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1-(3,5-dimethoxy phenyl)-3-substituted urea colon cancer inhibitor as well as preparation and application thereof

A kind of technology of dimethoxyphenyl and substituted urea, applied in the field of medicinal chemistry

Pending Publication Date: 2019-11-01
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The third-generation EGFR-TKI drugs such as AZD9291 and CO-1686 have good target selectivity, can inhibit T790M mutation (a point mutation in EGFR exon 20) and reduce side effects, however, acquired drug resistance It is also unavoidable during the treatment of such patients. For example, the third-generation inhibitors will have a C797S mutation (a point mutation in exon 19 of EGFR)

Method used

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  • 1-(3,5-dimethoxy phenyl)-3-substituted urea colon cancer inhibitor as well as preparation and application thereof
  • 1-(3,5-dimethoxy phenyl)-3-substituted urea colon cancer inhibitor as well as preparation and application thereof
  • 1-(3,5-dimethoxy phenyl)-3-substituted urea colon cancer inhibitor as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 compound

[0045] 1.1 The specific synthetic route of the compound is as follows:

[0046]

[0047] 1.2 Synthesis steps

[0048] a. the synthesis of the first step intermediate product:

[0049] Step 1: Take a dry three-neck reaction bottle and put it into a magnet. Add 4-amino-6-chloropyrimidine (1eq), KI (0.5eq), and dissolve with absolute ethanol (35mL). After heating with stirring for 10 min on a magnetic stirrer, trifluoroacetic acid (200 mL) was added. activation. After about 1 h, substituted benzylamine (0.8 eq) dissolved in absolute ethanol (15 mL) was added for reaction. Note that it should be added in a dropwise manner to achieve the effect of long-term excess reaction, and the dropping time should be controlled at about 1 hour.

[0050] Step 2: use TLC method to detect the reaction progress and reaction effect. Generally, after 36 hours of reaction, the reaction is almost complete. After the reaction is complete, first...

Embodiment 2

[0111] Example 2 compound anti-tumor cell activity

[0112] 2.1 MTT method to test the antitumor activity of compounds

[0113] This experiment uses the MTT method. The selected normal lung cells are BEAS-2B cells; the selected three cancer cells include SW116 cells (human colorectal cancer cells), SW480 cells (human colon cancer cells) and SW620 cells (human colon cancer cells). The above-mentioned cells with logarithmic growth were selected, digested, collected, and counted with a cell counting plate. Next, dilute the counted cells to an appropriate concentration (5*10^4 cells / mL~8*10^4 cells / mL), and add the diluted cell suspension to the 96-well plate at 100 μL per well culture medium, and remember to set blank control wells containing only medium on the same well plate; after overnight culture on the plate, replace with fresh medium, and add a series of concentration gradient dilutions of the test target compound to each well to wait for the drug effect After 72 hours,...

Embodiment 3

[0116] IC of Example 3 Compounds P13 and P14 to Three Kinds of Tumor Cells 50 experiment

[0117] 3.1 MTT method to test the IC of the compound 50 value

[0118] According to the results of the toxic effects of all target compounds on normal lung cells and the inhibitory effects on three colon cancer cell lines, we obtained compounds P13 and P14 that have inhibitory effects on all three colon cancer cell lines. We choose these two compounds, further to do IC 50 experiment. Six concentrations (20 μM, 10 μM, 1.0 μM, 0.50 μM, 0.10 μM and 0.01 μM) were first set for both compounds. Then, the three colon cancer cell lines were treated with different concentrations of these two compounds. Obtain the optical density (OD) value, calculate the inhibition rate, and calculate the IC of different compounds by GraphPad Prism5 software 50 value.

[0119] 3.2 The experimental results are shown in the table below:

[0120]IC of compounds acting on SW116, SW480, SW620 cell lines 50

...

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Abstract

The invention discloses a 1-(3,5-dimethoxy phenyl)-3-substituted urea compound acting on colon cancer, and a preparation method and application of the compound. The compound has no toxic effect on proliferation of BEAS-2B cells, but has a certain inhibition function on three selected colon cancer cell systems, including SW116 cells, SW480 cells and SW620 cells, and has certain anti-tumor activity.Inhibition rates of compounds P13 and P14 upon the three cancer cells are all greater than 50% at a concentration of 10[mu] M, and the compound P13 has a larger inhibition rate. IC50 values of the compound P13 upon three cancer cells are respectively 3.26+ / -0.74[mu] M, 4.62+ / -0.45[mu] M and 3.32+ / -1.21[mu] M. Results show that the compound P13 is an effective colon cancer inhibitor.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a 1-(3,5-dimethoxyphenyl)-3-(6-(substituted benzylamino)pyrimidin-4-yl)urea colon cancer small molecule Inhibitor and its preparation method and application. Background technique [0002] Colon cancer is a cancer with high morbidity and mortality. In the treatment of colon cancer, due to poor selectivity, it brings a lot of toxic and side effects, which limits its clinical application efficacy. [0003] In the past ten years, targeted therapy has become one of the research hotspots, among which the epidermal growth factor receptor (EGFR) has attracted much attention. After a period of treatment of cancer patients with first-generation EGFR inhibitors such as Gefitinib and Erlotinib, most of them develop resistance to EGFR-TKIs. Second-generation inhibitors such as afatinib (Afatinib) can effectively alleviate the drug resistance caused by the first-generation inhibi...

Claims

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Application Information

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IPC IPC(8): C07D239/48A61P35/00
CPCC07D239/48A61P35/00
Inventor 叶发青潘苏伟何琴王悦暄陈波谢自新
Owner WENZHOU MEDICAL UNIV
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