NZ550797A - Pharmaceutical combinations containing 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one for treating respiratory diseases - Google Patents

Abstract

Disclosed is a medicament combination which comprises 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one (as represented by the formula 1.5) and one or two compounds as another active substance 2 selected from anticholinergics (2a) and steroids (2c); wherein any anticholinergic (2a) is selected from the group comprising tiotropium salts (2a.1), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), trospium salts (2a.6) and any steroid 2c is selected from the group comprising prednisolone (2c.1), prednisone (2c.2), butixocortpropionate (2c.3), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), dexamethasone (2c.14), (S)-fluoromethyl 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-11b-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17b-carbothionate (2c.15), (S)-(2-oxo-tetrahydro-furan-3S-yl) 6a,9a-difluoro-11b-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17b-carbothionate (2c.16) and etiprednol-dichloroacetate (2c.17), optionally in the form of a racemate, enantiomer or diastereomer thereof and optionally in the form of a salt or functional derivative thereof, solvate and/or hydrate thereof. Also disclosed is the use of a medicament combination as defined above for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints (such as 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 , bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease)).

Description

NOW AMENDED Received at IPONZ on 2 July 2010 PHARMACEUTICAL COMBINATIONS C( FOR TREATING RESPIRA1 7AINING BENZOXAZINE DISEASES The present invention relates to new medicameny combinations which containin addition to one or more, preferably one, compound of general formula 1 OH R HN' O O fOb Me Me R° R wherein the groups R1, R2 and R3V have the meanings given below in the specification, at least one other active substan^fe 2/processes for preparing them and their use as pharmaceutical compositions.

The present invention pre of general formula 1.5 ot JetAled description of the invention Hd/s a medicament combination which comprises a compound and one or two compounds as another active substance 2 selected from anticholinergics (2a) and st^oists (2c); wherein any anticholinergic (2a) is selected from the group comprising tyotropium salts (2a.l), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropiuny salts (2a.4), glycopyrroniuin salts (2a.5), trospiuin salts (2a.6), and any steroid 2c is selected from the group comprising prednisolone (2c.1), prednisone (2c.2), butbj'Dcgatpropionate (2c.3), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2Q^7)/budesonide (2c.8), fluticasone (2c.9), mometasone (2c.l0), ciclesonide (2c.ll), ryftle/oiiide (2c. 12), dexamethasone (2c. 14), (S)-fluoromethyl 6a,9ot-difluoro-17a-[(2-iylcarbonyl)oxy]-11 (3-hydroxy-16 a-m ethyl-3 - ox o-andr os t a-1,4-diene-17 (3- (followed by page la) AS AMENDED Received at IPONZ on 18 October 2010 PHARMACEUTICAL COMBINATIONS CONTAINING BENZOXAZINE FOR TREATING RESPIRATORY DISEASES 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 below in the specification, at least one other active substance 2, processes for preparing them and their use as pharmaceutical compositions.

Detailed description of the invention 15 The present invention provides a medicament combination which comprises a compound of general formula 1.1 and one or two compounds as another active substance 2 selected from anticholinergics (2a) and steroids (2c); wherein any anticholinergic (2a) is selected from the group 20 comprising tiotropium salts (2a.l), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), trospium salts (2a.6), and any steroid 2c is selected from the group comprising prednisolone (2c.l), prednisone (2c.2), butixocortpropionate (2c.3), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.l0), ciclesonide (2c.ll), 25 rofleponide (2c.l2), dexamethasone (2c.l4), (S)-fluoromethyl 6a,9oc-difluoro-17a-[(2-furanylcarbonyl)oxy]-11 |3-hydroxy-16 a-m ethyl- 3 - ox o -andr ost a-1,4-diene-17(3- OH 1.1 (followed by page la) Received at IPONZ on 2 July 2010 carbothionate (2c. 15), (S)-(2-oxo-tetrahydro-furan-3S-yl) 6a.9a-difluoro-11 [3-hydroxy-16oc-methyl-3-oxo- 17oc-propionyloxy-androsta- 1,4-diene- 17(3-carbothionate (2c. 16) and etiprednol-dichloroacetate (2c. 17), optionally in the form of a racemate, enantiomer or diastereomer thereof and optionally in the form of a salt or functional derivative thereof, solvate and/or hydrate thereof.

Also disclosed are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1 OH wherein n R R R denotes 1 or 2, preferably 1; denotes hydrogen, halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl; denotes hydrogen, halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl; denotes Ci-C4-alkyl, OH, halogen, -0-Ci-C4-alkyl, -0-Ci-C4-alkylene-C00H, -0-Ci-C4-alkylene-C0-0-Ci-C4-alkyl, at least one other active substance 2.

[FOLLOWED BY PAGE 2] 2 Preferably the present invention relates to medicament combinations, which contain, in addition to one or more, preferably one, compound of formula 1 as a further active substance 2 one or more compounds selected from the categories of the anticholinergics 5 (2a), PDE IV inhibitors (2b), steroids (2c), LTD4-antagonists (2d) and EGFR-inhibitors Qe).

Preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1 or 2, preferably 1; R1 denotes hydrogen, fluorine, chlorine, methyl or methoxy; s"~~~ { R2 denotes hydrogen, fluorine, chlorine, methyl or methoxy; R3 denotes Q-C4-alkyl, OH, fluorine, chlorine, bromine, -0-Ci-C4-alkyl, -0-C,-C4-alkylene-C00H, -O-Ci -C4-alkylene-C0-0-C,-C4-alkyl, at least one other active substance 2.

Also preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen or Ci-C4-alkyl; R2 denotes hydrogen or Cj-C4-alkyl; R3 denotes CrC4-alkyl, OH, -0-Ci-C4-alkyl, -0-Ci-C4-alkylene-C00H or -O-C i -C4- alkylene-CO-O-C i -C4-alkyl, , at least one other active substance 2.

V, 25 Also preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; a R denotes hydrogen, methyl or ethyl; R denotes hydrogen, methyl or ethyl; R3 denotes methyl, ethyl, OH, methoxy, ethoxy, -O-CH2-COOH, -0-CH2-C00methyl or -0-CH2-C00ethyl, at least one other active substance 2. 3 Also preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen or methyl; R2 denotes hydrogen or methyl; R3 denotes methyl, OH, methoxy, -O-CH2-COOH or -0-CH2-C00ethyl, at least one other active substance 2.

Preferred medicament combinations according to the invention are those which contain in 10 addition to one or more, preferably one, compound of general formula 1, wherein R3 denotes methoxy, ethoxy, -O-CH2-COOH, -0-CH2-C00methyl or ( -0-CH2-C00ethyl, and R1, R2 and n may have the meanings given above, at least one other active substance 2.

The present invention also relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes halogen, Cj-C4-alkyl or -0-C]-CValkyl; R denotes halogen, Ci-C4-alkyl or -O-Ci-CValkyl; ■l R denotes halogen, Ci-C4-alkyl or -0-Ci-C4~alkyl, at least one other active substance 2.

The present invention also relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein ^ 25 n denotes 1; R1 denotes fluorine, chlorine, methyl or methoxy; R denotes fluorine, chlorine, methyl or methoxy; ■j R denotes fluorine, chlorine, methyl or methoxy at least one other active substance 2.

In another preferred aspect the present invention relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen; 4 ij R denotes hydrogen, fluorine, chlorine or methyl; R3 denotes methyl, ethyl, iso-propyl, tert.-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -0-CH2-C00H, -O-CH2-CH2-COOH, -0-CH2-CH2-CH2-COOH, 0-CH2-C00methyl, -0-CH2-C00ethyl, -0-CH2-CH2-C00methyl, -O-5 CH2-CII2-COOethyl, -0-CH2-CH2-CH2-C00methyl, -0-CH2-CH2-CH2-C00ethyl, at least one other active substance 2.

Particularly preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein 10 n denotes 1; R1 denotes hydrogen; R denotes hydrogen, fluorine, chlorine or methyl; R3 denotes OH, fluorine, chlorine, methyl, methoxy, ethoxy or -0-CH2-C00H, at least one other active substance 2.

Also preferred are those medicament combinations which contain in addition to one or more, preferably one compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen; R2 denotes halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl, preferably fluorine, chlorine, methoxy or methyl; R3 denotes halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl, preferably fluorine, chlorine, methoxy or methyl, at least one other active substance 2.

In another preferred aspect the present invention relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, 12 3 wherein n - 1 , R and R denote hydrogen and the group R may have the meanings given above, at least one other active substance 2.

In another preferred aspect the present invention relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 and R2 denote hydrogen; f f R3 denotes methyl, ethyl, iso-propyl, tert.-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -0-CH2-C00H, -0-CH2-CH2-C00H, -0-CH2-CH2-CH2-COOH, -0-CH2-C00methyl, -0-CH2-C00ethyl, -0-CH2-CH2-C00methyl, -0-CH2-CH2-C00ethyl, -0-CH2-CH2-CH2-C00methyl, -0-CH2-CH2-CH2-COOethyl, at least one other active substance 2.

Particularly preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula JL wherein n denotes 1; R1 and R2 denotes hydrogen; R3 denotes OH, fluorine, chlorine, methoxy, ethoxy,-0-CH2-C00H, preferably OH, fluorine, chlorine, ethoxy or methoxy, at least one other active substance 2, Particularly preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R! and R2 denotes hydrogen; R3 denotes fluorine, chlorine, methoxy or ethoxy, at least one other active substance 2.

The present invention also relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen, halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl; R2 denotes hydrogen, halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl; R3 denotes hydrogen, at least one other active substance 2.

Preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes hydrogen, fluorine, chlorine, methyl or methoxy; 6 2 R denotes hydrogen, fluorine, chlorine, methyl or methoxy; R denotes hydrogen, at least one other active substance 2.

The present invention also relates to medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1, wherein n denotes 1; R1 denotes fluorine, chlorine, methyl or methoxy; R2 denotes fluorine, chlorine, methyl or methoxy; R3 denotes hydrogen, at least one other active substance 2.

In the compounds of formula 1 the groups R1 and R2, if they do not represent hydrogen, may each be in the ortho or meta position relative to the bond to the benzylic 15 group. If neither of the groups R1 and R2 denotes hydrogen, preferred compounds of formula 1 for the medicament combinations according to the invention are those wherein either the two groups R1 and R2 are in the ortho configuration or both groups R1 and R2 are in the meta configuration, while compounds in which both groups R1 and R2 are in the ortho configuration are of particular importance.

In the compounds of formula 1 wherein one of the groups R1 and R2 does not denote hydrogen, it may be in the ortho or meta position relative to the bond to the benzylic "-CH2" group. In this case particularly preferred compounds of formula 1 for the medicament combinations according to the invention are those wherein the group R1 or R which does not denote hydrogen is in the ortho configuration.

Also particularly preferred are medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1 selected from the compounds - 6-hydroxy-8- {1 -hydroxy-2-[2-(4-methoxy-phenyl)-l, 1 -dimethyl-ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-one (LI); - 6-hydroxy-8-{l-hydroxy-2-[2-{ 4-phenoxyethyl -acetate)-1,1-dimethyl-ethylamino]-ethyl }-4H-benzo[l,4]oxazin-3-one (1.2): - 6-hydroxy-8- {1 -hydroxy-2-[2-(4-phenoxy-acetic acid)-l, 1 -dimethyl-ethylamino]-ethyl}-4H-benzo[ 1,4]oxazin-3-one (1.3): - 8- {2- [ 1,1 -dimethyl-2-(2,4,6-trimethylphenyl)-ethyl amino] -1 -hydroxy-ethyl} -6-35 hydroxy-4H-benzo[l,4]oxazin-3-one (1.4); 7 - 6-hydroxy- 8 - {1 -hydroxy-2-|"2-(4-hydroxy-pheny1)-1,1 -dimethyl-ethyl amino] -ethyl} 4H-benzo[l,4]oxazin-3-one (1.5); - 6-hydroxy-8-{l-hydrox}'r-2-[2-(4-isopropyl-phenyl)-l ,1 dimethyl-ethyl amino]-ethyl] 4H-benzo[l,4]oxazin-3-one (1.6); - 8- {2-[2-(4-ethyl-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H benzo [1,4]oxazin-3 -one (1.7); - 8- {2-[2-(4-fluoro -3 -methyl -phenyl)-1,1 -dimethyl- ethylamino] -1 -hydroxy- ethyl }-6-hydroxy-4H-b enzo [1,4] oxazin- 3 -one (1.8); - 8- {2-[2-(4-fluoro-2-methyl-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one (1.9): - 8- {2-[2-(2,4-difluoro-pheny1)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} - 6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.10): - 8- {2-[2-(3,5-difluoro-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.11): - 8- {2-[2-(4-ethoxy-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[l,4]oxazin-3-one (1.12): - 8-{2-[2-(3,5-dimethyl-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo [1,4] oxazin-3 -one (1.13); - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid (1.14): - 8 - {2-[2-(3,4-di fluoro-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl }-6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one (1.15): - 8- {2-[2-(2-chloro-4-fluoro-phenyI)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l ,4] oxazin-3-one (1.16): - 8-{2-[2-(4-chloro-phenyI)-1,1-dimethyl-ethylamino]-l-hydroxy-ethyl }-6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.17): - 8- {2- [2-(4-bromo-phenyl)-1,1 -dimethyl-ethyl amino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l,4]oxazin-3-one (1.18): - 8- {2-[2-(4-fluoro-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[l,4]oxazin-3-one (1.19): - 8- {2-[2-(4-fluoro-3 -methoxy-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.20): - 8-{2-[2-(4-fluoro-2,6-dimethyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl}-6-hydroxy-4H-benzo[l ,4] oxazin-3-one (1.21): 8 - 8-{2-[2-(4-chloro-2-methyl-phenyl)-l ,1-dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.22): - 8- {2-[2-(4-chloro-3-fluoro-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.23V. - 8- {2- [2-(4-chloro-2-fluoro-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3 -one (1.24); - 8- {2-[2-(3-chloro-4-fhioro-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo [ 1,4]oxazin-3 -one (1.25 ); - 8- {2-[2-(2,6-difluoro-4-methoxy-phenyl)-l, 1 -dimethyl-ethylamino]-l -hydroxy-10 ethyl }-6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.26); - 8- {2-[2-(2,5-difluoro-4-methoxy-phenyl)-l ,1 -dimethyl-ethylamino]-1-hydroxy-ethyl } -6-hydroxy-4H-benzo[ 1,4]oxazin-3-one (1.27); - 8-{2-[2-(4-fluoro-3,5-dimethyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one (1.28): - 8- {2-[2-(3,5-dichloro-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.29); - 8- {2-[2-(4-chloro-3-methyl-phenyl)-l ,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo [ 1,4]oxazin-3 -one (1.30); - 8- {2-[2-(3 ,■4,5-trifluoro-phenyl)-l ,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-20 hydroxy-4H-benzo[l,4]oxazin-3-one (1.31); - 8- {2-[2-(3-methyl-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.32) and - 8-{2-[2-(3,4-dichloro-phenyl)-1,1 -dim ethyl-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.33) at least one other active substance 2.

Particularly preferred are, especially, those medicament combinations which contain in addition to one or more, preferably one, compound of general formula 1 selected from the compounds 3 0 - 6-hydroxy-8- {1 -hydroxy-2-[2-(4-methoxy-phenyl)-1,1 -dimethyl-ethylamino] -ethyl} -4H-benzo[l,4]oxazin-3-one (1.1); - 6-hydroxy-8- {1 -hydroxy-2-[2-(4-phenoxyethyl-acetate)-1,1 -dimethyl-ethylamino] -ethyl}-4H-benzo[l,4]oxazin-3-one (1.2): - 6-hydroxy-8-{1 -hydroxy-2-[2-(4-phenoxy-acetic acid)-l, 1 -dimethyl-ethylamino]-35 ethyl}-4H-benzo[l,4]oxazin-3-one (1.3); 9 - B- {2- [ 1,1 -dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.4); - 6-hydroxy-8- {1 -hydroxy-2-[2-(4-hydroxy-phenyl)-1 ,l-dimethyl-ethylaniino]-cthyl}-4H-benzo[l,4]oxazin-3-one (1.5); - 6-hydroxy- 8 - {1 -hydroxy-2-[2-(4-isopropyl-phenyl)-1,1 dimethyl-ethyl amino] -ethyl} -4H-benzo[l,4]oxazin-3-one (1.6): - 8- {2-[2-(4-ethyl-phenyl)~1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[l,4]oxazin-3-one (1.7); - 8-{2-[2-(4-ethoxy-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3-one (1.12): - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yI)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid (1.14) and - 8- {2-[2-(3,4-difluoro-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[l ,4]oxazin-3-one (1.15). at least one other active substance 2.

In the medicament combinations according to the invention the compounds of formula 1 may be present in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates. Particularly preferred are those medicament combinations wherein one or more, preferably one compound of formula 1 is in the form of the enantioraerically pure compounds, preferably in the form of the R-enantiomers. Methods of separating racemates into the various enantiomers are known in the art and may be used to prepare the enantiomerically pure R- or S-enantiomers of the compounds of formula 1 analogously.

In another aspect the present invention relates to medicament combinations which contain the above-mentioned compounds of formula 1 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.

By acid addition salts with pharmacologically acceptable acids are meant for example salts selected from the group comprising the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-tofucncsulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. Of the above-mentioned acid addition salts, the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

Preferred medicament combinations contain in addition to one or more, preferably one compound of formula 1 as an additional active substance one or more, preferably one anticholinergic 2a, optionally in combination with pharmaceutically acceptable excipients.

In the medicament combinations according to the invention the anticholinergic 2a is preferably selected from among the tiotropium salts (2a. 1). oxitropium salts (2a.2 ), flutropium salts (2a.3), ipratropium salts (2a.4). glycopyrronium salts (2a.5), trospium salts (2a.6) and the compounds of formulae 2a.7 to 2a,13.

In the above-mentioned salts 2a.l to 2a.6 the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents. Explicit references to the above-mentioned cations are indicated by the numerals 2a.l' to 2a.6'. Each reference to the above-mentioned salts 2a.l to 2a.6 naturally includes a reference to the corresponding cations tiotropium (2a. l '). oxitropium (2a.2r). flutropium (2a.3'\ ipratropium (2a.4'). glycopyrronium (2a.5') and trospium (2a.6v).

By the salts 2a.l to 2a.6 are meant according to the invention those compounds which contain in addition to the cations tiotropium (2a.l'). oxitropium (2a.2'\ flutropium (2a.3T). ipratropium (2a.4'). glycopyrronium (2a.5') and trospium (2a.6' j as counter-ion (anion) chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate contain, while the chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chloride, bromide, iodide and methanesulphonate are particularly preferred.

In the case of the trospium salts (2a.6) the chloride is particularly preferred. Of the other salts 2a.l to 2a.5 the methanesulphonates and bromides are of particular importance. Of particular importance are medicament combinations which contain tiotropium salts (2a. 1), oxitropium salts (2a.2 ) or ipratropium salts (2a.41 while the respective bromides are particularly important according to the invention. Of particular importance is the tiotropium bromide (2a.l ), The above-mentioned salts may optionally be present in the 11 medicament combinations according to the invention in the form of their solvates or hydrates, preferably in the form of their hydrates. In the case of tiotropium bromide the medicament combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If 5 the tiotropium bromide is used in anhydrous form in the medicament combinations according to the invention, it is preferable to use the anhydrous crystalline tiotropium bromide which is known from WO 03/000265.

Examples of preferred medicament combinations according to the invention of preferred 10 compounds of formula 1 with the above-mentioned anticholinergics 2a.l to 2a.6 are combinations containing the compounds LI and 2a.l: 1.1 and 2a. 2; 1.1 and 2a.3; 1.1 and ( 2a.4; 1.1 and 2a.5; 1.1 and 2a.6:1.2 and 2a.l: 1.2 and 2a.2; 1.2 and 2a.3:1.2 and 2a.4; 1.2 and 2a.5; 1.2 and 2a.6; 1.3 and 2a.l; 1.3 and 2a.2:1.3 and 2a.3; 1.3 and 2a.4; 1.3 and 2a.5; 1.3 and 2a.6; 1.4 and 2a.l; 1.4 and 2a.2; 1.4 and 2a.3: 1.4 and 2a.4; 1.4 and 2a.5; 1.4 and 15 2a.6; 1.5 and 2a.l; 1.5 and 2a.2; 1.5 and 2a.3: 1.5 and 2a.4; 1.5 and 2a.5; 1.5 and 2a.6; 1.6 and 2a.l; 1.6 and 2a.2; 1.6 and 2a.3; 1.6 and 2a.4:1.6 and 2a.5; 1.6 and 2a.6; 1.7 and 2a.l; 1.7 and 2a.2; 1.7 and 2a.3; 1.7 and 2a.4; 1.7 and 2a.5; 1.7 and 2a.6; 1.12 and 2a. 1; 1.12 and 2a.2; 1.12 and 2a.3; 1.12 and 2a.4; 1.12 and 2a.5; 1.12 and 2a.6; 1.14 and 2a.l; 1.14 and 2a.2; 1.14 and 2a.3; 1.14 and 2a.4; 1.14 and 2a.5; 1.14 and 2a.6; 1.15 and 2a.l; 1.15 20 and 2a.2; 1.15 and 2a.3; 1.15 and 2a.4; 1.15 and 2a.5 or 1.15 and 2a.6, in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds LI, L5, L6, or 1.12, while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as compound 2a one of the compounds 30 2a.l, 2a.2 or 2a.4, while those combinations which contain the compound 2a.l are particularly important according to the invention.

The above-mentioned anticholinergics optionally have chiral carbon centres. In this case the medicament combinations according to the invention may contain the anticholinergics 12 in the form of their enantiomers, mixtures of enantiomers or racemates, while enantiomerically pure anticholinergics are preferably used .

In another preferred embodiment of the present invention the anticholinergics 2a contained in the medicament combinations according to the invention are selected from the salts of 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, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, optionally in the form of the racemates, enantiomers or hydrates thereof.

Preferred medicament combinations contain salts of formula 2a.7, wherein X" denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof.

Preferred medicament combinations contain salts of formula 2a.7, wherein X" denotes an anion with a single negative charge, preferably an anion selected from among the chloride, bromide and methanesulphonate, preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof.

Particularly preferred medicament combinations contain the compound of formula 2a.7 in the form of the bromide. 13 Of particular importance are those medicament combinations which contain the enantiomers of formula 2a.7-en 0-o "Q -n S 2a.7-en wherein X " may have the above-mentioned meanings.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.7 are combinations containing the compounds LI and 2a.7; 1.1 and 2a.7-en; 1.2 and 2a.7: 1.2 and 2a.7-en; 1.3 and 2a.7:1.3 and 2a.7-en; 1.4 and 2a.7; 1.4 and 2a.7-en; 1.5 and 2a.7:1.5 and 2a.7-en; 1.6 and 2a.7; 1.6 and 2a.7-en; 1.7 and 2a.7; 1.7 and 2a.7-cn; 1.12 and 2a.7; 1.12 and 2a.7-en; 1.14 and 2a.7; 1.14 and 2a.7-en; 1.15 and 2a.7; 1.15 and 2a.7-en, in each case 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.

Of the above-mentioned combinations preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1.1,1.5,1.6, or 1.12 , while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain the compound 2a.7-en as compound 2a.

In another preferred embodiment of the present invention the anticholinergics 2a contained in the medicament combinations according to the invention are selected from the salts of formula 2a.8 14 Me X Me 2a.8 wherein R denotes either methyl (2a.8.1) or ethyl (2a.8.2) and wherein X " may have the above-mentioned meanings. In an alternative embodiment the compound of formula 2a.8 is present in the form of the free base 2a.8-base The medicament combinations according to the invention may containthe anticholinergic of formula 2a.8 (or 2a.8-hase) in the form of the enantiomers, mixtures of enantiomers or racemates thereof. Preferably the anticholinergics of formula 2a.8 (or 2a.8-base ) are present in the form of their R-enantiomers.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.8 are combinations containing the compounds 1J. and 2a.8.1; 1.1 and 2a.8.2; 1.2 and 2a.8.1; 1.2 and 2a.8.2:1.3 and 2a.8.1; 1.3 and 2a.8.2: 1.4 and 2a.8.1; 1.4 and 2a.8.2; 1.5 and 2a.8.1; 1.5 and 2a.8.2; 1.6 and 2a.8.1; 1.6 and 2a.8.2; \J_ and 2a.8.1; L7 and 2a.8.2; 1.12 and 2a.8.1; 1.12 and 2a.8.2:1.14 and 2a.8.1: 1.14 and 2a.8.2; 1.15 and 2a.8.1; 1.15 and 2a.8.2. in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds LI. 1.5,1.6, or 1.12 , Me 2a.8-base WO 2005/102349 15 PCT/EP2005/004073 while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention.

In another preferred embodiment of the present invention the anticholinergics 2a contained 5 in the medicament combinations according to the invention are selected from the compounds of formula 2a.9 wherein A denotes a double-bonded group selected from the groups x 7 x-7 VV C 0 0 0 and *r\ / h2 h2 h h h o h X " denotes one of the above-mentioned anions with a single negative charge, preferably chloride, bromide or methanesulphonate, 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 15 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 N02; 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.

The compounds of formula 2a.9 are known in the art (WO 02/32899). 16 Within the scope of the medicament combinations according to the invention preferred compounds of formula 2a.9 are those wherein X" denotes bromide; R1 and R2 which may be identical or different, denote methyl or ethyl, preferably 5 methyl; R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine; R7 denotes hydrogen, methyl or fluorine.

Of particular importance are medicament combinations which contain compounds of formula 2a.9, wherein A denotes a double-bonded group selected from \ _ / C C and H H H o H Of particular importance are those medicament combinations which contain in addition to a compound of formula 1 one of the following compounds of formula 2a.9 : tropenol 2,2-diphenylpropionate methobromide (2a.9.1), scopine 2,2-diphenylpropionate methobromide (2a.9.2 ), scopine 2-fluoro-2,2-diphenylacetate methobromide (2 a. 9.3). - tropenol 2-fluoro-2,2-diphenylacetate methobromide (2a.9.4),; The compounds of formula 2a.9 may optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof, as well as optionally in the form of the hydrates and/or solvates thereof.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.9 are combinations containing the compounds 1J. and 2a.9.1; 1.1 and 2a.9.2; 1.1 and 2a.9.3; 1.1 and 2a.9.4; 1.2 and 2a.9.1; 1.2 and 2a.9.2; 1.2 and 2a.9.3; 1.2 and 2a.9.4:1.3 and 2a.9.1; 1.3 and 2a.9.2; 1.3 and 2a.9.3; 1.3 and 30 2a.9.4; 1.4 and 2a.9.1; 1.4 and 2a.9.2; 1.4 and 2a.9.3; 1.4 and 2a.9.4; 1.5 and 2a.9.1:1.5 and 2a.9.2:1.5 and 2a.9.3; 1.5 and 2a.9.4; 1.6 and 2a.9.1; 1.6 and 2a.9.2; 1.6 and 2a.9.3; 1.6 and 2a.9.4; 1.7 and 2a.9.1; 1.7 and 2a.9.2; 1.7 and 2a.9.3; 1.7 and 2a.9.4; 1.12 and 2a.9.1; 1.12 and 2a.9.2; 1.12 and 2a.9.3; 1.12 and 2a.9.4; 1.14 and 2a.9.1; 1.14 and 2a.9.2; 17 1.14 and 2a.9.3; 1.14 and 2a.9.4; 1.15 and 2a.9.1; 1.15 and 2a.9.2; 1.15 and 2a.9.3; 1.15 and 2a.9.4, in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1.1,1.5,1.6, or 1.12 , while those combinations which contain one of the compounds 1A or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred 10 according to the invention are those which contain as compound 2a,9 one of the compounds 2a,9.1 or 2a.9.2 , while those combinations which contain the compound 2a.9.2 are particularly important according to the invention.

In another preferred embodiment of the present invention the anticholinergics 2a contained 15 in the medicament combinations according to the invention are selected from the compounds of formula 2a.l0 wherein A, X" ? R1 and R2 may have the meanings given above and wherein 20 R7, R8, R9, R10, Rn and R12 , which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or N02s while at least one of the groups R7, R8, R9, R10, Rn and R12 may not be hydrogen.

The compounds of formula 2a.lQ are known in the art (WO 02/32898).

Within the scope of the medicament combinations according to the invention preferred compounds of formula 2a.lQ are those wherein A denotes a double-bonded group selected from 18 \ / c-c H H and h o h X" bromide; R1 and R2 which may be identical or different, denote methyl or ethyl, preferably methyl; R7, R8, R9, R10, R11 and R12 which may be identical or different, denote hydrogen, fluorine, chlorine or bromine, preferably fluorine, while at least one of the groups R7, R8, R9, R10, R11 and R12 may not be hydrogen.

Of particular importance are those medicament combinations which contain in addition to 10 a compound of formula 1 one of the following compounds of formula 2a.l0 : tropenol 3,3',4,4-tetrafluorobenzilate methobromide (2a.10.1), scopine 3,3',4,4'~tetrafluorobenzilate methobromide (2a.l0.2), tropenol 4,4'-difluorobenzilate methobromide (2a.l0.3), scopine 4,4'-difluorobenzilate methobromide (2a.l0.4). - tropenol 3.3'-difluorobenzilate methobromide (2a.l0.5). scopine 3,3'-difluorobenzilate methobromide (2a.10.6), The compounds of formula 2a.lQ may optionally be presentin the form of the enantiomers, mixtures of enantiomers or racemates thereof, as well as optionally in the form of the 20 hydrates and/or solvates thereof.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.l0 are combinations containing the compounds 1.1 and 2a,10.1:1.1 and 2a.l0.2; 1.1 and 2a.l0.3; 1.1 and 2a.l0.4; 1.1 and 2a.l0.5; 1.1 and 2a.l0.6 1.2 and 2a.l0.1 1.2 and 2a.l0.2:1.2 and 2a.l0.3:1.2 and 2a,10.4; 1.2 and 2a.l0.5 1.2 and 2a.l0.6 1.3 and 2a.l0.1:1.3 and 2a.l0.2:1.3 and 2a.l0.3; 1.3 and 2a.l0.4 1.3 and 2a.l0.5 1.3 and 2a.l0.6; 1.4 and 2a.l0.1; 1.4 and 2a.l0.2; 1.4 and 2a.l0.3 1.4 and 2a.l0.4 1.4 and 2a.l0.5; 1.4 and 2a.l0.6; 1.5 and 2a.l0.1; 1.5 and 2a.l0.2 1.5 and 2a.l0.3 1.5 and 2a.l0.4; 1.5 and 2a.l0.5; 1.5 and 2a.l0.6:1.6 and 2a.10.l 1.6 and 2a.l0.2 1.6 and 2a.l0.3; 1.6 and 2a.l0.4; 1.6 and 2a.l0.5; 1.6 and 2a.l0.6 1.7 and 2a.l0.1 1.7 and 2a.l0.2:1.7 and 2a.l0.3:1.7 and 2a.l0.4; 1.7 and 2a.l0.5 1.7 and 2a.l0.6 1.12 and 2a.l0.1; 1.12 and 2a.l0.2; 1.12 and 2a.l0.3; 1.12 and 2a.l0.4 1.12 and 2a.l0.5; 1.12 and 2a.l0.6; 1.14 and 2a.l0.1; 1.14 and 2a.l0.2:1.14 and 19 2a.l0.3; 1.14 and 2a.l0.4:1.14 and 2a.l0.5; 1.14 and 2a.l0.6:1.15 and 2a.l0.1: 1.15 and 2a.l0.2; 1.15 and 2a.l0.3:1.15 and 2a.lQ.4; 1.15 and 2a.l0.5; 1.15 and 2a.l0.6, in each case optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates 5 and/or hydrates thereof.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1.1.1.5.1.6, or 1.12 , while those combinations which contain one of the compounds LI or 1.12 are particularly 10 important according to the invention. Of the above-mentioned combinations, also preferred according to the invention are those which contain as compound 2a.l0 one of the compounds 2a.l0.1,2a.l0.2 , 2a.l0.3 or 2a.l0.4 , while those combinations which contain the compounds 2a.l0.1 or 2a.l0.2 arc particularly important according to the invention.

In another preferred embodiment of the present invention the anticholinergics 2a contained in the medicament combinations according to the invention are selected from the compounds of formula 2a.ll wherein 20 A and X 2a.ll may have the meanings given above and wherein R1S denotes hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine; R1 and R2 which may be identical or different, denote Cj-C^-alkyl, which may optionally be substituted by C3-C6-cycloalkyl, hydroxy or halogen, or R1 and R2 together denote a -C3-C5-alkylene bridge ; R13, R14, R13' and R14' which maybe identical or different, denote hydrogen, -Q-C^alkyl, -Ci-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen.

The compounds of formula 2a.ll are known in the art (WO 03/064419).

Within the scope of the medicament combinations according to the invention preferred compounds of formula 2a.ll are those wherein A denotes a double-bonded group selected from C ~S and h h h o h 9 X - denotes ail anion selected from chloride, bromide and methanesulphonate, preferably bromide; R15 denotes hydroxy, methyl or fluorine, preferably methyl or hydroxy; R1' and R2 which may be identical or different, denote methyl or ethyl, preferably methyl; R13, R14, R13 and R14 which may be identical or different, denote hydrogen, -CF3, -CHF2 15 or fluorine, preferably hydrogen or fluorine.

Within the scope of the medicament combinations according to the invention particularly preferred compounds of formula 2a.ll are those wherein A denotes a double-bonded group selected from \ _ / C ~~C and H h h o h C X" denotes bromide; R15 denotes hydroxy or methyl, preferably methyl; R1 and R2 which may be identical or different, denote methyl or ethyl, preferably methyl; R13, R14, R13 and R14 which may be identical or different, denote hydrogen or fluorine.

Of particular importance are those medicament combinations which contain in addition to a compound of formula 1 one of the following compounds of formula 2a.ll : tropenol 9-hydroxy-fluorene-9-carboxylate methobromide f2a.11.1V 30 - tropenol 9-fluoro-fluorene-9-carboxylate methobromide f2a.11.2); scopine 9-hydroxy-fluorene-9-carboxylate methobromide (2 a. 11.3 ); scopine 9-fluoro-fluorene-9-carboxylate methobromide (2a.11.4); 21 tropenol 9-methyl-fluorene-9-carboxylate methobromide (2 a. 11.5); scopine 9-methyl-fluorene-9-carboxylatemethobromide (2a.ll.6); The compounds of formula 2a.ll may optionally be presentin the form of the enantiomers, mixtures of enantiomers or racemates thereof, as well as optionally in the form of the hydrates and/or solvates thereof.

Examples of novel medicament combinations of preferred compounds of formula 1 with 10 the above-mentioned anticholinergics 2a.ll are combinations containing the compounds 1.1 and 2a.ll.l; 1.1 and 2a.ll.2; 1.1 and 2a.ll.3; 1.1 and 2a.ll.4:1.1 and 2a.ll.5; 1.1 and 2a.ll.6 1.2 and 2a.ll.l; 1.2 and 2a.ll.2; 1.2 and 2a.ll.3; 1.2 and 2a.ll.4; 1.2 and 2a.ll.5 1.2 and 2a.ll.6; 1.3 and 2a.ll.l; 1.3 and 2a.ll.2:1.3 and 2a.ll.3; 1.3 and 2a. 11.4 1.3 and 2a.ll.5; 1.3 and 2a.ll.6i 1.4 and 2a.ll.l: 1.4 and 2a.ll.2; 1.4 and 2a.ll.3 1.4 and 2a.ll.4; 1.4 and 2a.ll.5:1.4 and 2a.ll.6; 1.5 and 2a.ll.l; 1.5 and 2a.ll.2 1.5 and 2a.ll.3; 1.5 and 2a.ll.4i 1.5 and 2a.ll.5; 1.5 and 2a.ll.6; 1.6 and 2a.ll.l 1.6 and 2a.ll.2; 1.6 and 2a.ll.3:1.6 and 2a.ll.4; 1.6 and 2a.ll.5; 1.6 and 2a.ll.6 1.7 and 2a.ll.l; 1.7 and 2a.ll.2; 1.7 and 2a.ll.3; 1.7 and 2a.ll.4; 1.7 and 2a.ll.5 1.7 and 2a.ll.6:1.12 and 2a.ll.l; 1.12 and 2a.ll.2; 1.12 and 2a.ll.3; 1.12 and 2a.ll.4 1.12 and 2a.ll.5; 1.12 and 2a.ll.6; 1.14 and 2a.ll.l; 1.14 and 2a.ll.2; 1.14 and 2a.ll.3 1.14 and 2a.ll.4; 1.14 and 2a.ll.5; 1.14 and 2a.ll.6: 1.15 and 2a.ll.l; 1.15 and 2a.ll.2 1.15 and 2a.ll.3; 1.15 and 2a.ll.4; 1.15 and 2a.ll.5: 1.15 and 2a.ll.6, in each case optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates 25 and/or hydrates thereof.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1.1,1.5,1.6, or 1.12 , while those combinations which contain one of the compounds hi or 1.12 are particularly 30 important according to the invention. Of the above-mentioned combinations, also preferred according to the invention are those which contain as compound 2a.ll one of the compounds 2a.ll.2, 2a.ll.4 , 2a.ll.5 or 2a.ll.6 , while those combinations which contain the compounds 2a.ll.5 or 2a.ll.6 are particularly important according to the invention. 22 In another preferred embodiment of the present invention the anticholinergics 2a contained in the medicament combinations according to the invention are selected from the wherein X " may have the meanings given above and wherein D and B which may be identical or different, are preferably identical Mid denote O, S, NH, CH2, CH=CH or N(C1-C4-alkyl); R®6 denotes hydrogen, hydroxy, -C | -C4-alkyl, -C) -t^-alkyloxy, -C i -C'4-alkyl ene-hal ogen, -O-C ] -C4-alkylcnc-halogcn, -C1 -C4-alkylene-OH, -CF3, CHF2, -C j -C4-alkylcne-C\-C4-aIkyloxy, -O-COC j -C4-alkyl, -O-COC} -C4-alkylene-halogen, -C]-C4-alkylene-C3-C6-cycloalkyl, -O-COCF3 or halogen; R1 and R2 which maybe identical or different, denote -Ci-C5-alkyl, which may 15 optionally be substituted by -C^-Cg-cycloalkyl, hydroxy or halogen, or R1 and R2 together denote a -C3-C5-alkylene bridge ; R17, R18, R17' and R18, which may be identical or different, denote hydrogen, -Ci^-alkyl, -Ci-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02 or halogen; 20 Rx and Rx' which may be identical or different, denote hydrogen, -Ci-C4-alkyl, -Cj-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02 or halogen, or Rx and Rx' together denote a single bond or one of the double-bonded groups O, S, NH, CH2, CH2-CH2, N(C1-C4-alkyl), CH(Ci-C4-alkyl) and -C(C1-C4-alkyl)2.

The compounds of formula 2a.l2 are known in the art (WO 03/064418). 23 Within the scope of the medicament combinations according to the invention preferred compounds of formula 2 a. 12 are those wherein X " denotes chloride, bromide or methanesulphonate, preferably bromide; D and B which may be identical or different, are preferably identical and denote O, 5 S, NH or CH=CH; R16 denotes hydrogen, hydroxy, -Ci-C4-alkyl, -Cj-C^-alkyloxy, -CF3, -CHF2, fluorine, chlorine or bromine; R1 and R2 which may be identical or different, denote C \ -C4-alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine, 10 or 111 2" R and R together denote a -C3-C4-alkylene bridge ; 17 18 11* 1R1 R ,R ,R andR , which may be identical or different, denote hydrogen, Ci-C4-alkyl, Ci-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2, fluorine, chlorine or bromine; Rx and Rx' which may be identical or different, denote hydrogen, Ci-C4-alkyl, C4-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, N02, fluorine, chlorine or bromine, or Rx and Rx' together denote a single bond or a double-bonded group selected from O, S, NH- and CH2.

Within the scope of the medicament combinations according to the invention particularly preferred compounds of formula 2a.l2 are those wherein X ~ denotes chloride, bromide, or methanesulphonate, preferably bromide; D and B which may be identical or different, preferably identical, denote S or CH=CH; R16 denotes hydrogen, hydroxy or methyl; R1 and R2 which may be identical or different, denote methyl or ethyl; 17 18 I7r .

R , R , R and R , which may be identical or different, denote hydrogen, -CF3 or fluorine, preferably hydrogen; Rx and Rx' which may be identical or different, denote hydrogen, -CF3 or fluorine, preferably hydrogen, or Rx and Rx' together denote a single bond or -O.

Within the scope of the medicament combinations according to the invention, other particularly preferred compounds of formula 2a.l2 are those wherein 24 X" denotes bromide; D and B denotes -CH=CH-; R16 denotes hydrogen, hydroxy or methyl; R1 and R2 denotes methyl; 1 a 1 □ -| rjt Of R , R , R and R , which may be identical or different, denote hydrogen or fluorine, preferably hydrogen; Rx and Rx' which may be identical or different, denote hydrogen or fluorine, preferably hydrogen, or Rx and Rx' together denote a single bond or the group -O.

Of particular importance are those medicament combinations which contain in addition to a compound of formula 1 one of the following compounds of formula 2a.l2 : cyclopropyltropine benzilate methobromide (2a.l2J); cyclopropyltropine 2,2-diphenylpropionate methobromide (23.12.2): cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide (2a.l2.3); cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide (2a.12.4): cyclopropyltropine 9-mcthyl-xanthcne-9-carboxylate methobromide (2a. 12.5); cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide (2a.l2.6); cyclopropyltropine methyl 4,4'-difluorobenzilate methobromide (2a. 12.7).

The compounds of formula 2a.l2 may optionally be present in the form of the enantiomers, mixtures of enantiomers or racemates thereof, as well as optionally in the form of the hydrates and/or solvates thereof.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.l2 are combinations containing the compounds 1.1 and 2a.l2.1:1.1 and 2a.l2.2; 1.1 and 2a.l2.3; 1.1 and 2a.l2.4; 1.1 and 2a.l2.5; 1.1 and 2a.l2.6 1.1 and 2a.l2.7 1.2 and 2a.l2.1; 1.2 and 2a.l2.2 1.2 and 2a.l2.3; 1.2 and 2a.l2.4 1.2 and 2a.l2.5 1.2 and 2a.l2.6; 1.2 and 2a.l2.7 1.3 and 2a.l2,l; 1.3 and 2a.l2.2 1.3 and 2a.l2.3 1.3 and 2a.l2.4; 1.3 and 2a.l2.5 1.3 and 2a.l2.6:1.3 and 2a.l2.7 1.4 and 2a.l2.1 1.4 and 2a.l2.2; 1.4 and 2a.l2.3 1.4 and 2a.l2.4; 1.4 and 2a.l2.5 1.4 and 2a.l2.6 1.4 and 2a.l2.7; 1.5 and 2a.l2.1 1.5 and 2a.l2.2:1.5 and 2a.l2.3 1.5 and 2a.l2.4 1.5 and 2a.l2.5; 1.5 and 2a.l2.6 1.5 and 2a.l2.7:1.6 and 2a.l2.1 1.6 and 2a.l2.2 1.6 and 2a.l2.3; 1.6 and 2a.l2.4 1.6 and 2a.l2.5:1.6 and 2a,12.6 1.6 and 2a.l2.7 1.7 and 2a.l2.1; 1.7 and 2a.l2.2 1.7 and 2a.l2.3:1.7 and 2a.l2.4; L7 and 2a.l2.5: L7 and 2a.l2.6: L7 and 2a.l2.7; 1.12 and 2a.l2.1:1.12 and 2a.l2.2; 1.12 and 2a,12.3:1.12 and 2a.l2.4: 1.12 and 2a.l2.5; 1.12 and 2a.l2.6; 1.12 and 2a.l2.7; 1.14 and 2a.l2.1; 1.14 and 2a.l2.2:1.14 and 2a.l2.3; 1.14 and 2a.l2.4; 1.14 and 2a. 12.5:1.14 and 2a.l2.6:1.14 and 2a.l2.7:1.15 and 2a.l2.1; 1.15 and 2a.l2.2: 1.15 and 5 2a.l2.3:1.15 and 2a.l2.4; 1.15 and 2a.l2.5; 1.15 and 2a.l2.6:1.15 and 2a.l2.7. in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds LI, L5,1.6. or 1.12 , while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as compound 2a.ll one of the 15 compounds 2a.l2.L 2a.l2.2 , 2a.l2.5 or 2a.l2.7 , while those combinations which contain the compounds 2a.l2.1 or 2a.l2.2 are particularly important according to the invention.

In another preferred embodiment of the present invention the anticholinergics 2a contained in the medicament combinations according to the invention are selected from the 20 compounds of formula 2a.l3 ,2' R wherein X " may have the meanings given above and wherein A' denotes a double-bonded group selected from A' 26 PCT /EP2005/004073 R19 denotes hydroxy, methyl, hydroxymethyl, ethyl, -CF3, CHF2 or fluorine; R1 and R2 which may be identical or different, denote Ci-C5-a1kyl, which may optionally be substituted by C^-Cg-cycl oalkyl, hydroxy or halogen, or R1 and R2 together denote a -C3-C5-alkylene bridge ; R20, R21, R20 and R21 which may be identical or different, denote hydrogen, -Cj -C'4-alkyl, -Ci-C4-alkyloxy, hydroxy, -CF3, -CTIF2, CN, NO2 or halogen.

The compounds of formula 2a.l3 are known in the art (WO 03/064417).

Within the scope of the medicament combinations according to the invention preferred compounds of formula 2a.l3 are those wherein A' denotes a double-bonded group selected from S ~~S and h h h o h X" denotes chloride, bromide or methanesulphnat, preferably bromide; R19 denotes hydroxy or methyl; R1" and R2 which may be identical or different, denote methyl or ethyl, preferably methyl; R20, R21, R20' and R21 which may be identical or different, denote hydrogen, -CF3, -CHF2 20 or fluorine, preferably hydrogen or fluorine.

Within the scope of the medicament combinations according to the invention particularly preferred compounds of formula 2a.l3 are those wherein A' denotes a double-bonded group selected from \ _ / p ~~Q and h h h o h X" denotes bromide; R19 denotes hydroxy or methyl, preferably methyl; R1 and R2 which may be identical or different, denote methyl or ethyl, preferably methyl; R^, r4, r3' and R^' which may be identical or different, denote hydrogen or fluorine. 27 Of particular importance are those medicament combinations which contain in addition to a compound of formula 1 one of the following compounds of formula 2a.l3 : tropenol 9-hydroxy-xanthene-9-carboxylate methobromide f2a.13.ri; scopine 9-hydroxy-xanthene-9-carboxylate methobromide f2a.13.2); - tropenol 9-methyl-xanthene-9-carboxylate methobromide (2a.l3.3); scopine 9-methyl-xanthene-9-carboxylate methobromide f2a.!3.4); tropenol 9-ethyl-xanthene-9-carboxylate methobromide (2a. 13.5); tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide f2a.13.6V. scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide f2a.13.7V The compounds of formula 2a.l3 may optionally be present in the form of the ( enantiomers, mixtures of enantiomers or racemates thereof, as well as optionally in the form of the hydrates and/or solvates thereof.

Examples of novel medicament combinations of preferred compounds of formula 1 with the above-mentioned anticholinergics 2a.l3 are combinations containing the compounds 1.1 and 2a.l3.1; 1.1 and 2a.l3.2; 1.1 and 2a.l3.3; 1.1 and 2a.l3.4; 1.1 and 2a. 13.5:1.1 and 2a.l3.6; 1.1 and 2a.l3.7 1.2 and 2a.l3.1: 1.2 and 2a.l3.2; 1.2 and 2a.l3.3; 1.2 and 2a.l3.4; 1.2 and 2a.l3.5 1.2 and 2a.l3.6: 1.2 and 2a.l3.7; 1.3 and 2a.l3.1; 1.3 and 2a.l3.2; 1.3 and 2a.l3.3 1.3 and 2a.l3.4:1.3 and 2a.l3.5; 1.3 and 2a.l3.6; 1.3 and 2a.l3.7; 1.4 and 2a.l3.1 1.4 and 2a.l3.2; 1.4 and 2a.l3.3; 1.4 and 2a.l3.4; 1.4 and 2a.l3.5:1.4 and 2a.l3.6 1.4 and 2a.l3.7; 1.5 and 2a.l3.1; 1.5 and 2a.l3.2; 1.5 and 2a.l3.3; 1.5 and 2a.l3.4 1.5 and 2a.l3.5; 1.5 and 2a.l3.6; 1.5 and 2a.l3.7; 1.6 and 2a.l3.1; 1.6 and 2a.l3.2 1.6 and 2a.l3.3; 1.6 and 2a,13.4; 1.6 and 2a.l3.5; 1.6 and 2a.l3.6; 1.6 and 2a.l3.7 1.7 and 2a.l3.1: 1.7 and 2a.l3.2; 1.7 and 2a.l3.3; 1.7 and 2a.l3.4; 1.7 and 2a.l3.5 1.7 and 2a.l3.6: 1.7 and 2a.l3.7; 1.12 and 2a.l3.1; 1.12 and 2a,13.2; 1.12 and 2a.l3.3; 1.12 and 2a,13.4; 1.12 and 2a.l3.5; 1.12 and 2a,13.6: 1.12 and 2a.l3.7; 1.14 and 2a,13.1:1.14 and 2a,13.2; 1.14 and 2a.l3.3; 1.14 and 2a.l3.4; 1.14 and 2a.l3.5; 1.14 and 2a.l3.6:1.14 and 2a.l3.7; 1.15 and 2a.l3.1; 1.15 and 2a.l3.2; 1.15 and 30 2a.l3.3; 1.15 and 2a,13.4:1.15 and 2a.l3.5; 1.15 and 2a.l3.6; 1.15 and 2a13/7, in each case 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 28 Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds LI, L5,1.6, or 1.12 , while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred 5 according to the invention are those which contain as compound 2a.ll one of the compounds 2a.l3.2. 2a.l3.3 , 2a.l3.4 or 2a.l3.5 , while those combinations which contain the compounds 2a.l3.3 or 2a.l3.4 are particularly important according to the invention.

Within the scope of the present invention any reference to anticholinergics V_ is to be taken 10 as a reference to the pharmacologically active cations of the various salts . These cations are tiotropium f2a.l'). oxitropium f2a.2'). flutropium (2a.3'X ipratropium (2a.4'h glycopyrronium f2a.5'). trospium (2a.6' ) and the cations shown below: 2a.7'; 2a.8'; ,2 R ,2 R 2a.9': 2a.l0' 29 Other preferred medicament combinations according to the invention contain as an additional active substance, in addition to one or more, preferably one compound of formula 1, one or more, preferably one, PDE IV-inhibitor 2b, optionally in combination with pharmaceutically acceptable excipients.

In such medicament combinations the PDE TV-inhibitor 2b is preferably selected from among enprofyllin, theophyllin, roflumilast, ariflo (Cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-)p-[(4tfR*,10&S*)-9-ethoxy-l,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][ 1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-l-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4'(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l -carboxylic acid], 2- carbomethoxy-4-cyano-4-(3 -cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -oi], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, CDP840, Bay-5 198004, D-4418, PD-168787, T-440, T-2585, arofyllin, atizoram, V-l 1294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9//-pyrazolo[3,4-c]-l ,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(fer/-butyl)-9if-pyrazolo[3,4-c]-l,2,4-triazolo[4,3~a]pyridme, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the 10 form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

In particularly preferred medicament combinations the PDE IV-inhibitor 2b_ is selected from the group comprising enprofyllin (2b. 1), roflumilast (2b.2), aiiflo (cilomilast) (2b.3), 15 AWD-12-281 (GW-842470) (2b.4). N-(3,5-dichloro-1 -oxo-pyridin-4-yl)-4- difluoromethoxy-3-cyclopropylmethoxybenzamide (2h.5), T-440 (2b.6). T-2585 (2b.7), arofyllin (2b.8), cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1 -carboxylic acid] (2b.9), 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l -one (2b. 10). cis[4-cyano-4-(3-cyclopropylmethoxy-20 4-difluoromethoxyphenyl)cyclohexan-l-ol] (2b.lll PD-168787 (21x12), atizoram (2b. 13). V-11294A (2b.l4), Cl-1018 (2b.l5). CDC-801 (2b. 16). D-22888 (2b.l7). YM-58997 (2b.l8), Z-15370 (2b.l9), 9-cyclopentyl-556-dihydro-7-cthyl-3-(2-thienyl)-9/7-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine (2b.20) and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(fer/-butyl)-9/Tr-pyrazolo|3,4-c|-l,2,4-triazolo[4,3-a]pyridiiic (2b.21), optionally in 25 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.

In particularly preferred medicament combinations the PDE IV-inhibitor 2b is selected from the group comprising roflumilast (2b.2), ariflo (cilomilast) (2b.3), AWD-12-281 (GW-842470) (2b.4). arofyllin (2b.8). 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one (2b.10). cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -ol] (2b.1V). atizoram (2b.l3), Z-15370 (2b.19). 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9if-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine (2b.20) and 9-cyclopentyl-5,6-dihydro-7-35 ethyl-3-(tert-butyl)-9//-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine (2b.21). while 31 roflumilast (21x2), Z-15370 (2b. 19) and AWD-12-281 (2 b.4) are of particular significance, 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.

By the acid addition salts with pharmacologically acceptable acids which the compounds 2b may possibly be capable of forming are meant for example salts selected from the group comprising the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, 10 hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of novel preferred medicament combinations of preferred compounds of formula 1 with the above-mentioned PDE IV inhibitors 2b are combinations containing the compounds LI and 2b. 1; 1.1 and 2b.2:1.1 and 2b.3; 1.1 and 2b.4; 1.1 and 2b.5; 1.1 and 2b.6: LI and 2b/7; LI and 2bJ5; U. and H and 2b.l0: LI and 2b.ll: LI and 2b.l2; 1.1 and 2b.l3; 1.1 and 2b.l4:1.1 and 2b.l5; 1.1 and 2b.l6:1.1 and 2b.l7; 1.1 and 20 2b.l8:1.1 and 2b.l9; 1.1 and 2b.2Q: 1.1 and 2b.21; 1.2 and 2b.l: 1.2 and 2b.2:1.2 and 2b.3; 1.2 and 2b.4; 1.2 and 2b.5:1.2 and 2b.6; 1.2 and 2b.7:1.2 and 2b.8; 1.2 and 2b.9; L2 and 2b.l0: L2 and 2b.ll: L2 and 2b.l2.12 and 2b.l3; L2 and 2b.l4: L2 and 2b,15; L2 and 2b.l6: L2 and 2b.l7: L2 and 2b.l8. L2 and 2b.l9: L2 and 2b.20; L2 and 2b.21: 1.3 and 2b.l; 1.3 and 2b.2; 1.3 and 2b.3:1.3 and 2b.4; 1.3 and 2b.5; 1.3 and 2b.6; 1.3 and 25 2K7; L3 and 2M; M and 2M; M and 2b.l0; L3 and 2b.ll; L3 and 2b.l2; L3 and 2b.l3: L3 and 2b.l4; L3 and 2b.l5; L3 and 2b.l6: L3 and 2b.l7; L3 and 2b.l8; L3 and 2b.l9; 1.3 and 2b.20; 1.3 and 2b.21; 1.4 and 2b.l; 1.4 and 2b.2; 1.4 and 2b.3; 1.4 and 2b.4; 1.4 and 2b.5; 1.4 and 2b.6; 1.4 and 2b.7; 1.4 and 2b.8; 1.4 and 2b.9:1.4 and 2b.l0; 1.4 and 2b.ll: 1.4 and 2b.l2; 1.4 and 2b.l3; 1.4 and 2b.l4; 1.4 and 2b.l5; 1.4 and 2b.l6: 30 L4 and 2b.l7: 1.4 and 2b.l8; 1.4 and 2b.l9; 1.4 and 2b.2Q; 1.4 and 2b.21; 1.5 and 2b.l: 1.5 and 2b.2:1.5 and 2b.3; 1.5 and 2b.4:1.5 and 2b.5; 1.5 said 2b.6: 1.5 and 2b.7; 1.5 and 2b.8; 1.5 and 2b.9; 1.5 and 2b.10; 1.5 and 2b.ll: 1.5 and 2b.12; 1.5 and 2b.l3; 1.5 and 2b,14; 1.5 and 2b,15; 1.5 and 2b. 16; 1.5 and 2b.l7; 1.5 and 2b. 18; 1.5 and 2b.l9; 1.5 and 2b.20; 1.5 and 2b.21; 1.6 and 2b.l: 1.6 and 2b.2; 1.6 and 2b.3; 1.6 and 2b.4; 1.6 and 2b.5; L6 and 2b.6:1.6 and 2b.7; 1.6 and 21x8; L6 and 2b.9; 1.6 and 2b.l0; 1.6 and 2b.ll: 1.6 32 and 2b.l2; 1.6 and 2b.l3:1.6 and 2b.l4:1.6 and 2b.l5; 1.6 and 2b.l6; 1.6 and 2b.l7; 1.6 and 2b.l8; L6 and 2b.l9: L6 and 2b.20: L6 and 2b.21; L7 and 21x1; L7 and 2bJ; 1/7 and 2b.3; 1.7 and 2b.4; 1.7 and 2b.5; 1.7 and 2b.6; 1.7 and 2b.7:1.7 and 2b.8; 1.7 and 2b.9; 1J and 2b.l0: L7 and 2b.ll. L7 and 2b.l2; L7 and 2b.l3; L7 and 2b.l4. L7 and 5 2b.l5: L7 and 2b.l6: L7 and 2b,17; 1/7 and 2b.l8: L7 and 2b.l9: 1/7 and 2b.20: L7 and 2b.21: 1.12 and 2b.l; 1.12 and 2b/2; L12 and 2^3; L12 and 2bA; L12 and 2K5; LIZ and 2b.6; 1.12 and 2b.7:1.12 and 2b.8; 1.12 and 2b.9:1.12 and 2b,10; 1.12 and 2b.ll; 1.12 and 2b.l2:1.12 and 2b.l3; 1.12 and 2b.l4:1.12 and 2b.l5; 1.12 and 2b.l6:1.12 and 2b,17; 1.12 and 2b.l8:1.12 and 2b.l9; 1.12 and 2b.20; 1.12 and 2b.21; 1.14 and 2b.l; 10 1.14 and 2b.2; 1.14 and 2b.3; 1.14 mid 2b.4:1.14 and 2b.5; 1.14 and 2b.6:1.14 and 2b.7; 1.14 and 2b.8:1.14 and 2b.9; 1.14 and 2b.l0; 1.14 and 2b.ll; 1.14 and 2b.l2; 1.14 and 2b.l3:1.14 and 2b.l4:1.14 and 2b.l5:1.14 and 2b.l6:1.14 and 2b.l7; 1.14 and 2b.l8: 1.14 and 2b.l9:1.14 and 2b.20; 1.14 and 2b.21; 1.15 and 2bA; IA5 and 2K2; U5 and 2b.3; 1.15 and 2b.4:1.15 and 2b.5; 1.15 and 2b.6; 1.15 and 2b.7; 1.15 and 2b.8; 1.15 and 2b.9; 1.15 and 2b.l0:1.15 and 2b.ll: 1.15 and 2b.l2:1.15 and 2b.l3:1.15 and 2b.l4; 1.15 and 2b.15; 1.15 and 2b.l6; 1.15 and 2b.l7; 1.15 and 2b.l8; 1.15 and 2b.l9; 1.15 and 2b.20 or 1.15 and 2b.21. in each case 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, in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1.1.1.5.1.6. or 1.12 , 25 while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as compound 2b one of the compounds 2b.2. 2b.3. 2b.4. 2b.8. 2b.l0. 2b. 11. 2b.13. 2b.l9, 2b.20 or 2b.21. while those combinations which contain one of the compounds 21x2, 2b.4 or 2b.19 are particularly 30 important according to the invention.

Other preferred medicament combinations according to the invention contain as an additional active substance, in addition to one or more, preferably one compound of formula 1, one or more, preferably one steroid 2c, optionally in combination with 35 pharmaceutically acceptable excipients. 33 In such medicament combinations the steroid 2c is preferably selected from among prednisolone (2c.l), prednisone (2c.2). butixocortpropionate (2c.3), RPR-106541 (2c.4), flunisolide (2c.5). beclomethasone (2c.6). triamcinolone (2c.7), budesonide (2c.8), 5 fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.ll). rofleponide (2 c. 12 V ST-126 (2cJ3), dexamethasone (2c.l4V (S)-fluoromethyl 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy] -11 ^-hydroxy-16a-methyl- 3 -oxo-androsta-1,4-diene-17 p -carbothionate (2c.l5V (S)-(2-oxo-tetrahydro-furan-3S-yl)6a,9a-difluoro-l lp-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17)3-carbothionate (2c.l6) and 10 etiprednol-dichloroacetate (BNP-l 66, 2c.1T). 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.

In particularly preferred medicament combinations the steroid 2c is selected from the 15 group comprising flunisolide (2cJ5), beclomethasone (2c.6V triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9V mometasone (2c.10). ciclesonide (2c.11). rofleponide (2c. 12V ST-126 (2c.l3V dexamethasone (2c.l4V (S)-fluoromethyl 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy] -lip -hydroxy-16a-methyl -3-oxo-androsta-1,4-diene-17p-carbothionate (2c.l5), (S)-(2-oxo-tetrahydro-furan-3S-yl)6a,9a-difluoro-l lp-hydroxy-20 16a-methyl-3-oxo-17a-propionyloxy-androsta-l,4-diene-17p-carbothionate (2c.l6) and etiprednol-dichloroacetate (2c.l7). 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.

In particularly preferred medicament combinations the steroid 2c is selected from the group comprising budesonide (2c.8), fluticasone (2c.9), mometasone (2c.l0), ciclesonide (2c. 1 I K (S)-fluoromethyl 6a,9a-difluoro-l 7a-|(2-furanylcarbonyl)oxy]-l 1 P-hydroxy-16a-metbyl-3-oxo-androsta-1,4-dienc-l 7p-carbothionate (2c.l5) and etiprednol-dichloroacetate (2 c. 17), optionally in the form of the racemates, enantiomers or 30 diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.

Any reference to steroids 2c includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids 35 2c may be: alkali metal salts, such as for example sodium or potassium salts, 34 sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

Examples of novel preferred medicament combinations of preferred compounds of formula 5 1 with the above-mentioned steroids 2c are combinations containing the compounds LI and 2c.l; 1.1 and 2c.2; 1.1 and 2c.3; 1.1 and 2c.4; 1.1 and 2c.5; 1.1 and 2c.6; 1.1 and 2c.7; 1.1 and 2c.8; 1.1 and 2c.9; 1.1 and 2c.l0; 1.1 and 2c.ll; 1.1 and 2c.l2; 1.1 and 2c. 13; 1.1 and 2c.l4; 1.1 and 2c.l5; 1.1 and 2c.l6; 1.1 and 2c.l7; 1.2 and 2c.l; 1.2 and 2c.2; 1.2 and 2c.3; 1.2 and 2c.4; 1.2 and 2c.5; 1.2 and 2c.6; 1.2 and 2c.7; 1.2 and 2c.8:1.2 and 2c.9:1.2 10 and 2c.l0; 1.2 and 2c.ll: 1.2 and 2c.l2; 1.2 and 2c. 13; 1.2 and 2c.l4; 1.2 and 2c.l5; 1.2 and 2c.l6: 1.2 and 2c.l7: 1.3 and 2c.l: 1.3 and 2c.2:1.3 and 2c.3; 1.3 and 2c.4: 1.3 and C 2c.5:1.3 and 2c.6; 1.3 and 2c.7:1.3 and 2c.8; 1.3 and 2c.9:1.3 and 2c.l0; 1.3 and 2c.ll; 1.3 and 2c. 12; 1.3 and 2c.l3; 1.3 and 2c,14; 1.3 and 2c.l5; 1.3 and 2c.l6; 1.3 and 2c.l7; 1.4 and 2c.l; 1.4 and 2c.2; 1.4 and 2c.3; 1.4 and 2c.4; 1.4 and 2c.5; 1.4 and 2c.6; 1.4 and 2c.7; 1.4 and 2c.8; 1.4 and 2c.9; 1.4 and 2c. 10; 1.4 and 2c.ll; 1.4 and 2c.l2; 1.4 and 2c.l3; 1.4 and 2c.l4; 1.4 and 2c.l5; 1.4 and 2c.l6; 1.4 and 2c.l7; 1.5 and 2c.l; 1.5 and 2c.2; 1.5 and 2c.3; 1.5 mid 2c.4; 1.5 and 2c.5; 1.5 and 2c.6; 1.5 and 2c.7; 1.5 and 2c.8; 1.5 and 2c.9; 1.5 and 2c.l0; 1.5 and 2c.ll; 1.5 and 2c,12; 1.5 and 2c.l3; 1.5 and 2c.l4; 1.5 and 2c.l5; 1.5 and2c,16; 1.5 and 2c.l7; 1.6 and 2c.l; 1.6 and 2c.2; 1.6 and 2c.3; 1.6 and 2c.4; 1.6 and 20 2c.5; 1.6 and 2c.6; 1.6 and 2c.7; 1.6 and 2c.8; 1.6 and 2c.9; 1.6 and 2c.l0; 1.6 and 2c.ll; 1.6 and 2c.l2; 1.6 and 2c,13; 1.6 and 2c.l4; 1.6 and 2c.l5; 1.6 and 2c.l6; 1.6 and 2c.l7; 1.7 and 2c.l; 1.7 and 2c,2; 1.7 and 2c.3; 1.7 and 2c.4; 1.7 and 2c.5; 1.7 and 2c.6; 1.7 and 2c.7; 1.7 and 2c.8; 1.7 and 2c.9; 1.7 and 2c.l0; 1.7 and 2c.ll; 1.7 and 2c.l2; 1.7 and 2c.l3; ( L7 and 2c.l4; L7 and 2c.l5; L7 and2c.!6; L7 and 2c.l7; 1.12 and 2cJ.; L12 and 2c.2: 1.12 and 2c.3; 1.12 and 2c.4; 1.12 and 2c.5; 1.12 and 2c.6; 1.12 and 2c.7; 1.12 and 2c.8; 1.12 and 2c.9; 1.12 and 2c.l0. 1.12 and 2c.ll; 1.12 and 2c.l2; 1.12 and 2c,13; 1.12 and 2c.l4: 1.12 and 2c.l5; 1.12 and2c,16:1.12 and 2c,17; 1.14 and 2c.l; 1.14 and 2c.2: 1.14 and 2c,3; 1.14 and 2c.4; 1.14 and 2c.5; 1.14 and 2c.6; 1.14 and 2c.7; 1.14 and 2c.8; 1.14 and 2c.9:1.14 and 2c.lQ; 1.14 and 2c.ll; 1.14 and 2c.l2; 1.14 and 2c.l3; 1.14 and 2c,14; 30 1.14 and 2c,15; 1.14 and 2c,16; 1.14 and 2c,17; 1.15 and 2c.l; 1.15 and 2c.2; 1.15 and 2c.3; 1.15 and 2c.4; 1.15 and 2c.5; 1.15 and 2c.6; 1.15 and 2c.7; 1.15 and 2c.8; 1.15 and 2c.9; 1.15 and 2c.l0; 1.15 and 2c.ll; 1.15 and 2c.l2; 1.15 and 2c.l3; 1.15 and 2c.l4: 1.15 and 2c.l5:1.15 and 2c.l6 or 1.15 and 2c.l7 , in each case optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the 35 pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula X one of the compounds 1J., 1.5,1.6, or 1.12 , while those combinations which contain one of the compounds 1J. or 1.12 are particularly 5 important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as compound 2c one of the compounds 2c.5. 2c.6. 2c.7. 2c.8. 2c.9. 2c.l0. 2c.ll. 2c.l2. 2c.l3. 2c,14. 2c.l5. 2c,16 or 2c.l7 , while those combinations which contain one of the compounds 2c.8, 2c.9,2c.l0, 2c.ll, 2c. 15 or 2c.l7 are particularly important according to the invention.

Other preferred medicament combinations according to the invention contain, as an additional active substance, in addition to one or more, preferably one compound of formula 1, one or more, preferably one, LTD4 antagonist 2d, optionally in combination with pharmaceutically acceptable excipients.

In such medicament combinations the LTD4 antagonist 2d is preferably selected from among montelukast (2dJL), l-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyI)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid (2tL2), l-(((l(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(l -hydroxy-1 -20 methylethyl)phenyl)propyI)thio)methyl)cyclopropanacetic 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) (2d.91 VUF-5078 (2d.l(T>. 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 25 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.

In preferred medicament combinations the LTD4 antagonist 2d is selected from the group comprising montelukast (2d.l), pranlukast (2d.4). zafirlukast (2d.5). MCC-847 (ZD-3523) 30 (2cL7), MN-001 (2d.8). MEN-91507 (LM-1507) (2d.9). VUF-5078 (2d.l0). 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. 36 In particularly preferred medicament combinations the LTD4 antagonist 2d is selected from the group comprising montelukast (2dLl), pranlukast (2d.4), zafirlukast (2d.5h MCC-847 (ZD-3523) (2d.7). MN-001 (2d,8) and MEN-91507 (LM-1507) f2d.9I while montelukast (2d.l), pranlukast (2dL4) and zafirlukast (2d.5) are particularly preferred, 5 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.

By the acid addition salts with pharmacologically acceptable acids which the compounds 2d may possibly be capable of forming are meant for example salts selected from the i group comprising the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, 15 hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of possible salts and derivatives which the compounds 2d may possibly be capable of forming include for example: alkali metal salts, such as for example sodium or 20 potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

Examples of novel preferred medicament combinations of preferred compounds of formula 1 with the above-mentioned LTD4-antagonists 2d are combinations containing the V 25 compounds LI and 2d.l: 1.1 and 2d.2; 1.1 and 2d.3; 1.1 and 2d.4; 1.1 and 2d.5; 1.1 and 2d.6; 1.1 and 2d.7:1.1 and 2d.8:1.1 and 2d.9; 1.1 and 2d.lQ: 1.1 and 2d.ll; 1.1 and 2d.l2; 1.2 and 2d.l; 1.2 and 2d.2:1.2 and 2d.3; 1.2 and 2d.4:1.2 and 2d.5; 1.2 and 2d.6: 1.2 and 2d.7; 1.2 and 2d.8; 1.2 and 2d.9:1.2 and 2d.l0:1.2 and 2d.ll: 1.2 and 2d. 12; 1.3 and 2d.l; 1.3 and 2d.2; 1.3 and 2d.3; 1.3 and 2d.4; 1.3 and 2d.5; 1.3 and 2d.6; 1.3 and 30 2dJ; L3 and 2tL8; L3 and 2cL9; M and 2d.l0: L3 and 2d,ll; L3 and 2d.l2; L4 and 2d.l; 1.4 and 2d.2; 1.4 and 2d.3:1.4 and 2d.4; 1.4 and 2d.5; 1.4 and 2d.6; 1.4 and 2d.7: L4 and 2d.8; L4 and 2d.9: 1.4 and 2d.l0; L4 and 2d.ll; L4 and 2d.l2; L5 and 2rf.l; 1.5 and 2d.2; 1.5 and 2d.3:1.5 and 2d.4; 1.5 and 2d.5:1.5 and 2d.6; 1.5 and 2d.7; 1.5 and 2d.8; L5 and 2d.9; L5 and 2d.lQ; L5 and 2d.ll: L5 and 2d. 12. L6 and 2d.1; L6 and 35 2d.2, L6 and 2d.3; L6 and 2d.4; L6 and 2d.5; L6 and 2d.6; L6 and 2d.7: L6 and 2d.8; 37 L6 and 2cL9; L6 and 2d.l0; L6 and 2d.ll: L6 and 2d.l2: L7 and 2dJ; L7 and 2cL2; L7 and 2d.3; 1.7 and 2d.4: 1.7 and 2d.5; 1.7 and 2d.6; 1.7 and 2d.7; 1.7 and 2d.8; 1.7 and 2d.9: L7 and 2d.l0: L/7 and 2d.ll: LJ and 2d.l2; 1.12 and 2tLl; L12 and 2d.2:1.12 and 2d.3:1.12 and 2dL4; L12 and 2(L5; L12 and 2cL6; L12 and 2cL7; L12 and 2tL8; L12 and 5 2M; LI2 and 2d.l0; 1.12 and 2d.ll: 1.12 and 2d,12:1.14 and 2cU; L14 and 2cL2; 1M and 2d.3; 1.14 and 2d.4; 1.14 and 2d.5:1.14 and 2d.6:1.14 and 2d.7; 1.14 and 2d.8; 1.14 and 2d.9; 1.14 and 2d.l0:1.14 and 2d.ll; 1.14 and 2d.l2; 1.15 and 2d.l; 1.15 and 2d.2; 1.15 and 2d.3:1.15 and 2d.4:1.15 and 2d.5:1.15 and 2d.6; 1.15 and 2d,7:1.15 and 2d.8: 1.15 and 2d.9; 1.15 and 2d.l0; 1.15 and 2d.ll or 1.15 and 2d.l2. in each case optionally in 10 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds LI, 1.5.1.6. or 1.12 , 15 while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as compound 2d one of the compounds 2(1.1. 2d.4. 2d.5. 2d.7. 2d.8. 2d.9.2d.l0. 2d.ll or2d,12. while those combinations which contain one of the compounds 2d.l. 2d.4. 2d.5. 2d.7. 2d.8 or 2d.9 are particularly 20 important according to the invention, and those combinations which contain one of the compounds 2d.l. 2d.4 or 2d.5 are of exceptional importance.

Other preferred medicament combinations according to the invention contain as an additional active substance, in addition to one or more, preferably one compound of 25 formula 1, one or more, preferably one, EGFR-inhibitor 2e, optionally in combination with pharmaceutically acceptable excipients.

In such medicament combinations the EGFR-inhibitor 2e is selected for example from the group comprising 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-l -oxo-2-3 0 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-butcn-1 -yl]amino}-7-cyclopropylmethoxy-quinazoline, 1 - phenyl-cthyl)amino ] -6- {[4-{morpholin-4-yl)-1 -oxo-2-buten-1 -yl] amino} -7-35 cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((7?)-6-methyl- WO 2005/102349 38 PCT/EP2005/004073 2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 -yl] amino} -7-cyclopropylmethoxy-quinazoline, 4-[(3-chIoro-4-fluoro-phenyl)amino]-6-{[4-((i?)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-1 -yl] amino} -7-[(5)-(tetrahydrofuran-3 -yl)oxy] -quinazoline, 4- [(3 -chloro-4-fluoro-phenyl)amino] -6- {[4-((K)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1 -oxo-2 -buten-1 -5 yl] amino} -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- [2-((1S)-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- [(/?)-10 (1 -phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-l -oxo-2-buten-l - yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(i?)-(l-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N- ethyl- amino] -1 -oxo-2-buten-1 -yl} amino)-7 -cyclopropylmethoxy-quinazoline, 4-[(i?)-(l -phenyl-ethyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2-buten-1 -yl} amino)-7-cyclopropylmethoxy-quinazoline, 4- [(J?)-( 1 -phenyl-15 ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yI)-N-methyl-amino]-l -oxo-2-buten-l - yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophcnyi)amino]-6-{[4-(N.N-dimethylamino)-1 -oxo-2-buten-1 -yl] amino} -7-((if)-tetrahydrofuran-3 -yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-{N,N-dimethylamino)-l-oxo-2-buten-l-yl]amino}-7-((iS)-tetrahydrofLiran-3-yloxy)-quinazoline, 4-[(3-chloro-4-20 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-cyclop cntyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-l -oxo-2-buten-1 -yl|amino}-7-[(iv')-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-25 fluorophenyl)amino] -6- {[4-(N,N -dimethylamino)-1 -oxo-2-buten-1 -yl] amino } -7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-pbenyI)aiTiino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy] -6- [(vinyl carbonyI)amino] -quinazoline, 4- [ (/?)-(1 -phenyl -ethyl)amino] -6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-3 0 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)-l-oxo-35 2-buten-1 -yl] amino} -7- [(tetrahydrofuran-2-yI)methoxy] -quinazoline, 4-[(3-chloro-4- WO 2005/102349 39 PCT/EP2005/004073 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-phenyI)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-5 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-fIuoro-phenyl)ammo]-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-4-10 fluoro-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy- quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cycIohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyelohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-| (3-chloro-4-15 fluoro-phenyl)amino]-6-(l -methyl-pip eridin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6- {1 - [ (morpholin-4-yl)carbonyl] -piperidin-4-yloxy} -7-mcthoxy-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-niethoxy-qinnazoline, 4-[(3-chloro-4-fluoro-20 phenyl)amino] -6- [ 1 -(2-acetylamino-ethyl)-piperidin-4-yloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyI)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydroforan-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetfahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-25 [(dimethylamino)sulphonylamino]-cyclohexan-l -yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[ (morpholin-4-yl)sulphonylamino]-cycIohexan-1 -yloxy} -7-methoxy-quinazoline, 4- [ (3 -chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-30 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- mcthanesulphonylamino-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-(l-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-35 yl)carbonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro- WO 2005/102349 40 PCT/EP2005/004073 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-fIuoro-phenyl)amino] -6-(ci s-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-5 cyclohcxan-l-yloxy)-7-mcthoxy-quinazolinc, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1 -methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3 -chloro-4-fluoro-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chioro-4-fluoro-phenyI)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-10 acetylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[l-(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-l-yl)carbonyl]-N-methyl-amino}-cyclohexan-l-yIoxy)-7-methoxy-quinazoline, 4- [(3 - chloro-4-fluoro-phenyl)amino] -6-{cis-4- {N- [ (4-15 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)carbonyI amino]-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-{l-[(morpholin-4-yl)carbonyl]-20 piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(l-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-cthynyl-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3 -chloro-4-fluoro-phenyl)amino]-6-(l-methyl-piperidin-4-yIoxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-25 chloro-4-fluoro-phenyl)amino]-6-(l-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyI)-N-methyl-amino]-cyclohexan-l -yloxy}-7-methoxy-quinazoline, 4-[(3~ ethynyl-phenyl)amino] - 6-(piperidin-4-yloxy) -7-methoxy-quinazoline, 4- [(3 -ethynyl-30 phenyl)amino]-6-[l -(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-chIoro-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-35 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(S,S)-(2-oxa-5-aza- 41 / 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 -ethyI-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-5 {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-chIoro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l-yIoxy]-7-methoxy-10 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-i methanesulphonyl-N-methyl-amino)-cyclohexan-l -yloxy]-7-methoxy-quinazoline, 4-[(3- chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-15 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-yI)-ethoxy]-7-[(S)-(tctrahydrofuran-2-yl)mcthoxy |-quinazoline, 4-[(3-chloro-4-fluoro-phenyi)amino]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, cetuximab, 20 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.

In such medicament combinations the EGFR-inhibitor 2e is preferably selected from 25 among the 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)-l-oxo-2-buten-l-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-l -oxo-2-buten-l -yl]amino} -7-cyclopropylmethoxy-quinazoline, 4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-30 1 -oxo-2-buten-1 -yl] amino } -7-cyclopentyloxy-quinazoline, 4- [(3 -chloro-4- fluoro- phenyI)amino] -6- {[4-((R)-6-methyl-2-oxo-morphoIin-4-yl)-1 -oxo-2-buten-1 -yl] amino } -7-cyclopropylmethoxy-quinazoline, 4- [ (3-chIoro-4-fluoro-phenyI)amino] -6- {[4-((R)- 6-methyl-2-oxo-morpholin-4-yl)-l -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-6-3 5 oxo-morphoIin-4-yl)-1 -oxo-2-buten-1 -yl] amino } -7-cyclopropylmethoxy-quinazoline, 4- WO 2005/102349 42 PCT/EP2005/004073 [(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fhiorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino] -1 -oxo-2-butcn-1 -yl} amino)-7-cyclopropylmethoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl)amino]-6- {[4-(N,N-dirnethylamino)-l -oxo-2-buten-l -yl]amino} -7-5 cyclopentyloxy-quinazoline, 4-[(R)-(l-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 -phenyI-ethyl)amino]-6-( {4- pST-(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 -cy clopropylmethoxy-10 quinazoline, 4-[(R)-(l-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-fIuorophenyl)amino]-6- {[4-(N ,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino } -7-((S)-tetrahydrofuran-3 -yloxy)-quinazoline, 15 4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2-buten-l-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-4-2 0 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)-propy!oxy]-6-[(vinylcarbonyl)amino]-quinazolme, 4-[(R)-(l-phenyl-cthyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-25 fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-l -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}-fviran-2-yI)quinazoline, 4-[(R)-(l-phenyl-ethyl)amino]-6- {[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l -oxo-2-buten-l -yl]amino}-7-methoxy-quinazoline, 4- [(3 -chloro-4-fluorophenyl)amino] -6- {[4-(morpholin-4-yl)-1 -oxo-30 2-buten-1 -yl]amino} -7- [(tetrahydrofuran-2-yl)methoxy] -quinazoline, 4-[(3 -chloro-4-fluorophenyl)amino] -6-( {4- [N,N-bi s-(2-methoxy-ethyl)-amino] -1 -oxo-2-buten-1 -yl} amino)-7 - [ (tctrahydrofuran-2-yl)methoxy] -quinazoline, 4-[(3-cthynyl-phenyl)amino] -6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-quinazoline, 4-[(3-chIoro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-35 methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo- WO 2005/102349 43 PCT/EP2005/004073 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-l -yl]-ethoxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-5 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-4-10 fluoro-phenyl)amino]-6-( 1 -methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(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-15 phenyl)amino]-6-[l -(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)ammo] -6- {trans-4-20 [(dimethylamino)sulphonylamino]-cyclohexan-1 -yloxy} -7-methoxy-quinazoline, 4-[{3 -chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[ (morpholin-4-yl)su!phonylamino] -cyclohexan-1 -yloxy} -7 -methoxy-quinazoline, 4- [(3 -chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-25 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-{l-[(piperidin-1 -yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl)amino]-6-(l-aminocarbonylmethyl-pipeiidin-4-yloxy)-7-methoxy-quinazoline, 4- [(3 -chloro-4-fluoro-phenyl)amino] -6 -(cis-4- {N-[ (tetrahydropyran-4-30 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-(ci s-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-35 cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l - 44 methanesuIphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -6-( 1 -methanes ulph onyl-piper j din-4-yl o x y)-7-(2 -methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-5 acetylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl) amino] -6-(tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4- [(3 -chIoro-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-[(4-10 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-{l-[(morpholin-4-yl)carbonyl]-15 piperidin-4-yloxy} -7- (2-methoxy~ethoxy)-quinazoline, 4- [(3 -ethynyl-phenyl)amino] -6-( 1 -acetyI-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-(l-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fIuoro-phenyl)amino] -6-( 1 -methyl-piperidin-4-yloxy)-7 (2-methoxy-ethoxy)-quinazoline, 4- [ (3 -20 chloro-4-fluoro-phenyl)amino]-6-(l-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-phenyI)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-l-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-25 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- {l-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quina2;oline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-30 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[{S,S)-(2-oxa-5-aza- bicyclo[2.2.1 ]hept-5 -yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[ (3 -chloro-4-tluoro-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-(l-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4- [(3 -chl oro-4- fl uoro-phenyl)amino | -6-35 {1 -[(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3 -chl oro-4- 45 PCT/EP2 005/004073 fluoro-phenyl) amino] -6-{l-[(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-cliloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-5 quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-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-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phcnyl)amino]-6-(trans-4-{N-[(morphoIin-4-10 yl)carbonyl|-N-mcthyI-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)-i (tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l - methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[{3-chloro-4-fluoro-phenyl)amino]-6-(l -cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and cetuximab, 15 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.

Particularly preferably, the EGFR-inhibitors 2a used within the scope of the medicament 20 combinations according to the invention are selected from the group comprising 4-[(3-chloro-4-fluorophenyl)amino] -6- {[4-(morpholin-4-yl)-1 -oxo-2-butcn-1 -yl] amino }-7-cyclopropylmethoxy-quinazoline, 4-| (R)-( l -phcnyl-cthyl)amino |-6- {| 4-(moxpholin-4-yl)-1 -oxo-2-buten-1 -yl] amino} -7-cyclopentyloxy-quinazoline, 4- [(3 -chloro-4-fluoro-f 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-[2-((S)-6-methyl-2-oxo-moipholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[{3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(l -phenyI-ethyl)amino]-6-( {4-[N-(tetrahydropyran-4-yl)-N -methyl-amino] -1 -oxo-2-buten-1 -yl} amino)-7 -30 cyclopropylmethoxy-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,N-dimethylamino)-l -oxo-2-buten-1 -yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(R)-( 1 -phenyl-ethyl)amino]-6-3 5 (4-hydroxy-phenyl)-7H-pyrrolo[2,3 -d]pyrimidine, 3-cyano-4- [(3 -chloro-4- WO 2005/102349 46 PCT/EP2005/004073 fhiorophenyl)amino] -6- {[4-(N,N -dimethylamino)-1 -oxo-2-buten-1 -yl] amino} -7-ethoxy-quinoline, 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)-l -oxo-2-buten-l -yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-5 quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyI-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-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-(trans-4-amino-cycIohexan-1 -yloxy)-7-methoxy-quinaz oline, 4-[(3 -chloro-4-fluoro-phenyl)amino] - 6- (trans-4-methanesulphonylamino- cyclohexan-1 -10 yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyI)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(morpholin-4-yl)carbonyl]-piperidin-4-y! oxy} -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 -acetyl amino-ethyl)-piperidin-4-yloxy] -7-methoxy-quinazoline, 4-15 [(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3 -chloro-4-fluoro-phenyl)amino] -6- {trans-4- [(morpholin-4-yl)carbonyl amino] -cyclohexan-1 -yloxy} -7-methoxy-quinazoline, 4-[(3 -chloro-4-fluoro-phenyl)amino] -6- {1 -[(piperidin-l-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-20 cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4- [(3 -chloro-4-fluoro-phenyl)amino] -6- (trans-4-ethanesulphonyl amino-cyclohexan-1 -yloxy) -7-methoxy-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-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-25 (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-[(morpholin-4-yl)carbonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, 4-[(3-chIoro-4-fluoro-phenyl)amino]-6-{l-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-30 quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(l -acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4- [(3 -ethynyl-phenyl)amino] -6-( 1 -methyl-piperidin-4-yIoxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(l-methanesuIphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-methyl-piperidin-4-yIoxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6- {1 -[(morpholin-3 5 4-yl)carbonyI] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3 -chloro-4-fluoro- WO 2005/102349 47 PCT/EP2005/004073 phenyl)amino]-6-{l-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline, 4-[(3-5 chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l-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-mcthancsulphonyl-N-methyl-amino)-cyclohexan-1 -y]oxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1 -10 yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7- [(S)-(tctrahydrofuran-2-yl)methoxy]-quinazoline, 4-[{3 -chloro-4-fluoro-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-15 chloro-4-fluoro-phenyl)amino]-6-(l -cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and 4- [(3 -chloro-4~fluoro-phenyl)amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy}-7-methoxy-quinazoline, 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.

Particularly preferred medicament combinations according to the invention contain as EGFR-inhibitors 2e those compounds which are selected from the group comprising 4- [ (3 -chloro-4-fluorophenyl)amino] - 6- {[4-(morpholin-4-yl) -1 -oxo-2-buten-1 -yl] -amino } -7- cyclopropylmethoxy-quinazoline (2e.l), 25 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l -oxo-2-buten-1 -yl]amino}-7-[(S)-(tetrahydrofiaran-3-yI)oxy]-quinazoline (2c.2). 4-[(3-chIoro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline (2e.3)„ 4-[(3-chIoro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l -30 oxo-2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline (2e.4), 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline (2c.5), 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(morpholin-4-yl)-l -oxo-2-buten-1 -yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline (2e.6), 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-l-oxo-2-3 5 buten-1 -yl]amino } -quinazoline (2e.7)„ 48 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulpbonylarmno-cyclohexan-l-yloxy)-7-methoxy-quinazoline (2e.8). 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline (2e.9). - 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {1 -[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline (2eJ_0), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline (2e.ll), 4-[(3-ethynyl-phenyl)amino]-6-(l-acetyI-piperidin-4-yloxy)-7-methoxy-quinazoline 10 (2eJJ), 4-[(3-ethynyl-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline ( (2e.l3), 4-[(3-ethynyl-phenyl)amino]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline (2eJ_4), - 4-[(3-ethynyl-phenyl)amino]-6- {1 -[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline (2e.l5h 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline (2e.l6), 4- [ (3-chloro-4-fluoro~phenyl)amino] -6- [cis-4-(N-methanesulphonyl -N-methyl-20 amino)-cyclohexan-1 -yloxy j-7-methoxy-quinazoline (2e.l7), 4-[ (3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-eyclohexan-1-yloxy]-7-methoxy-quinazoline (2e.l8). 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7-f methoxy-quinazoline f2c,19), - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline (2e.20). 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-(trans-4-dimethylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline (2e.21), 4- [(3 -chloro-4-fluoro-phenyl) amino] -6-(trans-4- {N - [ (morpholin-4-yl)carbonyl] -N-30 methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-quinazoline (2e.22). 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxyJ-quinazoline (2e.23), 4- [ (3 -chloro-4-fluoro-phenyl) amino]-6-( 1 -methanesulphonyl-piperidin-4-yloxy)-7 -methoxy-quinazoline (2c.24) and 49 4-[(3-chloro-4-fluoro-phcnyl)amino]-6-(I-cyano-pipcridin-4-yloxy)-7-methoxy-quinazoline (2e.25), 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 5 and/or hydrates thereof.

By the acid addition salts with pharmacologically acceptable acids which the compounds 2e may possibly be capable of forming are meant for example salts selected from the group comprising the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, 10 hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, V hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of novel preferred medicament combinations of preferred compounds of formula !_ with the above-mentioned EGFR-inhibitors 2e are combinations containing the compounds LI and 2e.l; 1.1 and 2e.2; 1.1 and 2e.3; 1.1 and 2c.4; 1.1 and 2e.5; 1.1 and and 2e.8:1.1 and 2e.9; 1.1 and 2e.l0; 1.1 and 2e.ll; 1.1 and 2e.l2; 2e.l4; 1.1 and 2e.l5; 1.1 and 2e.l6; 1.1 and 2e.l7; 1.1 and 2e.l8; 2e.2Q; LI and2e.21; LI and 2e.22; LI and 2e.23; LI and 2e.24; 2e.l; 1.2 and 2e.2; 1.2 and 2e.3; 1.2 and 2e.4; 1.2 and 2e.5; 1.2 and and 2e.8:1.2 and 2e.9; 1.2 and 2e.l0:1.2 and 2e.ll: 1.2 and 2e.l2; 2e.l4:1.2 and 2e.l5; 1.2 and 2e,16; 1.2 and 2e.l7; 1.2 and 2e.l8; 2e.2Q; 1.2 and 2e.21:1.2 and 2e.22:1.2 and 2e.23; 1.2 and 2c.24: 2e.l: 1.3 and 2e.2; 1.3 and 2e.3; 1.3 and 2e.4; 1.3 and 2e.5; 1.3 and and 2e.8; 1.3 and 2e.9; 1.3 and 2e.l0: 1.3 and 2e.ll; 1.3 and 2e.l2; 2e.l4:1.3 and 2e.l5; 1.3 and 2e.l6:1.3 and 2e.l7:1.3 and 2e.l8: 2e.20:1.3 and 2e.2L 1.3 and 2e.22:1.3 and 2e.23:1.3 and 2e.24; 2e.l: 1.4 and 2e.2; 1.4 and 2e.3:1.4 and 2e.4:1.4 and 2e.5; 1.4 and and 2e.8; 1.4 and 2e.9; 1.4 and 2e.l0:1.4 and 2e.ll; 1.4 and 2e.l2; 2e.l4; 1.4 and 2e.l5; 1.4 and 2e.l6; 1.4 and 2e.l7; 1.4 and 2e.l8; 2e.20; L4 and 2e.21; L4 and 2e,22; L4 and 2e.23; L4 and 2e.24; 2e.l; 1.5 and 2e.2; 1.5 and 2e.3; 1.5 mid 2e.4; 1.5 and 2e.5; 1.5 and and 2e.8:1.5 and 2e.9; 1.5 and 2e.l0; 1.5 and 2c. 11; 1.5 and 2e.l2; 2e.6; 1.1 and 2e.7; 1.1 20 LI and 2e.l3; 1.1 and 1.1 and 2e.l9; 1.1 and 1.1 and 2e.25; 1.2 and 2e.6; 1.2 and 2e.7:1.2 1.2 and 2e.l3; 1.2 and 25 L2 and 2eL9; L2 and 1.2 and 2e.25; 1.3 and 2e.6; 1.3 and 2e.7:1.3 1.3 and 2e.l3; 1.3 and 1.3 and 2e.l9:1.3 and 30 L3 and 2e.25:1.4 and 2e.6; 1.4 and 2e.7; 1.4 1.4 and 2e.l3; 1.4 and 1.4 and 2e,19; 1.4 and 1.4 and 2e.25; 1.5 and 2e.6; 1.5 and 2e.7; 1.5 50 1,5 and 2e.l3; 1.5 and 2e.l4; 1.5 and 2e.l5; 1.5 and 2e.l6; 1.5 and 2e.l7; 1.5 and 2e.l8; 1.5 and 2e,19; 1.5 and 2e.20; 1.5 and 2e.21; 1.5 and 2e.22; 1.5 and 2e.23:1.5 and 2e.24; 1.5 and 2e.25; 1.6 and 2e.l; 1.6 and 2e.2; 1.6 and 2e.3; 1.6 and 2c.4; 1.6 and 2e.5; 1.6 and 2e.6; 1.6 and 2e.7; 1.6 mid 2e.8; 1.6 and 2e.9; 1.6 and 2e.l0; 1.6 and 2e.ll: 1.6 and 2e.l2; L6 and 2e.l3:1.6 and 2e.l4; 1.6 and 2e.l5; 1.6 and 2e.l6; 1.6 and 2e.l7:1.6 and 2e.l8; 1.6 and 2e.l9:1.6 and 2e.20; 1.6 and 2e.21; 1.6 and 2e.22; 1.6 and 2e.23; 1.6 and 2e.24; 1.6 and 2e.25; 1.7 and 2e.l; 1.7 and 2e.2; 1.7 and 2e.3; 1.7 and 2e.4; 1.7 and 2e.5:1.7 and 2e.6; 1.7 and 2e.7; 1.7 and 2e.8; 1.7 and 2e.9; 1.7 and 2e.l0; 1.7 and 2e.ll; 1.7 and 2e.l2: 1.7 and 2e.l3; 1.7 and 2e.l4; 1.7 and 2c.l5; 1.7 and 2e.l6; 1.7 and 2e.l7; 1.7 and 2e.l8: 10 L7 and 2e.l9; 1/7 and 2e.20:1/7 and 2c.21; L7 and 2e.22:1/7 and 2e.23:1/7 and 2e.24: 1.7 and 2e.25; 1.12 and 2e.l; 1.12 and 2e.2; 1.12 and 2e.3; 1.12 and 2e.4; 1.12 and 2e.5: ( 1.12 and 2e.6; 1.12 and 2e/7; 1.12 and 2e.8; 1.12 and 2e.9; 1.12 and 2e.l0; 1.12 and 2e.ll; 1.12 and 2e.l2; 1.12 and 2c.l3; 1.12 and 2e.l4; 1.12 and 2e.l5; 1.12 and 2e.l6; 1.12 and 2e.l7:1.12 and 2e.l8; 1.12 and 2e.l9i 1.12 and 2e.2Q: 1.12 and 2c.21; 1.12 and 2e.22; 1.12 15 and 2e.23; 1.12 and 2e.24; 1.12 and 2e.25: 1.14 and 2e.l: 1.14 and 2e.2i 1.14 and 2e.3; 1.14 and 2e.4; 1.14 and 2e.5; 1.14 and 2e.6i 1.14 and 2e.7; 1.14 and 2e.8:1.14 and 2e.9; 1.14 and 2e.l0; 1.14 and 2e.ll; 1.-14 and 2e,12; 1.14 and 2e.l3; 1.14 and 2e.l4; 1.14 and 2e.l5:1.14 and 2e.l6:1.14 and 2e.l7; 1.14 and 2e.l8; 1.14 and 2e.l9; 1.14 and 2e.20: 1.14 and 2e.21:1.14 and 2c.22; 1.14 and 2e.23; 1.14 and 2e.24:1.14 and 2e.25:1.15 mid 2e.l; 1.15 and 2e.2:1.15 and 2e.3; 1.15 and 2e.4; 1.15 and 2e.5; 1.15 and 2e.6; 1.15 and 2e.7; 1.15 and 2eJ; L15 and 2^; 1A5 and 2e.l0:1.15 and 2e.ll; 1.15 and 2e.l2:1.15 and 2e.l3; 1.15 and 2e.l4:1.15 and 2e,15; 1.15 and 2e.l6.1.15 and 2e.l7:1.15 and 2e.l8; 1.15 and 2e.l9:1.15 and 2e.20; 1.15 and 2e.21; 1.15 and 2e.22; 1.15 and 2e.23:1.15 and 2e.24 f or 1.15 and 2e.25, in each case 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.

Of the above-mentioned combinations, preferred ones according to the invention are those which contain as compound of formula 1 one of the compounds 1A, 1.5.1.6. or 1.12 , 30 while those combinations which contain one of the compounds LI or 1.12 are particularly important according to the invention. Of the above-mentioned combinations also preferred according to the invention are those which contain as the compound 2e one of the compounds 2e.l. 2e.2, 2e.3, 2e.4. 2e.l0, 2e.ll, 2e.l4, 2e.l6, 2e.l7, 2e.l8. 2e.l9. 2e.20, 2e.21, 2c.22, 2e.23.2e.24 or 2e.25 , while those combinations which contain one of the 35 compounds 2e.2, 2e.3 or 2e.4 are particularly important according to the invention. 51 The novel medicament combinations comprising compounds of formula 1 with at least one other active substance 2 are not restricted to binary combinations of active substances. The combinations mentioned above, partly by way of example, which contain in addition to a 5 compound of formula 1 one other active substance 2 , may also contain a third or fourth, preferably a third active substance, which is also selected from the above-mentioned group of anticholinergics (2a). PDE-IV inhibitors (2b), steroids (2c), LTD4-antagonists (2d) and EGFR-inhibitors (2e), Particularly preferred combinations which contain two other active substances in addition to a compound of formula 1 are selected from the active substance combinationslisted below . These are medicament combinations which may contain, for example : A) a compound of formula 1, an anticholinergic (2a), a PDEIV inhibitor (2b); B) a compound of formula 1, an anticholinergic (2a). a steroid (2c); C) a compound of formula 1, an anticholinergic (2a), an LTD4 antagonist (2d); D) a compound of formula 1, an anticholinergic (2a), an EGFR inhibitor (2e); E) a compound of formula 1, a PDEIV inhibitor (2b), a steroid (2c); F) a compound of formula 1, a PDEIV inhibitor (2b), an LTD4 antagonist (2d); G) a compound of formula 1, a PDEIV inhibitor (2b), an EGFR inhibitor (2e); 20 H) a compound of formula 1, a steroid (2c), an LTD4 antagonist (2d); I) a compound of formula 1, a steroid (2c), an EGFR inhibitor (2c ); J) a compound of formula 1, an LTD4 antagonist (2d), an EGFR inhibitor (2e).

Particularly preferred examples of medicament combinations of the above-mentioned 25 group A are selected from the group comprising the following combinations: compounds LI and 2a.l and 2b.2; 1.1 and 2a.l and 2b.4; 1.1 and 2a.l and 2b.ll; 1.1 and 2a.l and 2b,19; 1.1 and 2a.9.1 and 2b.2; 1.1 and 2a.9.1 and 2b.4; 1.1 and 2a.9.1 and 2b.ll; 1.1 and 2a.9.1 and 2b.l9; 1.1 and 2a.9.2 and 2b.2; 1.1 and 2a.9.2 and 2b.4; 1.1 and 2a.9.2 and 2b.ll; 1.1 and 2a.9.2 and 2b.l9; 1.1 and 2a. 10.1 and 2b.2; 1.1 and 2a. 10.1 and 30 2b.4; 1.1 and 2a.l0.1 and 2b.ll; 1.1 and 2a. 10.1 and 2b.l9; 1.1 and 2a,10.2 and 2b.2; 1.1 and 2a. 10.2 and 2b.4; 1.1 and 2a.l0.2 and 2b.ll; 1.1 and 2a,10.2 and 2b.19; 1.1 and 2a.ll.l and 2b.2; 1.1 and 2a.ll.l and 2b.4; 1.1 and 2a.ll.l and 2b.ll; 1.1 and 2a.ll.l and 2b.l9; 1.1 and 2a. 11.6 and 2b.2; 1.1 and 2a.ll.6 and 2b.4; 1.1 and 2a. 11.6 and 2b.11; 1.1 and 2a.ll.6 and 2b. 19; 1.12 and 2a.l and 2b.2; 1.12 and 2a. 1 and 2b.4; 1.12 and 2a.l and 2b.ll; 1.12 and 2a. 1 and 2b,19; 1.12 and 2a.9.1 and 2b.2; 1.12 and 2a.9.1 and 2b.4; 1.12 52 and 2a.9.1 and 2bJ1; 1.12 and 2a.9.1 and 2b.19; 1.12 and 2a.9.2 and 2b.2; 1.12 and 2a.9.2 and 2b.4; 1.12 and 2a.9.2 and 2b.11; 1.12 and 2a.9.2 and 2b.l9; 1.12 and 2a. 1Q.1 and 2b.2; 1.12 and 2a.l0.1 and 2b.4; 1.12 and 2a,10.1 and 2b.ll; 1.12 and 2a. 10.1 and 2b.l9; 1.12 and 2a.l0.2 and 2b.2; 1.12 and 2a.l0.2 and 2b.4; 1.12 and 2a. 10.2 and 2b.ll; 1.12 5 and 2a.l0.2 and 2b.l9; 1.12 and 2a.ll.12 and 2b.2; 1.12 and 2a.ll.12 and 2b.4; 1.12 and 2a.11.12 and 2b.ll; 1.12 and 2a.ll.12 and 2b,19; 1.12 and 2a. 11.6 and 2b.2; 1.12 and 2a.ll.6 and 2b.4; 1.12 and 2a.ll.6 and 2b.ll: 1.12 and 2a.ll.6 and 2b.l9. in each case optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates 10 and/or hydrates thereof.

Particularly preferred examples of particularly preferred medicament combinations of the above-mentioned group B according to the invention are selected from the group comprising the following combinations: compounds 1J. and 2a.l and 2c.8; 1.1 and 2aJ and 2c.9; 1.1 and 2a.l and 2c.l0; 1.1 and 2a. 1 and 2c.ll; 1.1 and 2a.l and 2c.l7:1.1 and 2a.9.1 and 2c.8; 1.1 and 2a.9.1 and 2c.9; 1.1 and 2a.9.1 and 2c,10; 1.1 and 2a.9.1 and 2c.ll; 1.1 and 2a.9.1 and 2c.l7; 1.1 and 2a.9.2 and 2c.8; 1.1 and 2a.9.2 and 2c.9; 1.1 and 2a.9.2 and 2c.l0; 1.1 and 2a.9.2 and 2c. 11; 1.1 and 2a.9.2 and 2c.l7:1.1 and 2a.l0.1 and 2c.8; 1.1 and 2a.10.1 and 2c.9; 1.1 20 and 2a.l0.1 and 2c.l0; 1.1 and 2a.l0.1 and 2c.ll; 1.1 and 2a.l0.1 and 2c.l7; 1.1 and 2a.10.2 and 2c.8; 1.1 and 2a,10.2 and 2c.9; 1.1 and 2a. 10.2 and 2c.l0: 1.1 and 2a. 10.2 and 2c.ll; 1.1 and 2a,10.2 and 2c.l7; 1.1 and 2a. 11.1 and 2c.8; 1.1 and 2a.ll.l and 2c.9:1.1 and 2a.ll.l and 2c.l0:1.1 and 2a. 11.1 and 2c. 11; 1.1 and 2a.ll.l and 2c.l7; 1.1 and 2a.ll.6 and 2c.8; 1.1 and 2a.ll.6 and 2c.9; 1.1 and 2a.ll.6 and 2c.l0; 1.1 and 2a.ll.6 and 25 2c.ll; 1.1 and 2a. 11.6 and 2c. 17; 1.12 and 2a.l and 2c.8; 1.12 and 2a.l and 2c.9:1.12 and 2a.l and 2c.l0; 1.12 and 2a.l and 2c.ll; 1.12 and 2a.l and 2c.l7; 1.12 and 2a.9.1 and 2c.8; 1.12 and 2a.9.1 and 2c.9; 1.12 and 2a.9.1 and 2c.l0:1.12 and 2a.9.1 and 2c.ll; 1.12 and 2a.9.1 and 2c. 17; 1.12 and 2a.9.2 and 2c.8; 1.12 and 2a.9.2 and 2c.9:1.12 and 2a.9.2 and 2c.10; 1.12 and 2a.9.2 and 2c.ll; 1.12 and 2a.9.2 and 2c. 17; 1.12 and 2a.l0.1 and 30 2c.8; 1.12 and 2a.l0.1 and 2c.9; 1.12 and 2a.l0.1 and 2c.10; 1.12 and 2a.l0.1 and 2c.ll; 1.12 and 2a.10.1 and 2c.l7; 1.12 and 2a. 10.2 and 2c.8; 1.12 and 2a.l0.2 and 2c.9; 1.12 and 2a.l0.2 and 2c.10; 1.12 and 2a.10.2 and 2c.ll; 1.12 and 2a.l0.2 and 2cJ7; 1.12 and 2a.ll.12 and 2c.8:1.12 and 2a.ll.12 and 2c.9; 1.12 and 2a.ll.12 and 2c. 10; 1.12 and 2a.ll.12 and 2c.ll; 1.12 and 2a.ll.12 and 2c.l7; 1.12 and 2a.ll.6 and 2c.8; 1.12 and 35 2a.ll.6 and 2c.9; 1.12 and 2a.ll.6 and 2c.l0; 1.12 and 2a.ll.6 and 2c.ll; 1.12 and 53 2a. 11.6 and 2c. 17., in each case 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.: Particularly preferred examples of medicament combinations of the above-mentioned group C are selected from the group comprising the following combinations: compounds LI and 2a. 1 and 2d.l; 1.1 and 2a.l and 2d.4:1.1 and 2a.l and 2d.5:1.1 and 2a.l and 2d.8:1.1 and 2a.9.1 and 2d.I; 1.1 and 2a.9.1 and 2d.4:1.1 and 2a.9.l and 2d.5; 1.1 and 2a.9.1 and 2d.8:1.1 and 2a.9.2 and 2d.l: 1.1 and 2a.9.2 and 2d.4; 1.1 and 2a.9.2 10 and 2d.5:1.1 and 2a.9.2 and 2d.8:1.1 and 2a.lQ.l and 2d.l; 1.1 and 2a.l0.1 and 2d.4:1.1 and 2a.l0.1 and 2d.5; 1.1 and 2a. 10.1 and 2d.8; 1.1 and 2a.l0.2 and 2d. 1; 1.1 and 2a.l0.2 \ and 2d.4:1.1 and 2a.l0.2 and 2d.5:1.1 and 2a. 10.2 and 2d.8; 1.1 and 2a. 11.1 and 2d.l; 1.1 and 2a.ll.l and 2d.4:1.1 and 2a.11.1 and 2d.5:1.1 and 2a.11.1 and 2d.8:1.1 and 2a.ll.6 and 2d.l; 1.1 and 2a.ll.6 and 2d.4; 1.1 and 2a. 11.6 and 2d.5; 1.1 and 2a. 11.6 and 15 2d.8; 1.12 and 2a.l and 2d.l: 1.12 and 2a. 1 and 2d.4:1.12 and 2a. 1 and 2d.5:1.12 and 2a.l and 2d.8; 1.12 and 2a.9.1 and 2d.l; 1.12 and 2a.9.1 and 2d.4; 1.12 and 2a.9.1 and 2d.5; 1.12 and 2a.9.1 and 2d.8:1.12 and 2a.9.2 and 2d.l: 1.12 and 2a.9.2 and 2d.4:1.12 and 2a.9.2 and 2d.5; 1.12 and 2a.9.2 and 2d.8: 1.12 and 2a. 10.1 and 2d.l: 1.12 and 2a.l0.1 and 2d.4:1.12 and 2a. 10.1 and 2d.5; 1.12 and 2a.10.1 and 2d.8; 1.12 and 2a.10.2 and 20 2d.l; 1.12 and 2a.l0.2 and 2d.4:1.12 and 2a. 10.2 and 2d.5; 1.12 and 2a.l0.2 and 2d.8: 1.12 and 2a.ll.12 and 2d.1; 1.12 and 2a.ll.12 and 2d.4; 1.12 and 2a.ll.12 and 2d.5:1.12 and 2a.ll.12 and 2d.8; 1.12 and 2a. 11.6 and 2d.l: 1.12 and 2a.ll.6 and 2d.4; 1.12 and 2a.ll.6 and 2d.5: 1.12 and 2a.ll.6 and 2d.8. in each case optionally in the form of the f racemates, enantiomers or diastereomers thereof and optionally in the form of the i;.. pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.: Particularly preferred examples of medicament combinations of the above-mentioned group D are selected from the group comprising the following combinations: compounds LI and 2a. 1 and 2e.2:1.1 and 2a.l and 2e.3:1.1 and 2a.l and 2e.4:1.1 and 30 2a. 1 and 2e,10; 1.1 and 2a.9.1 and 2e.2; 1.1 and 2a.9.1 and 2e.3; 1.1 and 2a.9.1 and 2c.4; 1.1 and 2a.9.1 and 2e,10; 1.1 and 2a.9.2 and 2c.2; 1.1 and 2a.9.2 and 2e.3:1.1 and 2a.9.2 and 2e.4:1.1 and 2a.9.2 and 2e.l0; 1.1 and 2a.l0.1 and 2e.2:1.1 and 2a.l0.1 and 2c.3; 1.1 and 2a.l0.1 and 2e.4:1.1 and 2a.lQ.l and 2e,10; 1.1 and 2a. 10.2 and 2e.2; 1.1 and 2a.l0.2 and 2e.3:1.1 and 2a.l0.2 and 2e.4; 1.1 and 2a.l0.2 and 2e.10; 1.1 and 2a.11.1 and 2e.2: 35 LI and 2a.l 1.1 and 2e.3:1.1 and 2a.11.1 and 2e.4:1.1 and 2a. 11.1 and 2e.l0:1.1 and 54 2a.ll.6 and 2e.2; 1.1 and 2a. 11.6 and 2c.3; 1.1 and 2a.ll.6 and 2e.4; 1.1 and 2a.ll.6 and 2e.l0; 1.12 and 2a.l and 2e.2; 1.12 and 2a. 1 and 2e.3; 1.12 and 2a. 1 and 2e.4; 1.12 and 2a.l and 2e.J0; 1.12 and 2a.9.1 and 2e.2:1.12 and 2a.9.1 and 2e.3; 1.12 and 2a.9.1 and 2e.4; 1.12 and 2a.9.1 and 2c.10; 1.12 and 2a.9.2 and 2e.2; 1.12 and 2a.9.2 and 2e.3; 1.12 5 and 2a.9.2 and 2e.4; 1.12 and 2a.9.2 and 2e,10; 1.12 and 2a.l0.1 and 2e.2; 1.12 and 2a. 10.1 and 2e.3; 1.12 and 2a.l0.1 and 2e.4; 1.12 and 2a,10.1 and 2e.l0; 1.12 and 2a.l0.2 and 2e.2: 1.12 and 2a.l0.2 and 2e.3; 1.12 and 2a. 10.2 and 2e,4; 1.12 and 2a.l0.2 and 2e.l0; 1.12 and 2a.ll.12 and 2e.2; 1.12 and 2a.11.12 and 2e.3; 1.12 and 2a.ll.12 and 2c.4; 1.12 and 2a.ll.12 and 2e.lO; 1.12 and 2a.11.6 and 2e.2: 1.12 and 2a.ll.6 and 2e.3; 1.12 10 and 2 a. 11.6 and 2e.4; 1.12 and 2a.ll.6 and 2e.l0, in each case 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.: Particularly preferred examples of medicament combinations of the above-mentioned 15 group E are selected from the group comprising the following combinations: compounds 1A and 2c.8 and 2b.2; 1.1 and 2c.8 and 2b.4; 1.1 and 2c.8 and 2b.ll: 1.1 and 2c.8 and 2b.l9;1.1 and 2c.9 and 2b.2; 1.1 and 2c.9 and 2b.4:1.1 and 2c.9 and 2b.ll: 1.1 and 2c.9 and 2h.l9; 1.1 and 2c. 10 and 2b.2; 1.1 and 2c. 10 and 2b.4; 1.1 and 2c.l0 and 2b.ll: 1.1 and 2c.l0 and 2b.l9:1.1 and 2c. 11 and 2b.2:1.1 and 2c.ll and 2b.4; 1.1 and 20 2c. 11 and 2b.ll: 1.1 and 2c. 11 and 2b.l9; 1.1 and 2c. 17 and 2b.2; 1.1 and 2c. 17 and 2b.4; LI and 2c,17 and 2b.ll: 1.1 and 2c.l7 and 2b,19:1.12 and 2c.8 and 2b.2:1.12 and 2c.8 and 2b.4;1.12 and 2c.8 and 2b. 11; 1.12 and 2c.8 and 2b.l9; 1.12 and 2c.9 and 2b.2; 1.12 and 2c.9 and 2b.4; 1.12 and 2c.9 and 2b.ll: 1.12 and 2c.9 and 2b.l9: 1.12 and 2c. 10 and 2b.2:1.12 and 2c. 10 and 2b.4; 1.12 and 2c,10 and 2b.ll: 1.12 and 2c. 10 and 2b.l9; 1.12 25 and 2c. 11 and 2b.2; 1,12 and 2c. 11 and 2h.4; 1.12 and 2e.ll and 2b. 11; 1.12 and 2c. 11 and 2b.l9.1.12 and 2c.l7 and 2b.2; 1.12 and 2c. 17 and 2b.4; 1.12 and 2c.l7 and 2b.ll: 1.12 and 2c.l7 and 2b.l9; in each case 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.

Particularly preferred examples of medicament combinations of the above-mentioned group F are selected from the group comprising the following combinations: compounds 1_J_ and 2d.l and 2b.2; 1.1 and 2d.l and 2b.4:1.1 and 2d.l and 2b.ll: 1.1 and 2d.l and 2b.19; 1.1 and 2d.4 and 2b.2; 1.1 and 2d.4 and 2b.4:1.1 and 2d.4 and 2b.ll; 1.1 35 and 2d.4 and 2b.19; 1.1 and 2d.5 and 2b.2; 1.1 and 2d.5 and 2b.4:1.1 and 2d.5 and 2b.ll: 55 1.1 and 2d.5 and 2b.l9; 1.1 and 2d.8 and 2b.2; 1.1 and 2d.8 and 2b.4; 1.1 and 2d.8 and 2b.ll; 1.1 and 2d.8 and 2b.l9; 1.12 and 2d.l and 2b.2; 1.12 and 2d.l and 2b.4:1.12 and 2d.l and 2b,ll; 1.12 and 2d.l and 2b. 19; 1.12 and 2d.4 and 2b.2; 1.12 and 2d.4 and 2b.4; 1.12 and 2d.4 and 2b.ll; 1.12 and 2d.4 and 2b.l9; 1.12 and 2d.5 and 2b.2; 1.12 and 2d.5 5 and 2b.4; 1.12 and 2d.5 and 2b.ll; 1.12 and 2d.5 and 2b.l9; 1.12 and 2d.8 and 21x2; 1.12 and 2d.8 and 2b.4; 1.12 and 2d.8 and 2b.11; 1.12 and 2d.8 and 2b,19, in each case 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.

Particularly preferred examples of medicament combinations of the above-mentioned group G are selected from the group comprising the following combinations: compounds LI and 2e.2 and 21x2; LI and 2e,2 and 2b.4; 1.1 and 2e.2 and 2b.ll; 1.1 and 2e.2 and 21x19; LI and 2e.3 and 21x2; LI and 2e.3 and 2b.4; 1.1 and 2e.3 and 2b.ll; 1.1 15 and 2e.3 and 2b.l9; 1.1 and 2e.4 and 2|x2; LI and 2e.4 and 2b.4:1.1 and 2e.4 and 2b.ll; 1.1 and 2e.4 and 2b.l9:1.1 and 2c. 10 and 21x2; LI and 2e.l0 and 2b.4; 1.1 and 2e.l0 and 2b.ll; 1.1 and 2e.l0 and 21x19; 1.12 and 2e.2 and 2b.2; 1.12 and 2e.2 and 2b.4:1.12 and 2e.2 and 2b.ll; 1.12 and 2e.2 and 21x19; 1.12 and 2e.3 and 2b.2; 1.12 and 2e.3 and 2b.4; 1.12 and 2e.3 and 2b.ll: 1.12 and 2e.3 and 2b.l9; 1.12 and 2e.4 and 2b.2; 1.12 and 2e.4 20 and 2b.4; 1.12 and 2c.4 and 2b.ll; 1.12 and 2e.4 and 2b.l9:1.12 and 2e.l0 and 2b.2; 1.12 and 2e.l0 and 2b.4; 1.12 and 2c. 10 and 2b.ll: 1.12 and 2c. 10 and 2b.l9, in each case 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.

Particularly preferred examples of medicament combinations of the above-mentioned group H are selected from the group comprising the following combinations: compounds LI and 2c.8 and 2d.1; 1.1 and 2c.8 and 2d.4; 1.1 and 2c.8 and 2d.5; 1.1 and 2c.8 and 2d.8; 1.1 and 2c.9 and 2d.l; 1.1 and 2c.9 and 2d.4:1.1 and 2c.9 and 2d.5; 1.1 and 30 2c.9 and 2d.8; LI and 2c.l0 and 2d.l: LI and 2c.l0 and 2d.4: 1.1 and 2c. 10 and 2d.5; 1.1 and 2c. 10 and 2d.8; 1.1 and 2c.ll and 2d.l: 1.1 and 2c. 11 and 2d.4; 1.1 and 2c.ll and 2d.5:1.1 and 2c. 11 find 2d.8; 1.1 and 2c. 17 and 2d.l; 1.1 and 2c. 17 and 2d.4; 1.1 and 2c.l7 and 2d.5; 1.1 and 2c. 17 and 2d.8; 1.12 and 2c.8 and 2d.1; 1.12 and 2c.8 and 2d.4; 1.12 and 2c.8 and 2d.5; 1.12 and 2c,8 and 2d.8; 1.12 and 2c.9 and 2d.l; 1,12 and 2c.9 and 35 2d.4; 1.12 and 2c.9 and 2d.5; 1.12 and 2c.9 and 2d.8: 1.12 and 2c.l0 and 2d.l; 1.12 and 56 2c.l0 and 2d.4:1.12 and 2c.l0 and 2d.5; 1.12 and 2c.l0 and 2d.8; 1.12 and 2c. 11 and 2d.l; 1.12 and 2c. 11 mid 2d.4:1.12 and 2c.ll and 2d.5; 1.12 and 2c. 11 and 2d.8,1.12 and 2c.l7 and 2d.l; 1.12 and 2c.l7 and 2d.4; 1.12 and 2c.l7 and 2d.5; 1.12 and 2c. 17 and 2d.8; in each case optionally in the form of the racemates, enantiomers or diastereomers 5 thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

Particularly preferred examples of medicament combinations of the above-mentioned group I are selected from the group comprising the following combinations: 10 compounds LI and 2c.8 and 2e.2; 1.1 and 2c.8 and 2e.3; 1.1 and 2c.8 and 2e.4; 1.1 and 2c.8 and 2e.lQ; 1.1 and 2c.9 and 2e.2; 1.1 and 2c.9 and 2e.3:1.1 and 2c.9 and 2e.4:1.1 and 2c.9 and 2e.lQ; 1.1 and 2c.l0 and 2e.2; 1.1 and 2c.10 and 2e.3; 1.1 and 2c. 10 and 2e.4; 1.1 and 2c.l0 and 2e.l0; 1.1 and 2c. 11 and 2e.2; 1.1 and 2c. 11 and 2e.3; 1.1 and 2c. 11 and 2e.4:1.1 and 2c.ll and 2e.l0; 1.1 and 2c. 17 and 2c.2; 1.1 and 2c. 17 and 2e.3; 1.1 and 15 2c. 17 and 2e.4:1.1 and 2c.l7 and 2e.l0; 1.12 and 2c.8 and 2e.2; 1.12 and 2c.8 and 2e.3; 1.12 and 2c.8 and 2e.4; 1.12 and 2c.8 and 2e,10; 1.12 and 2c.9 and 2e.2; 1.12 and 2c.9 and 2e.3; 1.12 and 2c.9 and 2e.4; 1.12 and 2c.9 and 2e.l0; 1.12 and 2c. 10 and 2e.2; 1.12 and 2c. 10 and 2e.3; 1.12 and 2c. 10 and 2e.4; 1.12 and 2c. 10 and 2e.lQ; 1.12 and 2c. 11 and 2c.2; 1.12 and 2c. 11 and 2c.3; 1.12 and 2c.ll and 2c.4:1.12 and 2c. 11 and 2c. 10.1.12 and 20 2c. 17 and 2e.2:1.12 and 2c. 17 and 2e.3:1.12 and 2c. 17 and 2e.4:1.12 and 2c.l7 and 2e.l0; in each case 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.

Particularly preferred examples of medicament combinations of the above-mentioned group J are selected from the group comprising the following combinations: compounds LI and 2d.l and 2c.2; 1.1 and 2d.l and 2e.3; 1.1 and 2d.l and 2e.4: 1.1 and 2d.l and 2e.l0; 1.1 and 2d.4 and 2e.2:1.1 mid 2d.4 and 2e.3:1.1 and 2d.4 and 2e.4; 1.1 and 2d.4 and 2e.l0:1.1 and 2d.5 and 2e.2; 1.1 and 2d.5 and 2e.3; 1.1 and 2d.5 and 2e.4; 30 LI and 2d.5 and 2e.l0; 1.1 and 2d.8 and 2e.2; 1.1 and 2d.8 and 2e.3; 1.1 and 2d.8 and 2e.4:1.1 and 2d.8 and 2e.l0; 1.12 and 2d.l and 2e.2:1.12 and 2d.l and 2e.3; 1.12 and 2d.l and 2c.4; 1.12 and 2d.l and 2e.l0: 1.12 and 2d.4 and 2e.2; 1.12 and 2d.4 and 2e.3; 1.12 and 2d.4 and 2e.4; 1.12 and 2d.4 and 2e.l0; 1.12 and 2d.5 and 2e.2:1.12 and 2d.5 and 2c.3; 1.12 and 2d.5 and 2e.4; 1.12 and 2d.5 and 2c. 10; 1.12 and 2d.8 and 2e.2; 1.12 35 and 2d.8 and 2e.3; 1.12 and 2d.8 and 2c.4; 1.12 and 2d.8 and 2e.l0, in each case optionally 57 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.

Of outstanding importance according to the invention are all those medicament combinations disclosed within the scope of the present invention which contain the compounds of formula 1 in the form of the R-enantiomers thereof.

Unless otherwise stated, the alkyl groups are straight-chained or branched alkyl groups 10 having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases the abbreviations Me, Et, Prop or Bu are used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and «o-propyl. butyl includes /.so-butyl, s<?c.butyl 15 and tert.-butyl, etc.

Unless otherwise stated, the cycloalkyl groups are alicyclic groups with 3 to 6 carbon atoms. They are the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups . Cyclopropyl is particularly important within the scope of the present invention .

Unless otherwise stated, the alkylene groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms . Examples include: methylene, ethylene, propylene or butylene.

Unless otherwise stated, the alkylene-halogen groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably disubstituted, by a halogen . Accordingly, unless otherwise stated, alkylene-OH-groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a hydroxy.

Unless otherwise stated, the term alkyloxy groups denotes branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom . Examples include: methyloxy, ethyloxy, propyloxy or butyloxy. In some cases the abbreviations MeO, EtO, PropO or BuO may be used to denote the methyloxy, ethyloxy, propyloxy or butyloxy 35 groups. Unless otherwise stated, the definitions propyloxy and butyloxy include all the 58 possible isomeric forms of the groups in question. Thus, for example, propyloxy includes /z-propyloxy and z.vo-propyloxy, butyloxy includes j'so-butyloxy, sec.butyloxy and tert-butyloxy, etc. In some cases the term alkoxy may be used instead of alkyloxy within the scope of the present invention. The groups methyloxy, ethyloxy, propyloxy or butyloxy 5 may therefore also be referred to by the names methoxy, ethoxy, propoxy or butoxy.

Unless otherwise stated, the term alkylene-alkyloxy refers to branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group.

Unless otherwise stated, the term -O-CO-alkyl groups refers to branched and unbranched aikyl groups with 1 to 4 carbon atoms which are linked by an ester group. The alkyl groups are attached directly to the carbonyl carbon of the ester group. The term -O-CO-alkyl-halogen should be understood analogously. The group -O-CO-CF3 denotes trifluoroacetate.

Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.

Within the scope of the present invention by a pharmaceutical combination of components 1 and 2 is meant the joint administration of both active substances in a single preparation or formulation or the separate administration of the two active substances in separate formulations. If the active substances 1 and 2 are administered in separate formulations, 25 this separate administration may be done simultaneously or at different times, i.e. successively.

In one aspect the present invention relates to the above-mentioned medicament combinations which contain in addition to therapeutically effective amounts of 1. and 2 a 30 pharmaceutically acceptable carrier. In one aspect the present invention relates to the above-mentioned pharmaceutical compositions which do not contain contain a pharmaceutically acceptable carrier in addition to therapeutically effective amounts of 1 and 2 .

The present invention also relates to the use of therapeutically effective amounts of the 59 active substances 1 for preparing a pharmaceutical composition also containing one or more, preferably one active substance 2 for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic 5 heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation.

In a preferred aspect the present invention relates to the use of therapeutically effective 10 amounts of the active substance 1 for preparing a pharmaceutical composition also containing one or more, preferably one, active substance 2 for the treatment of respiratory complaints selected from the group comprising obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, 15 bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.

Preferably the medicament combinations according to the invention are used as specified above for preparing a pharmaceutical composition for the treatment of obstructive 20 pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD.

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD (chronic obstructive pulmonary disease) or a 1-proteinase inhibitor deficiency.

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances, such as asbestosis or silicosis, and restriction caused by lung 35 tumours, such as for example lymphangiosis carcinomatosa, bronchoal vcolar carcinoma 60 and lymphomas.

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases 5 selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation-induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses, such as for example Boeck's disease, 10 idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis.

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of bronchitis, such as for example bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of bronchiectasis.

It is also preferable to use the medicament combinations according to the invention for 25 preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome).

It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary oedema, for 30 example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.

It is particularly preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of asthma or COPD. Also of particular 35 importance is the above-mentioned use of medicament combinations according to the 61 invention for preparing a pharmaceutical composition for once-a-day treatment of inflammatory and obstructive respiratory complaints, particularly for the once-a-day treatment of asthma or COPD.

The present invention also relates to the use of therapeutically effective amounts of an active substance of formula 1 in combination with therapeutically effective amounts of active substance 2 for preparing a pharmaceutical composition for the treatment of one of the above-mentioned diseases.

The present invention also relates to a process for treating one of the above-mentioned diseases, which is characterised in that therapeutically effective amounts of active substance of formula 1 are administered in combination with therapeutically effective amounts of active substance 2.

Within the scope of the medicament combinations according to the invention, for example, 0.1 -1000jig of a compound of formula 1 may be administered per single dose. Preferably, 1 -500 jj.g, particularly preferably 3 -100 p-g of the compound of formula 1 are administered per single dose, while a dosage range of from 5 - 75 (ig, preferably from 7 -50 jj.g is preferred according to the invention. Particularly preferably, the pharmaceutical 20 compositions according to the invention are administered in an amount such that 9-40 [ig, particularly preferably 11 - 30jig, more preferably 12 - 25 (xg of the compound of formula 1 are administered per single dose . For example, and without restricting the present invention thereto, 5 fig, 7.5(jg, 10(ig, 12.5jig, 15jig, 17.5|ug, 20pg, 22.5|j.g, 25^g, 27.5^g, 30^ig, 32.5p.g, 35pg, 37.5p,g, 40|ig, 42.5^g, 45^g, 47.5^ig, 50jig, 52.5^g, 55^ig, 57.5p.g; 25 60}ig, 62.5|jg, 65jig, 67.5|xg, 70p.g, 72.5^g or 75p.g of a compound of formula 1 may be administered per single dose.

The above-mentioned dosages relate to the compounds of formula 1 in the form of their free bases. If the compounds of formula 1 are administered in the form of their 30 pharmaceutically acceptable acid addition salts, the skilled man can easily calculate the corresponding dosage ranges for the acid addition salts from the dosage ranges specified above, taking into account the molecular weight of the acids used. Particularly preferably, the compounds of formula 1 are administered in the above-mentioned dosage ranges in the form of the enantiomerically pure compounds, particularly preferably in the form of the R-35 enantiomers thereof. 62 If the compounds of formula 1 are administered in conjunction with an anticholinergic 2a, the amount of anticholinergic used will fluctuate considerably depending on the choice of active substance.

Without restricting the invention thereto, in the case of tiotropium 2a.l' amounts of anticholinergic f2a.l') may be administered such that each single dose contains 0.1 - 80pg, preferably 0.5 - 60 pig, particularly preferably about 1 - 50jig of 2a.l'. For example and without restricting the present invention thereto, 2.5jag, 5jig, lOf-tg, 18|ig, 20jag, 36jig or 10 40(ig 2a.l' may be administered per single dose. The corresponding amount of salt 2a.l or of any hydrate or solvate used in each case can easily be calculated by the skilled man, depending on the choice of anion. If for example tiotropium bromide is used as the preferred tiotropium salt 2a.l according to the invention, the amounts of the active substance 2a.l' administered per single dose as specified by way of example hereinbefore 15 correspond to the following amounts of 2a.l administered per single dose: 3 jig, 6fig, 12pig, 21.7j.ig, 24.1 jig, 43.3 jig and 48.1 jig 2a.l. In the case of tiotropium 2a.l' the dosages specified above are preferably administered once or twice a day, while administration once a day is particularly preferred according to the invention .

Without restricting the invention thereto, in the case of the cation 2a.2' amounts of anticholinergic (2a.2r) may be administered such that each single dose contains 1 - 500pig, preferably 5 -300 jig, particularly preferably 15-200 lie 2a.2'. For example and without restricting the present invention thereto, 15jig, 20jig, 25 jig, 30jig, 35jig, 40pig, 45 jig, 50|ig, 55jig, 60jig, 65pig, 70jig, 75p.g, 80pg, 85|ig, 90pig, 95pig, lOOpig, 105p.g, llOjig, 115pig, 25 120 pig, 125(ig, 130pig, 135pig, 140pig, 145pig, 150pig, 155(ig, 160jig, 165pig, 170(ig, 175(ig, 180pig, 185pig, 190pig, 195jig or 200pig of 2a.2' may be administered per single dose. The corresponding amount of salt 2a.2 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on the choice of anion. In the case of oxitropium 2a.2' the dosages specified above are preferably administered one to 30 four times a day, while administration two to three times a day is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cation 2a.3' amounts of anticholinergic (2a.3r) may be administered such that each single dose contains 1 - 500jig, 35 preferably 5 - 300 pig, particularly preferably 15-200 jig 2a.3'. For example and without WO 2005/102349 63 PCT/EP2005/004073 restricting the present invention thereto, 15pig, 20pig, 25 pig, 30pig, 35 fag, 40pig, 45 pig, 50pig, 55pig, 60pig, 65jig, 70pig, 75jig, 80pig, 85pig, 90pig, 95pig, lOOpig, 105pig, llOfig, 115pig, 120 pig, 125 pig, 130pig, 135pig, 140pig, 145pig, 150jig, 155pig, 160pig, 165pig, 170pig, 175pig, 180pig, 185pig, 190pig, 195pig or 200iigof 2a.3' may be administered per single 5 dose. The corresponding amount of salt 2a.3 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on the choice of anion. In the case of flutropium 2a.3' the dosages specified above are preferably administered one to four times a day, while administration two to three times a day is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cation 2a.4' amounts of anticholinergic (2a.4') may be administered such that each single dose contains 1 - 500pig, preferably 5 - 300 pig, particularly preferably 20-200 pig 2a.4'. For example and without restricting the present invention thereto, 20pig, 25pig, 30pig, 35pig, 40pig, 45pig, 50pig, 55pig, 15 60jig, 65pig, 70pig, 75pig, 80pig, 85pig, 90pig, 95pig, lOOpig, 105pig, llOpig, 115pig, 120pig, 125 pig, 130pig, 135pig, 140pig, 145pig, 150pig, 155pig, 160pig, 165pig, 170pig, 175pig, 180pig, 185pig, 190pig, 195pig or 200pig of 2a.4' maybe administered per single dose . The corresponding amount of salt 2a.4 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on the choice of anion. In the case of 20 ipratropium 2a.4' the dosages specified above are preferably administered one to four times a day, while administration two to three times a day, more preferably three times a day, is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cation 2a.5' amounts of 25 anticholinergic (2a.5') may be administered such that each single dose contains 1 - 500pig, preferably 5-300 pig, particularly preferably 15-200 pig . For example and without restricting the present invention thereto, 15pig, 20pig, 25pig, 30pig, 35pig, 40pig, 45pig, 50pig, 55pig, 60pig, 65pig, 70pig, 75pig, 80pig, 85pig, 90pig, 95pig, lOOpig, 105pig, llOpig, 115pig, 120pig, 125pig, 130pig, 135 pig, 140pig, 145pig, 150pig, 155pig, 160pig, 165pig, 170jig, 30 175pig, 180pig, 185pig, 190pig, 195pig or 200pig of 2a.5' may be administered per single dose . The corresponding amount of salt 2a.5 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on the choice of anion. In the case of glycopyrronium 2a.5' the dosages specified above are preferably administered one to four times a day, while administration two to three times a day is particularly preferred 35 according to the invention.

WO 2005/102349 64 PCT/EP2005/004073 Without restricting the invention thereto, in the case of the cation 2a.6* amounts of anticholinergic (2a.6') may be administered such that each single dose contains 1000 -6500jig, preferably 2000 - 6000jig, particularly preferably 3000 - 5500pig, particularly 5 preferably 4000 - SOOOjig 2a.6' . For example and without restricting the present invention thereto, 3500pig, 3750pig, 4000(ig, 4250pig, 4500pig, 4750pig, or 5000pig of 2a.6' may be administered per single dose. The corresponding amount of salt 2a.6 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on the choice of anion. In the case of trospiums 2a.6' the dosages specified above are 10 preferably administered one to four times a day, while administration two to three times a day is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cation 2a.7' amounts of anticholinergic (2a.7') may be administered such that each single dose contains 50 -15 1OOOpig, preferably 100 - 800jig, particularly preferably 200 - 700pig, particularly preferably 300 - 600pig 2a.7'. For example and without restricting the present invention thereto, 300pig, 350pig, 400pig, 450pig, 500pig, 550pig, or 600pig of 2a.7* may be administered per single dose. The corresponding amount of salt 2a.7 used in each case or of any hydrate or solvate used can easily be calculated by the skilled man, depending on 20 the choice of anion. In the case of the cation 2a.7' the dosages specified above are preferably administered one to three times a day, while administration once or twice a day, more preferably once a day, is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cations 2a.9' and 2a.l0', 25 amounts of anticholinergic (2a.9T or 2a.l0') may he administered such that each single dose contains 1 - 500pig, preferably 5 - 300 jag, particularly preferably 15-200 lie 2a.9' or 2a.l0'. For example and without restricting the present invention thereto, 15pig, 20jig, 25pig, 30pig, 35pig, 40pig, 45pig, 50ptg, 55pig, 60pig, 65pig, 70pig, 75ptg, 80fig, 85pig, 90pig, 95pig, lOOpig, 105pig, llOpig, 115pig, 120 pig, 125pig, 130pig, 135pig, 140pig, 145pig, 150pig, 30 155pig, 160pig, 165pig, 170pig, 175pig, 180pig, 185pig, 190pig, 195ueor 200ug of 2a.9' or 2a.l0' may be administered per single dose. The corresponding amount of salt 2a.9' or 2a.l0' or of any hydrate or solvate used in each case can easily be calculated by the skilled man, depending on the choice of anion. In the case of the cations 2a.9' or 2a.l0' the dosages specified above are preferably administered one to three times a day, while 65 administration once or twice a day, more preferably once a day, is particularly preferred according to the invention.

Without restricting the invention thereto, in the case of the cations 2a.11' to 2a.l3' 5 amounts of anticholinergic (2a.ll1, 2a.l2' or 2a.l3') may be administered such that each single dose contains 1 - 500pig, preferably 5 - 300 pig, particularly preferably 10-200 pig 2a.ll', 2a.l2' or 2a.l3'. For example and without restricting the present invention thereto, lOpig, 15jxg, 20pig, 25pig, 30pig, 35pig, 40pig, 45pig, 50pig, 55pig, 60pig, 65pig, 70pig, 75pig, 80pig, 85pig, 90pig, 95pig, lOOpig, 105pig, llOpig, 115pig, 120pig, 125pig, 130pxg, 135pig, 10 140pig, 145pig, 150pig, 155pig, 160pig, 165pig, 170pig, 175pig, 180pig, 185pig, 190pig, 195pig or 200pig of 2a.ll'. 2a.l2' or. 2a. 13' may be administered per single dose . The corresponding amount of salt 2a.ll. 2a,12 or 2a.l3 or of any hydrate or solvate used in each case can easily be calculated by the skilled man, depending on the choice of anion. In the case of the cations 2a.ll, 2a.l2 or 2a.l3 the dosages specified above are preferably 15 administered one to three times a day, while administration once or twice a day, more preferably once a day, is particularly preferred according to the invention.

If the compounds of formula 1 are administered in combination with a PDE IV-inhibitor 2b , preferably about 1 - 10000 pig 2b are administered per single dose. Preferably, 20 amounts of 2b are administered such that each single dose contains 10 - 5000pig, preferably 50 - 2500 pig, particularly preferably 100-1000 pig of 2b . For example and without restricting the present invention thereto, lOOpig, 115pig, 120pig, 125pig, 130pig, 135pig, 140 pig, 145 pig, 150pig, 155pig, 160pig, 165ng, 170pig, 175pig, 180pig, 185pig, 190pig, 195pig, 200pig, 205pig, 210pig, 215pig, 220pig, 225pig, 230pig, 235pig, 240pig, 25 245pig, 250pig, 255pig, 260pig, 265pig, 270pig, 275pig, 280pig, 285pig, 290pig, 295pig, 300pig, 305pig, 310pig, 315pig, 320pig, 325pig, 330pig, 335pig, 340pig, 345pig, 350ptg, 355pig, 360pig, 365pig, 370pig, 375pig, 380pig, 385ptg, 390pig, 395pig, 400pig, 405pig, 410pig, 415pig, 420pig, 425pig, 430pig, 435pig, 440pig, 445pig, 450pig, 455pig, 460pig, 465pig, 470pig, 475pig, 480pig, 485pig, 490pig, 495pig, 500pig, 505pig, 510pig, 515pig, 30 520pig, 525pig, 530pig, 535pig, 540pig, 545pig, 550pig, 555ptg, 560pig, 565pig, 570pig, 575pig, 580pig, 585pig, 590pig, 595pig, 600pig, 605pig, 610pig, 615pig, 620pig, 625pig, 630pig, 635pig, 640pig, 645pig, 650pig, 655pig, 660pig, 665pig, 670pig, 675pig, 680pig, 685pig, 690pig, 695pig, 700pig, 705pig, 710pig, 715pig, 720pig, 725pig, 730pig, 735pig, 740pig, 745pig, 750pig, 755pig, 760pig, 765pig, 770pig, 775pig, 780pig, 785pig, 790pig, 35 795pig, 800pig, 805pig, SlOpig, 815pig, 820pig, 825pig, 830pig, 835pig, 840pig, 845pig, 66 850jig, 855jig, 860jig, 865jig, 870jig, 875jig, 880jig, 885jig, 890jig, 895jig, 900^g, 905jig, 910jig, 915jag, 920jig, 925jig, 930ng, 935jig, 940jig, 945^g, 950jig, 955pg, 960jig, 965jig, 970jig, 975jig, 980jig, 985jig, 990jig, 995jag or lOOOjig of 2b may be administered per single dose. In the event that acid addition salts of 2b are used, the 5 corresponding amount of salt used can easily be calculated by the skilled man from the values given hereinbefore, depending on the choice of acid.

If the compounds of formula 1 are administered in combination with a steroid 2c , preferably about 1 - 10000 jig of 2c are administered per single dose . Preferably, amouts 10 of 2c are administered such that each single dose contains 5 - 5000jig, preferably 5 - 2500 jig, particularly preferably 10-1000 Jig of 2c . For example and without restricting the present invention thereto, lOjig, 15jig, 20jig, 25jig, 30jj,g, 35jig, 40jig, 45jig, 50jig, 55jig, 60jig, 65jig, 70jig, 75jig, 80jig, 85^ig, 90jig, 95|ig, lOOjig, 115jig, 120jig, 125jig, 130^g, 135jj.g, 140 jig, 145 jig, 150jig, 155jig, 160jig, 165jig, 170jig, 175^g, 180jig, 185jig, 15 190jig, 195jig, 200jig, 205jig, 210jig, 215jig, 220jig, 225^g, 230^ig, 235jig, 240jig, 245jig, 250jig, 255jig, 260jig, 265jig, 270^g, 275jig, 280jig, 285jig, 290jig, 295jig, 300jig, 305jig, 310jig, 315jig, 320jig, 325^ig, 330jig, 335jig, 340jig, 345jig, 350jig, 355jig, 360jig, 365jig, 370jig, 375^g, 380jig, 385jig, 390jig, 395jig, 400jig, 405jig, 410jig, 415jig, 420jig, 425jig, 430jig, 435jig, 440jig, 445pg, 450jig, 455jig, 460fig, 20 465jig, 470pg, 475jig, 480jig, 485jig, 490jig, 495jig, 500jig, 505^g, 510jig, 515jig, 520jig, 525jig, 530jig, 535jig, 540jig, 545jig, 550jig, 555jig, 560^, 565jig, 570jig, 575jig, 580jig, 585|ig, 590jig, 595jig, 600jig, 605jig, 610jig, 615jig, 620jig, 625^g, 630jig, 635jig, 640jig, 645^g, 650jig, 655jig, 660jig, 665jig, 670jig, 675jig, 680}ig, 685jig, 690jig, 695jig, 700jig, 705jig, 710|ig, 715jig, 720jig, 725jig, 730jig, 735jig, 25 740jig, 745ju,g, 750jig, 755jig, 760jig, 765jig, 770jig, 775pg, 780jig, 785jig, 790jig, 795jig, 800jig, 805jig, 810jig, 815jig, 820jig, 825jig, 830jig, 835jig, 840jig, 845jig, 850jig, 855|ig, 860jig, 865jig, 870jig, 875jig, 880jig, 885jig, 890jig, 895jig, 900jig, 905jig, 910jig, 915jig, 920jig, 925jig, 930|ug, 935^ig, 940jig, 945jig, 950jig, 955jig, 960jig, 965pg, 970jig, 975jig, 980jig, 985jig, 990jig, 995jig or lOOOjig of 2c may be 30 administered per single dose. In the event that salts or derivatives of 2c are used, the corresponding amount of salt/derivative used can easily be calculated by the skilled man from the values given hereinbefore, depending on the choice of salt/derivative.

If the compounds of formula 1 are administered in combination with an LTD4-antagonist 35 2d , preferably about 0,01 - 500 mg 2d are administered per single dose . Preferably, WO 2005/102349 67 PCT/EP2005/004073 amounts of 2d are administered such that each single dose contains 0.1 - 250mg, preferably 0.5 - 100 mg, particularly preferably 1-50 mg of 2d . For example and without restricting the present invention thereto, lmg, 2.5mg, 5mg, 5.5mg, 7 mg, 7, 5mg, lOmg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 5 42,5mg, 45mg, 47.5mg or 50mg of 2d may be administered per single dose. In the event that acid addition salts, salts or derivatives of 2d are used, the corresponding amount of salt/derivative used can easily be calculated by the skilled man from the values given hereinbefore, depending on the choice of salt/derivative.

If the compounds of formula 1 are administered in combination with an EGFR-inhibitor 2e, preferably about 100 -15000 (ig of 2e are administered per single dose. Preferably, amounts of 2e are administered such that each single dose contains 500 - 10000p.g, preferably 750 - 8000 jig, particularly preferably 1000-7000 (ig of 2e . For example and without restricting the present invention thereto, lOOOjig, 1150(ig, 1200(ig, 1250jig, 15 1300jig, 1350(ig, 1400pg, 1450(ig, 1500(j.g, 1550^ig, 1600^g, 1650jig, 1700jag, 1750p.g, 1800fig, 1850^ig, 1900^ig, 1950(ig, 2000p.g, 2050^ig, 2100(ig, 2150(ig, 2200|ig, 2250p.g, 2300fj.g, 2350p,g, 2400^g, 2450|ig, 2500p.g, 2550(ig, 2600^g, 2650(ig, 2V00|ug, 2750ng, 2800(ig, 2850jj.g, 2900pg, 2950p.g, 3000(ig, 3050(ig, 3100jig, 3150ng, 3200p.g, 3250(ig, 3300pg, 3350jig, 3400pg, 3450p,g, 3500p.g, 3550ng, 3600(ig, 3650(ig, 3700p.g, 3750(ig, 20 3800pg, 3850fig, 3900jig, 3950p.g, 4000pig, 4050(ig, 4100(j.g, 4150p.g, 4200|jg, 4250jig, 4300^g, 4350jig, 4400jig, 4450^g, 4500pig, 4550(ig, 4600p.g, 4650(xg, 4700jig, 4750jig, 4800jig, 4850^ig, 4900fig, 4950jig, SOOO^ig, 5050jig, 5100p.g, 5150jig, 5200jig, 5250jig, 5300jig, 5350(ig, 5400jig, 5450fig, 5500^g, 5550^ig, 5600p.g, 5650jig, 5700jig, 5750^g, 5800(ig, 5850|ig, 5900jig, 5950^g, 6000p.g, 6050(ig, 6100jig, 6150jig, 6200|ig, 6250jig, 25 6300jwg, 6350|ig, 6400(ig, 6450fig, 6500p.g, 6550^ig, 6600[ig, 6650pg, 6700jug, 6750|wg, 6800(ig, 6850jig, 6900(ig, 6950(ig, or 7000jig of 2e may be administered per single dose. In the event that acid addition salts of 2e are used, the corresponding amount of the salt used can easily be calculated by the skilled man from the values given hereinbefore, depending on the choice of acid.

The two active substance components 1 and 2 may be administered - together or separately - in each case by inhalation or by oral, parenteral or some other route, in known manner, in substantially conventional formulations such as for example plain or coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, powders and solutions, using inert, 68 PCT7EP2005/004073 non-toxic, pharmaceutically suitable carriers or solvents.

Suitable preparations for administering the compounds of formula 1 and 2 include tablets, capsules, suppositories, solutions, powders, etc. The proportion of pharmaceutically active 5 compound or compounds should be in the range from 0.05 to 90 % by weight, preferably 0.1 to 50 % by weight of the total composition. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium 10 stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the 15 tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium 25 carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of 30 ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

WO 2005/102349 69 PCT/EP2005/004073 Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this 5 purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders 10 (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions 20 the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

Preferably, even when the two components l_and 2 are administered separately, at least 25 component 1 is administered by inhalation. If component 1 is administered by inhalation, when the two active substances are taken separately, component 2 may also be administered for example by oral or parenteral route using formulations conventional in the art such as plain or coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, powders and solutions, using inert, non-toxic, pharmaceutically suitable carriers or 30 solvents.

Preferably, however, the medicament combinations according to the invention are administered by inhalation by means of a single preparation containing both active substances J. and 2 or by means of separate preparations each containing only one of the 35 active substances 1 and 2, suitable for administration by inhalation. 70 Inhalable preparations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable solutions, Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active 5 substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations, 10 These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification, A) Inhalable powder containing the combinations of active substances according to the invention: The inhalable powders according to the invention may contain 1 and 2 either on their own 15 or in admixture with suitable physiologically acceptable excipients. If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. 20 dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose, trehalose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.

Within the scope of the inhalable powders according to the invention the excipients have a 25 maximum average particle size of up to 250pm, preferably between 10 and 150jj.ni, most preferably between 15 and 80 (am. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9(im to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, 30 micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 10pm, more preferably from 1 to 6pm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and finally mixing the ingredients together are known from the prior art. The inhalable 71 powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 or 2.

The inhalable powders according to the invention may be administered using inhalers 5 known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. The inhalable powders according to the invention which contain 1 and 2 10 optionally in conjunction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler® or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as 15 described, for example, in WO 94/28958.

A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.

This inhaler (Handihaler®) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there 20 are air inlet ports and which is provided with a screen 5 secured by a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut, and air through-holes 13 for adjusting the flow resistance, If the inhalable powders according to the invention are to be packaged in capsules, in accordance with the preferred method of administration described above, the capsules should preferably contain from 1 to 30 mg each. According to the invention they contain either together or separately the dosages per single dose specified for 1 and 2 hereinbefore.

B) Propellant gas-driven inhalation aerosols containing the combinations of active substances according to the invention: 72 Inhalation aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both 5 dissolved, both dispersed or only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, 10 cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TGI 1, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.

The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.

The inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.

If the active substances 1 and/or 2 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10 |im, preferably from 0.1 to 6 ]um, more preferably from 1 to 5 (.im.

The propellant-driven inhalation aerosols according to the invention mentioned above may 30 be administered using inhalers known in the art (MDIs — metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellaat-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-35 containing aerosols described above according to the invention.

WO 2005/102349 73 PCT/EP2005/004073 The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and 5 methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.

C) Propellant-free inhalable solutions or suspensions containing the combinations of active substances 1 and 2 according to the invention: Propellant-free inhalable solutions according to the invention contain for example aqueous or alcoholic, preferably ethanolic solvents, possibly ethanolic solvents in admixture with aqueous solvents. In the case of aqueous/ethanolic solvent mixtures the relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is 15 made up of water. The solutions or suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include 20 ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the 25 above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH, According to the invention, the addition of edetic acid (EDTA) or one of the known salts 30 thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than lOOmg/lOOml, preferably less than 50mg/100 ml, more preferably less than 20mg/ 100 ml. Generally, 74 inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100ml are preferred, Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention. Preferred co-solvents are those which contain hydroxyl groups 5 or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in 10 the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, 15 polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, for example, provided 20 that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.

Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in 25 the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/l 00ml.

Preferred formulations contain, in addition to the solvent water and the combination of active substances 1 and 2, only benzalkonium chloride and sodium edetate. In another 30 preferred embodiment, no sodium edetate is present. 75 Received at IPONZ on 2 July 2010 The propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred 5 inhalers are those in which a quantity of less than 100|llL, preferably less than 50|llL, more preferably between 10 and 30jaL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20jam, preferably less than lOjim, such that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.

An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are known by the name Respimat®.

The above-mentioned examples of the active substances 2 are known in the art. The 15 compounds of formula 1 by contrast are not known in the art.

The examples of synthesis described hereinafter serve to illustrate possible methods of synthesising the new compounds of formula 1. However, they are intended only as examples of procedures as mi illustration of the invention without restricting the invention to the subject-matter described by way of example. In addition, although some of these 20 Examples may fall outside the scope of the claims of this application, the Examples help to illustrate the invention and are therefore retained for clarity and completeness.

Example 1.1: 6-hvdroxv-8-{l-hvdroxv-2-12-('4-methoxv-phenvlVl,l-dimethvl-ethylaminol -ethylj-4H-benzo [ 1.41 oxazin-3-one a) 8-12-U.l-dimethyl-2-('4-methoxv-phenvlVethylaminol-1-hydroxy-ethvli-6-benzyloxv-4H-benzoll.41oxazin-3-one 7.5 g (6-benzyloxy-4H-benzo[l,4]oxazin-3-one)-glyoxalhydrate are added at 70°C to a 30 solution of 3.6 g l,l-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL ethanol and the OH 76 mixture is stirred for 15 minutes. Then 1 g sodium borohydride is added within 30 minutes at 10 to 20°C. It is stirred for one hour, combined with 10 mL acetone and stirred for a further 30 minutes. The reaction mixture is diluted with 150 mL ethylacetate, washed with water, dried with sodium sulphate and evaporated down. The residue is dissolved in 50 mL 5 methanol and 100 mL ethyl acetate and acidified with conc. hydrochloric acid. After the addition of 100 mL diethyl ether the product crystallises out. The crystals are filtered off, washed and recrystallised from 50 mL ethanol.

Yield: 7 g (68%; hydrochloride); m.p. = 232-234°C, b1 8-12-11.1 -dimethyl-2-f 4-metli oxv-phen vlV ethvl aminol -1 -hydroxy- ethvl I -6-hydroxv-4H-benzon .41 oxazin-3-one 6.8 g of the benzyl compound obtained previously are hydrogenated in 125 mL methanol with the addition of 1 g palladium on charcoal (5%) at ambient temperature and normal pressure. The catalyst is filtered off and the filtrate freed from solvent. After 15 recrystallisation of the residue from 50 mL acetone and some water a solid is obtained which is filtered off and washed.

Yield: 5.0 g (89 %; hydrochloride); m.p. = 155-160°C.

The (R)- and (S)-enantiomers of Example 1.1 maybe obtained from the racemate, for 20 example, by chiral HPLC (e.g. column: Chirobiotic T made by Messrs Astec, 250 x 22.1 mm, 5 (Am). Methanol with 0.05 % triethylamine and 0.05% acetic acid may be used as the mobile phase. The retention times of the R- or S-enantiomer are between 35 and 65 min depending on the flow, while the R-enantiomer is eluted first. Of outstanding importance according to the invention is the R-enantiomer of Example 1.1.

Example 1.2; 6-hvdroxy-8- f 1 -hvdroxy-2-r2-(4-t>henoxvethvl-acetateVl .1 -dimethyl- cthvlamino "{-ethyl I -4H-benzo [" 1.4]oxazin-3-one OH O a-) 8-l2-[T.l-dimethvl-2-(4-phenoxvethyl-acetateVethvlamino]-1 -hydroxy-ethyl)-6-benz vloxv-4H-benzo \ 1,4loxazin-3 -one 77 Analogously to the method described in Example 1.1a) the title compound is obtained from 15 g (6-benzyloxy-4H-benzo[ 1,4] oxazin-3-one)-glyoxalhydrate and 11.8 g l,l-dimethyl-2-(4-phenoxyethyl-acetate)-ethylamine hydrochloride.

Yield: 16.5 g (69%, hydrochloride); m.p. = 212-214°C. b) 8 - (2-1" 1.1 -dimethyl-2-( 4-phenoxvethyl-acetate)-eth vl am ino]-1 -hydroxy-ethyl 1 -6-hydroxy-4H-ben2of 1,41 oxazin-3 -one 8 g of the benzylalcohol obtained previously are dissolved in 100 mL ethanol, 100 mL methanol and 10 mL water and hydrogenated in the presence of 1 g palladium on charcoal 10 (5%). After the absorption of the theoretically calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated down. The product that crystallises out on distillation of the solvent is suction filtered and washed.

Yield: 5.5 g (81%; hydrochloride); m.p. = 137-140°C.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.3: 6-hydroxv-8-11 -hvdroxv-2-[2-f4-phenoxv-acetic acid)-1.1-dimethyl-ethylamino]-ethyl) -4H-benzo[ 1 -4]oxa7:in-3-one 11 g of 8-{2-[l,l-dimethyl-2-(4-phenoxyethyl-acetate)-ethylamino]-l-hydroxy-ethyl}-6-benzyloxy-4H-benzo[l ,4]oxazin-3-one hydrochloride (Example 4a) are dissolved in 125 25 mL methanol and hydrogenated in the presence of 1 g palladium on charcoal (5%). After the absorption of the theoretically calculated amount of hydrogen the catalyst is filtered off,.2.6 g sodium hydroxide dissolved in 20 mL water are added to the filtrate. The mixture is refluxed for 30 minutes, the methanol is distilled off and 10 mL water, 20 mL n-butanol and 3.9 mL acetic acid. The solid precipitated is suction filtered and washed with diethyl °^V^vO OH OH ether.

Yield: 7 g (87%). The hydrochloride is obtained by recrystallisation from 0.5 molar hydrochloric acid. M.p. = 152°C. 78 The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.4: 8-{2-[L1 -dimethyl-2-f2.4.6-trimethvlphenyl Vethvlamino]-1 -hydroxy-ethyl !• -6-hydroxv-4II-benzor 1.41oxazin-3-onc a) 1 -(6-benzvloxv-4H-benzo[T .41oxazin-3-oneV2-r 1.1 -dimethvl-2-(2 A6-trimethvlphenvlV ethvlimino] -ethanone 7.2 g (6-benzyloxy-4H-benzo[ 1,4] oxazin-3-one)-glyoxalhydrate and 3.6 g l,l-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamine are heated to 70°C for one hour in 100 mL ethanol. After cooling the precipitated crystals are filtered off and washed with ethanol and diethyl 15 ether. Yield: 8.6 g (94%); m.p. = 175°C. b) 8-(2-fl.l-dimethvl-2-(2A6-trimethvh)henvl)-ethvlamino1-l-hydroxy-ethyl I-6-benzvlox v-4H-benzo F1-4]oxayin-3 -one 8.6 g of the Schiff base obtained according to the prescribed method 1.4a) are dissolved in 20 100 mL ethanol and 20 mL THF, combined with 0.7 g sodium borohydride within 30 min at 10-20°C and stirred for one hour. After the addition of 10 mL acetone the mixture is stirred for 30 minutes and then diluted with ethyl acetate and water. The product that crystallises out during acidification with conc. hydrochloric acid is filtered off and washed. Yield: 7.4 g (80%, hydrochloride); m.p. = 235°C (decomposition). c) 8-(2-11.1 -dimethvl-2-(2.4.6-trimethylphenvl)-ethvlamino]-1 -hydroxy-ethvll-6-hydroxy-4H-benzoF 1,4]oxazin-3-one 7.4 g of the benzyl compound obtained in Step b) are hydrogenated in 125 mL methanol with the addition of 1 g palladium on charcoal (5%) at ambient temperature and normal 30 pressure. Then the catalyst is filtered off and the filtrate evaporated down. The product that crystallises out on the addition of acetone is suction filtered and washed with acetone and diethyl ether. Yield: 5 g (78%, hydrochloride); m.p. 160°C (decomposition).

OH 79 The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.5: 6-hydroxy-8-(l-hydroxv-2-l"2-(4-hydroxv-phenvlVl.1 -dimethyl-ethylamino]-ethyl|-4H-benzor 1.4] oxazin-3-one a) 8-12-PU -dimethyl-2-f 4-hvdroxv-phenylVethylaminol -1 -hydroxy-ethvl 1 -6-benzyloxy-4H-benzoj" 1.4] oxazin-3-one The title compound is prepared from 10 g (6-benzyloxy-4H-benzo[ 1,4] oxazin-3-one)-glyoxalhydrate and 4.6 g 1,1 -dimethyl-2-(4-hydroxy-phenyl)-ethylaminc analogously to the procedure laid down for Example 1.1a).

Yield: 9.0 g (64%, hydrochloride); m.p. = 255-258°C. b) 8-1211.1 -dimethvl-2-(4-hydroxv-phenvn-eth vlam i nol -1 -hydroxy-ethyl I -6-hvdroxv-4H-benzof 1.4]oxazin-3-one .7 g of the coupling product obtained previously are hydrogenated in the presence of 0.6 g 20 palladium on charcoal (5%) in 100 mL methanol. After the absorption of the theoretically calculated amount of hydrogen the catalyst is filtered off and the filtrate freed from solvent. The residue is dissolved in ethanol with heating and then combined with diethyl ether. The product precipitated is suction filtered and recrystallised once from water.

Yield: 3.6 g (72%, hydrochloride); m.p. = 159-162°C.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

°'V/Vv'0 OH OH Example 1.6: 6-hvdroxy-8-f l-hvdroxv-2-r2-(4-isopropvl-phenyl> ethylaminol-ethvl I -4H-benzof 1.41oxazin-3 -one WO 2005/102349 80 PCT/EP2005/004073 a) 1 -f4-isopropyl-phenvO-2-methvl-propan-2-ol The reaction of a Grignard compound, prepared from 20 g (119 mmol) 5 4-isopropylbenzyl chloride, with 11.4 ml (155 mmol) acetone yields the target compound as a colourless oil. Yield: 13.0 g (57%); mass spectrometry: [M+H]+ =193. b) N-r2-(4-isopropvl-phenvlVl .1 -dimethyl-ethyl!-acetamide A Ritter reaction is carried out with 10.2 g (53 mmol) l-(4-isopropyl-phenyl)-2-methyl-10 propan-2-ol in the manner described for Example 1,7b). The reaction mixture is poured onto ice water and made alkaline with sodium hydroxide solution, during which time a solid is precipitated. This is suction filtered and dried.

Yield: 9.90 g (80%); mass spectrometry: [M+H]+ - 234. c) 2-(4-isopropyl-phenvlVl .1-dimethyl-ethvlamine Reaction of 9.80 g (42 mmol) N-[2-(4-isopropyl-phenyl)-l,l-dimethyl-ethyl]-acetamide analogously to the procedure laid down for Example 1.7c).

Yield: 7.00 g (71%, hydrochloride); m.p. 202-206°C. d) 6-benzvloxy-8- f 1 -hydroxv-2-f2-(4-isopropyl-phenvlV 1.1 -dimeth yl-cth vlaminol-eth vl 1 -4H~benzo[ 1,41oxazin-3-one 2.18 g (6.1 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acctyl)-4H-benzo[l,4]oxazin-3-one and 1.1 g (5.8 mmol) 2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamine are stirred for one hour at 50-80°C in 40 mL ethanol. After cooling to ambient temperature 0.24 g (6.3 mmol) 25 sodium borohydride are added. The mixture is stirred for one hour, diluted with 5 mL acetone and stirred for a further 30 minutes. The reaction mixture is acidified with hydrochloric acid, combined with 100 mL water and 80 mL ethyl acetate and made alkaline with ammonia. The organic phase is separated off, dried with sodium sulphate and freed from solvent. The residue is dissolved in 20 mL ethyl acetate and 10 mL water, 30 acidified with conc. hydrochloric acid and diluted with diethyl ether. After the addition of a crystallisation aid the precipitated solid is suction filtered and washed. White solid. 81 Yield: 1.7 g (52 %, hydrochloride); m.p. 220-222°C. e) 6-hydrox y-8-{1 -hvdroxv-2-\2-( 4-isoprop vl-phen yl)-1.1 dimethyl-ethyl amino] -ethyl 1 -4H-benzol" 1,4]oxazin-3-one 5 1.6 g (3.0 mmol) 6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]~ethyl}-4H-benzo[l,4]oxazin-3-one are dissolved in methanol and hydrogenated with palladium on charcoal as catalyst at normal pressure and ambient temperature. The catalyst is suction filtered, the solvent is distilled off and the residue is recrystallised from isopropanol. White solid.

Yield: 1.1 g (85%, hydrochloride); m.p. 248-250°C; mass spectrometry: [M i ll]1" = 399.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.7: 8-(2-[2-(4-ethvl-phcnviyil-dimethvl-etbv1arninol-l-hvdroxy-ethvH-6-hydroxv-4H-benzor 1,41 oxa^in-3-one ( 20 a) 1 -f4-ethvl-phenvlV2-methvl-prot)an-2-ol 14.8 g (90 mmol) l-(4-ethyl~phenyl)-propan-2-one, dissolved in diethyl ether, are added dropwise to 39 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether, while being cooled with the ice bath, such that the temperature does not exceed 30°C. After the addition has ended the reaction mixture is left to reflux for 1.5 hours and then 25 hydrolysed with 10% ammonium chloride solution. After separation of the organic phase the aqueous phase is extracted with diethyl ether. The combined ether phases are washed with water, dried with sodium sulphate and evaporated down. The oil thus obtained is further reacted directly. Yield: 15.5 g (90%).

OH b) N-r2-(4-ethyl-phenvlVl .1-dimethyl-ethyl]-acetamide 82 6.2 mL conc. sulphuric acid are added dropwise within 15 minutes to 15.5 g (87 mmol) 1-(4-ethyl-phenyl)-2-methyl-propan-2-ol in 4.8 mL (91 mmol) acetonitrile and 15 mL glacial acetic acid, while the temperature rises to 65°C. Then the mixture is stirred for one hour, diluted with ice water and made alkaline with conc. sodium hydroxide solution. After 5 further stirring for 30 minutes the precipitated solid is suction filtered and washed with water. The crude product is dissolved in ethyl acetate, dried with sodium sulphate and evaporated down. The oil remaining is combined with petroleum ether, during which time a solid is precipitated, which is filtered off and dried. Yield: 16.3 g (85%); m.p. 90-92°C. c) 2-(4-ethyl-phenvf)-i ,1 -dimethyl-ethylamine 16.3 g (74 mmol) N-[2-(4-ethyl-phenyl)-l,l-dimethyl-ethyl]-acetamide and 8.0 g potassiumhydroxid are through 15 hours in 60 mL ethyleneglycol at reflux temperature heated. The reaction mixture is combined with ice water and extracted three times with 15 diethyl ether. The combined organic phases are washed with water, dried with sodium sulphate and freed from solvent To produce the hydrochlorides, the crude product is dissolved in acetonitrile and successively combined with ethereal hydrochloric acid and diethyl ether. The solid precipitated is suction filtered and dried. Yield: 11.0 g (69%, hydrochloride); m.p. 165-167°C. d) 6-benzvloxv-8-(2-\2-(4-ethvl--phenyl)-1,1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvlI-4H-benzol 1.41oxazin-3-one The target compound is prepared analogously to the procedure laid down for Example 1.6d) from 2.14 g (6.0 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-25 benzo[l ,4]oxazin-3-one and 1.0 g (5.6 mmol) 2-(4-ethyl-phenyl)-l ,1-dimethyl-ethylamine. White solid. Yield: 1.7 g (54%, hydrochloride); m.p. 210-214°C. e) 8-(2-r2-(4-ethvl-phenvF)-l. 1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvl 1 -6-hvdroxy-4H-benzor 1.41oxazin-3-one 3 0 The hydrogenolysis of 1.45 g (2.75 mmol) 6-benzyloxy-8- {2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]~l-hydroxy-ethyl}-4H~benzo[l,4]oxazin-3-one according to the prescribed method for Example 1.6e) yields the target compound in the form of a white solid. Yield: 1.07 g (92%; hydrochloride); m.p. 266-269°C; mass spectrometry: [M+H]+ = 385. 83 The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1,8: 8- (2-12~f4-fluoro-3-mcthyl-phenvlV 1.1 -dimethyl-ethylamino"!-1 -hydroxy-ethvn-6-hydroxv-4H-benzo[ 1.4"loxazin-3-one a) 1 -fluoro-2-methvl-4-(2-methvl-propenyl)-benzene 100 mL of a 0.5 molar solution of 4-fluoro-3-methyl-phenylmagnesium bromide in THF are combined within 30 minutes with 4.7 mL (50 mmol) isopropylaldehyde, while the temperature rises to 45°C. The mixture is stirred for 30 minutes, refluxed for 1 hour and then hydrolysed with 10% ammonium chloride solution. After separation of the organic phase the mixture is extracted with diethyl ether. The organic phases are combined, dried and evaporated down. The alcohol thus obtained is dissolved in 100 mL toluene, combined with 1 g p-toluenesulphonic acid monohydrate and refluxed for three hours using the water separator. The reaction mixture is poured onto water and made alkaline with conc. sodium hydroxide solution. After separation of the organic phase the latter is washed with water, dried with sodium sulphate and freed from solvent. Fractional distillation of the residue yields the product in the form of a colourless liquid (b.p. 80-85°C/10 mbar).

Yield: 4.1 g (50%). b) N-r2-('4-fluoro-3-methvl-phenvl')-l. 1 -dimethyl-cthvll-formamide 4.9 mL conc. sulphuric acid are added dropwise at 5-15°C to 1.5 g (31 mmol) sodium cyanide in 5 mL glacial acetic acid. Then the mixture is combined with 3.9 g (24 mmol) 1-fIuoro-2-methyl-4-(2-methyl-propenyl)-benzene, dissolved in 10 mL glacial acetic acid, and stirred for 1 hour at 50-60°C. The reaction mixture is diluted with ice water, made alkaline with conc. sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried with sodium sulphate and freed from the solvent in vacuo. The light yellow oil thus obtained is further reacted directly. Yield: 4.3 g (87%). 84 c) 2-r4-fluoro-3-methvl-phenylVl ,1 -dimethvl-ethvl amine 4.3 g (20.6 mmol) N-[2-(4-fluoro-3-methyl-phenyl)-l,l-dimethyl-ethyl]-forrn amide, 20 mL conc. hydrochloric acid and 20 mL water are refluxed for 2 hours. The reaction mixture is diluted with water, made alkaline with conc. sodium hydroxide solution and 5 extracted with dichloromethane. The organic phases are dried with sodium sulphate and evaporated down. The residue is dissolved in ethyl acetate, combined with ethereal hydrochloric acid and cooled. The crystals precipitated are suction filtered and washed with diethyl ether and dried. White solid.

Yield: 3.9 g (87%, hydrochloride); m.p. 196-198°C. d) 6-benzvlox v-8-12-1"2-( 4-fluoro-3-methyl-t>henvl) -1.1 -dimethvl-ethvlaminol -1 -hvdroxv- 1.10 g (3.1 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one and 0.50 g (2.8 mmol) 2-(4-fhioro-3-methyl-phenyl)-l,l-dimethyl-ethylamine are reacted 15 and worked up analogously to the procedure laid down for Example 1.6d). White solid. Yield: 0.75 g (47%, hydrochloride); m.p. 228-230°C. c) 8-(2-[2-(4-fluoro-3-methvl-phenvlV1.1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvl 1-6-hvdroxv-4H-benzor 1.41 oxazin-3-one 20 The hydrogenation of 0.70 g (1.4 mmol) 6-benzyloxy-8- {2-[2-(4-fluoro-3-methyl-phenyl)-1 ,l-dimethyl-ethylarnino]-l-hydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one yields the target compound as a white solid.

Yield: 0.50 g (87%, hydrochloride); m.p. 278-280°C; mass spectroscopy: [M+H]+ = 389.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.9: 8- (2-r2-(4-fluoro-2-methvl-phenvD-1.1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvl } -6-hydroxy-4H-benzor 1.41oxazin-3-one /r i ethyl }-4H-benzol"l .41oxazin-3-one OH 85 a) l-f4-fluoro-2-methvl-phenvD-2-methvl-propvl acetate 500 mL of a 0.5 molar solution of 4-fluoro-6-methylphenylmagnesium bromide and 23.2 mL (260 mmol) isopropylaldehyde are reacted analogously to Example 1.8a). After 5 hydrolysis with 10% ammonium chloride solution the aqueous phase is separated off and extracted with diethyl ether. The combined organic phases are dried with sodium sulphate and evaporated down. The alcohol thus obtained is then dissolved in 50 mL acetic anhydride, combined with 1 mL conc. sulphuric acid and stirred for three hours at reflux temperature. Then the reaction mixture is poured onto water, stirred for a further hour and 10 made alkaline. It is extracted with dichloroinethane, the organic phases are dried with sodium sulphate and the solvents are distilled off. Fractional distillation of the residue yields the product in the form of a colourless liquid (b.p. 105-110°C/8 mbar).

Yield: 29.0 g (52%). b) N-l 2-f4-fluoro-2-methvl--phenyI )-1.1 -dimethyl-ethvll-formamide 29.0 g (130 mmol) l-(4-fluoro-2-methyl-phenyl)-2-methyl-propyl acetate are reacted and worked up analogously to the procedure laid down for Example 1.8b).

Yellow oil. Yield: 27.0 g (99%). c) 2-(4-fluoro-2-methvl-phenvl)-1.1 -dimethyl-ethvlamine In order to prepare the amine 27.0 g (130 mmol) N-[2-(4-fluoro-2-methyl-phenyl)-l,l-dimethyl-ethyl]-formamide are reacted as described in the procedure laid down for Example 1.8c). White solid. Yield: 15.5 g (55%, hydrochloride); m.p. 277-280°C. d) 6-benzvloxv-8-f2-r2-r4-fiuoro-2-methvl-phenylVlJ-dimethvl-ethvlamino"|-l-hydroxy-ethvll-4H-benzol" 1.41 oxazin-3-one Prepared analogously to the procedure laid down for Example 1.6d) from 0.95 g (2.66 mmol)benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one and 0.43 g (2.37 mmol) 2-(4-fhioro-2-methyl-phenyl)-l,l-dimethyl-ethylamine.

Yield: 0.75 g (55%, hydrochloride); m.p. 233-236°C. e) 8- (2-[2-(4-fluoro-2-methvl-phenvlV1.1 -dimethyl -ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzof 1.4] oxazin-3-one 86 The debenzylation of 0.70 g (1.36 mmol) 6-benzyloxy-8-{2-[2-[4-fluoro-2-methyl-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-4H-benzo[ 1,4]oxazin-3-one yields the target compound in the form of a white solid.

Yield: 0.50 g (87%, hydrochloride); m.p. 278-280°C; mass spectroscopy: [M+H|+ - 389.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.10: 8- (2-r2-f2.4-difluoro-phenyl)-l, 1 -dimethvl-etlwlaminol-1 -hvdroxv-ethvl 1 -10 6-hvdroxv-4H-benzor 1.4] oxazin-3-one a) 1 -(2.4-difhioro-phenvlV2-methvl-propan-2-ol 11.0 mL acetone, diluted with 50 mL diethyl ether, are added drop wise within 20 minutes to a solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromide in diethyl ether. Then the mixture is stirred for 1.5 hours at reflux temperature and then hydrolysed with 10% ammonium chloride solution. The ether phase is separated off, washed with water, dried with sodium sulphate and evaporated down. The fractional distillation of the 20 residues yields the alcohol as a colourless liquid (b.p. 70-73°C/ 2 mmbar).

Yield: 20.0 g (86%). b) N-r2-r2.4-difluoro-phenyl]-l .1 -dimethyl-ethvn-formamide Ritter reaction with 20 g (110 mmol) l-(2,4-difluoro-phenyl)-2-methyl-propan-2-ol 25 according to the process described for Example 1.8b). Yellow oil. Yield: 22.0 g (94%). c) 2-(2,4-difluoro-phenvl)-l. 1 -dimethyl-ethvlamine Reaction of 22.0 g (100 mmol) N-[2-(2,4-difluoro-phenyl]-l,l-dimethyl-ethyl]-formamide analogously to the procedure laid down for Example 1.8c).

Yield: 16.0 g (72%, hydrochloride); m.p. 201-203°C.

O OH 87 d) 6-benzyloxy-8- (2-f2-(2,4-difluoro-phcnyl)-1.1 -dimethyl-ethyl amino] -1 -hydroxy-ethyl 1 -4H-benzoi" 1.41oxazin-3-one Reaction of 0.89 g (2.49 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[ 1,4]oxazin-3-one and 0.40 g (2.16 mmol) 2-(2,4-difluoro-phenyl)-l,l-dimethyl-ethyl amine in the manner described for Example 1.6d).

Yield: 0.80 g (62%, hydrochloride); m.p. 245-247°C. e) 8-l2-r2-f2.4-difluoro-phenvl)-1.1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvli-6-hydroxv-4H-benzof 1.41oxazin-3-one The hydrogenolysis of 0.70 g (1.35 mmol) 6-benzyloxy-8-{2-[2-(2,4-difluoro-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl}-4H-benzo[l,4]oxazin-3-one yields the target compound as a white solid.

Yield: 0.48 g (83%, hydrochloride); m.p. 279-280°C; mass spectroscopy: [M+H]+ = 393.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.11: 8-(2-f2-(3.5-difluoro-phenvl)-1.1 -dimethvl-ethvlaminol-1 -hydro xy-cthvH-6-hydroxv-4H-benzor 1.41 oxazin-3-one a) 1 -f3,5-difluoro-phenyl)-2-methvl-propan-2-ol The target compound is obtained by reacting a Grignard compound, prepared from 25.0 g (121 mmol) 3,5-difluorobenzylbromide, with 12.6 mL (171 mmol) acetone. Yellow oil. Yield: 13.5 g (60%). h) 2-f3,5-difluoro-phenvlV 1.1 -dimethyl-ethvlamine The Ritter reaction of 5.5 g (29.5 mmol) l-(3,5-difluoro-phenyl)-2-methyl-propan-2-ol and 1.8 g sodium cyanide yields 7.0 g form amide, which is treated with hydrochloric acid in order to cleave the formyl group. Light yellow oil. Yield: 4.6 g (75%).

OH F 88 c) 6-benz yloxy-8-|2~|2-f3,5-difluoro-phenvl)-1.1 -dimethvl-ethvlaminol-1 -hydroxy-ethylI-4H-henzor 1,41oxazin-3-one Prepared from 1.73 g (4.84 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-5 benzo[l ,4]oxazin-3-one and 0.80 g (4.32 mmol) 2-(3,5 -difluoro-phenyl)-1,1 -dim ethyl -ethylamine in the conventional manner.

Yield: 1.50 g (58 %, hydrochloride); m.p. 240-244°C. dl8-(2-[2-(3.5-difluoro-phenvl)-1.1 -dimethvl-ethvlaminol -1 -hvdroxv-ethvl I -6-hvdroxv-10 4H-benzo[ 1.41 oxazin-3 -one Hydrogenolysis of 1.30 g (2.43 mmol) 6-benzyloxy-8-{2-[2-(3,5-difluoro-phenyI)-l,l-dimethyl-ethylamino]-1 -hydroxy-ethyl}-411-benzo[ 1,4] oxazin-3-one yields the target compound as a white solid.

Yield: 0.90 g (86%, hydrochloride); m.p. 150-158°C; mass spectroscopy: [M+H]+ = 393.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.12: 8-(2-|2-(4-ethoxy-t>henylV 1,1 -dimeth vl-ethvlaminol-1 -hvdroxv-ethvl}-6-20 hvdroxy-4H-benzo[ 1.4]oxayin-3-one a) benzyl [2-(4-ethoxv-phenvl)-lJ-dimethvl-ethyl]-carbamate .0 g (50 mmol) benzyl [2-(4-hydroxy-phenyl)-i,1 -dimethyl-ethyl]-carbamate are stirred with 7.5 mL (92 mmol) ethyl iodide and 21 g (150 mmol) potassium carbonate for 10 hours at 90-100°C. The reaction mixture is combined with ethyl acetate, washed twice with water and dried with sodium sulphate. After the solvents have been distilled off 30 a yellow oil remains (15.0 g, 92%), which is further reacted directly.

OH 89 b) 2-(4-ethoxv-phenvD-l ,1-dimethyl-ethvlamine A solution of 15.0 g (49 mmol) benzyl [2-(4-ethoxy-phenyl)-l,l-dimethyl-ethyl]~ carbamate in 100 mL glacial acetic acid is combined with 2 g palladium on charcoal (10%) and then hydrogenated at 5 bar and 40 to 50°C. The catalyst is filtered off and the filtrate 5 freed from solvent. The residue is dissolved in a little water, made alkaline with conc. sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with water, dried with sodium sulphate and evaporated down. The crude product is dissolved in acetonitrile and acidified with ethereal hydrochloric acid. The solid precipitated after the addition of diethyl ether is suction filtered and dried.

Yield: 8.8 g (hydrochloride, 84%); m.p. 198-200°C. c) 6-benzvlox v-8-l2-r2-r4-etboxv-pheny1t-l .1 -dimeth vl-ethvlarm'no]-l-hydroxy-ethyl}-4H-benzor 1.4] oxazin-3-one 2.14 g (6.0 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one 15 and 1.0 g (5.2 mmol) 2-(4-ethoxy-phenyl)-l ,1 -dimethyl-ethylamine are stirred in 40 mL ethanol for one hour at 50-80°C. After cooling to ambient temperature 0.23 g (6.0 mmol) sodium borohydride are added and the mixture is stirred for a further hour. The reaction mixture is combined with 5 ml acetone, stirred for 30 minutes, acidified with glacial acetic acid and evaporated down. The residue is combined with water and ethyl acetate and made 20 alkaline. The organic phase is separated off, washed with water, dried with sodium sulphate and freed from solvent in vacuo. The residue is dissolved again in ethyl acetate and water, combined with conc. hydrochloric acid and diluted with diethyl ether. The solid precipitated is suction filtered and washed with diethyl ether. White solid.

Yield: 2.0 g (61%, hydrochloride); m.p. 214-216°C. d) 8- !2-[2-(4-ethoxv-r>h en yl)-1.1 -dimethvl-ethvlaminol -1 -hydroxv-ethvll -6-hvdroxy-4H-benzo)" 1,41 oxazin-3-one 1.5 g (2.8 mmol) 6-benzyloxy-8-{2-[2-(4-ethoxy-phenyl)-l,l-dimethyl-ethylamino]-l~ hydroxy-ethyl}-4H-benzo[l,4]oxazin-3-one in 80 mL methanol are hydrogenated with 250 30 mg palladium on charcoal (10 %) as catalyst at ambient temperature and normal pressure. The catalyst is suction filtered and the filtrate is evaporated down. The residue is dissolved in 5 mL ethanol by heating, inoculated and diluted with ethyl acetate. The solid precipitated is filtered off and washed. White solid.

Yield 1.0 g (83%, hydrochloride); m.p. 232-235°C; mass spectrometry: [M+H]+ = 401. 90 The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.13: 8-(2-r2-(3.5-dimethyl-phenyft-l -1-dimethvl-ethvlaminol-l-hvdroxy-5 ethvl l-6-hydroxv-4H-benzo[ 1,41 oxazin-3-one a) l-(3.5-dimethyl-phenylV2-methvl-propanol-2-ol 10 Obtained from the reaction of ethyl (3,5-dimethyl-phenyl)-acetate with methylmagnesium b) 2-(3,5-dimethvl-phenyD-1.1 -dimethyl-ethvlamine By reacting 6.00 g (34 mmol) l-(3,5-dimethyl-phenyl)-2-methyl-propanol-2-ol and 2.00 g 15 (41 mmol) sodium cyanide in a Ritter reaction, 2.40 g 2-(3,5-dimethyl-phenyl)-l,l- dimethyl-ethylformamide (35% yield) are obtained. To liberate the amine the foraiamide (2.40 g, 11.7 mmol) is treated with hydrochloric acid. The preparation and working up are carried out analogously to the procedure laid down for Example 1.8c). Oil.

Yield: 1.70 g (82%); mass spectroscopy: [M+H]+ = 178. c) 6-benzvlox v-8 -(2-|2-(3,5 -dimethyl-phenyD-1.1 -dimethvl-ethvlaminol -1 -hvdroxy-ethvH-4H-benzo| 1,41oxazin-3-one Prepared analogously to the procedure laid down for Example 1.6d) from 1.47 g (4.1 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3~one and 0.65 g 25 (3.7 mmol) 2-(3,5-dimethyl-phenyI)-l,l-dimethyl-ethylamine.

Yield: 1.1 g (51 %, hydrochloride); m.p. 220-222°C. d') 8 - (2-|"2-(3.5 -di meth vl-phenvlV1.1 -dimethyl-ethylamino"] -1 -hvdroxv-ethvl 1 -6-hydroxy-4H-benzo|T .4] oxazin-3-one 30 The target compound was obtained after hydrogenolysis of 0.90 g (1.71 mmol) 6- benzyloxy-8- {2-[2-(3,5-dimethyl-phenyl)-l, 1 -dimethyl-ethylamino]-! -hydroxy-ethyl }-4H- OH bromide.

WO 2005/102349 91 PCT/EP2005/004073 benzo[l,4]oxazin-3-one and recrystallisation of the crude product from isopropanol. White solid.

Yield: 0.50 g (69%, hydrochloride); m.p. 235-238°C; mass spectroscopy: [M+H]+ = 385.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.14: 4-(4-(2-|"2-hydroxv-2-(6-hvdroxy-3-oxo-3.4-dihydro-2H-benzo! 1.41oxazin-8-vl)-ethvlaminol-2-methyl-propvl) -phenoxvVbutvric acid °H H HN a! ethvl 4-r4-f2-amino-2-methyl-propvD-phenoxvl-butvrate 4.5 g (15.0 mmol) benzyl [2-(4-hydroxy-phenyl)-l,l-dimethyl-ethyl]-carbamate, 2.3 mL 15 (16.0 mmol) ethyl 4-bromo-butyrate, 2.3 g (16.6 mmol) potassium carbonate and 0.3 g (1.8 mmol) potassium iodide in 20 mL dimethylformamide are heated to 120°C for 13 h. The reaction mixture is diluted with ethyl acetate and washed successively with water, sodium hydroxide solution and water. The organic phase is dried with sodium sulphate and evaporated down. The residue is purified by chromatography (eluant: cyclohexane/ethyl 20 acetate ~ 9:1). 5.0 g of a yellow oil is isolated, which is dissolved in 50 mL acetic acid and hydrogenated with 1.0 g palladium on charcoal as catalyst at 40°C and 3 bar. The catalyst is filtered off and the filtrate is freed from solvent. The residue is dissolved in diethyl ether and combined with ethereal hydrochloric acid. The solid precipitated is suction filtered and dried. Yield: 2.9 g (66% over two steps, hydrochloride); m.p. = 103-105°C. b) ethvl 4-(4-(2-l 2-f6-benzvloxv-3-oxo-3.4-dihvdro-2H-benzor 1.41oxazin-8-vl)-2-hvdroxy- ethylamino! -2-mcthvl--propvl 1 -phenox vVbutvrate 1.20 g (3.36 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one and 0.90 g (3.22 mmol) ethyl 4-[4-(2-amino-2-methyl-propyl)-phenoxy]-butyrate are 30 reacted in the manner described for Example 1,6d). The crude product is dissolved in 10 mL ethyl acetate and 10 mL water and combined with oxalic acid with stirring. The 92 s'"" c ( ' solution is diluted with diethyl ether and the solid precipitated is suction filtered and washed with diethyl ether. Yield: 1.20 g (54%, oxalate); m.p. 223-227°C. c) 4-{ 4-12-f 2-f6-benzvloxy-3-oxo-3.4-dihydro-2II-benzor 1.4] oxazin-8-vl V2-hydroxy-ethvlammol-2-methyl-propvl) -phenoxvVbutvric acid A solution of 1.00 g (1.73 mmol) ethyl 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[ 1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-2-methyl-propyl}-phenoxy)-butyrate in 25 mL methanol is combined with 2.5 mL 1 N sodium hydroxide solution, refluxed for 30 minutes and then neutralised with 1 N hydrochloric acid. The solution is evaporated down and the oil remaining is dissolved in 5 mL n-butanol by heating. After the addition of a crystallisation aid a solid is precipitated, which is suction filtered and washed with acetone and diethyl ether. Yield: 0.75 g (79%); m.p. 216-218°C. d) 4-f4-(2-r2-hydroxv-2-f6-hydroxv-3-oxo-3,4-dihvdro-2H-bcnzo[' 1.41 oxazin-8-vlV eth ylaminol-2-methvl-propyl I -phenox vVbutyri c acid 0.70 g (1.28 mmol) 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)-2-hydroxy-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid are dissolved in 25 mL methanol and 2 mL acetic acid and hydrogenated in the presence of 150 mg palladium on charcoal (10%) at ambient temperature and normal pressure. The catalyst is filtered off and the filtrate is freed from solvent. The product is obtained by crystallisation from a methanol/acetone mixture.

Yield: 0.40 g (68%); m.p. 201-204°C; mass spectroscopy: [M+H]+ = 459.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.15: 8-(2-r2-(3,4-difhioro-phenvlM.l-dimethvl~ethvlamino1-l-hydroxy-ethyl}-6-hvdroxv-4H-benzo|" 1,41 oxazin-3-one OH 93 a) 1-G .4-di fl uoro-ph en yl) -2-m ethvl--prop an-2-ol A Grignard reagent is prepared from 23.0 g (111 mmol) 3,4-dilluorobcnzylbromide and is then reacted with 11.6 mL (158 mmol) acetone. Light yellow oil.

Yield: 9.7 g (47%); Rf value: 0.55 (ethyl acetate/petroleum ether = 1:3). b) N-[2-f3.4-difluoro-phenylVl 1 -dimethyl-ethyl ]-formamide The target compound is obtained by a Ritter reaction with 4.0 g (21.5 mmol) l-(3,4-difluoro-phenyl)-2-methyl-propan-2-ol. Light yellow oil.

Yield: 4.0 g (87%); mass spectrometry: [M+H]+ = 214. c) 2-C3.4-difluoro-phen vlV 1.1 -dimethyl-ethvlamine ^ 4.00 g (18.5 mmol) N-[2-(3,4-difluoro-phenyl)-l,l-dimethyl-ethyl]-formamide are dissolved in ethanol, combined with conc. hydrochloric acid and heated overnight at reflux temperature. The reaction solution is poured onto ice water, made alkaline with sodium 15 hydroxide and extracted with tert-butylmethylether. The organic phases are washed with water, dried with sodium sulphate and evaporated down. Yellow oil.

Yield: 3.2 g (92%); mass spectrometry: [M+H]+ = 186. d) 8-!2-|"2-(3.4-difluoro-phenvD-1.1 -dimethvl-ethvlamino]-1 -hvdroxv-ethvl) -6-hydroxy-20 4H-benzolT ,41oxazin-3-one 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-b enzo [1,4] oxazin-3-one and 185 mg (1 mmol) 2-(3,4-difluoro-phenyl)-1,1-dimeth yl-ethylamine are stirred for 30 minutes in 5 mL tetrahydrofuran at ambient temperature. The mixture is cooled to 0°C and I under an argon atmosphere 1.5 mL of a 2 molar solution of lithium borohydride in tetrahydrofuran is added dropwise thereto. The resulting mixture is stirred for 30 min at ambient temperature, combined with 10 mL dichloromethane and 3 mL water, stirred for a further hour and then filtered through Extrelut ®. The eluate containing the ethanolamine is freed from solvent. The residue is dissolved in methanol and hydrogenated with palladium on charcoal (10%) as catalyst at 2.5 bar and ambient temperature. Then the catalyst is 30 separated off and the crude product is purified by chromatography. White solid.

Yield: 31 mg (6%, trifluoroacetate); mass spectroscopy: [M+H]+ = 393.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art. 94 Example 1.16: 8-(2-f2-f2-cMoro-4-fluoro-phenvl")-1 .l-dimethvl-ethvlaminol-l-hvdroxv- ethvl I -6-hvdroxv-4H-benzo f 1,41oxazin-3 -one a) l-f2-chloro-4-fl uoro-phen vf)-2-methvl-propan-2-ol Prepared from 20 g (97 mmol) methyl (2-chloro-4-fIuoro-phenyl)-acetate and 98 mL of a 3 molar solution of methylmagnesium bromide analogously to the procedure laid down for Example 1.6a). b) N-r2-f2-chloro-4-fluoro-phenyiy 1.1-dimethvl-ethvll-formamide 7.5 g (37 mmol) l-(2-chloro-4-fluoro-phenyl)-2-mcthyl-propan-2-ol were reacted and worked up according to the procedure described for Example 1.8b), The oil thus obtained was chromatographed for further purification on a short silica gel column (petroleum ether/ethyl acetate = 9:1). Oil. Yield: 7.4 g (87%); mass spectrometry: [M+H]+ = 230/232. c) 2-(2-chloro-4-fluoro-phenvlM .1-dimethyl-ethvlamine Reaction of 7.4 g (32 mmol) N-[2-(2-chloro-4-fluoro-phcnyl)-l, 1 -dimethyl-ethyl]-formamide as described in the procedure laid down for Example 1,15c). Brown oil.

Yield: 5.14 g (79%); mass spectrometry: [M+H]+ = 202/204. d) 8- (2-r2-(2-chloro-4-fluoro-phenvl>-1.1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvlI -6-hvdroxv-4H-benzor 1,41oxazin-3-one 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one and 202 mg (1 mmol) 2-(2-chloro-4-fluoro-phenyl)-l,l-dimethyl-ethylamine are reacted 25 with lithium borohydride analogously to the procedure laid down for Example 1.8d). To debenzylate the ethanolamine thus obtained it is dissolved in 3 mL dichloromethane and cooled to -78°C. At this temperature 2 ml of a 1 molar solution of boron tribromide in dichloromethane is added dropwise and the mixture is slowly left: to come up to ambient temperature. The reaction mixture is combined with 10 mL dichloromethane and 3 mL 30 water and filtered through Extrelut®. The eluate is freed from solvent and the residue is purified by chromatography. White solid.

OH 95 Yield: 70 mg (13%, trifluoroacetate); mass spectroscopy: [M+H]+ = 409/11.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.17: 8-12-r2-(4-chloro-phenyl> 1.1 -dimethvl-ethvlaminol -1 -hydroxy-ethyl I -6-hvdroxv-4H-benzo|" 1.41 oxazin-3-one A solution of 300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[l ,4]oxazin-3-one and 200 mg (1.09 mmol) 2-(4-chloro-phenyl)-l,l-dimethyl-ethylamine in 3 mL ethanol was combined with molecular sieve and stirred for 90 minutes at 80°C. The mixture was allowed to cool to ambient temperature, 35 mg (0.91 mmol) of 15 sodium borohydride were added and the resulting mixture was stirred for 1 hour. Then the reaction mixture was combined with sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases were freed from solvent and the residue was chromatographed (eluant: hexane/ethyl acetate/methanol), thus yielding 305 mg ethanolamine. This was dissolved in 3 mL dichloromethane and cooled to -78°C under an / 20 argon atmosphere. 3 mL of a 1 molar solution of boron tribromide in dichloromethane were added dropwise and the mixture was stirred for one hour at -78°C and 20 minutes at ambient temperature. Then at -78°C 3 mL conc. ammonia solution were added dropwise and the mixture was stirred for 5 minutes. The reaction mixture was combined with ammonium chloride solution and extracted with ethyl acetate. The combined organic 25 phases were evaporated down and the residue was chromatographed for further purification (silica gel; eluant: dichloromethane/methanol + 1% ammonia). Beige solid: 93 mg (26%); mass spectrometry: [M+H]+ = 391.

OH The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art. 96 Example 1.18: 8- {2-f2-(4-bromo-phenvl')-1.1 -dimethvl-ethvlaminol-1 -hydroxy-ethyl' -6- hydroxy-4H-benzo f 1.41 oxazin-3-one The preparation and debenzylation of the ethanolamine were carried out as described for Example 1.17 from 300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one and 250 mg (1.09) mmol) 2-(4-bromo-phenyl)-l,l-dimethyl-ethylamine. Beige solid. Yield: 54 mg (14%); mass spectrometry: [M+H]+ = 435,437.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

Example 1.19: 8- (2-F2-f4-fluoro-phenyP-1.1 -dimethvl-ethvlaminol-1 -hvdroxv-ethvl) -6-15 hvdroxy-4H-benzor 1.41 oxazin-3-one OH 300 mg (0.91 mmol) 6-benzyIoxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[l,4]oxazin-3-one 20 and 183 mg (1.09 mmol) 2-(4-fluoro-phenyl)-l ,1 -dimethyl-ethylamine were dissolved in 3 ml ethanol. Molecular sieve was added and the mixture was heated to 80°C for 30 minutes. After cooling to ambient temperature 35 mg (0.91 mmol) sodium borohydride were added. The mixture was stirred for 1 hour at ambient temperature ruhren, then sodium hydrogen carbonate solution was added to the reaction mixture and this was extracted with ethyl 25 acetate. The organic phases were evaporated down and the residue was chromatographed (eluant: hexane/ethyl acetate/methanol). The ethanolamine thus obtained (223 mg) was dissolved in methanol in order to cleave the benzyl protecting group and hydrogenated 97 with 150 rag palladium hydroxide as catalyst at ambient temperature and normal pressure. The catalyst was separated off by filtration through Celite®, the filtrate was freed from solvent and the residue was chromatographed (silica gel; eluant: dichloromethane/methanol). Beige solid.

Yield: 76 mg (22%); mass spectrometry: [M+H]+ = 375.

The (R)- and (S)-enantiomers of this embodiment may be obtained by separation of the racemate analogously to common methods known in the art.

The following compounds of formula 1 according to the invention may also be obtained ;1, analogously to the synthesis examples described hereinbefore: i Example 1.20: 8- {2-[2-(4-fluoro-3-methoxy-phenyl)-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4]oxazin-3-one; Example 1.21:8-{2- [2-(4-fluoro-2,6-dimethyl-phenyl)-1,1 -dimethyl-ethyl amino] -1 -hydroxy-ethyl} -6-hydroxy-4I I-benzo [ 1,4]oxazin-3-one; Example 1.22: 8-{2-[2-(4-chloro-2-methyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-20 ethyl} -6-hydroxy-4H-benzo[ 1,4]oxazin-3 -one; Example 1.23: 8- {2-[2-(4-chloro-3 -fluoro-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl } -6-hydroxy-4H-benzo [ 1,4] oxazin-3-one; (' ■ Example 1.24: 8-{2-[2-(4-chloro-2-fluoro-phenyl)-l,1 -dimethyl-ethylamino]-!-hydroxy-ethyl}-6-hydroxy-4H-benzo[l,4|oxazin-3-one; Example 1.25: 8-{2-[2-(3-chloro-4-fluoro-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4]oxazin-3 -one; Example 1.26: 8-{2-[2-(2,6-difluoro-4-methoxy-phenyl)-l,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one; Example 1.27: 8- {2-[2-(2.5-difluoro-4-methoxy-phenyl)-l, 1 -dimethyl-ethylamino]-1 -hydroxy-ethyl} -6-hydroxy-4H-benzo [ 1,4]oxazin-3 -one; 98 Example 1.28: 8- {2~[2-(4-fluoro-3,5-dimethyl-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4] oxazin-3-one; Example 1.29: 8-{2-[2-(3,5-dich.Ioro-phenyl)-l,l-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one; Example 1.30: 8- {2-[2-(4-chloro-3-methyl-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl } -6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one; Example 1.31: 8- {2-[2-(3,4.5-trifluoro-phenyl)-l ,1-dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one; Example 1.32: 8- {2-[2-(3 -methyl-phenyl)-1,1 -dimethyl-ethylamino]-l -hydroxy-ethyl} -6-15 hydroxy-4H-benz:o[l ,4]oxazin-3-one; Example 1.33: 8- {2-[2-(3,4-dichloro-phenyl)-1,1 -dimethyl-ethylamino] -1 -hydroxy-ethyl} -6-hydroxy-4H-benzo[ 1,4Joxazin-3-one.

NOW AMENDED

Claims (20)

1. What is claimed is Received at IPONZ on 2 July 2010 l.

1.5 A medicament combination which comprises k compound of general formula O OH and one or two compounds as another activeysub stance 2 selected from antichohnergics (2a) and steroids (2c); wherein any antichohnergic (2a) is sejfectdd from the group comprising tiotropium salts (2a.l), oxitropium salts (2a.2), flutrdpiimi salts (2a.3), ipratropium salts (2a.4), 10 glycopyrronium salts (2a.5), trosppm/alts (2a.6) and any steroid 2c is selected from tlte group comprising prednisolone (2c.l), prednisone (2c.2), butixocortpropionate (2a.3)/flunis oli de (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesomde/2c.8), fluticasone (2c.9), mometasone (2c.l0), ciclesonide (2c.ll), roflepomcW(2c.l2), dexamethasone (2c.l4), (S)-fluoromethyl 6 a, 9 a-15 difhioro-17a-[(2-furanylcstfbanyl)oxy]-l 1 p-hydroxy-16oc-methyl-3-oxo-androsta-l,4- diene-17p-carbothionate/2cn5), (S)-(2-oxo-tetrahydro-fLiran-3S-yl) 6ot,9a-difluoro-llp-hydroxy-16 a-me thyl - ox/-17a-propionyloxy-androsta-1,4-diene-17 (3 - c arbothi onat e (2c.l6) and etiprednqc-di/hloroacetate (2c.l7), optionally in the form of a racemate, enantiomer or diastdreamer thereof and optionally in the form of a salt or functional 20 derivative thereof/sowate and/or hydrate thereof.

2. A jfiedfcament combination according to claim 1, which contains a compound of general fonmifa L5 in the form of an individual optical isomer, mixture of the individual eaiamiomer or racemate.

3. / A medicament combination according to claim 1 or 2, which contains a compound' of general formula L5 in the form of an acid addition salt with a pnamiacolosically acceptable acid as well as optionally inthe form of a solvate and/or hydrat/ AS AMENDED 99 Received at IPONZ on 18 October 2010 What is claimed is 1A medicament combination which comprises a compound of general formula 1J. and one or two compounds as another active substance 2 selected from anticholinergics (2a) and steroids (2c); wherein any anticholinergic (2a) is selected from the group comprising tiotropium salts (2a.l), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), trospium salts (2a.6) and any steroid 2c is selected from the group comprising prednisolone (2c.l), prednisone (2c.2), butixocortpropionate (2c.3), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.l0), ciclesonide (2c.11), rofleponide (2c.l2), dexamethasone (2c 14. , (S)-fluoromethyl 6 a,9 a-difluoro- 17a- [(2-furanylcarbonyl)oxy] -lip -hydroxy- 16 a-methyl-3-oxo-androsta-l,4-diene-17p-carbothionate (2c.l5), (S)-(2-oxo-tetrahydro-furan-3S-yl) 6a,9a-difluoro-11 p-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-l,4-diene-17p-carbothionate (2c.l6) and etiprednol-dichloroacetate (2c 17. , optionally in the form of a racemate, enantiomer or diastereomer thereof and optionally in the form of a salt or functional derivative thereof, solvate and/or hydrate thereof. 2A medicament combination according to claim 1, which contains a compound of general formula 1.1 in the form of an individual optical isomer, mixture of the individual enantiomer or racemate. 3A medicament combination according to claim 1 or 2, which contains a compound of general formula 1A in the form of an acid addition salt with a pharmacologically acceptable acid as well as optionally in the form of a solvate and/or hydrate. OH 1.1 NOW AMENDED

4. A medicament combination according to any; am claims 1 to 3, which contains, in addition to a compound of general formula^ an anticholinergic (2a) as an additional active substance 2. Received at IPONZ on 2 July 2010 5

5. A medicament combination according/o apy one of claims 1 to 4, which contains in addition to a compound of general loom lya li a steroid (2c) as an additional active substance 2. j I

6. A medicament combination according tof any one of claims 1 to 3, which also 10 contains, in addition to a compound of Ibrvnuln 1.5, an anticholinergic (2a) and a steroid (2C) /

7. Use of a medicament combinaaioi/ according to any one of claims 1 to 6 for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive 15 respiratory complaints, for inhibiting /remature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart m atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume)/s well as for the treatment of skin irritations and inflammation. / / 20 / /

8. Use according tar claim 7, for preparing a pharmaceutical composition for the treatment of respiratory complaints selected from the group comprising obstructive pulmonary diseases Jf v/rious origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis 25 of various origins^ bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmo/ar/oedema.

9. Use /ccGfrding to claim 8, for preparing a pharmaceutical composition for the treatment m obstructive pulmonary diseases selected from among bronchial asthma, 30 paediatri/asinma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chroni/ obstructive pulmonary disease).

10. / Fse according to claim 9, for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD. 35 / / AS AMENDED im Received at IPONZ on 18 October 2010 4. A medicament combination according to any one of claims 1 to 3, which contains, in addition to a compound of general formula 1.1an anticholinergic (2a) as an additional active substance 2. 5. A medicament combination according to any one of claims 1 to 4, which contains in addition to a compound of general formula LI a steroid (2c) as an additional active substance 2. 6. A medicament combination according to any one of claims 1 to 3, which also contains, in addition to a compound of formula 1.1an anticholinergic (2a) and a steroid (2c). 7. Use of a medicament combination according to any one of claims 1 to 6 for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation. 8. Use according to claim 7, for preparing a pharmaceutical composition for the treatment of respiratory complaints selected from the group comprising 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. 9. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease). 10Use according to claim 9, for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD. 101 Received at IPONZ on 2 July 2010

11. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD or a 1-proteinase inhibitor deficiency. 5

12. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances including asbestosis or silicosis, and restriction caused by lung tumours including lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas. 10

13. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases selected from among pneumonia caused by infections including infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors including aspiration and left heart 15 insufficiency, radiation-induced pneumonitis or fibrosis, collagenoses including lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses including Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

14. Use according to claim 8, for preparing a pharmaceutical composition for the 20 treatment of cystic fibrosis or mucoviscidosis.

15. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of bronchitis including bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis. 25

16. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of bronchiectasis.

17. Use according to claim 8, for preparing a pharmaceutical composition for the 30 treatment of ARDS (adult respiratory distress syndrome).

18. Use according to claim 8, for preparing a pharmaceutical composition for the treatment of pulmonary oedema. 102 Received at IPONZ on 2 July 2010

19. Medicament combinations as defined in any one of claims 1 to 6 substantially as hereinbefore described.

20. A use as defined in any one of claims 7 to 18 substantially as hereinbefore 5 described.