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Fluorine-substituted bimolecular carbazole derivatives, preparation method and application thereof

A molecular carbazole and derivative technology, applied in the field of medicinal chemistry, can solve the problems of high toxicity and side effects, affecting the overall stability of chromosomes, and low selectivity

Active Publication Date: 2022-04-22
GUANGZHOU UNIVERSITY OF 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
[0004] Non-nucleoside (cytosine) analogs have a wide variety of chemical structures, but most are less selective and less active

Method used

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  • Fluorine-substituted bimolecular carbazole derivatives, preparation method and application thereof
  • Fluorine-substituted bimolecular carbazole derivatives, preparation method and application thereof
  • Fluorine-substituted bimolecular carbazole derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Example 1 Compound 1: 1-((1,3-bis(3,6-difluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(isopropylamino) -2-propanol (1-((1,3-bis(3,6-difluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(isopropylamino)propan-2-ol) Synthesis

[0121] It includes the following steps:

[0122] (1) Intermediate 3,6-difluoro-9-(oxiran-2-ylmethyl)-9H-carbazole (3,6-difluoro-9-(oxiran-2-ylmethyl)-9H- Synthesis of carbazole, b4):

[0123] The synthetic route is as follows:

[0124]

[0125] Concrete synthetic steps include:

[0126] Take 2.70g (13.3mmol) 3,6-difluoro-9H-carbazole (b3) to a 100mL round bottom flask, add an organic solvent (in this embodiment, the organic solvent is DMF, in other embodiments, organic The solvent can also be dissolved in about 50 mL of an aprotic solvent such as DMSO (dimethyl sulfoxide), and then 0.82 g (14.6 mmol) of the basic catalyst KOH is added, and stirred for 5 minutes in an ice bath to cool down. 2.46g (26.6mmol) epichlorohydrin was added dropwise in batche...

Embodiment 2

[0157] Example 2 Compound 2: 1-((1,3-bis(3-fluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(isopropylamino)-2- Synthesis of propanol (1-((1,3-bis(3-fluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(isopropylamino)propan-2-ol)

[0158] It includes the following steps:

[0159] (1) Intermediate 3-fluoro-9-(oxiran-2-ylmethyl)-9H-carbazole (3-fluoro-9-(oxiran-2-ylmethyl)-9H-carbazole, a4) synthesis:

[0160] The synthetic route is as follows:

[0161]

[0162] Concrete synthetic steps include:

[0163] Get 2.40g (13.0mmol) 3-fluoro-9H-carbazole (a3) ​​to a 100mL round bottom flask, add an organic solvent (in this embodiment, the organic solvent is DMF, in other embodiments, the organic solvent can also An aprotic solvent such as DMSO) was dissolved in about 50 mL, and then 0.80 g (14.3 mmol) of the basic catalyst KOH was added, stirred for 5 minutes in an ice bath and cooled. Add 2.40 g (26.0 mmol) of epichlorohydrin dropwise in batches, and then return to room temperature and stir f...

Embodiment 3

[0195] Example 3 Compound 3: 1-((1,3-bis(3-fluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(tert-butylamino)-2- Synthesis of propanol (1-((1,3-bis(3-fluoro-9H-carbazol-9-yl)propan-2-yl)oxy)-3-(tert-butylamino)propan-2-ol)

[0196] Including the following steps:

[0197] Take 120.0 mg (0.2 mmol) of intermediate d4 into a 10 mL sealed tube, add 5 mL of isopropanol, add 182.5 mg (2.5 mmol) of tert-butylamine, and heat at 60°C for reaction. TLC detection (PE:EA:MeOH=5:20:3 developed) complete reaction, adding water, extraction with ethyl acetate, organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 0.11 g. Purified by column chromatography (EA:MeOH=20:1) to obtain 26.0 mg of a white solid with a yield of 18.84%.

[0198] Wherein, the synthesis method of intermediate d4 is the same as that in Example 2.

[0199] The synthesized compound 3 was analyzed by infrared spec...

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Abstract

The invention discloses a fluorine-substituted bimolecular carbazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 as defined in the specification. The fluorine-substituted bimolecular carbazole derivatives provided by the present invention or their pharmaceutically acceptable salts can be used to prepare DNA methyltransferase inhibitors or histone demethylase inhibitors, which are confirmed by in vitro cancer cell anti-proliferation tests, The fluorine-substituted bimolecular carbazole derivative of the present invention has anti-proliferation activity on cancer cells.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a fluorine-substituted bimolecular carbazole derivative, a preparation method and application thereof. Background technique [0002] Among DNMTs, DNMT1 is the most abundant in mammalian cells, and its abnormal expression can lead to abnormal development of tumors and embryonic development. Cancer research has found that abnormal expression of DNMT1 can lead to genome-wide hypomethylation and hypermethylation of some tumor suppressor genes, resulting in cancerous cells, which are closely related to the occurrence and development of various tumors. For example, during the development of pancreatic cancer, the expression of DNMT1 gradually increases and is positively correlated with the degree of methylation of various tumor suppressor genes. In bladder cancer cells, the tumor suppressor gene CDKN2A is inactivated by methylation, and the use of antisense inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/88C07D403/14C07D405/14C07D405/06A61K31/403A61K31/496A61K31/4045A61P35/00
CPCC07D209/88C07D403/14C07D405/14C07D405/06A61P35/00
Inventor 刘博梁微红韩晓东陆金健周文王凯潘琪吴云山陈伟英徐方方钟金浪李恩念郑作亮王晓婉张玉琴祝春香
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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