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Sulfhydryl pyrrolidine formyl arylamine heterocycle substituted penem derivant

A methyl and carboxyl technology, applied in the field of pharmaceutical compositions of some compounds, can solve problems such as low clinical availability, weak MRSA antibacterial activity, and inability to meet clinical needs.

Inactive Publication Date: 2009-02-18
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the continuous increase of bacterial resistance and the limitation of digestive tract absorption due to the abuse of antibiotics, the carbapenems currently on the market 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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  • Sulfhydryl pyrrolidine formyl arylamine heterocycle substituted penem derivant
  • Sulfhydryl pyrrolidine formyl arylamine heterocycle substituted penem derivant
  • Sulfhydryl pyrrolidine formyl arylamine heterocycle substituted penem derivant

Examples

Experimental program
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Effect test

Embodiment 1

[0098] Example 1 Preparation of (2S, 4S)-4-acetylthio-2-formyl [3-(4,5-dihydro-1H-imidazol-2-yl) aniline]-pyrrolidine

[0099] Add 5.7 g (30 mmol) of (2S, 4S)-4-acetylthio-2-carboxy-1-pyrrolidine and 100 ml of anhydrous tetrahydrofuran into a dry reaction flask, and add 1,1- Carbonyldiimidazole 6.5g (40mmol), react for 0.5h, add 6.4g (40mmol) 3-(4,5-dihydro-1H-imidazol-2-yl) aniline in 100ml of tetrahydrofuran solution below 0°C, continue the reaction for 0.5 h, 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 acetone solution to obtain 11.4g of solid. Yield: 87.5%.

Embodiment 2

[0100] Example 2 Preparation of (2S, 4S)-4-acetylthio-2-formyl [3-(4H-1,2,4-triazol-3-yl)aniline]-pyrrolidine

[0101] Referring to the preparation method of Example 1, 5.7 g (30 mmol) of (2S, 4S)-4-acetylthio-2-carboxy-1-pyrrolidine, 3-(4H-1,2,4-triazole-3 -yl) aniline 6.4g (40mmol), the product: 11.0g, yield: 85.2%.

Embodiment 3

[0102] Example 3 (2S, 4S)-4-mercapto-2-formyl [3-[4,5-dihydro-1-(tert-butoxycarbonyl) imidazol-2-yl]aniline]-1-(tert-butyl oxygen Preparation of carbonyl)pyrrolidine

[0103] Add (2S,4S)-4-acetylthio-2-formyl[3-(4,5-dihydro-1H-imidazol-2-yl)aniline]-pyrrolidine 10.8g (25mmol) into the reaction flask 80ml of dichloromethane solution, cooled in an ice bath to 5°C, added 10ml of triethylamine, stirred for 5min, then added dropwise 15g 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 alkaline with dilute alkali solution, and precipitate a solid, which is recrystallized from a mixed solution of acetonitrile and acetone (2:1) to obtain 11.2g of the product, yiel...

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Abstract

The present invention relates to a penem derivative substituted by mercaptopyrrolidine formylarylamine heterocycles shown in the formula (I), an easily hydrolyzed ester, a pharmaceutically acceptable salt, an isomer, a hydrate and a hydrate of the ester or the salt thereof, a method for preparing the compound shown in the formula (I), the applications of the compounds used as medical active substances, in particular the applications in the preparation of drugs for treating and / or preventing infective diseases, and drug combinations containing the compound shown in the formula (I). In the formula (I), R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and R<7> are defined in the description.

Description

1. Technical field [0001] The present invention relates to penem derivatives substituted by mercaptopyrrolidinecarboxamide heterocycles, their easily hydrolyzed esters, their pharmaceutically acceptable salts, their isomers, their hydrates, and the hydration of their esters or salts Compounds, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds for the preparation of drugs 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 inclu...

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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