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Tricyclic anaplastic lymphoma kinase inhibitors

A heterocyclic group, selected technology, applied in the field of tricyclic anaplastic lymphoma kinase inhibitors, and can solve problems such as easy generation of drug resistance

Active Publication Date: 2018-11-02
SHANDONG XUANZHU PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, Pfizer's Crizotinib has been successfully marketed, but a large number of clinical trials have proved that the first-generation ALK inhibitor Crizotinib is prone to drug resistance. Therefore, designing and screening patients who are resistant to Crizotinib also has good curative effect A second-generation ALK inhibitor with significant clinical significance

Method used

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  • Tricyclic anaplastic lymphoma kinase inhibitors
  • Tricyclic anaplastic lymphoma kinase inhibitors
  • Tricyclic anaplastic lymphoma kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0075] The present invention also provides the preparation method of above-mentioned compound, but not limited to following method, and reaction equation is as follows:

[0076]

[0077] Reaction steps:

[0078] Step 1 Preparation of intermediate 1

[0079] Intermediate 1 can be purchased or prepared by appropriate methods.

[0080] Step 2 Preparation of Intermediate 2

[0081] Intermediate 1 is dissolved in a solvent (such as methanol), added with palladium carbon, reacted at 25°C under the protection of hydrogen (for example, 15-25 hours), filtered, and concentrated to obtain Intermediate 2.

[0082] Step 3 Preparation of Intermediate 3

[0083] Dissolve intermediate 2 in a suitable solvent (such as acetonitrile), cool to 0°C, add N-bromosuccinimide, stir at room temperature (for example, 0.5-1.5 hours), after the reaction is complete, add water to quench, organic solvent (such as acetic acid ethyl ester), concentrated, and purified (eg, silica gel column chromatograp...

experiment example 1

[0108] Experimental example 1 In vitro enzymatic activity test of the compound of the present invention

[0109] Test product: compound 1 of the present invention, its chemical name and preparation method are shown in the preparation examples of compound 1.

[0110] The control drug ceritinib is self-made (prepared with reference to the preparation method of compound 66 in patent WO2008 / 073687A2).

[0111] The meanings represented by the abbreviations of the following experiments are as follows:

[0112] DMSO: dimethyl sulfoxide

[0113] DTT: Dithiothreitol

[0114] ALK: Anaplastic Lymphoma Kinase

[0115] HEPES: 4-Hydroxyethylpiperazineethanesulfonic acid

[0116] Brij-35: lauryl polyethylene glycol ether

[0117] EDTA: ethylenediaminetetraacetic acid

[0118] Experimental method: Determination of the inhibitory activity of ALK kinase by Caliper Mobility Shift method

[0119] 1.1x kinase buffer preparation:

[0120] Take HEPES at pH 7.5, Brij-35 with a concentratio...

experiment example 2

[0140] Experimental example 2 In vitro cell activity test of the compound of the present invention

[0141] Test product: compound 1 of the present invention, its chemical name and preparation method are shown in the preparation examples of compound 1.

[0142] The control drug Ceritinib is self-made (prepared by referring to the preparation method of compound 66 in patent WO2008 / 073687A2).

[0143] The meanings represented by the abbreviations of the following experiments are as follows:

[0144] rpm: revolutions per minute

[0145] DMSO: dimethyl sulfoxide

[0146] MTS: Thiazolium blue tetrazolium bromide

[0147] RPMI1640: 1640 medium (RPMI: Roswell Park Memorial Institute)

[0148] "×" in 500×, 1000×, 10×: times

[0149] experimental method:

[0150] NCI-H3122 cells:

[0151] (1) Medium preparation:

[0152] RPMI1640 medium containing 2.5% fetal bovine serum was prepared for use.

[0153] (2) Cell culture:

[0154] at 5% CO 2 1. In an incubator at 37°C, put NC...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to tricyclic and fused-cyclic ALK (anaplastic lymphoma kinase) inhibitors represented in a general formula (I), pharmaceutically acceptable salts, esters and solvates of the tricyclic and fused-cyclic ALK inhibitors or stereoisomers of the tricyclic and fused-cyclic ALK inhibitors, wherein definitions of R<1>, R<2>, R<3>, R<4>, a ring A and a ring B are shown in the specification. The invention further relates to a preparation method of the compounds, pharmaceutic preparations and pharmaceutic composition which contain the compounds, as well as an application of the compounds, the pharmaceutically acceptable salts, esters and solvates of the compounds or the stereoisomers of the compounds in preparation of drugs for treating and / or preventing cancer related diseases mediated by ALK.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and in particular relates to a tricyclic anaplastic lymphoma kinase inhibitor, a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, a preparation method of these compounds, and a compound containing these compounds Pharmaceutical preparations and pharmaceutical compositions, and the compound, its pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof in the preparation of medicines for treating and / or preventing cancer-related diseases mediated by anaplastic lymphoma kinase in the application. Background technique [0002] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family, which can recruit downstream proteins through autophosphorylation, and then express specific genes to regulate cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and later found...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/048C07D491/056C07D491/052A61K31/506A61P35/00A61P17/00A61P13/08
CPCC07D491/048C07D491/052C07D491/056
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD