A kind of tyrosine kinase inhibitor and its use

A compound and selected technology, applied in the field of medicine, can solve the problems of no EGFR TKI drugs on the market, drug resistance, and changes in EGFR kinase affinity, etc.

Active Publication Date: 2019-09-06
吉林升通化工有限公司 +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The possible mechanism is that methionine occupies a larger space than threonine, forming steric hindrance, which changes the affinity of EGFR kinase to ATP, resulting in the inability of EGFR-TKI small molecule drugs to effectively block EGFR activation signals , thus losing the killing effect on tumor cells and producing drug resistance
[0007] So far, there are still no EGFR TKI drugs targeting the T790M mutation on the market

Method used

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  • A kind of tyrosine kinase inhibitor and its use
  • A kind of tyrosine kinase inhibitor and its use
  • A kind of tyrosine kinase inhibitor and its use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0203] The present invention also provides the preparation method of formula (I) compound, but not limited to following method:

[0204] Process route one:

[0205]

[0206] Process route two:

[0207]

[0208]Among them, R in the above reaction equation 1 , R 2 , R 3 ,Z 1 ,Z 2 , A, B, C, X, and Y are as previously described

[0209] Reaction step one:

[0210] 1. Preparation of Intermediate 1

[0211] Dissolve raw material 1 in a suitable organic solvent (such as tetrahydrofuran, ethanol, methanol), and add raw material 2 (R 2 Cl), stirred at room temperature until the reaction is complete, quenched with water, extracted with an organic solvent (such as ethyl acetate, dichloromethane), dried and concentrated the organic phase, and purified to obtain intermediate 1.

[0212] 2. Preparation of Intermediate 3

[0213] Intermediate 1 and a base (such as triethylamine, diethylamine) are dissolved in a suitable solvent (such as tetrahydrofuran, ethanol, methanol), s...

specific Embodiment approach

[0259] The following descriptions of specific embodiments will further illustrate the present invention, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements according to the teaching of the present invention without departing from the basic idea and scope of the present invention.

[0260] Experimental program

[0261]Exemplary experimental schemes of some compounds of the present invention are provided below to show the advantageous activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental scheme is only an example of the content of the present invention, rather than limiting the scope of the present invention. Those skilled in the art can make appropriate modifications or changes to the technical solution of the present invention under the teaching of this specification without departing from the spirit and ...

experiment example 1

[0262] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0263] Test product: some compounds of the present invention, see the preparation examples of each compound for its chemical name and preparation method.

[0264] Control drug: CO-1686, self-made (prepared with reference to the method in WO2012061299A1), its structural formula is as described in the background technology.

[0265] The meanings represented by the abbreviations in the following experiments are as follows:

[0266] EDTA: ethylenediaminetetraacetic acid

[0267] DMSO: dimethyl sulfoxide

[0268] SD: standard deviation

[0269] FAM: carboxyfluorescein

[0270] Brij-35: lauryl polyethylene glycol ether

[0271] HEPES: Carboxyethylpiperazineethanesulfonic acid

[0272] DTT: Dithiothreitol

[0273] Experimental method: Using the Mobility Shift Assay method, in the case of Km ATP, the kinases EGFR and EGFR_T790M were used to screen the compounds.

[02...

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Abstract

The present invention relates to compounds represented by general formula (I) that can be used as tyrosine kinase inhibitors, their pharmaceutically acceptable salts, their esters, their solvates and their stereoisomers, wherein R 1 , R 2 , R 3 ,Z 1 ,Z 2 , A, B, C, X, Y are as defined in the specification. The present invention also relates to preparation methods of these compounds, pharmaceutical compositions and kits containing these compounds, and uses of these compounds. For example, the compounds of the present invention can be used as tyrosine kinase inhibitors, or for reducing or inhibiting the activity of EGFR or its mutants (such as EGFR mutants comprising T790M mutation) in cells, or for treating and / or preventing Diseases (eg cancer) associated with EGFR overactivity, especially diseases (eg cancer) with drug resistance caused by EGFR mutations (eg T790M mutation of EGFR).

Description

technical field [0001] The invention belongs to the technical field of medicine. In particular, the present invention relates to a novel compound useful as a tyrosine kinase inhibitor, its pharmaceutically acceptable salt, its ester, its solvate and its stereoisomer, containing said compound, its pharmaceutical Pharmaceutical compositions and kits of pharmaceutically acceptable salts, esters thereof, solvates and / or stereoisomers thereof, preparation of the compounds, pharmaceutically acceptable salts thereof, esters thereof, solvates and stereoisomers thereof Methods of isomerization, and uses of said compounds, their pharmaceutically acceptable salts, their esters, their solvates, and their stereoisomers. For example, the compounds of the present invention can be used as tyrosine kinase inhibitors, or for reducing or inhibiting the activity of EGFR or its mutants (such as EGFR mutants comprising T790M mutation) in cells, or for treating and / or preventing Diseases associate...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12C07D471/10C07D487/08C07D471/08C07D487/04A61K31/506A61P35/00
CPCC07D403/12C07D401/14C07D401/12C07D487/04C07D487/08A61K31/506A61K31/4545A61K31/496A61K31/505A61K31/5377A61K45/06C07D213/74C07D239/48C07D403/04C07D405/14C07D451/02C07D487/10A61P35/00A61K2300/00
Inventor吴永谦
Owner吉林升通化工有限公司