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7-(3-oximido-4-amido-4-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof

A technology of amino protecting group and alkyl group, which is applied in the field of medicinal chemistry and can solve problems such as poor water solubility, limited application range, and weak activity of Staphylococcus aureus

Inactive Publication Date: 2009-06-10
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is poor water solubility, so it can only be made into oral preparations, which limits its application
[0004] In 1994, Korean scholars disclosed the synthesis and biological activity of fluoroquinolones with 3-oximino-4-aminomethyl-1-pyrrolidinyl at the 7-position (KR: 13604 / 1994; KR: 39915 / 1994; KR : 39930 / 1994; CN: 1114959A / 1996), the outstanding representative of which is gemifloxacin (gemifloxacin), which has been successfully developed and approved by the FDA to be marketed in the United States. In addition to its broad-spectrum activity, its outstanding advantage is that it is effective against pneumonia chain The activity of cocci is superior to other quinolone antibacterial drugs that have been listed, and its disadvantage is that it is not active against clinically common Staphylococcus aureus (including the increasing number of MRSA), thus limiting its clinical application range

Method used

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  • 7-(3-oximido-4-amido-4-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof
  • 7-(3-oximido-4-amido-4-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof
  • 7-(3-oximido-4-amido-4-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1 1-tert-butoxycarbonyl-4-methyl-3-oxopiperidine-4-carboxylic acid ethyl ester

[0079] N 2 Under protection, ethyl 1-tert-butoxycarbonyl-3-oxopiperidine-4-carboxylate (43.36g, 0.16mol), K 2 CO 3 (41.40g, 0.3mol), a mixture of iodomethane (42.60g, 0.3mol) and acetone (450ml) was stirred at 40°C for 2.0h. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (170 ml), washed with water and saturated brine in turn, and dried over anhydrous magnesium sulfate. After filtration, the concentrated residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain 34.70 g of light yellow oil (yield 76.1%).

[0080] 1 H NMR (300MHz, CDCl 3 )δppm: 1.23-1.39 (15H, m, Boc, OCH 2 CH 3 , CH 3 ), 2.21-2.28 (2H, m, C 5 -2H), 3.32-3.49(4H, m, C 2 -2H,C 6 -2H), 3.82-3.85(2H, m, OCH 2 CH 3 ).

[0081] MS (FAB, m / z): 286 (M + +1). ...

Embodiment 2

[0082] Example 2 1-tert-butoxycarbonyl-4-(N-tert-butoxycarbonyl)amino-4-methyl-3-hydroxypiperidine

[0083] Under cooling in an ice bath, potassium borohydride (7.56 g, 0.14 mol) was added in batches to a solution of the compound of Example 1 (34.20 g, 0.12 mol) in 95% ethanol (120 ml), stirred at the same temperature for 0.5 h, and then continued at room temperature The reaction was stirred for 2.5h. The reaction solution was poured into water (200ml), extracted with dichloromethane (3×110ml), the extracts were combined, washed with water (3×60ml), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was added with methanol (200ml) and ammonia water (100ml). In the autoclave, ammonia gas was passed to 1.2Mpa, and the reaction was stirred at 30-35°C for 12h. Concentrate under reduced pressure to obtain a colorless oil.

[0084] Dissolve sodium hydroxide (5.60g, 0.14mol) in water (44.4ml),...

Embodiment 3

[0087] Example 3 1-tert-butoxycarbonyl-4-(N-tert-butoxycarbonyl)amino-4-methyl-3-oxopiperidine

[0088] Under cooling in an ice bath, Jones reagent (26.5ml) was added dropwise to a solution of the compound of Example 2 (12.54g, 0.038mmol) in acetone (100ml) for 0.5h, and stirred at the same temperature for 1.5h. An appropriate amount of methanol was added to the reaction solution, and after the color of the solution turned from red to green, it was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, the residue was dissolved in chloroform (65ml), and washed with saturated saline until the water layer had no obvious green color. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain a crude product, which was separated by VLC (gradient elution with ethyl acetate and petroleum ether) to obtain 10.73 g of a solid product (yield 86.1%).

[0089] 1 H NMR (300MHz, CDCl 3 )δppm: 1.21-1.52 (21H...

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Abstract

The invention provides 7-(3-oximido-4-amino-4-alkyl-1-piperidyl) quinoline carboxylic acid derivatives with excellent antibacterial activities, preparation methods thereof, antibacterial agents containing the compounds, and uses of the compounds as antibacterial agents and feed additives. A substituent of (3-oximido-4-amino-4-alkyl-1-piperidyl) is at a 7-position of a carbostyril nucleus. Compared with the prior fluoroquinolone antibacterial drugs, the antibacterial agents have more excellent anti-gram-positive-bacteria activities and broad-spectrum antibacterial activities.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to novel quinoline carboxylic acid derivatives with excellent antibacterial activity and a preparation method thereof, as well as antibacterial pharmaceutical compositions containing them; specifically, to 7-(3-oximino-4-amino -4-Alkyl-1-piperidinyl)quinolinecarboxylic acid derivatives and preparation methods thereof. Background technique [0002] Quinolones have developed from nalidixic acid (J.Med.Chem.1962, 5, 1063) in 1962 to now a class of anti-infection chemotherapy drugs with broad spectrum, high efficiency and low toxicity. Due to their widespread use and even abuse, drug-resistant bacteria have rapidly increased, especially methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant epistaphylococcus (MRSE) and vancomycin-resistant enterococci (VRE ) infection has become one of the thorny problems faced by clinicians. People urgently need to find new quinolon...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D401/04A61K31/4709A61K31/4375A61P31/04
CPCY02P20/55
Inventor 郭慧元王菊仙章怡彬刘秉全刘明亮王玉成李春波
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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