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Novel tyrosine protein kinase inhibitor

A technology of amino and alkylamino, applied in the field of medicinal chemistry

Active Publication Date: 2013-12-04
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

c-Met is also directly linked to cancers for which there are currently no successful treatment options, such as pancreatic cancer, glioma, and liver cancer

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1 2-amino-N-(3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-yl)propionamide

[0120]

[0121] Step A: 1-(2,6-Dichloro-3-fluorophenyl)ethanol

[0122] Under the condition of ice bath, add 20.6g of 2,6-dichloro-3-fluoroacetophenone and 50ml of methanol into a 250ml one-necked flask, slowly add NaBH 4 5.7g, after the addition, continue to react for 4h, evaporate methanol under reduced pressure to obtain an oil, add 20ml of water, adjust the pH to neutral with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and precipitate under reduced pressure. The title compound was obtained.

[0123] Step B: 2-nitro-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine

[0124] Under a nitrogen atmosphere, add 0.23 g of the product from step A and 10 ml of THF to a 50 ml three-necked flask, then add 0.175 g of 2-nitro-3-hydroxypyridine and 0.44 g of triphenylphosphine, and stir at room temperature for 1 h. Diisopropyl azodi...

Embodiment 2

[0131] Example 2 2-amino-N-(3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H- Pyrazol-4-yl)pyridin-2-yl)propionamide

[0132]

[0133] Step A 2-amino-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-bromopyridine

[0134] Under ice-bath conditions, add 20ml of acetonitrile to a 50ml three-neck flask, 0.7g of the product obtained in step C of Example 1, slowly add 0.4g of NBS, stir at room temperature for 2 hours, filter, wash the filter cake twice with acetonitrile, and obtain 0.7 g of the title compound.

[0135] Step B 2-amino-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(N-tert-butoxycarbonylpiperidin-4-yl)- 1H-pyrazol-4-yl)pyridine

[0136] Under the protection of nitrogen, add 3-(4-(4,4,5,5-tetramethyl-1,3-diketonylboronic acid pentane-2-yl)-1H-pyrazole-1 into a 50ml three-necked flask - Base) tert-butyl piperidine-1-carboxylate 0.25g, DME 10ml, step A product 0.2g, then add palladium catalyst 0.018g, cesium carbonate aqueous solution, reflux at 85°C...

Embodiment 3

[0141] Example 3 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-(N-methylamino)pyridine

[0142]

[0143] Under the protection of nitrogen, add 0.5 g of the result of step C of Example 1 into a 50 ml three-necked bottle, dissolve it in THF, and add excess (BOC) at 25 ° C 2 O, stirred at 50°C for 24 hours, TLC monitored that the basic reaction of the raw materials was complete, desolvated under reduced pressure, added saturated sodium bicarbonate solution to adjust the pH to between 7-8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and reduced pressure The title compound was obtained by precipitation.

[0144] Under nitrogen protection, mix 0.5g of the above product, 0.48g of methyl iodide, 0.23g of potassium carbonate, and 10ml of DMF, and stir at 60°C for 6h. After the reaction is complete, pour the reaction solution into 100mL of saturated saline, and extract with ethyl acetate (20mL×3) , dried over anhydrous sodium sulfate, filtered, precipita...

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PUM

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Abstract

The invention provides a novel and effective tyrosine protein kinase inhibitor, its isomer, pharmaceutically acceptable salts and chemical protection form, and pharmaceutical composition of the novel tyrosine protein kinase inhibitor and a pharmaceutical carrier or a diluent. The novel tyrosine protein kinase inhibitor can effectively treat protein kinase abnormity-caused diseases, and can effectively inhibit c-Met or c-Met mutant, and ALK or ALK fusion protein.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a novel tyrosine protein kinase inhibitor, a preparation method, a pharmaceutical composition containing the tyrosine protein kinase inhibitor, and the use of the inhibitor for treating abnormal cell growth. Background technique [0002] Protein kinases are enzymes that catalyze hydroxyl phosphorylation of protein tyrosine, serine, and threonine residues, and abnormal protein kinase activity is closely related to many diseases, such as cancer. Among these, overexpression of tyrosine-protein kinases has been observed in many human cancers and shows increased expression as the disease progresses. A large number of studies have also shown that the inhibition of tyrosine protein kinase can reduce cell proliferation and induce cell apoptosis. [0003] c-Met (also known as HGFR) is a transmembrane receptor tyrosine protein kinase encoded by the Met proto-oncogene, and is ...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07D401/14C07D213/74C07D401/04C07D295/088A61K31/44A61K31/4545A61K31/454A61K31/495A61K31/5375A61P35/00
Inventor 王勇张小猛毕胜张仓方锐张迪徐信
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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