Use of isoquinoline derivatives for treating cancer and MAP kinase related diseases

A technology for kinases and uses, which is applied in the field of isoquinoline derivatives for the treatment of cancer and MAP kinase-related diseases, and can solve the problems of no isoquinoline compounds and no therapeutic benefits.

Inactive Publication Date: 2006-04-12
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these publications do not suggest that isoquinoline compounds have RAF kinase inhibitory properties nor do they suggest that the compounds have therapeutic benefits associated with RAF kinase inhibitory properties

Method used

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  • Use of isoquinoline derivatives for treating cancer and MAP kinase related diseases
  • Use of isoquinoline derivatives for treating cancer and MAP kinase related diseases
  • Use of isoquinoline derivatives for treating cancer and MAP kinase related diseases

Examples

Experimental program
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preparation example Construction

[0196]In the preparation of raw materials, if necessary, any functional groups that should not participate in the reaction are in a protected form. The preferred protecting groups, their introduction and their removal are described in method a) or the examples. Salts of the raw materials and intermediates may be used instead of the raw materials and intermediates to perform the reaction, provided that a group forming a salt exists, and the reaction may also be performed using a salt. Therefore, any raw materials mentioned above and below are also intended to include their salts, as long as they are advantageous and possible.

[0197] For G is -CH 2 -O-, -CH 2 -S-, -CH 2 -NH-, oxa, thia or -NR- and other symbols are as defined in formula I for the preparation of compounds of formula II, for example, by reacting a compound of formula IV with a compound of formula V, preferably with a compound of formula II Under the conditions similar to those mentioned in the reaction method a) of ...

Embodiment S1

[0226] Example S1: 1-(3,5-dimethylanilino)-4-[(pyridin-4-yl)-methyl]-isoquinoline (=N-(3,5-dimethylphenyl) )-[4-(pyridin-4-ylmethyl)-isoquinolin-1-yl]-amine)

[0227] Under anhydrous conditions, 100 mg (0.825 mmol) of 3,5-dimethylaniline was dissolved in 4 ml of ethanol, and 196 μl (0.784 mmol) of HCl (present in dioxane at a concentration of 4N) was added. After adding 200 mg (0.785 mmol) of 1-chloro-4-[(pyridin-4-yl)-methyl]-isoquinoline, the mixture was heated at 90°C for 8 hours. Then it is concentrated by evaporation; the residue is placed in 4ml water, 1ml saturated ammonia solution and 20ml CH 2 Cl 2 And separate the organic phase with Na 2 SO 4 (Anhydrous) Dry and concentrate again by evaporation. After column chromatography (SiO 2 ; Ethyl acetate / hexane 3:1) and crystallization from ethyl acetate / hexane to obtain the title compound: m.p.156-158°C; FAB-MS: (M+H) + =340; Anal.calc.(C 23 H 21 N 3 ·0.1H 2 O) C 80.95%, H 6.26%, N 12.31%; found C 80.9%, H 6.2%, N 12.4%.

[0228...

Embodiment S2

[0239] Example S2: 1-(3-Chlorobenzylamino)-4-[(pyridin-4-yl)-methyl]-isoquinoline

[0240] Under anhydrous conditions, 1.6ml (13.1mmol) of 3-chlorobenzylamino and 800mg (3.14mmol) of 1-chloro-4-(pyridin-4-ylmethyl)-isoquinoline (Example 1e) in 150 Stir at °C for 2 hours. The mixture was suspended in ethyl acetate, 1 ml of concentrated ammonia solution was added, washed with water and brine and the organic phase was dried (Na 2 SO 4 ) And concentrated by evaporation. Column chromatography (SiO 2 ; Ethyl acetate) to obtain the title compound: m.p.141-142°C; FAB-MS: (M+H) + =360; Anal.calc.(C 22 H 18 N 3 Cl) C 73.43%, H 5.04%, N 11.68%, Cl 9.85%; found C 73.2%, H 5.1%, N 11.6%, Cl 9.9%.

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Abstract

This invention relates to the treatment of a disease that is characterized by an aberrant MAP kinase signaling pathway by administering a compound of the formula (I) wherein the variable substituents are defined herein, to a patient in need of such treatment. The inventive method is especially useful for the treatment of cancers that have a mutated RAF kinase, especially melanoma.

Description

Summary of the invention [0001] The present invention relates to the discovery that certain compounds can inhibit the serine / threonine kinase-RAF kinase that plays a role in the MAP kinase signal transduction pathway, as well as the compounds used in the treatment of excessive signalling in the MAP kinase signal transduction pathway. Use of characteristic diseases (e.g., proliferative diseases like certain cancers). Background technique [0002] Cells use a variety of signal transduction pathways to make their nucleus communicate with the extracellular environment in many ways. Many of these signals are transmitted by protein kinases that can activate multiple factors by transferring phosphate groups. As demonstrated by the bcr-abl kinase inhibitor imatinib, the disruption of signal transduction caused by the inhibition of appropriate kinase activity is of clinical interest, and the mesyl salt of the inhibitor is released under the trademark GLEEVEC (in the United States) or GLIV...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4725A61K31/472A61P35/00A61K31/4035A61K31/47
CPCA61K31/472A61K31/47A61K31/4035A61K31/4725A61P35/00A61P43/00
Inventor D·B·巴特G·博尔德S·金T·M·拉姆齐M·L·萨比奥
Owner NOVARTIS AG
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