Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases

• US 20020082270A1
• Filed: 08/22/2001
• Published: 06/27/2002
• Est. Priority Date: 08/26/2000
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Himmelsbach, Frank, Langkopf, Elke, Jung, Birgit, Solca, Flavio, Blech, Stefan
• Application Number:
  US09/934,753
• Publication Number:
  US 20020082270A1
• Time in Patent Office: Days
• US Class Current: 514/266.2
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/10 Spiro-condensed systems

Abstract

Compounds of the formula

having an inhibitory effect on signal transduction mediated by tyrosinekinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.

Claims

1. A compound of the formula

2. A compound of the formula I according to claim 1, wherein

R_a denotes a hydrogen atom,

R_b denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,

R_c denotes a hydrogen atom,

X denotes a nitrogen atom,

A denotes a 1,2-vinylene or ethynylene group,

B denotes a hydrogen atom,

C denotes an —

O—

CH₂CH₂—

, —

O—

CH₂CH₂CH₂—

or —

O—

CH₂CH₂CH₂CH₂—

group, whilst the alkylene moiety in each case is linked to the group D, and

D denotes a piperidino group in which the two hydrogen atoms in the 4-position are replaced by a —

CH₂—

O—

CO—

CH₂, —

CH₂CH₂—

O—

CO—

, —

CH₂CH₂—

O—

CO—

CH₂—

, —

O—

CO—

CH₂—

NCH₃—

CH₂—

or —

O—

CO—

CH₂—

O—

CH₂—

bridge,

a piperazino group in which a hydrogen atom in the 3-position together with the hydrogen atom in the 4-position are replaced by a —

CO—

O—

CH₂—

CH₂—

or —

CH₂—

O—

CO—

CH₂—

bridge, whilst in each case the left-hand ends of the above-mentioned bridges are bound to the 3-position of the piperazino ring,

a piperidino group which is substituted in the 4-position by a 2-oxo-morpholino or 2-oxo-morpholinomethyl group, whilst the 2-oxo-morpholino moiety may be substituted in each case by one or two methyl groups,

a piperazino group which is substituted in the 4-position by a 2-oxo-tetrahydrofuran-3-yl- or 2-oxo-tetrahydrofuran-4-yl group,

a piperidino group which is substituted in the 4-position by a R₆S group, whilst

R₆ denotes a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,

a piperazino group which is substituted in the 4-position by a 2-oxo-tetrahydrofuranylmethyl or 2-oxo-tetrahydrofuranyl-carbonyl group,

a piperazino group which is substituted in the 4-position by a [2-(2-oxo-tetrahydrofuran-3-ylsulphenyl)ethyl] group,

a piperidin-4-yl group which is substituted in the 1-position by a 2-oxo-tetrahydrofuran-3-yl or 2-oxo-tetrahydrofuran-4-yl group,

a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group,

a 2-oxo-morpholin-4-yl group in which the two hydrogen atoms of a methylene group are replaced by a —

CH₂CH₂CH₂CH₂—

, —

CH₂CH₂CH₂CH₂CH₂—

, —

CH₂—

O—

CH₂CH₂—

or —

CH₂CH₂—

O—

CH₂CH₂—

bridge, or a tautomer or salt thereof.

3. A compound of the formula I according to claim 1, wherein

R_a denotes a hydrogen atom,

R_b denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R_c denotes a hydrogen atom,

X denotes a nitrogen atom,

A denotes a 1,2-vinylene group,

B denotes a hydrogen atom,

C denotes an —

O—

CH₂CH₂—

, —

O—

CH₂CH₂CH₂—

or —

O—

CH₂CH₂CH₂CH₂—

group, whilst the alkylene moiety in each case is linked to the group D, and

D denotes a piperazino group which is substituted in the 4-position by a 2-oxo-tetrahydrofuran-4-yl or 2-oxo-tetrahydrofuran-5-ylcarbonyl group,

or a tautomer or salt thereof.

5. A physiologically acceptable salt of a compound according claim 1, 2, 3, or 4, formed with an inorganic or organic acid or base.

6. A pharmaceutical composition containing a compound according claim 1, 2, 3, or 4 or a pharmaeceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

7. A method of treating a benign or malignant tumour, a disease of the respiratory tract or lungs, polyps, a disease of the gastro-intestinal tract, bile duct or gall bladder, a disease of the kidneys or of the skin, which comprises administering a therapeutically effective amount of a compound according claim 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of:

(1) 4-[(3-chloro-4-fluorophenyl)amino]-7-{3-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-propyloxy}-6-[(vinylcarbonyl)amino]-quinazoline,

(2) 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,

(3) 4-[(R)-(1-phenylethyl)amino]-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-[(vinylcarbonyl)amino]-quinazoline and

(4) 4-[(3-chloro-4-fluorophenyl)amino]-7-{2-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-ethoxy}-6-[(vinylcarbonyl)amino]-quinazoline,

or a tautomer or salt thereof.