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Fluorine-substituted monocarbazole derivatives, preparation method and application thereof

A technology for monocarbazoles and derivatives, applied in the field of their preparation, fluorine-substituted monocarbazole derivatives, can solve the problems of large toxic and side effects, low selectivity, affecting the overall stability of chromosomes and the like

Active Publication Date: 2022-03-15
GUANGDONG HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, nucleoside analogs have poor selectivity and high toxic side effects, which may be related to their ability to penetrate into DNA or RNA
Most nucleoside analogs can only act on non-solid tumors. While inhibiting DNMT, they will also hypomethylate centromere satellite DNA and affect the overall stability of chromosomes
Non-nucleoside analogs have a wide variety of chemical structures, but most are less selective and less active

Method used

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  • Fluorine-substituted monocarbazole derivatives, preparation method and application thereof
  • Fluorine-substituted monocarbazole derivatives, preparation method and application thereof
  • Fluorine-substituted monocarbazole derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Synthesis and characterization of embodiment 1 compound 1

[0129] Take 120.0mg (0.5mmol) of compound a4 into a 10mL sealed tube, add 5mL of absolute ethanol, add 318.7mg (2.0mmol) of tryptamine, and heat at 60°C for reaction. TLC detection (PE:EA:MeOH=5:20:2 developed) the reaction is complete, add water, extract with ethyl acetate, the organic phase is washed with sat.NaCl, anhyd.Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 0.37 g of a crude product. Purified by column chromatography (PE:EA=1:1) to obtain 64.0 mg of white solid with a yield of 32.10%. Carry out infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum NMR and DEPT spectrum analysis to compound 1, such as Figures 17-21 As shown, the specific data of infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum are as follows:

[0130] IR(KBr),ν,cm -1 :3273,2930,1487,1459,1439,1351,1281,1170,889,795,727.

[0131] m.p.137-139℃.HRMS-...

Embodiment 2

[0135] Synthesis and characterization of embodiment 2 compound 2

[0136] Take 120.0 mg (0.5 mmol) of compound a4 into a 10 mL sealed tube, add 5 mL of absolute ethanol, add 277.0 mg (2.0 mmol) of 4-fluorophenethylamine, and heat at 60°C for reaction. TLC detection (PE:EA:MeOH=5:20:2 developed) the reaction is complete, add water, extract with ethyl acetate, the organic phase is washed with sat.NaCl, anhyd.Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 0.35 g of a crude product. Purified by column chromatography (PE:EA=1:1) to obtain 94.0 mg of white solid with a yield of 49.67%.

[0137] Carry out infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum NMR analysis and DEPT spectrum analysis to compound 2, such as Figures 22 to 26 As shown, the specific data of infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum NMR analysis are as follows:

[0138] IR(KBr),ν,cm -1 :3059,2822,1603,1511,1486,1465...

Embodiment 3

[0143] Synthesis and characterization of embodiment 3 compound 3

[0144] Take 158.0mg (0.7mmol) of compound a4 into a 10mL sealed tube, add 5mL of absolute ethanol, add 359.5mg (2.6mmol) of p-hydroxyphenylethylamine, and heat at 60°C for reaction. TLC detection (PE:EA:MeOH=5:20:1 development) the reaction is complete, add water, extract with ethyl acetate, the organic phase is washed with sat.NaCl, anhyd.Na 2 SO 4 After drying, the solvent was distilled off under reduced pressure to obtain 0.39 g of a crude product. Purified by column chromatography (PE:EA=1:2) to obtain 119.0 mg of white solid with a yield of 47.98%.

[0145] Carry out infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum NMR analysis and DEPT spectrum analysis to compound 3, such as Figures 27 to 31 As shown, the specific data of infrared spectrum, mass spectrum, hydrogen spectrum and carbon spectrum are as follows:

[0146] IR(KBr),ν,cm -1 :2932,1597,1518,1488,1465,1465,1271,1245,11...

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Abstract

The invention belongs to the field of medicinal chemistry and relates to a fluorine-substituted monocarbazole derivative, which is one or more of the compounds shown in formula (I) and formula (II), or formula (I) or formula (II) One or more of the medically acceptable soluble salts formed by the indicated compounds. The fluorine-substituted monocarbazole derivatives obtained in the present application can be used to prepare DNA methyltransferase inhibitors or histone demethylase inhibitors. The fluorine-substituted monocarbazole derivatives of the invention have inhibitory effect on the proliferation of cancer cells and can be used to prepare medicines for treating and / or preventing cancer. The in vitro cancer cell proliferation inhibition test shows that the fluorine-substituted monocarbazole compounds obtained in the present invention exhibit inhibitory effects on human lung cancer cells (A549), human colon cancer cells (HCT116), human gastric cancer cells (MNK-45), human liver cancer Antiproliferative activity of cells (HepG2), RPMI‑8226 and Karpas 299.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a fluorine-substituted monocarbazole derivative, a preparation method and application thereof. Background technique [0002] At present, the small molecule inhibitors of DNMT found in domestic and foreign research can be mainly divided into two categories: nucleoside analogs and non-nucleoside analogs. Nucleoside inhibitors mainly combine with DNA by simulating the structure of cytosine, and then capture DNMT to form a covalent The complex inhibits its methylated DNA, including azacitidine (5-azacytidine, Vidaza), decitabine (5-aza-2'-deoxycytidine, Dacogen), 5-fluoro-2-deoxycytidine (5 -Fluoro-2'-deoxycytidine, FdCyd), Zebularine (Zebularine), Dihydro-5-azacytidine (5,6-dihydro-5-azacytidine), Guadecitabine (SGI-110) and 2-( p-nitrophenyl)-ethoxycarbonyl azacitidine (NPEOC-DAC), etc., among which, azacitidine and decitabine have been used as marketed drugs for the treatment of a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/88C07D403/06C07D471/04C07D405/06A61P35/00A61K31/496A61K31/4045A61K31/403A61K31/437
CPCC07D209/88C07D403/06C07D471/04C07D405/06A61P35/00
Inventor 刘博梁微红韩晓东蔡桦杨吴云山周文潘琪钟金浪陈伟英徐方方李恩念王凯郑作亮王晓婉张玉琴祝春香
Owner GUANGDONG HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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