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1H-imidazo[4,5-C]quinoline derivatives in the treatment of protein kinase dependent diseases

A compound and a low-level technology applied in the field of 1H-imidazo[4,5-C]quinoline derivatives for the treatment of protein kinase-dependent diseases

Inactive Publication Date: 2006-12-20
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The result is p210 bcr / abl - Induced transformation, ultimately leading to CML

Method used

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  • 1H-imidazo[4,5-C]quinoline derivatives in the treatment of protein kinase dependent diseases
  • 1H-imidazo[4,5-C]quinoline derivatives in the treatment of protein kinase dependent diseases
  • 1H-imidazo[4,5-C]quinoline derivatives in the treatment of protein kinase dependent diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0060] With regard to the preferred groups of compounds of the formula (I) mentioned below, the definitions of substituents from the general definitions mentioned above can be used rationally, for example by more specific definitions or in particular by definitions which are found to be preferred general definition.

[0061] The present invention relates in particular to compounds of formula (I),

[0062] in

[0063] x and y are 0 or 1 independently of each other;

[0064] R 1 is an organic moiety capable of bonding to nitrogen;

[0065] X is C=O or C=S, provided that the dotted line bonding X to N is absent, so that X is bonded to the adjacent N via a single bond, provided that y is 1 and R is hydrogen or capable of bonding to nitrogen the organic portion of

[0066] or

[0067] X is (CR 7 ), where R 7 is hydrogen or an organic or inorganic moiety, provided that the dotted line bonding X to N is a bond such that X is bonded to an adjacent N via a double bond, provided...

example

[0160] Example: Reference compound in experiment 0.4 μM, average 0.3 μM

[0161] Test compound in the experiment 1.0 μM, normalized: 0.3 / 0.4 = 0.75 μM

[0162] For example, use staurosporine or a synthetic staurosporine derivative as a reference compound.

[0163] Using this protocol, the IC for PDK1 inhibition of compounds of formula (I) was found 50 Values ​​are in the range 0.001-20 μM, preferably in the range 0.01-2 μM.

[0164] The compounds of formula I and their pharmaceutically acceptable salts are useful as medicines. In particular, they exhibit an inhibitory effect on phosphatidylinositol 3-kinase (PI3K kinase), especially the gamma isoform (p110γ), which is responsible for the generation of phosphorylated signal transduction products. The inhibitory properties of the compounds of formula I can be demonstrated in the following test procedures.

[0165] Baculoviruses expressing different fragments of PI3Kγ fused to GST were previously described in Stoyanova et al....

Embodiment 1

[0394] 2-[4-(8-Phenylethynyl-imidazo[4,5-c]quinolin-1-yl)-phenyl]-ethylamine

[0395] 74 mg (0.151 mmol) {2-[4-(8-phenylethynyl-imidazo[4,5-c]quinolin-1-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (Example 1h) was dissolved in 2mL TFA-H 2 O (19:1 or 1:1), the progress of the reaction was monitored by analytical HPLC. After complete removal of the Boc protecting group, the solvent was evaporated to dryness and the residue was purified by prep.HPLC. Concentrate the pure fractions with NaHCO 3 Basified and extracted with ethyl acetate (3x). The organic layer was washed with MgSO 4 Dry, filter and evaporate to dryness to give 2-[4-(8-phenylethynyl-imidazo[4,5-c]quinolin-1-yl)-phenyl]-ethylamine as an off-white solid : ES-MS: 389 (M+H) + ; Analytical HPLC: t ret = 2.98 minutes (Grad 1).

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Abstract

The invention relates to the use of imidazoquinolines and salts thereof in the treatment of protein kinase diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, imidazoquinolines for use in the treatment of protein kinase dependent diseases, a method of treatment against said diseases, comprising administering the imidazoquinolines to a warm-blooded animal, especially a human, pharmaceutical preparations comprising an imidazoquinoline, especially for the treatment of a protein kinase dependent disease, novel imidazoquinolines, and a process for the preparation of the novel imidazoquinolines.

Description

[0001] The present invention relates to the use of imidazoquinoline compounds and salts thereof in the treatment of protein kinase-dependent diseases and in the preparation of pharmaceutical preparations for treating the diseases; imidazoquinoline compounds for the treatment of protein kinase-dependent diseases; Method for treating said diseases, comprising administering imidazoquinolines to warm-blooded animals, especially humans; pharmaceutical preparations comprising imidazoquinolines, especially for the treatment of protein kinase-dependent diseases; novel imidazole and quinolines; and methods of preparing novel imidazoquinolines. Background technique [0002] Recently, the concept of treating proliferative diseases with drugs specifically designed to act against abnormally active protein kinases has been well established in the treatment of chronic myelogenous leukemia (CML), with the first product now approved for Successful treatment. Clinical studies have shown that t...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/41A61P35/00C07D235/00C07D221/00
CPCA61K31/41C07D471/04A61P1/04A61P1/12A61P1/16A61P11/00A61P11/02A61P11/06A61P13/08A61P13/12A61P17/00A61P17/06A61P17/14A61P19/00A61P19/02A61P21/00A61P21/04A61P25/00A61P27/02A61P27/06A61P27/14A61P29/00A61P3/10A61P35/00A61P35/02A61P3/04A61P35/04A61P37/02A61P37/08A61P43/00A61P7/06A61P9/00A61P9/10
Inventor H-G·卡普拉罗P·菲雷C·加西亚-埃切维里亚F·施陶费尔
Owner NOVARTIS AG
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