochloric acid to the residue, stir for 2h, adjust to basicity with dilute alkaline solution, and precipitate a solid, which is recrystallized with an equal volume of acetonitrile and acetone mixed solution to obtain 9.4...

Embodiment 3

[0098] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-4-mercapto-2-formyl[(2-(N-tert-butoxycarbonyl-tert-butylamino)-acetyl-1- base) Amino]-1-(tert-butoxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo- [3, 2, 0] G Preparation of -2-ene-2-carboxylic acid p-nitrobenzyl ester

[0099]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-acetylthio-2-formyl[(2-(N-tert-butoxycarbonyl-tert-butylamino)-acetyl-1-yl)amino]-1-(tert-butyl Oxycarbonyl)pyrrolidine 10.1g (22mmol) in 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 10.4 g o...

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Abstract

The invention relates to carbapenem compounds expressed by general formula (I), and easily-hydrolyzed ester, pharmaceutically acceptable salt, isomer, hydrate and hydrate of salt or ester thereof, and a method for preparing the compounds expressed by the general formula (I); and the invention relates to application of the compounds as medical active substances, in particular to application of the compounds for preparing medicine for treating and / or preventing infectious diseases, and medicament composition containing the compounds expressed by the general formula (I). In the general formula (I), R<1>, R<2>, R<3>, R<4> and R<5> are defined as description in detail.

Description

1. Technical field [0001] The present invention relates to carbapenem compounds, their easily hydrolyzed esters, their pharmaceutically acceptable salts, their isomers, their hydrates, and the hydrates of their esters or salts, and the preparation methods of these compounds, which contain these The pharmaceutical composition of the compounds and the use of these compounds in 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, panipenem, meropenem, doripenem...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/407A61P31/04
CPCY02P20/55
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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