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Clinafloxacin amino derivatives and application thereof

A derivative, star amino technology, applied in the field of chemistry and pharmacy, can solve problems such as solution instability, poor solubility, toxicity, etc.

Inactive Publication Date: 2011-04-27
CHONGQING BASHIDI ANIMAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Clinafloxacin, the chemical name is 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-chloro-1,4-dihydro-4-oxo-3 -Quinoline carboxylic acid is the fourth generation quinolone antibacterial drug developed by Warner-Lambert Drug Company in the United States. It has completed Phase III clinical evaluation abroad. It has attracted much attention due to its high activity against Gram-positive bacteria, anaerobic bacteria and Mycoplasma pneumoniae, but the research and development was stopped due to serious toxicity problems found in clinical use
In addition, clinfloxacin still has problems such as poor solubility and unstable solution in pharmaceuticals
How to reduce toxicity and improve solubility and solution stability of Clinfloxacin while maintaining excellent broad-spectrum antibacterial activity through structural modification has not been reported at home and abroad.

Method used

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  • Clinafloxacin amino derivatives and application thereof
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  • Clinafloxacin amino derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, the synthesis of some Clinfloxacin sulfonamido derivatives

[0061] Synthesis of compounds HHY-1~HHY-8: Add 0.8g (20mmol) of sodium hydroxide, 3.66g (10mmol) of clinfloxacin and 50mL of water into the reaction flask, stir to dissolve, then slowly add the corresponding The acetone solution of the reaction raw material (11-15 mmol) was added, and the temperature was raised to 40-80° C. to control the temperature and stir for reaction, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction, adjust the pH of the reaction solution to 3-4 with 2mol / L hydrochloric acid solution, let it stand overnight at room temperature, filter it with suction, wash the filter cake with anhydrous methanol, and suspend it in anhydrous methanol, ethanol or isopropanol 60 -200mL, stir at room temperature for 2-4 hours, filter with suction, wash the filter cake with anhydrous methanol, and dry to obtain the corresponding target compound. The ...

Embodiment 2

[0093] Embodiment 2, the synthesis of some Clinfloxacin carbonyl amino derivatives

[0094] A, the synthesis of compound HHY-10~HHY-24

[0095] Add the corresponding reaction materials (24mmol), 3.24g (24mmol) of 1-hydroxybenzotriazole (HOBt) and 20mL of tetrahydrofuran (THF) into the reaction flask, stir to dissolve, then add dicyclohexyl carbonization under ice bath stirring Diimine (DCC) 4.94g (24mmol) and triethylamine (TEA) 2.02g (20mmol), after stirring in an ice bath for 30 minutes, add 7.32g (20mmol) of Clinfloxacin, and add an appropriate amount of THF (to facilitate stirring) , the temperature was raised to 20-45° C., the temperature was controlled and the reaction was stirred, and the reaction progress was monitored by TLC method. After the reaction, the reaction solution was left standing overnight at 4°C, filtered with suction, the filter cake was fully washed with dichloromethane (DCM), the washing liquid was combined with the filtrate, and the solvent was disti...

Embodiment 3

[0230] Embodiment 3, the agar diffusion antibacterial test of partial clinfloxacin amino derivatives

[0231] Melt common agar medium, cool to 55-60℃, add 1.0×10 6 CFU / mL test bacteria suspension (Staphylococcus aureus ATCC29213, Salmonella SR96-1 or Pseudomonas aeruginosa ATCC27853) 1.0mL, poured into a 90mm diameter petri dish, solidified and punched for later use. A phosphate buffer solution (100 mmol / L, pH 7.2) containing clinfloxacin amino derivatives was added to the above agar wells, and the amount of clinfloxacin amino derivatives added was 2 μg / well. After adding, culture at 37°C for 24 hours, and measure the diameter of the inhibition zone. The results are shown in Table 5. It can be seen that the amino derivatives of Clinfloxacin of the present invention have an inhibitory effect on Staphylococcus aureus ATCC29213, Salmonella SR96-1 and Pseudomonas aeruginosa ATCC27853, and the intensity of action of most derivatives is close to or superior to that of Staphylococcu...

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Abstract

The invention belongs to the field of chemistry and pharmacy, and particularly relates to clinafloxacin amino derivatives and application thereof. The clinafloxacin amino derivatives are the compounds shown in the formula 1 (R is -SO2R1 or -COR2) or pharmaceutically acceptable salts thereof. The antibacterial activity of the derivatives is close to or superior to that of clinafloxacin, the toxicity of the derivatives is lower than that of clinafloxacin, and the solubility and the stability of the solution of the derivatives are superior to those of clinafloxacin. The derivatives can be used for preparing antibacterial medicines, thereby providing more efficient and safe alternative medicines for clinical treatment of infectious diseases and satisfying the demands for clinical treatment in many aspects.

Description

technical field [0001] The invention belongs to the fields of chemistry and pharmacy, and relates to a compound derivative and its application in pharmacy, in particular to an amino derivative of clinfloxacin and its application in pharmacy. Background technique [0002] Since the advent of nalidixic acid in 1962, tens of thousands of quinolone antibacterial drugs have been synthesized and their activities evaluated. On the basis of the mother nucleus (quinolone nucleus or 1,8-naphthyridone nucleus), through structural modification such as the introduction of substituents (ethyl, cyclopropyl, fluorophenyl, etc.) at the 1-position, and the introduction of fluorine at the 6-position Atom, 7-position introduces cyclic amino group (piperazinyl, 3-aminopyrrolidinyl, etc.), 8-position introduces methoxy group, etc., so that the antibacterial spectrum, antibacterial activity and pharmacokinetic properties of this class of drugs continue to Improved. At present, quinolone antibact...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D405/14C07D409/14C07D401/14A61K31/4709A61K31/635A61P31/04
Inventor 杨大成陈力徐兴然韩海燕范莉杨艳
Owner CHONGQING BASHIDI ANIMAL PHARMA
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