Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds

A compound, methyl technology, applied in the field of mercaptopyrrolidine carbapenem compounds substituted by carboxamide alkylbenzene, can solve the problems of not meeting clinical needs, weak antibacterial activity of MRSA, and low clinical utilization

Active Publication Date: 2008-12-31
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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  • Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds
  • Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds
  • Formamide alkylbenzene substituted mercapto pyrrolidine carbapenem compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0090] The preparation of embodiment 1 (2S, 4S)-4-mercapto-2-formyl [N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl) pyrrolidine prepare

[0091] 14.5 g (50 mmol) of (2S,4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine and 150 ml of anhydrous tetrahydrofuran were added to a dry reaction flask. Under the protection of nitrogen, 13g (80mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 0.5h, and 8.3g (51mmol) of N-benzyl-2-methylpropyl-2-amine was added below 0°C. Tetrahydrofuran solution 100ml, continue to react for 1h. Then 60ml of 1mol / L hydrochloric acid was added dropwise, extracted with ethyl acetate (100ml×2), the organic phase was washed with water and saturated sodium chloride solution successively, concentrated under reduced pressure, the residue was added with 150ml of 3mol / L hydrochloric acid, stirred for 2h, and The dilute alkali solution was adjusted to be alkaline, and a solid was precipitated, which was recrysta...

Embodiment 2

[0092] Example 2 (2S, 4S)-4-mercapto-2-formyl [N-(4-fluorobenzyl)-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrole Preparation of alkane

[0093] Refer to Example 1 for the specific preparation method. Cast (2S, 4S)-4-acetylthio-2-carboxy-1-(tert-butoxycarbonyl)pyrrolidine 14.5g (50mmol), N-(4-fluorobenzyl)-2-methylpropyl- 2-amine 9.2 g (51 mmol). 16.3 g of the product was obtained, yield: 79.3%.

Embodiment 3

[0094] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl ) Pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept 2-ene- 2-Carboxylic acid p-nitrobenzyl ester preparation of

[0095] 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 5ml of diisopropylethylamine and (2S, 4S)-4-mercapto-2-formyl [N-benzyl-2-methylpropyl-2-amino]-1-(tert-butoxycarbonyl)pyrrolidine 8.6g (22mmol) 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 in sequence, the organic layer was dried and concentrated to obtain 10.1 g of solid, yield: 68.3%.

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Abstract

The invention relates to a formamide alkylbenzene-substituted sulfhydryl pyrrolidine carbapenem compound as shown in general formula (I), and also relates to the easy hydrolysis esters of the compound, the pharmaceutical acceptable non-toxic salts of the compound, the isomers of the compound, the hydrates of the compound, the hydrates of the esters or salts of the compound, the preparation methods for the compounds in formula (I), the purposes of the compounds as medicinal active substances and especially the applications of the compounds in the preparation of drugs for curing and/or preventing infectious diseases, as well as the drug combinations containing the compounds in formula (I). The detailed definitions of R1, R2, R3, R4, R5, R6 and n in the formula (I) are shown in the instruction book.

Description

1. Technical field [0001] The present invention relates to carboxamide alkylbenzene-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 include i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/407A61P31/00
CPCY02P20/55
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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