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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

Active Publication Date: 2019-05-21
GUANGZHOU LIUSHUN BIO TEC CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sustained signaling leads to hyperproliferation of cells, thus leading to tumorigenesis and progression

Method used

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  • Multi-target kinase inhibitor, pharmaceutical composition and preparation method and application of multi-target kinase inhibitor
  • Multi-target kinase inhibitor, pharmaceutical composition and preparation method and application of multi-target kinase inhibitor
  • Multi-target kinase inhibitor, pharmaceutical composition and preparation method and application of multi-target kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The invention belongs to the technical field of biological medicines, in particular relates to a multi-target kinase inhibitor and a pharmaceutical composition containing the multi-target kinase inhibitor, and also relates to a preparation method and application of the multi-target kinase inhibitor. The structural general formula of the multi-target kinase inhibitor provided by the invention is shown in a formula (I), wherein the structure of R is selected from a formula (a), a formula (b), a formula (c), a formula (d), a formula (f) and the formula (d); the multi-target kinase inhibitor can effectively inhibit the enzymatic activity of RET, VEGFR3 and PDGFRA, and can effectively treat diseases which are regulated and controlled by multi-target kinase and are related to the abnormal signaltransduction pathway of the multi-target kinase, such as cancers of breast, respiratory tract, brain, reproductive organ, digestive tract, urinary tract, eye, liver, skin, head and / or neck, as well as distal metastatic cancers, such as lymphoma, sarcoma, leukemia and the like. The active ingredient of the pharmaceutical composition comprises the multi-target kinase inhibitor, and the weight percentage of the multi-target kinase inhibitor in the composition is 1-50%. (See the instruction for specific formulas.).

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a multi-target kinase inhibitor and a pharmaceutical composition containing the multi-target kinase inhibitor, and also relates to a preparation method and application of the multi-target kinase inhibitor. Background technique [0002] Cells contain complex signal transduction pathways, which are mediated by tyrosine protein kinases and involve changes in the structure and function of many proteins in the human body. Abnormal signal transduction of cells is one of the key factors in the occurrence and development of tumors. The target of tyrosine protein kinase has been a hotspot in the research of anticancer drugs in recent decades. With the deepening of research and the clinical application of drugs, it is found that the therapeutic effect of blocking the specific signal transduction pathway of tumor cells through single-target drugs may not be objective enough, ...

Claims

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Application Information

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IPC IPC(8): C07D239/88A61P35/00A61P35/02A61K31/517
CPCA61P35/00A61K31/517C07D239/88A61P35/02A61K9/08A61K9/2054A61K9/4866A61K9/009A61K47/20
Inventor 刘兵戴静思王嫣钱学启董俊军刘希红邓联武谢爽李大萍陈能安马进
Owner GUANGZHOU LIUSHUN BIO TEC CO LTD
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