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Penem derivative containing isothioureido sulfhydryl pyrrolidine

A carboxyl-protecting group and amino-protecting group technology, applied in the field of penem derivatives containing isothiourea-mercaptopyrrolidine, can solve the problems of not meeting clinical needs, weak antibacterial activity of MRSA, and low clinical utilization

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 derivative containing isothioureido sulfhydryl pyrrolidine
  • Penem derivative containing isothioureido sulfhydryl pyrrolidine
  • Penem derivative containing isothioureido sulfhydryl pyrrolidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] The preparation of embodiment 1 (2S, 4S)-4-acetylthio-2-formyl [(S-2-isothioureido-ethane-1-yl) amino]-pyrrolidine

[0107]

[0108] 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, 6.5g (40mmol) of 1,1-carbonyldiimidazole was added at room temperature, reacted for 0.5h, and 6.0g (50mmol) of S-2-isothioureido-1-ethylamine was added below 0°C. Tetrahydrofuran solution 100ml, continue to react for 1h. 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 isopropanol solution to obtain 6.2g of solid. Yield: 71.5%.

Embodiment 2

[0109] Example 2 (2S, 4S)-4-mercapto-2-formyl [(S-2-(N, N'-tert-butoxycarbonyl) isothiourea-ethane-1-yl) amino]-pyrrole Preparation of alkane

[0110]

[0111] Add (2S, 4S)-4-acetylthio-2-formyl [(S-2-isothioureido-ethane-1-yl)amino]-pyrrolidine 8.7g (30mmol) in the reaction flask 100ml of dichloromethane solution, cooled in an ice bath to 5°C, added 12ml of triethylamine, stirred for 5min, then added dropwise 25g of (Boc) 2 O 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 alkaline solution, and a solid was precipitated, which was recrystallized from a mixed solution of acetonitrile and acetone to obtain 14.6 g of the product, with a yield o...

Embodiment 3

[0112] Example 3 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl[(S-2-(N, N'-tert-butoxycarbonyl)isothiourea-ethane-1 -yl) ammonia Base]-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo-[3,2,0]heptane -2-ene-2-carboxylic acid p-nitro Preparation of benzyl esters

[0113]

[0114]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 18g (30mmol) in 200ml of acetonitrile solution, cooled to below -20°C, add diisopropylethylamine 8ml and (2S,4S)-4-mercapto-2-formyl[(S-2-(N,N'-tert-butoxycarbonyl)isothioureido-ethan-1-yl)amino]-pyrrolidine 17.6 g (32mmol) in 200ml of acetonitrile, stirred at 0°C for 24h. After the reaction was completed, 600 ml of ethyl acetate was added to dilute, washed with water and saturated brine successively, the organic layer was dried and concentrated to obtain 19.4 g of solid, yield: 72.5%.

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Abstract

The invention relates to an ertapenem derivative which contains heter-thioureido sulfhydryl pyrrolidine, the ester which is easy to be hydrolyzed, the salt acceptable in pharmacy, the isomer thereof, the hydrate thereof and the hydrate of ester or salt thereof shown in the formula (I) and a preparing method of the compound shown in the formula (I). The compounds are used as active materials, in particular to be used for preparing the medicine for curing or preventing infectious diseases and to be used as a drug combination containing the compound shown in the formula (I). In the formula (I), the definitions of R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, and n are elaborately described in an introduction.

Description

1. Technical field [0001] The present invention relates to penem derivatives containing isothiouridyl mercaptopyrrolidine, their easily hydrolyzed esters, their pharmaceutically acceptable salts, their isomers, their hydrates, and hydrates of their esters or salts. The preparation method of the compounds, 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 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 antibiotics. At present, such drugs that have been marketed include imipenem, panipenem, merope...

Claims

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Application Information

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