A kind of 4,5-diazafluorene derivative and its preparation method and application

A technology of diazafluorene and derivatives is applied in the field of 4,5-diazafluorene derivatives and their preparation, which can solve the problem of not targeting human telomere G-quadruplex anti-tumor clinical drug reports, etc. quality, the effect of improving the reaction yield

Active Publication Date: 2020-03-17
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, so far, there are no reports of clinical drugs targeting human telomere G-quadruplex against tumors.

Method used

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  • A kind of 4,5-diazafluorene derivative and its preparation method and application
  • A kind of 4,5-diazafluorene derivative and its preparation method and application
  • A kind of 4,5-diazafluorene derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of Example 1 Compound 11c Its synthetic route is as follows:

[0043]

[0044] 1) Preparation of Intermediate 2c Dissolve p-bromoacetophenone (1.99g, 10.0mmol) in 25mL of absolute ethanol, add semicarbazide hydrochloride (1.23g, 11.0mmol) and anhydrous sodium acetate (0.90g, 11.0mmol) , reacted at 75°C for 6 hours, concentrated, cooled, precipitated a white solid, filtered, recrystallized with ethanol / water (4:1), filtered, washed with a small amount of water, dried to obtain 2.30 g of white solid 2c, yield 89.84% ;

[0045] 2) Preparation of Intermediate 4c Stir 15.5mL of DMF in an ice bath for ten minutes, slowly add 3.1mL of phosphorus oxychloride dropwise to it, keep the temperature below 5°C, stir for fifteen minutes, then add compound 2c (2.0 g, 7.8mmol), and kept stirring at the temperature for half an hour. Then slowly raise the temperature to 80° C., react for 5 hours, and detect by TLC until the reaction is complete. Pour the mixture into cru...

Embodiment 2

[0065] The preparation of embodiment 2 compound 8a

[0066] Compound 8a: 5-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methylene)-5H-cyclopenta[2,1-b:3,4-b']di Pyridine (8a)

[0067] (1) 8a chemical structural formula:

[0068]

[0069] (2) Chemical reaction steps:

[0070] The test method and steps are the same as 11c. After purification, a light yellow solid (8a) was obtained with a yield of 85%; m.p.217-219°C, purity: 98.1% (HPLC). Characterization data:

[0071] 1 H NMR (DMSO-d 6 ,500MHz,ppm):δ13.498(br.s,1H,N-H),8.680-8.668(dd,J=5.0,1.5Hz,1H,pyridine-H 8 ), 8.646-8.634 (dd, J=5.0, 1.5Hz, 1H, pyridine-H 2 ), 8.496-8.478 (dd, J=8.0, 1.5Hz, 1H, pyrazol-H 11 ), 8.227-8.212 (d, J=7.5Hz, 1H, pyridine-H 6 ),7.895(br.s,1H,C-H 10 ), 7.743-7.716 (dd, J=5.0, 1.5Hz, 2H, benzene-H), 7.480-7.455 (dd, J=5.0, 1.5Hz, 1H, pyridine-H 4 ),7.363-7.338(dd,J=5.0,1.5Hz,1H,benzene-H),7.302(m,3H,pyridine-H 3,7 and benzene-H).MS(ESI)calcd for C 21 h 13 FN 4 :340.11,found:341.1(M+H + )....

Embodiment 3

[0072] The preparation of embodiment 3 compound 8b

[0073] Compound 8b: 5-((3-(4-chlorophenyl)-1H-pyrazol-4-yl)methylene)-5H-cyclopenta[2,1-b:3,4-b']di Pyridine (8b)

[0074] (1) 8b chemical structural formula:

[0075]

[0076] (2) Chemical reaction steps:

[0077] The test method and steps are the same as 11c. After purification, a light yellow solid (8b) was obtained with a yield of 83%; m.p.242-244°C, purity: 97.8% (HPLC). Characterization data:

[0078] 1 H NMR (DMSO-d 6 ,500MHz,ppm):δ13.576(br.s,1H,N-H),8.682-8.674(d,J=4.0Hz,1H,pyridine-H 8 ), 8.646-8.638 (d, J=4.0Hz, 1H, pyridine-H 2 ), 8.506-8.491 (d, J=7.5Hz, 1H, pyrazol-H 11 ), 8.218-8.205 (d, J=6.5Hz, 1H, pyridine-H 6 ),7.905(br.s,1H,C-H 10 ), 7.722-7.707 (d, J=7.5Hz, 2H, benzene-H), 7.522 (br.s, 3H, pyridine-H 4 andbenzene-H), 7.484-7.459 (dd, J=7.5, 5.0Hz, 1H, pyridine-H 7 ), 7.363-7.338 (dd, J=7.5, 5.0Hz, 1H, pyridine-H 3 ).MS(ESI)calcd for C 21 h 13 ClN 4 :356.08,found:357.1(M+H + ).

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Abstract

The invention relates to a 4,5-diazafluorene derivative, a preparation method and applications thereof, wherein a 1,10-phenanthroline monohydrate and potassium permanganate are subjected to an oxidizing reaction to obtain a 4,5-diazafluoren-9-one intermediate, and the 4,5-diazafluoren-9-one intermediate is sequentially subjected to a reduction reaction and a condensation reaction to obtain the target product 4,5-diazafluorene derivative represented by a formula (I). According to the present invention, the cytotoxicities of all target compounds to lung cancer cells, gastric cancer cells, breastcancer cells, liver cancer cells and human normal embryonic lung fibroblasts are evaluated through a CCK-8 experimental technology, and the compounds 11a-c with good activity are used for the research on the interaction on the human chromosome telomere 26nt DNA sequence, wherein the compounds can well act on the guanine G-rich human chromosome telomere 26nt DNA sequence, and can stabilize the telomere G-quadruplex structure, such that the significant reference value is provided for the discovery of new anti-tumor small molecule drugs, especially for the clinical drug research and developmentof 4,5-diazafluorene derivatives.

Description

technical field [0001] The invention relates to a 4,5-diazofluorene derivative and a preparation method and application thereof, in particular to an application in the preparation of antitumor drugs. Background technique [0002] Cancer is a high-profile public health problem causing incalculable losses, with lung cancer being the most common and fatal cancer. Among men, lung cancer accounts for 17% of new cancer cases worldwide and accounts for about a quarter of global cancer deaths. Among lung cancer cases, 85% of patients belong to non-small cell lung cancer, and only 15% of patients belong to small cell lung cancer, and most cancer patients are resistant to clinical drugs. Lung cancer has always been the leading cause of death in cancer deaths around the world. Although the global medical level has gradually improved in recent years, the 5-year survival rate of lung cancer patients is still lower than 18% in most countries. Breast cancer is the most common malignancy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P35/00A61P35/04A61K31/4375
CPCA61P35/00A61P35/04C07D471/04
Inventor 张文刘佳春胡晓琳成梅
Owner ZHEJIANG UNIV OF TECH
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