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Penem compound containing dihydroimidazole formamido

A compound and amide technology, applied in the field of matter, can solve the problems of not meeting clinical needs, weak antibacterial activity of MRSA, and low clinical availability.

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

[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 compound containing dihydroimidazole formamido
  • Penem compound containing dihydroimidazole formamido
  • Penem compound containing dihydroimidazole formamido

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1 (2S, 4S)-4-acetylthio-2-formyl[(4-formylamino-4,5-dihydro-1H-imidazol-5-yl)amino]-pyrrolidine preparation of

[0101] 5.7 g (30 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-pyrrolidine and 100 ml of anhydrous tetrahydrofuran were added to the dry reaction flask. Under the protection of nitrogen, add 6.5g (40mmol) of 1,1-carbonyldiimidazole at room temperature, react for 0.5h, add 5-amino-4-formylamino-4,5-dihydro-1H-imidazole below 0°C 6.4g (50mmol) of tetrahydrofuran solution in 100ml, continue to react 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, and the solid was recrystallized from ethanol solution to obtain 7.1g of solid. : 78.6%.

Embodiment 2

[0102] Example 2 (2S, 4S)-4-mercapto-2-formyl [(4-formamido-4,5-dihydro-1-tert-butoxycarbonyl-imidazol-5-yl) ammonia Preparation of base]-1-(tert-butoxycarbonyl)pyrrolidine

[0103] Add (2S,4S)-4-acetylthio-2-formyl[(4-formylamino-4,5-dihydro-1H-imidazol-5-yl)amino]-pyrrolidine 9g into the reaction flask (30mmol) of dichloromethane solution in 90ml, cooled in an ice bath to 5°C, added 12ml of triethylamine, stirred for 5min, then added dropwise 20g of (Boc) 2O in dichloromethane solution 100ml, stirred for 1h. Add 100ml of water under ice water cooling, separate the water layer, extract the water layer with 50ml×3 dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate to dryness, add 100ml of 3mol / L hydrochloric acid to the residue, and stir After 2 hours, it was adjusted to basicity with a dilute alkali solution, and a solid was precipitated, which was recrystallized from a mixed solution of acetonitrile and acetone to obtain 11.7 g o...

Embodiment 3

[0104] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(4-formylamino-4,5-dihydro-1-tert-butoxycarbonyl-imidazole-5- 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

[0105] 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 35.8g (60mmol) in 400ml of acetonitrile solution, cooled to below -20°C, add diisopropylethylamine 16ml and (2S, 4S)-4-mercapto-2-formyl [(4-formylamino-4,5-dihydro-1-tert-butoxycarbonyl-imidazol-5-yl)amino]-1-( A solution of 29.7 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, and the organic layer was dried and...

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PUM

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Abstract

The invention relates to a method for preparing an ertapenem compound as shown in general formula (I) which contains glyoxalidine formamido, the ester which is easy to be hydrolyzed, the pharmaceutically acceptable salt, the isomer, the hydrate, the ester or salt hydrate thereof and the compound as shown in formula (I); the compounds are used for producing medical active materials, particularly preparing medicines for curing and / or preventing infectious diseases and pharmaceutical combination of the compounds as shown in formula (I). Definitions of R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7> and R<8> in the general formula (I) can be seen in the specification.

Description

1. Technical field [0001] The present invention relates to penem compounds containing dihydroimidazole carboxamide groups, their easily hydrolyzed esters, their pharmaceutically acceptable salts, their isomers, their hydrates, and hydrates of their esters or salts. The preparation method, the pharmaceutical composition 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 marketed include imipenem, panipenem, meropenem, doripenem, b...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/4178A61P31/04
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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