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Chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative and its preparation method and application

A technology of fluoroquinolone carboxylic acid and isoniazid, which is applied in organic chemistry and antibacterial drugs, can solve the problems of affecting animal cartilage development, easy to produce drug resistance, and low therapeutic index, so as to increase anti-tuberculosis activity and drug resistance. Strong effect and high selectivity

Inactive Publication Date: 2016-05-18
HENAN UNIVERSITY +1
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Isoniazid and fluoroquinolones are the first-line and second-line anti-tuberculosis drugs widely used clinically, but isoniazid has certain liver toxicity, and fluoroquinolones are likely to affect the cartilage development of animals and have phototoxicity. are prone to develop drug resistance, resulting in low therapeutic index

Method used

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  • Chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative and its preparation method and application
  • Chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative and its preparation method and application
  • Chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative and its preparation method and application

Examples

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Comparison scheme
Effect test

Embodiment 1

[0050] The chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative in this example is (S)-3-methyl-9-fluoro-10-[3-methyl- 4-(Pyridine-4-carbohydrazino)ylidenemethyl-5-piperazin-1-yl-pyrazol-1-yl]-2,3-dihydro-[1,4]oxazino[2 ,3,4-ij] quinoline-7(4H)-one-6-carboxylic acid, its chemical structural formula is:

[0051]

[0052] That is, R in formula (I) 1 is a hydrogen atom, R 2 for a hydrogen atom.

[0053] The preparation method of the chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative of this example is: take 1.0 g (2.0 mmol) of (S)-3-methyl- 9-fluoro-10-[3-methyl-5-chloro-4-(pyridine-4-formylhydrazino)ylidenemethyl-pyrazol-1-yl]-2,3-dihydro-[1, 4] Oxazino[2,3,4-ij]quinolin-7(4H)-one-6-carboxylic acid (VI) and 0.34g (4.0mmol) of anhydrous piperazine were added to 20ml of anhydrous acetonitrile The reaction was refluxed for 12 hours and left overnight...

Embodiment 2

[0055] The chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative in this example is (S)-3-methyl-9-fluoro-10-[3-methyl- 4-(pyridine-4-carboxhydrazino)ylidenemethyl-5-(4-methyl-piperazin-1-yl)-pyrazol-1-yl]-2,3-dihydro-[1, 4] oxazino[2,3,4-ij]quinolin-7(4H)-one-6-carboxylic acid, whose chemical structural formula is:

[0056]

[0057] That is, R in formula (I) 1 is methyl, R 2 for a hydrogen atom.

[0058] The preparation method of the chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative of this example is: take 1.0 g (2.0 mmol) of (S)-3-methyl- 9-fluoro-10-[3-methyl-5-chloro-4-(pyridine-4-formylhydrazino)ylidenemethyl-pyrazol-1-yl]-2,3-dihydro-[1, 4] oxazino[2,3,4-ij]quinolin-7(4H)-one-6-carboxylic acid (VI) and 0.4g (4.0mmol) of anhydrous methylpiperazine, add 20ml of anhydrous Reflux reaction in acetonitrile for 16h, left overnight; The resulting...

Embodiment 3

[0060] The chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative in this example is (S)-3-methyl-9-fluoro-10-[3-methyl- 4-(pyridine-4-carboxhydrazino)ylidenemethyl]-5-(4-ethyl-piperazin-1-yl)-pyrazol-1-yl]-2,3-dihydro-[1 ,4]oxazino[2,3,4-ij]quinolin-7(4H)-one-6-carboxylic acid, whose chemical structural formula is:

[0061]

[0062] That is, R in formula (I) 1 is ethyl, R 2 for a hydrogen atom.

[0063] The preparation method of the chiral 7-(piperazine substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative of this example is: take 1.0 g (2.0 mmol) of (S)-3-methyl- 9-fluoro-10-[3-methyl-5-chloro-4-(pyridine-4-formylhydrazino)ylidenemethyl-pyrazol-1-yl]-2,3-dihydro-[1, 4] oxazino[2,3,4-ij]quinolin-7(4H)-one-6-carboxylic acid (VI) and 0.46g (4.0mmol) of anhydrous ethylpiperazine, add 20ml of anhydrous Reflux reaction in acetonitrile for 24h, left overnight; The resulting s...

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Abstract

The invention discloses a chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative as well as a preparation method and application thereof. The chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative is a compound with the general structural formula (I), wherein R1 is H, methyl or ethyl, and R2 is H or methyl. According to the chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative provided by the invention, fluoroquinolone, isoniazide and pyrazole aldehyde hydrazone are effectively combined to form a compound with a new structure; superposition and cooperation of activity are achieved; superposition of the three pharmacophores of fluoroquinolone, isoniazide and pyrazole aldehyde hydrazone is realized, the antituberculosis activity is improved, the toxic and side effects of fluoroquinolone and isoniazide to normal cells are decreased, and meanwhile, the probability that mycobacterium tuberculosis resists such drugs can be lowered; the chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative can serve as an antituberculous active substance used for development of an antituberculous drug with a new structure.

Description

technical field [0001] The invention belongs to the technical field of fluoroquinolone carboxylic acid derivatives, and specifically relates to a chiral 7-(piperazine-substituted pyrazole aldehyde isoniazid hydrazone) fluoroquinolone carboxylic acid derivative, and also relates to a chiral 7- (Piperazine substituted pyrazole aldehyde isoniazid hydrazone) preparation method and application of fluoroquinolone carboxylic acid derivatives. Background technique [0002] Mycobacterium tuberculosis infection is a major disease that threatens global public health security, especially the emergence of drug resistance of Mycobacterium tuberculosis, which has brought great harm to public health; expect the development of new anti-tuberculosis drugs as soon as possible to overcome the current increasingly serious Mycobacterium tuberculosis drug resistance problem. Because it is very difficult to create an anti-tuberculosis drug with a new chemical structure, no new chemical entity drug...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06A61P31/06
CPCC07D498/06
Inventor 刘中华刘芳薛德明李涛高留州谢玉锁冯焱飞闫强吴书敏倪礼礼胡国强
Owner HENAN UNIVERSITY
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