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Pyridine-ion-containing vinyl cephalosporin derivative as well as preparation method and application thereof

An ion and alkenyl technology, applied in the field of medicine, can solve problems such as incomplete clinical data

Inactive Publication Date: 2016-11-30
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In 2008, Ceftobiprole (Ceftobiprole), as the world's first anti-Methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin, was launched in Canada, Switzerland and other countries successively, although the drug did not pass the US FDA review due to incomplete clinical data And withdrew from the market in 2010, but the brief appearance of Ceftobiprole still brings new hope for the research and development of new cephalosporin antibiotics

Method used

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  • Pyridine-ion-containing vinyl cephalosporin derivative as well as preparation method and application thereof
  • Pyridine-ion-containing vinyl cephalosporin derivative as well as preparation method and application thereof
  • Pyridine-ion-containing vinyl cephalosporin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0110] (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-acetylamino]-3-hydroxymethyl Preparation of Benzyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[0111]

[0112] At 15℃, treat 11.5g (50mmol) (6R,7R)-7-amino-3-hydroxymethyl-8-oxo-5-sulfide with 6.3ml 1,1,3,3-tetramethyl biguanide Hetero-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 100ml N,N-dimethylformamide (DMF) suspension, stirring until it becomes a solution (5min) . Use 23.5 g (67 mmol) of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-thioacetic acid-S-benzene at 0°C After treatment with thiazol-2-yl ester, stirring was continued at 0°C for 5h, and the reaction was detected to be complete. The solution was diluted with 200 ml of water, and the aqueous layer was washed 3 times with 100 ml of ethyl acetate. The aquifer was cooled to 0°C, 400ml of dichloromethane solution containing 28g (144mmol) of diphenyldiazomethane was added, the pH value was adjusted to 3 with hydrochloric ac...

preparation example 2

[0114] (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-ethoxyimino-acetylamino]-3-hydroxymethyl Preparation of benzhydryl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.

[0115]

[0116] At 15℃, treat 11.5g (50mmol) (6R,7R)-7-amino-3-hydroxymethyl-8-oxo-5-sulfide with 6.3ml 1,1,3,3-tetramethyl biguanide Hetero-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 100ml N,N-dimethylformamide (DMF) suspension, stirring until it becomes a solution (5min) . Use 24.5 g (67 mmol) of (Z)-(5-amino-[1,2,4]thiadiazol-3-yl)-ethoxyimino-thioacetic acid-S-benzene at 0°C After treatment with thiazol-2-yl ester, stirring was continued at 0°C for 5h, and the reaction was detected to be complete. The solution was diluted with 200 ml of water, and the aqueous layer was washed 3 times with 100 ml of ethyl acetate. The aquifer was cooled to 0°C, 400ml of dichloromethane solution containing 28g (144mmol) of diphenyldiazomethane was added, the pH value was adjusted to 3 with hydrochloric...

preparation example 3

[0118] (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-acetylamino]-3-formyl Preparation of -8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[0119]

[0120] Add 5g (8.62mmol) of 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-acetylamino]-3-hydroxymethyl under 20℃ Benzyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, 0.5g TEMPO dissolved in 60ml dichloromethane, divided Add 30 g (345 mmol) of active manganese dioxide in 3 batches. After reacting at room temperature for 5 hours, it was detected that the raw materials were exhausted, filtered, and the filtrate was evaporated to dryness to obtain a red solid. The product was obtained by column chromatography with petroleum ether / ethyl acetate = 1:1, and the yield was 58.2%. TOF-MS[M+H+]579.6; 1H NMR(300MHz, CDCl 3 )δ=9.70(s,1H),8.30(d,1H),7.3-7.4(m,10H),7.07(s,1H,CHPh 2 ), 6.40 (s, 2H), 6.27 (dd, 1H), 5.16 (d, 1H), 4.11 (s, 3H), 4.00 (d, J = 18.7, 1H), 3.31 (d, J = 18.7, 1H ).

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Abstract

The invention relates to a pyridine-ion-containing vinyl cephalosporin derivative of structural formula I as shown in the specification, a pharmaceutically acceptable salt of the vinyl cephalosporin derivative, a preparation method of the derivative, and application of the derivative in preparing medicines for preventing and / or treating diseases, symptoms and the like related to bacterial infection.

Description

Technical field [0001] The invention belongs to the field of medical technology. It relates to a novel vinyl cephalosporin derivative represented by the general formula I, and a pharmaceutically acceptable salt thereof, as well as a preparation method of the compound represented by the general formula I, a pharmaceutical composition, and the preparation method for preventing and / or treating bacterial infections Related to the application of infectious disease drugs. Background technique [0002] Bacterial infection is a disease that seriously threatens human health. Bacterial infectious diseases are currently the most common type of clinical disease. Severe infections can cause death. The wide application of cephalosporin antibiotics provides a new type of medicine with broad antibacterial spectrum, strong antibacterial power and good curative effect for clinic. Since the first cephalosporin antibiotic species came out in the early 1960s, cephalosporin antibiotics have been use...

Claims

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Application Information

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IPC IPC(8): C07D501/56C07D501/04A61K31/546A61P31/04
CPCC07D501/04C07D501/56Y02A50/30Y02P20/55
Inventor 冯文化任来阳
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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