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Naphthalimide-containing celecoxib derivatives with anti-tumor activity targeting DNA, pharmaceutical composition, preparation method and application thereof

A technology containing naphthalene diimide with anti-tumor activity, which is applied in the field of compounds and can solve problems such as weak activity

Inactive Publication Date: 2017-03-08
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that celecoxib, as a COX-2 inhibitor, has anti-tumor activity, but its activity is weak. Therefore, we are committed to modifying the structure of celecoxib, hoping to obtain new compounds with better anti-tumor activity

Method used

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  • Naphthalimide-containing celecoxib derivatives with anti-tumor activity targeting DNA, pharmaceutical composition, preparation method and application thereof
  • Naphthalimide-containing celecoxib derivatives with anti-tumor activity targeting DNA, pharmaceutical composition, preparation method and application thereof
  • Naphthalimide-containing celecoxib derivatives with anti-tumor activity targeting DNA, pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Preparation of compound 2:

[0098] Add compound 1 (N-(N,N-dimethylaminoethyl)-4-bromo-1,8-naphthalene diimide) 3g (0.88mmol) in a 100mL single-necked flask, volume percentage 80% Hydrazine hydrate aqueous solution 19mL, absolute ethanol 42mL, heated to reflux at 80°C until the reaction was identified by TLC as complete, cooled, and the solid was collected by suction filtration and dried in vacuo to obtain compound 2 (N-(N,N-dimethylaminoethyl)-4- hydrazino-1,8-naphthalimide), the yield was 92%.

Embodiment 2

[0100] Compound 5a [N-(N,N-dimethylaminoethyl)-4-(5-phenyl-3-trifluoromethyl-1H-pyrazole-1-yl)-1,8-naphthalimide 】Preparation:

[0101] ①Put 14.9mmol of acetophenone (compound 3a) and 30mL of dry THF into a 100mL round bottom flask, cool down to -5~0°C, add 0.715g (29.8mmol) of NaH in batches under the protection of nitrogen, at this temperature Stir for 30 min, add 3.175 g (22.4 mmol) of ethyl trifluoroacetate, stir at room temperature for 6 h, distill off the solvent under reduced pressure, add 30 mL of ice water for dilution, adjust the pH value of the solution to 6 with 1 mol / L HCl, and use ethyl acetate Extracted three times (10mL×3), recovered and combined the organic layers, then washed with 5mL of water, dried with anhydrous magnesium sulfate, precipitated, and dried the concentrated product to obtain compound 4a (4,4,4-trifluoro -1-phenyl-1,3-butanedione), yield 86%;

[0102] ②Add compound 4a (1mmol), compound 2 (1mmol), absolute ethanol 15mL, 1mol / L HCl 1.2mL in a ...

Embodiment 3

[0111] Compound 5b [N-(N,N-dimethylaminoethyl)-4-(5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole-1-yl)-1, The preparation of 8-naphthalimide]:

[0112] ①Add 14.9mmol of 4-methylacetophenone (compound 3b) and 30mL of dry THF into a 100mL round bottom flask, cool down to -5~0°C, add 0.715g (29.8mmol) of NaH in batches under nitrogen protection, Stir at this temperature for 30 min, add 3.175 g (22.4 mmol) of ethyl trifluoroacetate, stir at room temperature for 6 h, evaporate the solvent under reduced pressure, add ice water to dilute the solution, and adjust the pH of the solution to 6 with 1 mol / L HCl. Extracted three times with ethyl acetate (10mL×3), recovered and combined the organic layers, washed the organic layer with 5mL of water, dried with anhydrous magnesium sulfate, desolventized, and dried the concentrated product to obtain compound 4b(4,4 , 4-trifluoro-1-(4-methylphenyl)-1,3-butanedione), the yield was 89%;

[0113] ②Add compound 4b (1mmol), compound 2 (1mmol), ...

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Abstract

The invention discloses targeted DNA (deoxyribonucleic acid) naphthyldiimide-structure-containing celecoxib derivatives with antitumor activity, of which the structure is disclosed as Formula (I), wherein R is hydrogen, alkyl group or alkoxy group. The invention also discloses a preparation method of the derivatives and application of the derivatives in preparing drugs for resisting mammary cancer, cervical carcinoma and lung adenocarcinoma. The celecoxib structure is modified, and the naphthyldiimide group is used instead of sulfaphenyl group in the celecoxib, thereby designing and synthesizing a series of celecoxib derivatives containing the naphthyldiimide structure unit. The synthesized compounds 5a-5t have certain inhibiting actions on human mammary cancer cells, Hela cells and human lung adenocarcinoma cells. Part of the compounds have excellent antitumor activity, wherein the compounds 5o and 5h have very high selectivity for Hela cells, and the compound 5i has high selectivity for MCF-7 cells. The IC50 value is greatly lower than that of amonafide and higher than that of cis-platinum and celecoxib.

Description

technical field [0001] The invention relates to compounds, in particular to a celecoxib derivative containing a naphthalimide structure targeting DNA and having antitumor activity, a pharmaceutical composition, a preparation method and application thereof. Background technique [0002] Cancer is one of the leading causes of death worldwide, and the word "cancer" often brings shudders to people. In the past 30 years, the incidence of cancer in the world has been increasing at an average annual rate of 3% to 5%, and 70% of new cases occur in emerging and developing countries. Relevant data also show that in 2008, the number of new cases worldwide was 12.7 million, and the number of deaths reached 7.6 million. Now the number of patient cases is as high as 28 million, of which the number of cases in developing countries accounts for 56%, and the proportion of deaths in it is even higher, reaching 64%. World Health Organization (WTO) experts warned in Geneva that by 2020, the n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/473A61P35/00
CPCC07D401/04
Inventor 李胜辉许胜杰张金超王书香周国强
Owner HEBEI UNIVERSITY
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