bicyclic anaplastic lymphoma kinase inhibitor

A kind of technology of heterocyclic group and alkyl group, applied in the field of bi-cyclic anaplastic lymphoma kinase inhibitor

Active Publication Date: 2018-09-18
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 clinically proven first-generation ALK inhibitors, Crizotinib, are prone to drug resistance. Therefore, it is necessary to design and screen small molecule inhibitors that are active against ALK mutations and Efforts to improve the physical and chemical properties of the compound and improve the druggability (such as increasing the bioavailability of the compound) have significant clinical significance

Method used

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  • bicyclic anaplastic lymphoma kinase inhibitor
  • bicyclic anaplastic lymphoma kinase inhibitor
  • bicyclic anaplastic lymphoma kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0142] The preparation of step 1 intermediate 1

[0143] Intermediate 1 was purchased or prepared separately.

[0144] Step 2 Preparation of Intermediate 2

[0145] Intermediate 1 was dissolved in a suitable solvent, sodium hydride was added at 0°C, stirred, and then raw material 1 was added, the reaction mixture was stirred at room temperature (for example, 1-12h), quenched by adding water, extracted with an organic solvent (for example, ethyl acetate), concentrated, and purified by Purification (eg silica gel column chromatography) affords intermediate 2.

[0146] Step 3 Preparation of the compound of general formula (I) of the present invention

[0147] Dissolve intermediate 2 and intermediate 3 in a suitable solvent (such as 1,4-dioxane), under nitrogen protection, heat (such as 70°C-120°C) for reaction (such as 4-16 hours), filter, and add water Dilute, extract with an organic solvent (such as ethyl acetate), dry, concentrate, and obtain the compound of general formula...

experiment example 1

[0175] Experimental Example 1 The in vitro enzymatic activity test of the compound of the present invention

[0176] Test product: trifluoroacetate salt of compound 2, compound 3 and compound 4 of the present invention, prepared according to the preparation examples of trifluoroacetate salt of compound 2, compound 3 and compound 4.

[0177] The meanings represented by the abbreviations of the following experiments are as follows:

[0178] DMSO: dimethyl sulfoxide

[0179] DTT: Dithiothreitol

[0180] SEB: Enzyme Catalyst Buffer

[0181] ATP: adenosine triphosphate

[0182] ALK: Anaplastic Lymphoma Kinase

[0183] SA-XL665: Streptavidin-labeled donor

[0184] 2.5×, 5×, 10× “×” among them: times

[0185] experimental method:

[0186] ALK kinase buffer preparation:

[0187] Take an appropriate amount of MgCl with a mother liquor concentration of 1000mM 2 , 2500nM SEB, 100mM DTT, and 5×enzyme buffer were added to ultrapure water so that the final concentrations were: 5mM...

Embodiment 1

[0208] Example 1 4-(5-chloro-2-((2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidine-4- base)-3,4-dihydro-2H-benzo[b][1,4]thiazine 1,1-dioxide (compound 1) trifluoroacetate

[0209]

[0210] (1) Preparation of 2-((2-chloroethyl)thio)aniline

[0211]

[0212] In a 250mL three-neck flask, add 2-aminothiophenol (10g, 79.88mmol) and 1,2-dichloroethane (78g, 788.3mmol). The reaction mixture was heated to reflux under the protection of nitrogen, and then a methanol solution of sodium methoxide (15 g) was added dropwise. After the addition was complete, it was heated to reflux for 3 hours. After the reaction was completed, the reaction solution was cooled and poured into ice water, then extracted with dichloromethane (3×100mL), the organic layers were combined, washed with saturated sodium bicarbonate, the organic layer was separated, dried with anhydrous sodium sulfate, and concentrated to obtain the product (8 g, 53% yield).

[0213] (2) Preparation of N-(2-...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a dibenzocyclo type anaplastic lymphoma kinase inhibitor as shown in a general formula (I), and a salt compound, an ester compound, a solvent compound, or a stereoisomeric body thereof, which are acceptable in pharmacy, wherein R<1>, R<2>, R<3>, R<4>, R<5>, n, X and Y are as defined in the description. The invention further relates to a preparation method of the compounds, and the application of a medicinal preparation containing the compounds, a medicinal composition containing the compounds, the compounds, and the salt compound, the ester compound, the solvent compound or the stereoisomeric body thereof, which are acceptable in the pharmacy, in preparing medicines for treating and / or preventing diseases relevant to anaplastic lymphoma kinase mediated cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to dihecyclic anaplastic lymphoma kinase inhibitors, pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, methods for preparing these compounds, and preparations 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 to be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/5415A61K31/506A61P35/00A61P13/08
Inventor 吴永谦
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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