1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof

A compound, chlorophenyl technology, applied in the field of medicinal chemistry, can solve problems such as drug interactions, toxic side effects, and inconvenience for patients with medication

Active Publication Date: 2018-12-21
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Considering that different types of drugs are used in combination, there are often inconveniences to...

Method used

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  • 1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof
  • 1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof
  • 1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The synthesis of embodiment 1 compound

[0034] 1.1 The specific synthetic route of the compound is as follows:

[0035]

[0036] 1.2 Synthesis steps

[0037] a. the synthesis of the first step intermediate product:

[0038] 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 aniline (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.

[0039] 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 spin ...

Embodiment 2

[0066] Example 2 compound anti-tumor cell activity

[0067] 2.1 MTT method to test the antitumor activity of compounds

[0068] This experiment uses the MTT method. The selected normal lung cells were BEAS-2B cells; the selected five non-small cell lung cancer cells included lung adenocarcinoma cell A549 (WT EGFR), lung adenocarcinoma cell PC-9 (EGFR d746-750), lung squamous cell carcinoma Cancer cell H520 (FGFR amplification), large cell lung cancer H1581 (FGFR amplification) and lung squamous cell carcinoma H226 (FGFR amplification / overexpressed EGFR). 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 and remember to set blank control wells containing only medium on the same well plate; after plating overnight, replace with fr...

example 3

[0071] IC of example 3 compounds F1, F2 and F8 to five kinds of tumor cells 50 experiment

[0072] 3.1 MTT method to test the IC of the compound 50 value

[0073] According to the results of the toxic effects of all target compounds on normal lung cells and the results of their inhibitory effects on five NSCLC cell lines, we obtained compounds F1, F2 and F8 that all have inhibitory effects on five NSCLC cell lines. We choose these three 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, five non-small cell lung cancer cell lines, including A549 cells, PC-9 cells, H520 cells, H1581 cells and H226 cells, 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 GraphPadPrism 5 software 50 value.

[0074] 3.2 Experimental results

[0075] IC for...

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Abstract

The invention discloses a 1-(2,6-dichlorophenyl)-3-(substituted pyrimidine-4-yl)urea compound and preparation and application thereof. The structure of the compound is shown in a formula (I). The compound has no toxicity function on the proliferation of BEAS-2B cells (lung normal cells), but has certain inhibiting functions on the selected five types of non-small cell lung cancer cell lines, suchas A549 cells (WT EGFR), PC-9 cells (EGFRdel E746-A75), H520 cells (FGFR amplification), H1581 cells (FGFR amplification), and H226 cells; the certain anti-tumor activity is realized, and the compoundis an effective EGFR/FGFR (epidermal growth factor receptor/fibroblast growth factor receptor) inhibitor. The formula (I) is shown in the attached figure.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a 1-(2,6-dichlorophenyl)-3-(6-(substituted anilino)pyrimidin-4-yl)urea double small molecule inhibitor of EGFR / FGFR Agents and their preparation methods and applications. . Background technique [0002] Receptor tyrosine kinases (RTKs) are the largest type of enzyme-linked receptors in the human body. There are 58 known RTKs in the human genome. RTKs play a vital role in cell growth, proliferation, migration, and differentiation. From epidermal growth factor receptors (EGFRs), fibroblast growth factor receptors (FGFRs) ), hepatocyte growth factor receptors (hepatocyte growth factor receptors, HGFRs), and platelet-derived growth factor receptors (platelet-derived growth factor receptors, PDGFR) and many other RTKs have been pharmacologically proven to have a positive effect on the expression of related proteins Survival of mutated forms of cancer is critical. Tyros...

Claims

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Application Information

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IPC IPC(8): C07D239/48A61P35/00
CPCA61P35/00C07D239/48
Inventor 叶发青程冬华韩超潘苏伟潘雅倩谢自新
Owner WENZHOU MEDICAL UNIV
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