Novel medicament combinations for the treatment of respiratory diseases

• US 20050239778A1
• Filed: 04/19/2005
• Published: 10/27/2005
• Est. Priority Date: 04/22/2004
• Status: Abandoned Application

• 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: Pairet, Michel, Lustenberger, Philipp, Pieper, Michael P., Konetzki, Ingo, Hoenke, Christoph, Rudolf, Klaus, Bouyssou, Thierry, Pestel, Sabine, Schnapp, Andreas
• Application Number:
  US11/109,094
• Publication Number:
  US 20050239778A1
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention relates to new medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1
wherein the groups R¹, R² and R³ may have the meanings given in the claims and in the specification, at least one other active substance 2, processes for preparing them and their use as pharmaceutical compositions.

Claims

1. ) A pharmaceutical composition comprising one or more compounds of formula 1

wherein

n denotes 1 or 2;

R¹ denotes hydrogen, halogen, C₁-C₄-alkyl or —

O—

C₁-C₄-alkyl;

R² denotes hydrogen, halogen, C₁-C₄-alkyl or —

O—

C₁-C₄-alkyl;

R³ denotes C₁-C₄-alkyl, OH, halogen, —

O—

C₁-C₄-alkyl, —

O—

C₁-C₄-alkylene-COOH, —

O—

C₁-C₄-alkylene-CO—

O—

C₁-C₄-alkyl, and

at least one other active substance 2.

2. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 is one or more compounds which are selected from the group consisting of anticholinergics (2a), PDE IV inhibitors (2b), steroids (2c), LTD4-antagonists (2d) and EGFR-inhibitors (2e).

3. ) The pharmaceutical composition according to claim 1 comprising one or more compounds of formula 1, wherein

n denotes 1 or 2;

R¹ denotes hydrogen, fluorine, chlorine, methyl or methoxy;

R² denotes hydrogen, fluorine, chlorine, methyl or methoxy;

R³ denotes C₁-C₄-alkyl, OH, fluorine, chlorine, bromine, —

O—

C₁-C₄-alkyl, —

O—

C₁-C₄-alkylene-COOH, —

O—

C₁-C₄-alkylene-CO—

O—

C₁-C₄-alkyl.

4. ) The pharmaceutical composition according to claim 1 comprising one or more compounds of formula 1, wherein

n denotes 1;

R¹ denotes hydrogen or C₁-C₄-alkyl;

R² denotes hydrogen or C₁-C₄-alkyl;

R³ denotes C₁-C₄-alkyl, OH, —

O—

C₁-C₄-alkyl, —

O—

C₁-C₄-alkylene-COOH or —

O—

C₁-C₄-alkylene-CO—

O—

C₁-C₄-alkyl.

5. ) The pharmaceutical composition according to claim 1, wherein the one or more compounds of formula 1 are in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.

6. ) The pharmaceutical composition according to claim 1, wherein the one or more compounds of formula 1 are in the form of the acid addition salts with pharmacologically acceptable acids as well as optionally in the form of the solvates and/or hydrates.

7. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 is an anticholinergic (2a).

8. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic (2a) is selected from the group consisting of tiotropium salts (2a.1), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), and trospium salts (2a.6).

9. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.7

wherein

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate,

optionally in the form of the racemates, enantiomers or hydrates thereof.

10. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.8

wherein R denotes either methyl (2a.8.1) or ethyl (2a.8.2) and

wherein

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate,

optionally in the form of the racemates, enantiomers or hydrates thereof.

11. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.9

wherein

A denotes a double-bonded group selected from the groups

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate;

R¹ and R² which may be identical or different denote a group selected from methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;

R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃ or NO₂;

R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —

CH₂—

F, —

CH₂—

CH₂—

F, —

O—

CH₂—

F, —

O—

CH₂—

CH₂—

F, —

CH₂—

OH, —

CH₂—

CH₂—

OH, CF₃, —

CH₂—

OMe, —

CH₂—

CH₂—

OMe, —

CH₂—

OEt, —

CH₂—

CH₂—

OEt, —

O—

COMe, —

O—

COEt, —

O—

COCF₃, —

O—

COCF₃, fluorine, chlorine or bromine,

optionally in the form of the racemates, enantiomers or hydrates thereof.

12. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.10

wherein

A denotes a double-bonded group selected from the groups

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate;

R¹ and R² which may be identical or different denote a group selected from methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; and

R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF₃ or NO₂, while at least one of the groups R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² may not be hydrogen,

optionally in the form of the racemates, enantiomers or hydrates thereof.

13. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.11

wherein

A denotes a double-bonded group selected from the groups

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate;

R¹⁵ denotes hydrogen, hydroxy, methyl, ethyl, —

CF₃, CHF₂ or fluorine;

R^1′

and R^2′

which may be identical or different, denote C₁-C₅-alkyl, which may optionally be substituted by C₃-C₆-cycloalkyl, hydroxy or halogen, or

R^1′

and R^2′

together denote a —

C₃-C₅-alkylene bridge;

R¹³, R¹⁴, R^13′

and R^14′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen,

optionally in the form of the racemates, enantiomers or hydrates thereof.

14. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.12

wherein

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate;

D and B which may be identical or different, preferably identical, denote O, S, NH, CH₂, CH═

CH or N(C₁-C₄-alkyl);

R^{1 6} denotes hydrogen, hydroxy, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, —

C₁-C₄-alkylene-halogen, —

O—

C₁-C₄-alkylene-halogen, —

C₁-C₄-alkylene-OH, —

CF₃, CHF₂, —

C₁-C₄-alkylene-C₁-C₄-alkyloxy, —

O—

COC₁-C₄-alkyl, —

O—

COC₁-C₄-alkylene-halogen, —

C₁-C₄-alkylene-C₃-C₆-cycloalkyl, —

O—

COCF₃ or halogen;

R^1″

and R^2″

which may be identical or different, denote —

C₁-C₅-alkyl, which may optionally be substituted by —

C₃-C₆-cycloalkyl, hydroxy or halogen, or

R^1″

and R^2″

together denote a —

C₃-C₅-alkylene bridge;

R¹⁷, R¹⁸, R^17′

and R^18′

, which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen;

R^X and R^X′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen, or

R^X and R^X′

together denote a single bond or one of the double-bonded groups O, S, NH, CH₂, CH₂—

CH₂, N(C₁-C₄-alkyl), CH(C₁-C₄-alkyl) and —

C(C₁-C₄-alkyl)₂,

optionally in the form of the racemates, enantiomers or hydrates thereof.

15. ) The pharmaceutical composition according to claim 7, wherein the anticholinergic is of the formula 2a.13

wherein

X⁻

denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate;

A′

denotes a double-bonded group selected from

R¹⁹ denotes hydroxy, methyl, hydroxymethyl, ethyl, —

CF₃, CHF₂ or fluorine;

R<sup>1′

″</sup>

and R<sup>2′

″</sup>

which may be identical or different, denote C₁-C₅-alkyl, which may optionally be substituted by C₃-C₆-cycloalkyl, hydroxy or halogen, or

R<sup>′

″</sup>

and R<sup>2′

″</sup>

together denote a —

C₃-C₅-alkylene bridge;

R²⁰, R²¹, R^20′

and R^21′

which may be identical or different, denote hydrogen, —

C₁-C₄-alkyl, —

C ₁-C₄-alkyloxy, hydroxy, —

CF₃, —

CHF₂, CN, NO₂ or halogen,

optionally in the form of the racemates, enantiomers or hydrates thereof.

16. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 a PDE IV-inhibitor (2b).

17. ) The pharmaceutical composition according to claim 16, wherein the PDE IV-inhibitor 2b is selected from the group consisting of enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), CP-325.366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (−

)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a.10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′

-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(−

)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofyllin, atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4.3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

18. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 is a steroid (2c).

19. ) The pharmaceutical composition according to claim 18, wherein the steroid 2c is selected from the group consisting of prednisolone (2c.1), prednisone (2c.2), butixocortpropionate (2c.3), RPR-106541 (2c.4), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9 , mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), dexamethasone (2c.14), (S)-fluoromethyl 6α

,9α

-difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothionate (2c.15), (S)-(2-oxo-tetrahydro-furan-3S-yl) 6α

,9α

-difluoro-11β

-hydroxy-16α

-methyl-3-oxo-17α

-propionyloxy-androsta-1,4-diene-17β

-carbothionate (2c.16) and etiprednol-dichloroacetate (2c.17), optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.

20. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 is a LTD4-antagonist (2d).

21. ) The pharmaceutical composition according to claim 20, wherein the LTD4 antagonist 2d is selected from the group consisting of montelukast (2d.1), 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)-methylcyclopropane-acetic acid (2d.2), 1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid (2d.3), pranlukast (2d.4), zafirlukast (2d.5), [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid (2d.6), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8), MEN-91507 (LM-1507) (2.9), VUF-5078 (2d.10), VUF-K-8707 (2d.11) and L-733321 (2d.12), optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.

22. ) The pharmaceutical composition according to claim 1, wherein the additional active substance 2 is an EGFR-inhibitor (2e).

23. ) The pharmaceutical composition according to claim 22, wherein EGFR inhibitors 2e are selected from the group consisting of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2.3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5 .5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-(methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof.

24. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of one or more of compounds of formula 1, therapeutically effective amounts of an anticholinergic (2a) and therapeutically effective amounts of a PDEIV-inhibitor (2b), and optionally pharmaceutically acceptable carriers or excipients thereof.

25. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of an anticholinergic (2a), and therapeutically effective amounts of a steroid (2c), and optionally pharmaceutically acceptable carriers or excipients thereof.

26. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of an anticholinergic (2a) and therapeutically effective amounts of an LTD4-antagonist (2d), and optionally pharmaceutically acceptable carriers or excipients thereof.

27. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of an anticholinergic (2a) and therapeutically effective amounts of an EGFR-inhibitor (2e), and optionally pharmaceutically acceptable carriers or excipients thereof.

28. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of a PDEIV-inhibitor (2b), and therapeutically effective amounts of a steroid (2c), and optionally pharmaceutically acceptable carriers or excipients thereof.

29. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of a PDEIV-inhibitor (2b), and therapeutically effective amounts of an LTD4-antagonist (2d), and optionall pharmaceutically acceptable carriers or excipients thereof.

30. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of a PDEIV-inhibitor (2b) and therapeutically effective amounts of an EGFR-inhibitor (2e), and optionally pharmaceutically acceptable carriers or excipients thereof.

31. ) The pharmaceuticals composition according to claim 1, comprising therapeutically effective amounts of 1, therapeutically effective amounts of a steroid (2c), and therapeutic amounts of an LTD4-antagonist (2d) and optionally a pharmaceutically acceptable carrier.

32. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula 1, therapeutically effective amounts of a steroid (2c), and therapeutically effective amounts of an EGFR-inhibitor (2e), and optionally pharmaceutically acceptable carriers or excipients thereof.

33. ) The pharmaceutical composition according to claim 1, comprising therapeutically effective amounts of compounds of formula a, therapeutically effective amounts of an LTD4-antagonist (2d), and therapeutically effective amounts of an EGFR-inhibitor (2e), and optionally pharmaceutically acceptable carriers or excipients thereof.

34. ) The pharmaceutical composition according to claim 1, further comprising pharmaceutically acceptable carriers or excipients thereof.

35. ) The pharmaceutical composition according to claim 1, wherein the composition does not comprise any pharmaceutically acceptable carriers or excipients thereof.

36. ) The pharmaceutical composition according to claim 1, which is in the form of a formulation suitable for inhalation.

37. ) The pharmaceutical composition according to claim 36, wherein the inhalation formulation is selected from the group consisting of inhalable powders, propellant-driven metered-dose aerosols and propellant-free inhalable solutions or suspensions.

38. ) The pharmaceutical composition according to claim 37, wherein the inhalable powder comprises one or more compounds of formula 1 and active substance 2 in admixture with suitable physiologically acceptable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures thereof.

39. ) The pharmaceutical composistion according to claim 37, wherein the propellant-drive inhalable aerosol comprises one or more compounds of formula 1 and active substance 2 in dispersed form.

40. ) The pharmaceutical composition according to claim 39, wherein the inhalable aerosol comprises as the propellant gas hydrocarbons selected from n-propane, n-butane or isobutane or halohydrocarbons selected from chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.

41. ) The pharmaceutical composition according to claim 40, wherein the propellant gas is selected from TG11, TG12, TG134a, TG227 or mixtures thereof.

42. ) The pharmaceutical composition according to claim 37, wherein the propellant-free inhalable solution or suspension comprises solvent water, ethanol or a mixture of water and ethanol.

43. ) A method of treating inflammatory and obstructive respiratory complaints, inhibiting premature labour in midwifery (tocolysis), sinus rhythm in the heart in atrioventricular block, bradycardic heart rhythm disorders (antiarrhythmic), circulatory shock (vasodilatation and increasing the heart volume) and skin irritations and inflammation comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to claim 1.

44. ) The method according to claim 43, wherein the respiratory complaints are selected from the group consisting of obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.

45. ) The method according to claim 44, wherein the obstructive pulmonary diseases are selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease.

46. ) The method according to claim 44, wherein the pulmonary emphysema which has its origins in COPD or α

1-proteinase inhibitor deficiency.

47. ) The method according to claim 44, wherein the restrictive pulmonary diseases are selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours selected from lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.

48. ) The method according to claim 44, wherein the interstitial pulmonary diseases are selected from among pneumonia caused by infections selected from viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors selected from aspiration and left heart insufficiency, radiation-induced pneumonitis or fibrosis, collagenoses selected from lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses selected from Boeck'"'"'s disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

49. ) The method according to claim 44, wherein the respiratory complaint is cystic fibrosis or mucoviscidosis.

50. ) The method according to claim 44, wherein the respiratory complaint is bronchitis caused by bacterial or viral infection, allergic bronchitis or toxic bronchitis.

51. ) The method according to claim 44, wherein the respiratory complaint is bronchiectasis.

52. ) The method according to claim 44, wherein the respiratory complaint is ARDS (adult respiratory distress syndrome).

53. ) The method according to claim 44, wherein the respiratory complaint is pulmonary oedema.