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Cephalosporin derivative

A technology of drugs and compounds, applied in the field of medicine, can solve problems such as drug resistance and lack of pharmacological activity

Active Publication Date: 2010-06-02
JILIN ZHENAO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Cefodizime is a semi-synthetic third-generation cephalosporin antibiotic, which was first launched in Japan in 1990. It has antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, is stable to β-lactamase, and is resistant to cephalosporinase. It is extremely stable with penicillinase, but it also produces drug resistance due to long-term application. Patent US4278793 also discloses a variety of similar compounds, but does not provide pharmacological activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Embodiment 1 Preparation method one of compound A and its sodium salt A'

[0138] (1) (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazol-3-yl)-2-oximino]acetamido]-3-acetoxymethyl Preparation of yl-5-thia-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0139] In the dry reaction bottle, add 27.2g 7-ACA (0.1mol), 40.5g (0.12mol) (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl) - 2-oximinothioacetic acid (S-2-benzothiazole) ester and 500ml of dichloromethane, stir rapidly and control the temperature below 5°C, adjust the pH to 8 with triethylamine, quickly warm up to room temperature, and react 4 Hour. After the reaction was completed, the reaction solution was extracted twice with water (100ml / time), and the pH was adjusted to 2 to 3 with 2mol / L dilute hydrochloric acid after merging the water phases. A white solid was precipitated, filtered, and dried in vacuo to obtain 34.8g of a white solid. The yield was 78.7%.

[0140] (2) (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazol 3-yl)2-oxi...

Embodiment 2

[0150] Embodiment 2 Preparation method two of compound A and its sodium salt A'

[0151] (1) (6R, 7R)-7-amino-3-(4-methyl-5-acetoxy-thiazol-2-yl)thiomethyl-8-oxo-5-thia-1-aza Preparation of bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0152] Add (6R,7R)-7-amino-3-(acetoxy)methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2 to the Erlenmeyer flask -Alkene-2-carboxylic acid (ie 7-ACA) 2.8g (0.01mol), water 15ml, shake to make a uniform suspension for use. Add 2.9g (0.015mol) of 2-mercapto-4-methyl-5-thiazoleacetic acid and 40ml of water into a 250ml three-necked flask, add 0.56g (0.014mol) of NaOH solid in batches under stirring, and then use saturated NaHCO 3 Adjust the pH of the solution to 6.4, control the temperature in a water bath at 70°C, then add 7-ACA suspension dropwise and add saturated NaHCO dropwise 3 solution to make the pH of the reaction solution about 6.4, add it in 15 minutes, react for 35 minutes after the addition, then add activated carbon and stir for 10 mi...

Embodiment 3

[0164] Embodiment 3 Compound B and its sodium salt B' preparation method one

[0165] (1) (6R, 7R)-7-[2-[(5-amino-1,2,4-thiadiazol-3-yl)-Z-2-(methoxyimino)]acetamido] - Preparation of 3-acetoxymethyl-5-thia-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0166] In a dry reaction flask, sequentially add (6R,7R)-7-amino-3-(acetyloxy)methyl-8-oxo-5-thia-1-azabicyclo[4.2.0] Oct-2-ene-2-carboxylic acid (7-ACA) 27.2g (0.1mol), (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-Z- 43.9 g (0.12 mol) of 2-(methoxyimino)thioacetic acid (S-2-benzothiazole) ester and 500 ml of dichloromethane, stir rapidly and control the temperature below 5°C, adjust the pH to 8 with triethylamine , rapidly warming up to room temperature, reacted for 4 hours, extracted the reaction solution with water twice (100ml / time) after the completion of the reaction, adjusted the pH to 2-3 with 2mol / L dilute hydrochloric acid after the combined water phase, separated out a white solid, filtered, vacuum After drying...

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Abstract

The invention relates to compounds of novel cephalosporin derivatives as well as pharmaceutically acceptable salts, easy hydrolysis ester, isomer, hydrates and hydrates of salts or esters thereof shown in the general formula (1), wherein, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are defined as the instruction. The invention also relates to the preparation methods of the compounds, medical composition, which contains the compounds, and the application of the compounds in preparation of drugs, which are used for curing and / or preventing diseases caused by viral infection, and pertains to the fieldof medical technologies.

Description

1. Technical field [0001] The present invention relates to new cephalosporin derivatives, their pharmaceutically acceptable salts, their easily hydrolyzed esters, their isomers, their hydrates and the hydrates of their salts or esters, and the preparation methods of these compounds, which contain these The pharmaceutical composition of the compounds and the use 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] Cephalosporin antibiotics are widely used in clinical antibacterial drugs and have been developed to the fourth generation. However, due to long-term clinical use, bacteria are resistant to cephalosporin antibiotics, which greatly affects the antibacterial efficacy of cephalosporin antibiotics. In particular, infectious diseases caused by methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and drug-resi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36A61P31/04A61K31/546
CPCY02P20/55
Inventor 黄振华
Owner JILIN ZHENAO PHARMA CO LTD
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