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Mercaptopyrrolidone carbon penems derivatives

A methyl compound technology, applied in the field of new-type mercaptopyrrolidone carbapenem derivatives, can solve the problems of not meeting clinical needs, narrow antibacterial spectrum, unsatisfactory effect, etc.

Active Publication Date: 2008-09-10
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The derivatives, salts or esters of the compounds are mainly used in the preparation of anti-helicobacter pylori medicines, and are mainly used for the treatment and prevention of infectious diseases caused by helicobacter pylori. Although they have good antibacterial activity, due to At present, the drug resistance of clinical bacteria continues to increase, and the effect on drug-resistant bacteria is still unsatisfactory. The antibacterial spectrum is relatively narrow, and the effect is not satisfactory. At the same time, due to the limitations of injection administration, it can no longer meet the clinical needs.

Method used

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  • Mercaptopyrrolidone carbon penems derivatives
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  • Mercaptopyrrolidone carbon penems derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1 Preparation of (3S)-2-oxo-3-mercapto-1-(N-tert-butoxycarbonylpyrrolidin-3-yl)pyrrolidine

[0120] In the dry reaction bottle, add (3S)-3-formylmercapto-2-oxopyrrolidine 14.5g (0.1mol) and 200ml tetrahydrofuran, stir to dissolve, add powdery potassium carbonate 14g, heat up to reflux. A tetrahydrofuran solution of 25 g (0.1 mol) / 100 ml of N-1-tert-butoxy-3-bromo-pyrrolidine was added dropwise. After the dropwise addition, keep stirring for 2 hours. The reaction solution was filtered, concentrated to dryness under reduced pressure, added 100ml of 3mol / L hydrochloric acid, stirred for 2h, and adjusted to a pH above 8 with a dilute alkali solution, and a yellow solid was precipitated, which was recrystallized from a methanol / acetone mixed solution to obtain 21g of a light yellow solid. Yield: 73.4%.

Embodiment 2

[0121] Example 2 Preparation of (3S)-2-oxo-3-mercapto-1-(N-tert-butoxycarbonylazetidin-3-yl)pyrrolidine

[0122] In the dry reaction bottle, add (3S)-3-formylmercapto-2-oxopyrrolidine 14.5g (0.1mol) and 300ml tetrahydrofuran, stir to dissolve, add powdery potassium carbonate 14g, heat up to reflux. Add 26 g (0.11 mol) of 3-bromo-N-tert-butoxycarbonyl azetidine in batches. After the addition, keep stirring and react for 4 hours, filter the reaction solution, concentrate to dryness under reduced pressure, add 100 ml of 3 mol / L hydrochloric acid, Stir for 2 hours, adjust to alkaline with dilute alkali solution, and precipitate a yellow solid, which is recrystallized from a methanol / acetone mixed solution to obtain 18.7 g of a light yellow solid, yield: 65.3%.

Embodiment 3

[0123] Example 3 (4R, 5S, 6S)-3-[(3S)-2-oxo-1-(N-tert-butoxycarbonylpyrrolidin-3-yl)pyrrolidin-3-yl]thio -6-[(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]-2-ene-2-carboxylic acid p-nitrobenzyl Preparation of esters

[0124] In a dry reaction flask, add (4R, 5S, 6S)-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo-[3,2,0]-2-ene-2-carboxylic acid p-nitrobenzyl ester 17.8g (30mmol) in acetonitrile (180ml) solution cooled to below -10°C, add diisopropylethylamine 7ml and (3S)-2-oxo-3-mercapto-1-(N-tert-butoxycarbonylpyrrolidin-3-yl)pyrrolidine 10g (35mmol) in acetonitrile 100ml solution, stirred at 0°C for 15h. After the reaction was completed, 500 ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 15.8 g of light yellow solid, yield: 82.7%.

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Abstract

The invention belongs the medical and pharmaceutical technical field, in particular to novel derivatives of thiol pyrrolidone carbapenem shown in formula (I), as well as pharmaceutically acceptable salts, easily hydrolyzed esters and isomers thereof, and hydrates of the derivatives, and hydrates of the esters or the salts of the derivatives, wherein R<1>, R<2>, R<3> and n are defined in the instruction. The invention also relates to a preparation method for the compounds, combinations containing the compounds, and an application of the compounds to medicines used to treat and / or prevent the contagious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to novel mercaptopyrrolidone carbapenem derivatives, pharmaceutically acceptable salts thereof, easily hydrolyzed esters, isomers thereof, hydrates thereof, and hydration of esters or salts thereof substances, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and applications of these compounds in the preparation of medicines for treating and / or preventing infectious diseases. 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 imipen...

Claims

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Application Information

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