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Combination therapy

A composition and compound technology, applied in the direction of drug combination, active ingredient of heterocyclic compound, active ingredient of amide, etc., can solve the problem of no targeted therapy

Active Publication Date: 2019-11-22
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Therefore, direct inhibition of KRAS and NRAS remains challenging and, to date, there are no studies in patients with KRAS-mutant cancers (such as KRAS-mutant NSCLC) and NRAS-mutant cancers (such as NRAS-mutant melanoma). Available Approved Targeted Therapies

Method used

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  • Combination therapy
  • Combination therapy
  • Combination therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0204] Example 1 :N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

[0205] The compound with formula (I) is a morpholine substituted biaryl compound with the following structure

[0206]

example 1

[0209] Compounds of formula (I) are type II inhibitors of both b-Raf and c-Raf.

[0210] Table 1. The half-maximum inhibitory concentration (IC-50) of compounds of formula (I) on b-Raf and c-Raf

[0211] Compound b-RafIC-50(μM) c-Raf FLIC-50(μM) Compounds of formula (I)0.000730.00020

example 1

[0213] Compounds of formula (I) show activity in many human cancer cell lines expressing mutations in the MAPK pathway, as shown in the table below. For cell lines with at least one mutation in BRAF or RAS, the activity is particularly strong.

[0214] Table 2. The effect of compounds of formula (I) on the proliferation of a group of human cancer cell lines.

[0215]

[0216]

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PUM

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Abstract

The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor as defined herein, or a pharmaceutically acceptable salt thereof and (b) a MEK inhibitor, particularly trametinib, particularly for use in the treatment of a proliferative disease. This invention also relates to uses of such combination for preparation of a medicament for the treatment of a proliferative disease; methods of treating a proliferative disease in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; use of such combination for the treatment of proliferative disease; pharmaceutical compositions comprising such combination and commercial packages thereto.

Description

Technical field [0001] The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor selected from the group consisting of: a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or as defined herein The compound of formula (II) or a pharmaceutically acceptable salt thereof; and (b) an MEK inhibitor (especially trametinib) or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a pharmaceutical combination comprising (a) a Raf inhibitor selected from the group consisting of: a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or as defined herein The defined compound of formula (II) or a pharmaceutically acceptable salt thereof; and trametinib or a pharmaceutically acceptable salt or solvate thereof. [0002] The present invention also relates to such combinations for use in the treatment of proliferative diseases (especially cancer), t...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/18A61K31/44A61K31/4523A61K31/519A61K31/5377A61P35/00
CPCA61K45/06A61K31/18A61K31/44A61K31/4523A61K31/519A61K31/5377A61P35/00A61K2300/00
Inventor V·库克
Owner NOVARTIS AG
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