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Cephalosporins compound and pharmaceutically acceptable salt thereof

A technology of cephalosporins and compounds, applied in the field of medicine

Inactive Publication Date: 2013-03-20
广州烜华生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The third-generation cephalosporins have a stronger antibacterial effect on Gram-negative bacteria than the second-generation cephalosporins, and the β-lactamase produced by negative bacteria is more stable. The antibacterial activity against Enterobacteriaceae is particularly prominent, and some cephalosporins Bacterin has a strong effect on Pseudomonas aeruginosa, but in general it has a poor effect on Gram-positive bacteria, especially Staphylococcus aureus, so it is mainly used for Gram-negative infections
Due to the widespread clinical use of fourth-generation cephalosporins, it has produced certain drug resistance to fourth-generation cephalosporins, which greatly affects the antibacterial efficacy and limits its clinical application. new antibiotics

Method used

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  • Cephalosporins compound and pharmaceutically acceptable salt thereof
  • Cephalosporins compound and pharmaceutically acceptable salt thereof
  • Cephalosporins compound and pharmaceutically acceptable salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (compound 1)

[0052] Trans-hydroxyproline 40g, dissolved in THF: water (2:1) 500ml, add 10% NaOH solution 170ml, the solution becomes clear; di-tert-butyl dicarbonate 90g dissolved in THF: water (2:1) 250ml, Added to the above solution, stirred overnight at room temperature. THF was distilled off under reduced pressure, 10% KHSO4 solution was adjusted to pH=2, extracted with 400ml×3 ethyl acetate, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the crystallization was repeated twice with ethyl acetate to obtain 57.98 g of granular white crystals, mp127-129, and the yield was 82.2%. TOF-MS (254.10[M+Na],485.21[2M+Na])

Embodiment 2

[0054] (2S,4R)-2-Dimethylcarbamoyl-4-methylsulfonyl-1-tert-butoxycarbonylpyrrolidine (compound 2)

[0055] Compound 1 (23.1 g, 0.1 mol) was dissolved in CH at -15 °C 2 Cl 2 200ml, add triethylamine (25.3g, 2.5eq), dropwise add methanesulfonyl chloride (25.5g, 2.2eq), stir for 1 hour, add dimethylamine hydrochloride (16g, 2eq), triethylamine ( 34g), continue to react for 1 hour. To terminate the reaction, the reaction solution was respectively mixed with water, 0.5NHCl solution, water, 5% NaHCO 3 solution, washed with saturated brine, the organic layer was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, crystallized with ethyl acetate-petroleum ether to obtain about 25 g of a solid with crystal luster, and recrystallized with isopropanol to obtain 25.8 g of block Solid, mp 130°C.

Embodiment 3

[0057] (2S,4S)-2-Dimethylcarbamoyl-4-acetylthio-1-tert-butoxycarbonylpyrrolidine (compound 3)

[0058] Compound 2 (6.73g), dissolved in 80ml of DMF:EtOAc (2:3), added 3.42g of potassium thioacetate, heated to 65°C and stirred for 10 hours, the reaction solution was cooled, diluted with 30ml of water, and diluted with 30ml of ethyl acetate ×3 extraction, the extract was washed with 1% sulfuric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized with ethyl acetate-petroleum ether to obtain 5.80 g of crystals, Mp99-101°C, yield 91.62 %.

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Abstract

The invention discloses a cephalosporins compound and pharmaceutically acceptable salt thereof, preparation methods of the compounds, a pharmaceutical composition comprising the compounds or the salt thereof, and applications in preparing the pharmaceutics for treating and / or preventing infectious diseases. The cephalosporins compound has a good bacteriostatic activity to gram-positive bacteria such as MRSA (Methicillin-resistant Staphylococcus aureus), MSSA (Methicillin Sensitive Staphylococcus Aureus) and MRSE (Methicillin Resistant Staphylococcus Epidermidis), and gram-negative bacteria such as drug-resistant bacteria producing ESBLs (Extended Spectyum beta Lactamase), is wide in antibacterial spectrum, strong in antibacterial activity, low-toxicity, and anti-drug resistance, thereby having extremely high research and development values.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a cephalosporin compound and a pharmaceutically acceptable salt thereof, a preparation method of these compounds, a pharmaceutical composition containing these compounds or their salts, and preparations for treating and / or preventing infectious diseases. Use in medicine for disease. Background technique [0002] Bacterial infection is the most common pathogenic factor and the most common disease affecting human health. Severe infection can cause death. There are more than 1,000 pharmaceutical companies producing various types of antibiotics in my country. However, because most manufacturers do not have proprietary varieties with independent intellectual property rights, the homogeneity of production is serious and the competition is fierce. [0003] Antibiotic drugs mainly include β-lactams, macrolides, tetracyclines, and aminoglycosides. Among them, β-lactams ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06A61K31/546A61P31/04
CPCY02P20/55
Inventor 邓世碧
Owner 广州烜华生物科技有限公司
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