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Acrylketone derivative of N-methyl gatifloxacin and preparation method and application of acrylketone derivative

A technology of gatifloxacin and acrylone, which is applied to the acrylone derivative of N-methyl gatifloxacin and its preparation field, can solve the problems such as the uncertainty of the effect of the C-3 carboxyl group of fluoroquinolone, and achieve an increase in anti-tumor effect. Activity and anti-drug resistance, the effect of reducing side effects

Inactive Publication Date: 2020-09-11
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is uncertain whether the C-3 carboxyl group of fluoroquinolones can be replaced by different groups to obtain the effect

Method used

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  • Acrylketone derivative of N-methyl gatifloxacin and preparation method and application of acrylketone derivative
  • Acrylketone derivative of N-methyl gatifloxacin and preparation method and application of acrylketone derivative
  • Acrylketone derivative of N-methyl gatifloxacin and preparation method and application of acrylketone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-3-cinnamoyl-8-methoxy-quinoline-4(1 H )-ketone (I-1), its chemical structural formula is:

[0032]

[0033] That is, Ar in formula I is phenyl.

[0034] The preparation method of this compound is:

[0035] (1) Using N-methylgatifloxacin shown in Formula II as a raw material, react with carbonyldiimidazole (CDI) to prepare N-methylgatifloxacin imidazole amide compound shown in Formula III, and its specific preparation Methods as below:

[0036]

[0037] Take 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-8-methoxy-quinoline-4(1 H 20 g (51.0 mmol) of )-keto-3-carboxylic acid II was dissolved in 500 mL of anhydrous acetonitrile, 15.2 g (94.0 mmol) of carbonyldiimidazole was added, and the mixed reaction was stirred and refluxed in a water bath until the raw material II disappeared. Leave it at room temperature, collect the resulting solid by filtration, and recrystallize with acetone to obtain the light...

Embodiment 2

[0046] 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-3-(4-methoxycinnamoyl)-8-methoxy-quinoline-4 (1 H )-ketone (I-2), its chemical structural formula is:

[0047]

[0048] That is, Ar in formula I is p-methoxyphenyl.

[0049] The preparation method of this compound is:

[0050] (1) 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-8-methoxy-quinoline-4(1 H )-ketone-3-ethanone V is prepared with reference to steps (1)-(3) of Implementation 1, the solvent in step (1) is replaced by tetrahydrofuran, the mixture of N-methylgatifloxacin and carbonyldiimidazole The molar ratio is 1:1.0;

[0051] (2) Take 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-8-methoxy-quinoline-4(1 H 1.2 g (3.0 mmol) of )-keto-3-ethanone V was dissolved in 20 mL of absolute ethanol, and 0.57 g (4.2 mmol) of 4-methoxybenzaldehyde and base catalyst piperidine (0.1 mL) were added. The mixed reactants were refluxed for 20 h, left at room temperature, and the resulting solid was coll...

Embodiment 3

[0053] 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-3-(3,4-dioxymethylenecinnamoyl)-8-methoxy- Quinoline-4(1 H )-ketone (I-3), its chemical structural formula is:

[0054]

[0055] That is, Ar in formula I is 3,4-(dioxymethylene)phenyl.

[0056] The preparation method of this compound is:

[0057] (1) 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-8-methoxy-quinoline-4(1 H )-keto-3-ethanone V is prepared with reference to steps (1)-(3) of Implementation 1, and the solvent in step (1) is replaced by dioxane, N-methylgatifloxacin and carbonyl The mol ratio of diimidazole is 1:2.0;

[0058] (2) Take 1-cyclopropyl-6-fluoro-7-(3,4-dimethylpiperazin-1-yl)-8-methoxy-quinoline-4(1 H )-keto-3-ethanone V1.2 g (3.0 mmol) was dissolved in 20 mL of absolute ethanol, 0.53 g (3.5 mmol) of 3,4-dioxymethylene benzaldehyde and base catalyst piperidine (0.1 mL). The mixed reactants were refluxed for 20 h, left at room temperature, and the resulting solid was collected b...

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Abstract

The invention belongs to the field of drug synthesis, and relates to a derivative of N-methyl gatifloxacin, in particular to an acrylketone derivative of N-methyl gatifloxacin and a preparation methodand application of the acrylketone derivative of N-methylgatifloxacin. The compound has a structural general formula (I) as shown in the specification, wherein in the formula I, Ar is any one of a benzene ring, a substituted benzene ring, a furan ring or a pyridine ring. According to the acrylketone derivative of N-methyl gatifloxacin, a fluoroquinolone skeleton and an acrylketone skeleton are effectively spliced, so that a novel fluoroquinolone chalcone-like compound is constructed, the anti-tumor activity and the anti-drug resistance of the novel compound are improved, the toxic and side effects on normal cells are reduced, and the novel fluoroquinolone chalcone-like compound can be used as an anti-tumor active substance to develop an anti-tumor drug with a brand-new structure.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to derivatives of N-methylgatifloxacin, in particular to a propenone derivative of N-methylgatifloxacin, a preparation method and application thereof. Background technique [0002] N-methylgatifloxacin belongs to in vitro antibacterial and belongs to fluoroquinolones. The in vitro antibacterial effect is similar to norfloxacin, slightly worse than ciprofloxacin, but its antibacterial activity in vivo includes Escherichia coli, pneumoniae bacteria, green The effects of Pseudomonas and Staphylococcus aureus were significantly better than norfloxacin. The mechanism of action is the same as norfloxacin. At present, the drug is mainly used for genitourinary system infection and intestinal infection. As the lead of new drugs, based on the structure or mechanism of N-methylgatifloxacin, the discovery of new drugs is an effective method for new drug innovation. [0003] The acrylone structure...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D405/14C07D401/14A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/04C07D401/14C07D405/14
Inventor 姜原黄帅崔红艳胡国强
Owner HENAN UNIVERSITY
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