Acrylketone derivative without N-methyl ofloxacin and preparation method and application thereof

A technology of methyl ofloxacin and methyl ofloxacin imidazolamide, applied in the fields of drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems such as the uncertain effect of fluoroquinolone C-3 carboxyl group, and achieve increase Anti-tumor activity and anti-drug resistance, the effect of reducing toxic and side effects

Active Publication Date: 2020-09-11
HENAN UNIVERSITY +1
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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 without N-methyl ofloxacin and preparation method and application thereof
  • Acrylketone derivative without N-methyl ofloxacin and preparation method and application thereof
  • Acrylketone derivative without N-methyl ofloxacin and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1,8-Isopropoxy-6-fluoro-7-piperazin-1-yl-3-cinnamoyl-quinoline-4(1 H )-ketone (I-1), its chemical structural formula is:

[0033]

[0034] That is, Ar in formula I is phenyl.

[0035] The preparation method of this compound is:

[0036] (1) Using de-N-methylofloxacin shown in formula II as raw material, reacting with carbonyldiimidazole (CDI) to prepare de-N-methylofloxacin imidazole amide compound shown in formula III, which The specific preparation method is as follows:

[0037]

[0038] Take 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4(1 H 21.0 g (60.0 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 reactant 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 des-N-methylofloxacin imidazolamide as light y...

Embodiment 2

[0047] 1,8-Isopropoxy-6-fluoro-7-piperazin-1-yl-3-(4-methoxycinnamoyl)-quinoline-4(1 H )-ketone (I-2), its chemical structural formula is:

[0048]

[0049] That is, Ar in formula I is p-methoxyphenyl.

[0050] The preparation method of this compound is:

[0051] (1) 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4(1 H )-ketone-3-ethanone V is prepared by referring to steps (1)-(3) of implementation 1, replacing the solvent in step (1) with tetrahydrofuran solution, removing N-methylofloxacin and carbonyl di The molar ratio of imidazole is 1:1.0;

[0052] (2) Take 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4(1 H 1.0 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 collected by filtration and recrystallized from absolute ethanol to obta...

Embodiment 3

[0054] 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-3-(3,4-dioxymethylenecinnamoyl)-quinoline-4(1 H )-ketone (I-3), its chemical structural formula is:

[0055]

[0056] That is, Ar in formula I is 3,4-(dioxymethylene)phenyl.

[0057] The preparation method of this compound is:

[0058] (1) 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-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 dioxane solution, and N-methylofloxacin is removed The molar ratio with carbonyldiimidazole is 1:1.0;

[0059] (2) Take 1,8-isopropoxy-6-fluoro-7-piperazin-1-yl-quinoline-4(1 H )-keto-3-ethanone V1.0g (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 by filtration and recrystallized from anhydrous ethano...

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Abstract

The invention belongs to the field of drug synthesis, and relates to a derivative without N-methyl ofloxacin, in particular to an acrylketone derivative without N-methyl ofloxacin and a preparation method and application thereof. 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, afuran ring or a pyridine ring. According to the acrylketone derivative without N-methyl ofloxacin and the preparation method thereof, a fluoroquinolinone skeleton and an acrylketone skeleton are effectively spliced, so that a novel fluoroquinolinone chalcone-like compound is constructed, the antitumor activity and the drug resistance of the novel compound are improved, the toxic and side effects on normal cells are reduced, and the fluoroquinolinone chalcone-like compound can be used as an antitumor active substance to develop antitumor drugs with brand new structures.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to derivatives of des-N-methylofloxacin, in particular to a propenone derivative of des-N-methylofloxacin and its preparation method and application. Background technique [0002] Ofloxacin is a synthetic, broad-spectrum antibacterial fluoroquinolone drug, which was synthesized in 1982. It has the advantages of easy and fast and complete oral absorption, high and long-lasting blood drug concentration, and wide drug distribution in the body. Ofloxacin is a high-efficiency broad-spectrum antibacterial drug, which has strong effects on Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus) and Gram-negative bacteria (including Pseudomonas aeruginosa). Mycoplasma pneumoniae, Neisseria, anaerobes and Mycobacterium tuberculosis are also active. As the lead of new drugs, based on the structure or mechanism of ofloxacin, the discovery of new drugs is an effective method ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D498/06
Inventor 黄帅梁佩芳曹玉辉仵钊锋王爱丽胡国强
Owner HENAN UNIVERSITY
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