Isorcryptolepine analogue prepared by taking enoxacin as raw material as well as preparation method and application of iso-cryptolepine analogue

A technology of isoberaline and enoxacin, applied in organic chemistry, antibacterial drugs, etc., can solve the problems of poor water solubility, difficult source of albino alkaloids, low bioavailability, etc., to increase penetration Function, excellent in vitro growth inhibition activity of Mycobacterium tuberculosis, effect of improving water solubility

Inactive Publication Date: 2022-01-25
ZHENGZHOU UNIV OF IND TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, due to the difficulty in the source of vine alkaloids, coupled with poor water solubility, resulting in low bioavailability and other defects, the clinical application is limited.

Method used

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  • Isorcryptolepine analogue prepared by taking enoxacin as raw material as well as preparation method and application of iso-cryptolepine analogue
  • Isorcryptolepine analogue prepared by taking enoxacin as raw material as well as preparation method and application of iso-cryptolepine analogue
  • Isorcryptolepine analogue prepared by taking enoxacin as raw material as well as preparation method and application of iso-cryptolepine analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 2-fluoro-3-piperazin-1-yl-5-ethyl-5H-indolo[3,2-c][1,8]naphthyridine (I-1), its chemical structure is:

[0036]

[0037] That is, R in formula I is an H atom.

[0038] The preparation method of the compound (I-1) is: take 6-fluoro-1-ethyl-7-piperazin-1-yl-2,3-dihydro-[1,8]naphthyridine-4(1H) - Dissolve 1.0 g (3.6 mmol) of ketone III in 15 mL of absolute ethanol, add 0.50 g (4.6 mmol) of phenylhydrazine, stir and react at room temperature for 20 h (the disappearance of raw material III was observed by TLC), and a large amount of precipitates are formed. Concentrated hydrochloric acid (0.50 mL) was added as a cyclization catalyst, and the mixed reactants were refluxed for 20 h and left overnight (12 h, the same below). Collect the resulting solid by filtration, dissolve the solid with 50 mL of deionized water, add an appropriate amount of activated carbon, and reflux for 1 h for decolorization. Filtrate hot, and adjust the pH of the filtrate to ≈10.0 with ammonia wat...

Embodiment 2

[0040] 2-fluoro-8-methoxy-3-piperazin-1-yl-5-ethyl-5H-indolo[3,2-c][1,8]naphthyridine (I-2), which The chemical structural formula is:

[0041]

[0042] That is, R in formula I is methoxy.

[0043] The preparation method of this compound (I-2) is: take 6-fluoro-1-ethyl-7-piperazin-1-yl-2,3-dihydro-[1,8]naphthyridine-4(1H) - Dissolve 1.0 g (3.6 mmol) of ketone III in 15 mL of absolute ethanol, add 0.62 g (4.5 mmol) of p-methoxyphenylhydrazine, stir and react at room temperature overnight (the disappearance of raw material III was observed by TLC), and an obvious precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixed reactants were refluxed for 16 h and left overnight. Collect the resulting solid by filtration, dissolve the solid with 50 mL of deionized water, add an appropriate amount of activated carbon, and reflux for decolorization for 1 h. Filtrate hot, and adjust the pH of the filtrate to ≈10.0 with ammonia water. The resulting soli...

Embodiment 3

[0045] 2-fluoro-9-methoxy-3-piperazin-1-yl-5-ethyl-5H-indolo[3,2-c][1,8]naphthyridine (I-3), Its chemical structural formula is:

[0046]

[0047] That is, R in formula I is methoxy.

[0048] The preparation method of this compound (I-3) is: take 6-fluoro-1-ethyl-7-piperazin-1-yl-2,3-dihydro-[1,8]naphthyridine-4(1H) - Dissolve 1.0 g (3.6 mmol) of ketone III in 15 mL of absolute ethanol, add 0.83 g (6.0 mmol) of m-methoxyphenylhydrazine, stir and react at room temperature for 24 hours (the disappearance of raw material III was observed by TLC), and an obvious precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixed reactant was refluxed for 16 h and left overnight. Collect the resulting solid by filtration, dissolve the solid with 50 mL of deionized water, add an appropriate amount of activated carbon, and reflux for 1 h for decolorization. Filtrate hot, and adjust the pH of the filtrate to ≈10.0 with ammonia water. The resulting solid was...

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Abstract

The invention discloses an iso-cryptolepine analogue as well as a preparation method and application thereof. The chemical structure of the iso-cryptolepine analogue is shown as a formula I, wherein a substituent group R in the formula I can be independently -H, -OCH3, -F, -Cl or -SO2NH2. According to the isocryptolepine analogue disclosed by the invention, enoxacin is taken as a raw material, so that effective chemical construction from a fluoroquinolone structure to an indolonaphthyridine skeleton is realized, and a new way for structural modification of isocryptolepine is expanded. By means of the method, the complementary advantage structures of fluoroquinolone medicines and natural indoloquinoline alkaloids are achieved, the anti-tubercle bacillus activity and the anti-drug resistance of the compound are improved, the toxicity to normal cells is reduced, and the compound can be further developed as an anti-tubercle medicine with a brand new structure.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry related to organic synthesis and new drug research and development, and specifically relates to an isoalbino analogue, and also relates to a method for preparing an isoalvanine analogue using enoxacin as a raw material , and its application in the preparation of anti-tuberculosis drugs. Background technique [0002] Tuberculosis is a chronic infectious disease with a high incidence rate caused by Mycobacterium tuberculosis. Due to the lack of effective treatment drugs, it has become an urgent public health and social problem facing the world. At the same time, coupled with the fact that Mycobacterium tuberculosis is prone to drug resistance to existing drugs, especially the generation of multidrug resistance, it poses new challenges to the development of anti-tuberculosis drugs. There is not yet a new compound for the treatment of tuberculosis. Therefore, the research and development...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14A61P31/06
CPCC07D471/14A61P31/06
Inventor 冯爽耿胜男舒胜男邱明恒吕双双
Owner ZHENGZHOU UNIV OF IND TECH
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