Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound

A compound, pyrrolidine technology, applied in organic chemistry, bulk chemical production, medical preparations containing active ingredients, etc., can solve the problems of low clinical availability, unable to meet clinical needs, weak MRSA antibacterial activity, etc.

Active Publication Date: 2012-07-04
XUANZHU BIOPHARMACEUTICAL 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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  • Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound
  • Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound
  • Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Preparation of Example 1 (2S, 4S)-4-mercapto-2-formyl [(4-dimethylamino-phen-1-yl) amino]-1-(tert-butoxycarbonyl)pyrrolidine

[0123] 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 the protection of nitrogen, add 6.5g (40mmol) of 1,1-carbonyldiimidazole at room temperature, react for 0.5h, add 4.8g (35mmol) of tetrahydrofuran solution of 4-dimethylaminoaniline below 0°C in 100ml, and 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, the residue was added with 100ml of 3mol / L hydrochloric acid, stirred for 2h, and The dilute alkaline solution was adjusted to be basic, and a solid was precipitated, which was recrystallized from a mixed solution of ...

Embodiment 2

[0124] Example 2 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(4-dimethylamino-phen-1-yl)amino]-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

[0125] 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 12g (20mmol) in 100ml of acetonitrile solution, cooled to below -20°C, add diisopropylethylamine 5ml and (2S, 4S)-4-mercapto-2-formyl[(4-dimethylamino-phen-1-yl)amino]-1-(tert-butoxycarbonyl)pyrrolidine 7.7g (21mmol) of acetonitrile The solution was 100ml, stirred at 0°C for 24h. After the reaction was completed, 200 ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 10.1 g of solid, yield: 71.2%.

Embodiment 3

[0126] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(4-dimethylamino-phen-1-yl)amino]-pyrrolidin-4-yl] Thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (ie Compound 1) Preparation

[0127] (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(4-dimethylamino-phen-1-yl)amino]-1-(tert-butoxycarbonyl)pyrrole Alkyl-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene- 14.2g (20mmol) of p-nitrobenzyl 2-carboxylate was dissolved in 100ml of dichloromethane, 20ml of anisole and 30ml of nitromethane were added, and 1mol / L of nitromethane of aluminum trichloride was added dropwise at -40°C. 200ml of methane solution, stirred at -30°C for 4h, added 300ml of water, precipitated solid, filtered, dissolved the filter cake in a mixture of 600mlTHF and 50ml of water, added 5g of 10% palladium-carbon, stirred at room temperature for 1h under hydrogen pressure of 5MPa, Palladium carbon was filtered off, THF150ml was added to the filtrate, t...

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Abstract

The present invention relates to a mercaptopyrrolidine carbapenem compound substituted by six-member ring methanamide shown in the formula (I), an easily hydrolyzed ester, a pharmaceutically acceptable non-toxic salt, an isomer, a hydrate and a hydrate of the ester and 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 six-membered ring carboxamide-substituted mercaptopyrrolidine carbapenem compound, its easily hydrolyzed ester, its pharmaceutically acceptable non-toxic salt, its isomer, its hydrate, and its ester or salt The hydrate, the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the application 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 derivatives. At present, such drugs that have been marketed incl...

Claims

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Application Information

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