Isorcryptolepine analogue, preparation method of isorcryptolepine analogue from lomefloxacin, and application thereof

A technology of isoflephyrine and selemenine, applied in the field of medicinal chemistry, can solve the problems of few reports of anti-tuberculosis activity, low bioavailability, poor water solubility, etc. The effect of low drug resistance and good growth inhibitory activity

Active Publication Date: 2022-01-21
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Due to its unique structure and good anti-plasmodium, anti-tumor and other biological activities, it has attracted research interest, but there are few reports on its anti-tuberculosis activity
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, preparation method of isorcryptolepine analogue from lomefloxacin, and application thereof
  • Isorcryptolepine analogue, preparation method of isorcryptolepine analogue from lomefloxacin, and application thereof
  • Isorcryptolepine analogue, preparation method of isorcryptolepine analogue from lomefloxacin, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] A kind of isoalbinine analogue, the general chemical structure formula is as shown in formula I:

[0044]

[0045] In this example, the substituent R in formula I is an H atom, then 2,4-difluoro-3-(3-methyl-piperazin-1-yl)-5-ethyl-5H-indole The chemical structural formula of [3,2-c] quinoline is:

[0046]

[0047] This example uses a preparation method from lomefloxacin to isobrainine analogues to prepare the above-mentioned isoberaline analogues (I-1), which specifically includes the following steps:

[0048] S1. Reductive decarboxylation reaction of lomefloxacin shown in formula II with potassium borohydride to prepare 2,3-dihydroquinolin-4-one shown in formula III.

[0049]

[0050] Specifically, it includes the following steps: Y1. Mix lomefloxacin with a solvent to make a suspension, slowly add potassium borohydride to the suspension in portions under normal temperature stirring, heat the mixed reactant in a water bath, stir and reflux to react to Lomefloxa...

Embodiment 2

[0058] A kind of isoberaline analogue, the difference between this embodiment and embodiment 1 is that the substituent R in the formula I is methoxyl group, then the isoberaline analogue is 2,4-difluoro-5- The chemical structural formula of ethyl-8-methoxy-3-(3-methyl-piperazin-1-yl)-5H-indolo[3,2-c]quinoline is:

[0059]

[0060] This example uses a preparation method from lomefloxacin to isobrainine analogues to prepare the above-mentioned isobrainine analogues (I-2), which specifically includes the following steps: taking 1-ethyl- 6,8-Difluoro-(3-methyl-piperazin-1-yl)-2,3-dihydro-quinolin-4(1H)-one III 1.0g (3.2mmol) ketone was dissolved in 15mL of anhydrous Add 0.62 g (4.5 mmol) of p-methoxyphenylhydrazine to ethanol, stir and react at room temperature overnight, and an obvious precipitate is formed. Concentrated hydrochloric acid (0.50 mL) was added, and the mixed reactants were refluxed for 15 h and left overnight. Collect the resulting solid by filtration, dissolv...

Embodiment 3

[0063] A kind of isoberaline analogue, the difference between this embodiment and embodiment 1 is that the substituent R in the formula I is methoxyl group, then the isoberaline analogue is 2,4-difluoro-5- The chemical structural formula of ethyl-9-methoxy-(3-methyl-piperazin-1-yl)-5H-indolo[3,2-c]quinoline is:

[0064]

[0065] This example uses a preparation method from lomefloxacin to isobrainine analogues for the preparation of the above-mentioned isobrainine analogues (I-3), which specifically includes the following steps: taking 1-ethyl- 6,8-Difluoro-(3-methyl-piperazin-1-yl)-2,3-dihydro-quinolin-4(1H)-one III 1.0g (3.2mmol) was dissolved in 15mL absolute ethanol 0.83 g (6.0 mmol) of m-methoxyphenylhydrazine was added, stirred at room temperature for 24 hours, and an obvious precipitate was 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 t...

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PUM

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Abstract

The invention provides an isocryptolepine analogue, a preparation method of the isocryptolepine analogue from lomefloxacin and an application thereof, which are used for solving the technical problem of how to design an indoloquinoline antituberculosis drug with a novel structure by taking cryptolepine alkaloid as a primer and using an atom economic strategy. According to the invention, the isocryptolepine analogue is prepared from lomefloxacin, so that effective chemical construction from a fluoroquinolone structure to an indoloquinoline skeleton is realized, a new way for structural modification of iso-cryptolepine is expanded, and complementation of dominant structures of fluoroquinolone drugs and natural indoloquinoline alkaloids is achieved. An in-vitro anti-tuberculosis activity test result shows that the compound has relatively good growth inhibition activity on a tested tubercle bacillus strain, the activity of parts of the compound is equivalent to that of a control isoniazide, and the compound has drug resistance and relatively low cytotoxicity, and can be further developed and prepared as an anti-tuberculosis drug with a brand new structure.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry related to organic synthesis and new drug research and development, in particular to a kind of isoalbinine analogues, and also relates to a preparation method from lomefloxacin to isoalbinine analogues, 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 of anti-t...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P31/06A61K31/496
CPCC07D471/04A61P31/06C07B2200/13Y02A50/30
Inventor 崔红艳晋秋芝张堋梁胡国强
Owner HENAN UNIVERSITY
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