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7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same

An amino protecting group, carboxylic acid technology, applied in the field of medicinal chemistry, can solve the problems of poor water solubility, limited wide application, limited application scope and the like

Active Publication Date: 2009-06-10
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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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 wide 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-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same
  • 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same
  • 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Embodiment 1, 4-hydroxyl-1-benzyl-piperidine-3-carboxylic acid ethyl ester

[0172] Add triethylamine (1.4ml) dropwise to a solution of ethyl 1-benzyl-4-oxo-piperidine-3-carboxylate (6.0g, 20mmol) and 95% ethanol (20ml) under ice-cooling , then added potassium borohydride (1.7g, 27mmol) in batches, poured into water after reacting for 2h, extracted with dichloromethane, washed with water, dried, and concentrated under reduced pressure to give 3.1g of light yellow oil with a yield of 58.4%.

[0173] 1 H NMR (300MHz, CDCl 3 +D 2 O) δ ppm: 1.298 (3H, s, CH 3 ), 1.782~1.915 (2H, m, C 5 -2H), 2.357~2.791 (5H, m, C 2 -2H,C 3 -1H,C 6 -2H), 3.727~4.391 (5H, m, phCH 2 , C 4 -1H,CH 2 CH 3 ), 7.132~7.268 (5H, m, ph-5H).

[0174] MS (FAB, m / z): 264 (M + +1).

Embodiment 2

[0175] Embodiment 2, 4-hydroxyl-1-benzyl-piperidine-3-carboxamide

[0176] Compound of Example 1 (5.5 g, 13.8 mmol) was added ammonia water (20 ml), stirred at room temperature for 12 h, concentrated under reduced pressure, dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4.8 g of a colorless oily product , yield 65.4%.

[0177] 1 HNMR (300MHz, DMSO+D 2 O) δ ppm: 1.592~1.599 (2H, s, C 5 -2H), 2.343~2.523 (5H, m, C 2 -2H,C 3 -1H,C 6 -2H), 3.436~3.499 (2H, m, ph CH 2 ), 4.020 (1H, s, C 4 -1H), 4.821 (1H, s, OH), 6.953 (1H, s, NH), 7.222~7.331 (5H, m, ph-5H), 7.382 (1H, s, NH).

[0178] MS (FAB, m / z): 235 (M + +1).

Embodiment 3

[0179] Embodiment 3, 3-amino-4-hydroxyl-1-benzyl-piperidine

[0180] Method one: add sodium hydroxide (6.8g, 0.17mol) in batches to the mixed solution of 12% sodium hypochlorite (25.9ml) and water (5ml) under ice-cooling, add embodiment 2 compound (3.0g , 12.9mmol), stirring and reacting at room temperature for half an hour, raising the temperature to 70°C for 3h, lowering to room temperature, adjusting pH=9, extracting with dichloromethane, washing with water, drying, and evaporating to dryness to obtain 1.33g of a colorless oil, yield 50%.

[0181] Method 2: The compound of Example 2 (3.0g, 12.9mmol) was dissolved in 6% NaOH solution (10ml), and 12% sodium hypochlorite (25.9ml) was added dropwise under ice-cooling conditions, stirred at room temperature for 0.5h, and heated to React at 70°C for 3 hours, lower to room temperature, adjust pH to about 9, extract with dichloromethane, wash with water, dry, and evaporate the solvent to give 1.38 g of a colorless oil. Yield 52%....

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Abstract

The invention relates to a 7-(4-ketoxime-3-amino-1-piperidine) new quinolyl carboxylic acid derivation, the preparation process and the medical use as well as antimicrobials and feed additives containing the derivations thereof, in particular to a new fluoroquinolone formate derivation. A 4-ketoxime-3-amino-1-piperidine are on the fluoroquinolone nucleus 7-position of the derivation, a methoxyl is on 8-position, and a cyclopropyl is on 1-position. Compared with the prior fluoroquinolone antibacterial drugs, the derivation has more excellent Gram positive bacteria activity and extended-spectrum antibacterial activity.

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, the present invention relates to 7-(4-oximino-3- Amino-1-piperidinyl) new quinolinecarboxylic acid derivatives. 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 quinolone ant...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/4709A61P31/04
CPCC07D401/04A61P31/04
Inventor 郭慧元王秀云蒋锦王玉成刘秉权刘明亮李春波
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY