Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof

• US 7,998,949 B2
• Filed: 01/30/2008
• Issued: 08/16/2011
• Est. Priority Date: 02/06/2007
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Ostermeier, Markus, Himmelsbach, Frank, Jung, Birgit, Lotz, Ralf
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): MCDOWELL, BRIAN E
• Application Number:
  US12/525,742
• Publication Number:
  US 20100022505A1
• Time in Patent Office: 1,294 Days
• Field of Search: 544/293
• US Class Current: 514/211.01
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to bicyclic heterocycles of general formula

wherein

• R^a, R^b and R^c are defined as in claim 1, their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids and bases, which have valuable pharmacological properties, in particular an inhibitory action on the signal transduction mediated by tyrosine kinases, their use for the treatment of illnesses, in particular of tumoral diseases and of benign prostatic hyperplasia (BPH), of diseases of the lung and of the airways, and the preparation thereof.

Claims

1. A compound of formula (I)

2. The compound of formula (I) according to claim 1, wherein

R^a denotes a phenyl, 1-phenylethyl or indan-4-yl group, wherein the phenyl nucleus is substituted in each case by the groups R¹ to R³, wherein

R¹ denotes:

a hydrogen, fluorine, chlorine or bromine atom,

a methyl, trifluoromethyl or ethynyl group,

a phenyloxy or phenylmethoxy group, wherein the phenyl moiety of the above-mentioned groups may optionally be substituted by a fluorine or chlorine atom, or

a pyridyloxy or pyridinylmethoxy group, wherein the pyridinyl moiety of the above-mentioned groups is optionally substituted by a methyl or trifluoromethyl group,

R² denotes a hydrogen, fluorine or chlorine atom or a methyl group and

R³ denotes a hydrogen atom,

R^b denotes an azetidin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, piperazin-1-yl, 4-(C_1-3-alkyl-carbonyl)-piperazin-1-yl,4-(C_1-3-alkyl-sulphonyl)piperazin- 1 -yl, homopiperazin- 1-yl, 4-(C_1-3-alkyl-carbonyl)-homopiperazin-1-yl or 4-(C_1-3-alkyl-sulphonyl)-homopiperazin-1-yl group which may be mono- or disubstituted in each case by R⁴, wherein the substituents may be identical or different and

R⁴ denotes;

a fluorine atom,

a C_1-3-alkyl group,

an amino, C_1-3-alkylamino, di-(C_1-3 -alkyl)amino, C_1-3-alkyl-carbonylamino, N—

(C_{1-3-alkyl)-C1-3} -alkyl-carbonylamino, C_1-3-alkyl-sulphonylamino or

N—

(C_1-3-alkyl)-C_1-3-alkyl-sulphonylamino group,

an amino-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, di-(C_1-3-alkyl)amino-C_1-3-alkyl, C_1-3-alkyl-carbonylamino-C_1-3-alkyl, N—

(C_1-3-alkyl)-C_1-3-alkyl-carbonylamino-C_1-3-alkyl, C_1-3-alkyl-sulphonylamino-C_1-3-alkyl or N—

(C_1-3-alkyl)-C_1-3 -alkyl-sulphonylamino-C_1-3-alkyl group,

a hydroxy, C_1-3-alkyloxy or C_1-3-alkyl-carbonyloxy group,

a hydroxy-C_1-3-alkyl, C_1-3-alkyloxy-C_1-3-alkyl or C_1-3 -alkyl-carbonyloxy-C_1-3-alkyl group,

a C_1-3-alkyl-carbonyl, cyano, C_1-4-alkyl-oxycarbonyl, carboxy, aminocarbonyl, C_1-3-alkyl-aminocarbonyl or di-(C_1-3-alkyl)amino-carbonyl-group,

a C_1-3-alkylcarbonyl-C_1-3-alkyl, cyano-C_1-3-alkyl, C_1-4-alkyloxycarbonyl-C_1-3-alkyl-group, aminocarbonyl-C_1-3-alkyl, C_1-3-alkylaminocarbonyl-C_1-3-alkyl or di-(C_1-3 -alkyl)aminocarbonyl-C_1-3-alkyl group,

a C_1-4-alkylsulphanyl, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, aminosulphonyl,

C_1-3-alkyl-aminosulphonyl or di-(C_1-3-alkyl)amino-sulphonyl group,

a C_1-4-alkylsulphanyl-C_1-3-alkyl, C_1-4-alkylsulphinyl-C_1-3-alkyl, C_1-4-alkylsulphonyl-C_1-3-alkyl, aminosulphonyl-C_1-3-alkyl, C_1-3 -alkyl-aminosulphonyl-C_1-3-alkyl or di-(C_1-3 -alkyl)amino-sulphonyl-C_1-3-alkyl group, and wherein the heterocycles mentioned above under R^b - may additionally be substituted by an oxo group,

R^c denotes;

a hydrogen atom,

a hydroxy group,

a C_1-3-alkyloxy group,

a methoxy group which is substituted by one to three fluorine atoms,

an ethyloxy group which is substituted in the 2 position by an R⁵ group, wherein

R⁵ denotes a hydroxy, C_1-3-alkyloxy, amino, C_1-3-alkylamino, di-(C_1-3-alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl or a 4-C _1-3-alkyl-piperazin-1-yl group,

a propyloxy group which is substituted in the 3 position by the group R⁵, wherein R⁵ is as hereinbefore defined, or

a butyloxy group which is substituted in the 4 position by a group R⁵, wherein R⁵ is as hereinbefore defined, and

wherein, unless stated otherwise, the above-mentioned alkyl groups may be straight-chain or branched,

a tautomer, stereoisomer, mixture thereof or physiologically acceptable salt thereof.

3. The compound of formula (I) according to claim 1, wherein

R^a denotes a 1-phenylethyl, 3-ethynylphenyl, 3-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro-phenyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan-4-yl group, or

R^a denotes a 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-methyl-4-(pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-chloro-4-(pyridin-3-yloxy)-phenyl or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

R^b denotes an azetidin-1-yl, piperazin-1-yl, 4-(C_1-3-alkyl-carbonyl)-piperazin-1-yl or 4-(C_1-3-alkyl-sulphonyl)-piperazin-1-yl group which may be mono- or disubstituted in each case by R⁴, wherein the substituents may be identical or different and

R⁴ denotes:

a fluorine atom,

a C_1-3-alkyl group,

an amino, C_1-3-alkylamino, di-(C_1-3-alkyl)amino, C_1-3-alkyl-carbonylamino, N—

(C_1-3-alkyl)-C_1-3 -alkyl-carbonylamino, C_1-3-alkyl-sulphonylamino or N—

(C_1-3-alkyl)-C_1-3-alkyl-sulphonylamino group,

an amino-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, di-(C_1-3-alkyl)amino-C_1-3-alkyl, C_1-3-alkyl-carbonylamino-C_1-3-alkyl, N—

(C_1-3-alkyl)-C_1-3-alkyl-carbonylamino-C_1-3-alkyl, C_1-3-alkyl-sulphonylamino-C_1-3-alkyl or N—

(C_1-3-alkyl)-C_1-3-alkyl-sulphonylamino-C_1-3-alkyl group,

a hydroxy, C_1-3-alkyloxy or C_1-3-alkyl-carbonyloxy group,

a hydroxy-C_1-3-alkyl, C_1-3-alkyloxy-C_1-3-alkyl or C_1-3-alkyl-carbonyloxy-C_1-3-alkyl group,

a C_1-3-alkyl-carbonyl, cyano, C_1-4-alkyl-oxycarbonyl, carboxy, aminocarbonyl, C_1-3-alkyl-aminocarbonyl or di-(C_1-3-alkyl)amino-carbonyl group,

a C_1-3 -alkylcarbonyl-C_1-3-alkyl, cyano-C_1-3-alkyl, C_1-4-alkyloxycarbonyl-C_1-3-alkyl-group, aminocarbonyl-C_1-3-alkyl, C_1-3-alkylaminocarbonyl-C_1-3-alkyl or di-(C_1-3-alkyl)aminocarbonyl-C_1-3-alkyl group,

a C_1-4-alkylsulphanyl, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, aminosulphonyl, C_1-3 -alkyl-aminosulphonyl or di-(C_1-3-alkyl)amino-sulphonyl group,

a C_1-4-alkylsulphanyl-C_1-3-alkyl, C_1-4-alkylsulphinyl-C_1-3-alkyl, C_1-4-alkylsulphonyl-C_1-3-alkyl, aminosulphonyl-C_1-3-alkyl, C_1-3 -alkyl-aminosulphonyl-C_1-3-alkyl or di-(C_1-3-alkyl)amino-sulphonyl-C_1-3-alkyl group,

and wherein the heterocycles mentioned above under R^b may additionally be substituted by an oxo group,

R^c denotes;

a hydrogen atom,

a methoxy or ethyloxy group,

an ethyloxy group which is substituted in the 2 position by the group R⁵, wherein

R⁵ denotes a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or

4-ethylpiperazin-1-yl group,

a propyloxy group which is substituted in the 3 position by the group R⁵, wherein R⁵ is as hereinbefore defined, or

a butyloxy group which is substituted in the 4 position by the group R⁵, wherein R⁵ is as hereinbefore defined, and

wherein, unless stated otherwise, the above-mentioned alkyl groups may be straight-chain or branched,

a tautomer, stereoisomer, mixture thereof or physiologically acceptable salt thereof.

4. The compound of formula (I) according to claim 1, wherein

R^a denotes a 1-phenylethyl, 3-ethynylphenyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan-4-yl group,

R^b denotes an azetidin-1-yl, piperazin-1-yl, 4-(C_1-3-alkyl-carbonyl)-piperazin-1-yl or 4-(C_1-3-alkyl-sulphonyl)-piperazin-1-yl group which may be mono- or disubstituted in each case by R⁴, wherein the substituents may be identical or different and

R⁴ denotes:

a fluorine atom,

a C_1-3-alkyl group,

an amino, C_1-2-alkylamino, di-(C_1-2-alkyl)amino, C_1-2-alkyl-carbonylamino, N—

(C_1-2alkyl)-C_1-2-alkyl-carbonylamino, C_1-2-alkyl-sulphonylamino or N—

(C_1-2-alkyl)-C_1-2-alkyl-sulphonylamino group,

an amino-C_1-2-alkyl, C_1-2-alkylamino-C_1-2-alkyl, di-(C_1-2-alkyl)amino-C_1-2-alkyl, C_1-2-alkyl-carbonylamino-C_1-2-alkyl, N—

(C_1-2-alkyl)-C_1-2-alkyl-carbonylamino-C_1-2-alkyl, C_1-2-alkyl-sulphonylamino-C_1-2-alkyl or N—

(C_1-2- alkyl)-C_1-2-alkyl-sulphonylamino-C_1-2-alkyl group,

a hydroxy, C_1-2-alkyloxy or C_1-2-alkyl-carbonyloxy group,

a hydroxy-C_1-2-alkyl, C_1-2-alkyloxy-C_2-4-alkyl or C_1-2-alkyl-carbonyloxy-C_1-2-alkyl group,

a C_1-2-alkyl-carbonyl, cyano, C_1-2-alkyl-oxycarbonyl, carboxy, aminocarbonyl, C_1-2-alkyl-aminocarbonyl or di-(C_1-2-alkyl)amino-carbonyl group,

a C_1-2-alkylcarbonyl-C_1-2-alkyl, cyano-C_1-2-alkyl, C_1-2-alkyloxycarbonyl-C_1-2-alkyl group, aminocarbonyl-C_1-2-alkyl, C_1-2-alkylaminocarbonyl-C_1-2-alkyl or di-(C_1-2-alkyl)aminocarbonyl-C_1-2-alkyl group,

a C_1-2-alkylsulphanyl, C_1-2-alkylsulphinyl or C_1-2-alkylsulphonyl group,

a C_1-2-alkylsulphanyl-C_1-2-alkyl, C_1-2-alkylsulphinyl-C_1-2-alkyl or C_1-2-alkylsulphonyl-C_1-2-alkyl group,

and wherein the heterocycles mentioned above under R^b may additionally be substituted by an oxo group,

R^c denotes;

a hydrogen atom,

a methoxy, ethyloxy or 2-(methoxy)-ethyloxy group,

a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group,

a tautomer, stereoisomer, mixture thereof or physiologically acceptable salt thereof.

5. The compound of formula (I) according to claim 1, wherein

R^a denotes a 1-phenylethyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan-4-yl group,

R^b denotes an azetidin-1-yl or 3-oxo-piperazin-1-yl group which may be mono- or disubstituted in each case by R⁴, wherein the substituents may be identical or different and

R⁴ denotes a methyl, hydroxy, cyano, aminocarbonyl, methylamino-carbonyl or dimethylamino-carbonyl group, and

R^c denotes a methoxy group,

a tautomer, stereoisomer, mixture thereof or physiologically acceptable salt thereof.

6. A compound according to claim 1 selected from:

(a) 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[cis-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

(b) 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

(c) 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

(d) 4-[(2-fluoro-3-methyl-phenyl)amino]-6-[trans-4-(3-oxo-piperazin- 1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

(e) 4-[(2-fluoro-5-methyl-phenyl)amino]-6-[trans-4-(3-oxo-piperazin- 1-yl)-cyclohexyloxy]-7-methoxy-quinazoline,

(f) 4-[(2,4-difluoro-3-methyl-phenyl)amino]-6-[trans-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline and

(g) 4-[(3-chloro-2-methyl-phenyl)amino]-6-[trans-4-(3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline

or a physiologically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to claim 1, or a physiologically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.

8. A pharmaceutical composition comprising the compound according to claim 6, or a physiologically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.

9. A process for preparing a compound according to claim 1, comprising:

(a) reacting a compound of formula (II)