Multi-target kinase inhibitor, pharmaceutical composition and preparation method and application of multi-target kinase inhibitor
A point kinase and inhibitor technology, which is applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve problems such as excessive cell proliferation, and achieve the effects of improving dissolution and absorption in vivo, good inhibitory activity, and good antitumor effect
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Embodiment 1
[0054] The present embodiment is multi-target kinase inhibitors (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) and their Preparation method, the general structural formula of the multi-target kinase inhibitor is shown in formula (I):
[0055]
[0056] Wherein, the structure of R is selected from following formula (a), formula (b), formula (c), formula (d), formula (e), formula (f):
[0057]
[0058] The preparation method of the multi-target kinase inhibitor of this embodiment is as follows:
[0059] (1) Preparation of compound 4-((6,7-dimethoxyquinoline imidazol-4-yl) oxy)aniline [compound (IV)]:
[0060] Add 4-aminophenol [compound (Ⅲ)] (3.46g, 31.2mmol) in the 250ml three-necked flask, NaOH (1.26g, 31.2mmol) and dimethyl sulfoxide 50ml are mixed and stirred, and dimethyl sulfoxide 50ml is mixed with 4-Chloro-6,7-dimethoxyquinazoline [compound (II)] (5g, 22.3mmol) was mixed and added to the above reaction solution. After the dropwise addition, the temperature was raised to...
Embodiment 2
[0100] This example studies the inhibitory activity of the multi-target kinase inhibitors of the present invention on RET, VEGFR3 and PDGFRA.
[0101] (1) Experimental steps:
[0102] 1. Accurately weigh the compound to be tested, add DMSO solvent to form a mother solution, and then use buffer to prepare the solution of the compound to be tested to the required concentration;
[0103] 2. Add RET or VEGFR3 or PDGFRA kinase solution, Z’-LYTE corresponding substrate solution, buffer or test compound, ATP into the 384 reaction vessel, and react at room temperature for 1 hour;
[0104] 3. Add fluorescence enhancer to each well and incubate at room temperature for 1 hour;
[0105] 4. Use the fluorescence analyzer to read the data separately.
[0106] (2) Data processing
[0107] 1. Calculate the relative inhibition rate of each well according to the formula;
[0108] 2. The relative inhibition rate detected after concentration dilution of the active sample is calculated by using...
Embodiment 3
[0115] In this example, the in vivo antitumor activity (liver cancer\esophageal cancer) of the multi-target kinase inhibitor [compound (I-1)] provided by the present invention was studied according to the requirements of the "Guiding Principles of Antitumor Drug Pharmacodynamics". The experimental method results are as follows:
[0116] (1) Experimental method
[0117] Nude mice were used to establish tumor models with SMMC-7721 liver cancer cells and KYSE 410 esophageal cancer cells that met the modeling conditions, and the mice that had been modeled were divided into 5 groups: model group, compound (I-1) 5mg / kg group, Compound (I-1) 10mg / kg group, compound (I-1) 20mg / kg group, positive control group (positive control: sorafenib or cabozantinib), the day of grouping started to be administered as day1, For 21 consecutive days, the 21st day was recorded as day21, and the tumor volume was measured twice a week during the administration period for statistical detection. The tes...
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