Three-level cyclic amine ALK kinase inhibitor used for treating cancer

A heterocyclic and aromatic ring technology, applied in the field of cyclic amine compounds and their preparation, can solve problems such as cell proliferation and uncontrolled cell cycle

Active Publication Date: 2014-09-24
ZHEJIANG DTRM BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Uncontrolled activation of this ALK kinase and the resulting downstream s

Method used

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  • Three-level cyclic amine ALK kinase inhibitor used for treating cancer
  • Three-level cyclic amine ALK kinase inhibitor used for treating cancer
  • Three-level cyclic amine ALK kinase inhibitor used for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101]

[0102] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetic acid

[0103] Step A:

[0104]

[0105] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetic acid methyl ester

[0106] Steps:

[0107] The compound methyl 2-chloroacetic acid (11 mg, 0.12 mmol, 1.2 equivalents), potassium carbonate (0.5 mmol, 5 equivalents) and sodium iodide (2 mg) were added to the compound 3-[1-(2 , 6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridin-2-amine (45 mg, 0.1 mmol, 1 equivalent) in 2 ml of ethanol solution, heated to reflux for 2 hours and then quenched with water, then added the water layer and dichloromethane, layered, the water layer was extracted three times with dichloromethane, after the organic phases were combined, dried After spin-drying, the product was directly used in the next step (40 mg, yield 77%).

[0108] Step B:

[0109]...

Embodiment 2

[0117]

[0118] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetamide

[0119] Steps:

[0120]2-Chloroacetamide (132 mg, 1.44 mmol, 1.2 equivalents), potassium carbonate (4.8 mmol, 4 equivalents) and sodium iodide (12 mg) were added to compound 3-[1-(2,6- Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-pyridyl)pyrazol-4-yl]piperidinyl-2-amine (0.54 mg, 1.2 mmol, 1 equivalent ) in 15 ml of ethanol solution, heated to reflux for 2 hours and then quenched with water, then added the water layer and dichloromethane, layered, the water layer was extracted three times with dichloromethane, after the organic phases were combined, dried and spin-dried, The crude product was purified by chromatography (instrument: SHIMADZU LC-8A, chromatographic column: synergi-10μm, 250×50mmI.D. mobile phase: A is water (containing 1‰TFA, v / v) and B is acetonitrile, concentration gradient: B30-80%. Flow rate: 80mL / min). Using the HPLC purified solut...

Embodiment 3

[0124]

[0125] 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1

[0126] -piperidinyl]-N-methyl-acetamide

[0127] Steps:

[0128] The compound 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Methyl]-1-piperidinyl]acetate (0.8 g, 1.53 mmol, 1.0 equiv) was dissolved in a solution of methylamine in THF. Then spin dry the solvent after reacting in a microwave at 80 degrees for a total run time of 45. The target compound was purified by HPLC (instrument: SHIMADZU LC-8A, chromatographic column: synergi-10μm, 250×50mmI.D. mobile phase: A for water (Add1‰TFA, v / v) and B for CAN, concentration gradient: B30-80%. Flow rate: 80mL / min). Use the HPLC purified solution to adjust the pH value to 7-8 with sodium bicarbonate, extract the aqueous layer three times with dichloromethane, combine the organic layers, backwash with saturated saline, and dry Spin-dry to obtain the target compound (582.4 mg).

[0129] S...

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PUM

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Abstract

Provided are substituted cyclic amine compounds, and pharmaceutically acceptable salts and pharmaceutical preparations thereof as an anaplastic lymphoma kinase (ALK) inhibitor. Also provided is the use of the compound and pharmaceutical preparations thereof in the preparation of drugs for the treatment and inhibition of diseases including non-small cell lung cancer (NSCLC), neuroblastomas, anaplastic large cell lymphoma (ALCL), liver cancer and other diseases caused by the rise of the ALK activity level.

Description

[0001] technical field of invention [0002] The invention relates to a series of new substituted cyclic amine compounds and their preparation method, a pharmaceutical composition containing them as active ingredients and their application in treating tumors and other diseases. Background of the invention [0003] Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor family. In humans, it is a kinase encoded by the ALK gene. As a receptor tyrosine kinase, it consists of an extracellular domain, a transmembrane region and an intracellular tyrosine kinase domain. ALK plays an important role in the development of the brain and central nervous system. However, the function of ALK in adults is unknown. [0004] In humans, abnormal ALK signaling is associated with the pathogenesis of various cancers. These aberrant ALK signaling activities result from ALK gene rearrangements (including translocations, amplifications, and mutations) and ALK kinase overexpression. ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14A61K31/5377A61K31/4545A61P35/00
CPCC07D401/14A61K31/5377C07D487/04C07D401/04C07D413/14A61P35/00
Inventor 何伟
Owner ZHEJIANG DTRM BIOPHARMA
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