DE102004019540A1 - Composition, useful for treatment of e.g. inflammatory and obstructive respiratory complaint, sinus rhythm in heart in atrioventricular block and circulatory shock, comprises 6-hydroxy-4H-benzo1,4oxazin-3-one derivatives and other actives - Google Patents

Abstract

A composition comprises at least one 6-hydroxy-4H-benzo[1,4]oxazin-3-one derivative and at least one other active substance. A composition comprises at least one 6-hydroxy-4H-benzo[1,4]oxazin-3-one compounds of formula (I) and at least one other active substance. n : 1 or 2; R 1 and R 2 : H, halo, 1-4C alkyl or -O-1-4C alkyl;and R 3 : 1-4C alkyl, OH, halo, -O-1-4C alkyl, -O-1-4C alkylene-COOH or -O-1-4C alkylene-CO-O-1-4C alkyl. [Image] ACTIVITY : Antiinflammatory; Respiratory-Gen.; Antiasthmatic; Dermatological; Immunosuppressive; Antiallergic; Cardiant; Vasotropic. MECHANISM OF ACTION : None given.

Description

worin die Reste R¹, R² und R³ die in den Ansprüchen und in der Beschreibung genannten Bedeutungen haben können, wenigstens einen weiteren Wirkstoff 2 enthalten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel.The present invention relates to novel drug combinations, in addition to one or more, preferably a compound of general formula 1

wherein the radicals R ¹ , R ² and R ³ may have the meanings mentioned in the claims and in the description, contain at least one further active compound 2, processes for their preparation and their use as medicaments.

Detailed description the invention

worin
n 1 oder 2, bevorzugt 1;
R¹ Wasserstoff, Halogen, C₁-C₄-Alkyl oder -O-C₁-C₄-Alkyl;
R² Wasserstoff, Halogen, C₁-C₄-Alkyl oder -O-C₁-C₄-Alkyl;
R³ C₁-C₄-Alkyl, OH, Halogen, -O-C₁-C₄-Alkyl, -O-C₁-C₄-Alkylen-COOH, -O-C₁-C₄-Alkylen-CO-O-C₁-C₄-Alkyl,
bedeuten, wenigstens einen weiteren Wirkstoff 2 enthalten.The present invention relates to drug combinations which, in addition to one or more, preferably a compound of general formula 1

wherein
n is 1 or 2, preferably 1;
R ^{1 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{2 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{3 is} C ₁ -C ₄ -alkyl, OH, halogen, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH, -OC ₁ -C ₄ -alkylene-CO-OC ₁ -C ₄ alkyl,
mean, at least one further active ingredient 2 included.

Prefers The present invention relates to drug combinations which in addition to one or more, preferably a compound of the formula 1 as another active ingredient 2 one or more compounds containing the selected are from the classes of anticholinergics (2a), PDEIV inhibitors (2b), steroids (2c), LTD4 antagonists (2d) and EGFR inhibitors (2e).

Preference is given to drug combinations which, in addition to one or more, preferably a compound of general formula 1, wherein
n is 1 or 2, preferably 1;
R ^{1 is} hydrogen, fluorine, chlorine, methyl or methoxy;
R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy;
R ^{3 is} C ₁ -C ₄ -alkyl, OH, fluorine, chlorine, bromine, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH, -OC ₁ -C ₄ -alkylene-CO-OC C ₁ -C ₄ -alkyl,
mean, at least one further active ingredient 2 included.

Also preferred are drug combinations which, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen or C ₁ -C ₄ -alkyl;
R ^{2 is} hydrogen or C ₁ -C ₄ -alkyl;
R ^{3 is} C ₁ -C ₄ -alkyl, OH, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH or -OC ₁ -C ₄ -alkylene-CO-OC ₁ -C ₄ -alkyl .
mean, at least one further active ingredient 2 included.

Also preferred are drug combinations which, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen, methyl or ethyl;
R ^{2 is} hydrogen, methyl or ethyl;
R ^{3 is} methyl, ethyl, OH, methoxy, ethoxy, -O-CH ₂ -COOH, -O-CH ₂ -COOMethyl or -O-CH ₂ -COOethyl,
mean, at least one further active ingredient 2 included.

Also preferred are drug combinations which, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen or methyl;
R ^{2 is} hydrogen or methyl;
R ^{3 is} methyl, OH, methoxy, -O-CH ₂ -COOH or -O-CH ₂ -COOethyl,
mean, at least one further active ingredient 2 included.

Preference according to the invention is given to medicament combinations which, in addition to one or more, preferably one compound of the general formula 1, in which
R ^{3 is} methoxy, ethoxy, -O-CH ₂ -COOH, -O-CH ₂ -COOMethyl or -O-CH ₂ -COOethyl,
and R ¹ , R ² and n may have the abovementioned meanings, contain at least one further active ingredient 2.

The present invention further relates to drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{2 is} halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{3 is} halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl, at least one
contain further active ingredient 2.

The present invention further relates to drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} fluorine, chlorine, methyl or methoxy;
R ^{2 is} fluorine, chlorine, methyl or methoxy;
R ^{3 is} fluorine, chlorine, methyl or methoxy
contain at least one further active ingredient 2.

Another preferred aspect of the present invention are drug combinations, which in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen;
R ^{2 is} hydrogen, fluorine, chlorine or methyl;
R ^{3 is} methyl, ethyl, iso-propyl, tert-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH ₂ -COOH, -O-CH ₂ -CH ₂ -COOH, -O-CH ₂ -CH ₂ -CH ₂ -COOH, -O-CH ₂ -COOMethyl, -O-CH ₂ -COOethyl, -O-CH ₂ -CH ₂ -COOMethyl, -O-CH ₂ -CH ₂ -COOethyl, -O -CH ₂ -CH ₂ -CH ₂ -COOMethyl, -O-CH ₂ -CH ₂ -CH ₂ -COOethyl,
contain at least one further active ingredient 2.

Particularly preferred are drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen;
R ^{2 is} hydrogen, fluorine, chlorine or methyl;
R ^{3 is} OH, fluorine, chlorine, methyl, methoxy, ethoxy or -O-CH ₂ -COOH,
contain at least one further active ingredient 2.

Furthermore, those drug combinations are preferred which, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen;
R ^{2 is} halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl, preferably fluorine, chlorine, methoxy or methyl;
R ^{3 is} halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl, preferably fluorine, chlorine, methoxy or methyl,
contain at least one further active ingredient 2.

Another preferred aspect of the present invention are drug combinations which, in addition to one or more, preferably one compound of general formula 1, wherein n = 1, R ¹ and R ^{2 are} hydrogen and the radical R ³ may have the meanings given above, at least one further Active ingredient 2 included.

Another preferred aspect of the present invention are drug combinations, which in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ¹ and R ^{2 are} hydrogen;
R ^{3 is} methyl, ethyl, iso-propyl, tert-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH ₂ -COOH, -O-CH ₂ -CH ₂ -COOH, -O-CH ₂ -CH ₂ -CH ₂ -COOH, -O-CH ₂ -COOMethyl, -O-CH ₂ -COOethyl, -O-CH ₂ -CH ₂ -COOMethyl, -O-CH ₂ -CH ₂ -COOethyl, -O -CH ₂ -CH ₂ -CH ₂ -COOMethyl, -O-CH ₂ -CH ₂ -CH ₂ -COOethyl,
contain at least one further active ingredient 2.

Particularly preferred are drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ¹ and R ^{2 are} hydrogen;
R ^{3 is} OH, fluorine, chlorine, methoxy, ethoxy, -O-CH ₂ -COOH, preferably OH, fluorine, chlorine, ethoxy or methoxy,
contain at least one further active ingredient 2.

Particularly preferred are drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ¹ and R ^{2 are} hydrogen;
R ^{3 is} fluorine, chlorine, methoxy or ethoxy,
contain at least one further active ingredient 2.

The present invention further relates to drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{2 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl;
R ^{3 is} hydrogen,
contain at least one further active ingredient 2.

Preference is given to drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} hydrogen, fluorine, chlorine, methyl or methoxy;
R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy;
R ^{3 is} hydrogen,
contain at least one further active ingredient 2.

The present invention further relates to drug combinations, in addition to one or more, preferably a compound of general formula 1, wherein
n 1;
R ^{1 is} fluorine, chlorine, methyl or methoxy;
R ^{2 is} fluorine, chlorine, methyl or methoxy;
R ^{3 is} hydrogen,
contain at least one further active ingredient 2.

In the compounds of the formula 1, the radicals R ¹ and R ² , if they are not hydrogen, may each be arranged ortho or meta with respect to the linkage to the benzylic "-CH ₂ " group. If none of the radicals R ¹ and R ^{2 is} hydrogen, are for the drug combinations according to the invention those compounds of formula 1 are preferred in which both radicals R ¹ and R ² are configured either ortho or both radicals R ¹ and R ² meta, wherein compounds in which both radicals R ¹ and R ^{2 are} ortho-configured, are of particular importance ,

In the compounds of formula 1 in which one of the radicals R ¹ and R ^{2 is} not hydrogen, this may be ortho or meta with respect to the link to the benzylic "-CH ₂ " group. In this case, those compounds of the formula 1 are particularly preferred for the drug combinations according to the invention, in which the radical R ¹ or R ² , which is not hydrogen, is ortho-configured.

• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.1);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.2);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäure)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.3);
• – 8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.4);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.5);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.6);
• – 8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.7);
• – 8-{2-[2-(4-Fluoro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.8);
• – 8-{2-[2-(4-Fluor-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.9);
• – 8-{2-[2-(2,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.10);
• – 8-{2-[2-(3,5-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.11);
• – 8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.12);
• – 8-{2-[2-(3,5-Dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.13);
• – 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-buttersäure (1.14);
• – 8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.15);
• – 8-{2-[2-(2-Chlor-4-fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.16);
• – 8-{2-[2-(4-Chlor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.17);
• – 8-{2-[2-(4-Brom-phenyl)-1,1-dimethyl-ethylamino)-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.18);
• – 8-{2-[2-(4-Fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.19);
• – 8-{2-[2-(4-Fluor-3-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.20);
• – 8-{2-[2-(4-Fluor-2,6-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.21);
• – 8-{2-[2-(4-Chlor-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.22);
• – 8-{2-[2-(4-Chlor-3-fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.23);
• – 8-{2-[2-(4-Chlor-2-fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.24);
• – 8-{2-[2-(3-Chlor-4-fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.25);
• – 8-{2-[2-(2,6-Difluor-4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.26);
• – 8-{2-[2-(2,5-Difluor-4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.27);
• – 8-{2-[2-(4-Fluor-3,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.28);
• – 8-{2-[2-(3,5-Dichlor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.29);
• – 8-{2-[2-(4-Chlor-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.30);
• – 8-{2-[2-(3,4,5-Trifluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.31);
• – 8-{2-[2-(3-Methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.32) und
• – 8-{2-[2-(3,4-Dichlor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.33)

wenigstens einen weiteren Wirkstoff 2 enthalten.Also particularly preferred are drug combinations which, in addition to one or more, preferably a compound of general formula 1, are selected from the compounds

• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.1);
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.2);
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one (1.3);
• - 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one (1.4);
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.5);
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.6 );
• - 8- {2- [2- (4-ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.7);
• - 8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.8);
• - 8- {2- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.9);
• - 8- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.10);
• - 8- {2- [2- (3,5-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.11);
• - 8- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.12);
• - 8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.13);
• - 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2 -methyl-propyl} -phenoxy) -butyric acid (1.14);
• - 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.15);
• - 8- {2- [2- (2-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.16);
• - 8- {2- [2- (4-Chloro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.17);
• - 8- {2- [2- (4-Bromo-phenyl) -1,1-dimethyl-ethylamino) -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.18);
• - 8- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.19);
• - 8- {2- [2- (4-fluoro-3-methoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.20);
• - 8- {2- [2- (4-Fluoro-2,6-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one (1.21);
• - 8- {2- [2- (4-Chloro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.22);
• - 8- {2- [2- (4-Chloro-3-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.23);
• - 8- {2- [2- (4-Chloro-2-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.24);
• - 8- {2- [2- (3-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.25);
• - 8- {2- [2- (2,6-Difluoro-4-methoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one (1.26);
• - 8- {2- [2- (2,5-Difluoro-4-methoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one (1.27);
• - 8- {2- [2- (4-Fluoro-3,5-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one (1.28);
• - 8- {2- [2- (3,5-dichloro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.29);
• - 8- {2- [2- (4-Chloro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.30);
• - 8- {2- [2- (3,4,5-trifluorophenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one (1.31);
• - 8- {2- [2- (3-Methylphenyl) -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-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.33)

contain at least one further active ingredient 2.

• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.1);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.2);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäure)-1,1-dimethyl-ethylamino)-ethyl}-4H-benzo[1,4]oxazin-3-on (1.3);
• – 8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.4);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on (1.5);
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4)oxazin-3-on (1.6);
• – 8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.7);
• – 8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.12);
• – 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-buttersäure (1.14) und
• – 8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on (1.15),

wenigstens einen weiteren Wirkstoff 2 enthalten.Particularly preferred are in particular drug combinations, in addition to one or more, preferably a compound of general formula 1 selected from the compounds

• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.1);
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.2);
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino) ethyl} -4H-benzo [1,4] oxazin-3-one (1.3);
• - 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one (1.4);
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.5);
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one (1.6 );
• - 8- {2- [2- (4-ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one (1.7);
• - 8- {2- [2- (4-Ethoxy-phenyl) -1,1-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 [1,4] oxazin-8-yl) -ethylamino] -2 -methyl-propyl} -phenoxy) -butyric acid (1.14) and
• - 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -on (1.15),

contain at least one further active ingredient 2.

In the drug combinations according to the invention can the compounds of the formula 1 in the form of the individual optical isomers, Mixtures of the individual enantiomers or racemates may be included. Especially preferred are those drug combinations in which one or more, preferably a compound of formula 1 in the form the enantiomerically pure compounds, preferably in the form of the R-enantiomers is. Process for the separation of racemates into the respective enantiomers are known in the art and can be used to prepare the enantiomerically pure R- or S-enantiomers of the compounds of formula 1 in analog Way to apply.

One Another aspect of the present invention relates to drug combinations, the aforementioned compounds of formula 1 in the form of the acid addition salts with pharmacologically acceptable acids and optionally in Form of solvates and / or hydrates included.

Acid addition salts with pharmacologically acceptable acids of the compounds 1 are, for example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroio did, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood. Of the above-mentioned acid addition salts, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred in the present invention.

preferred Drug combinations contain, in addition to one or more, preferred a compound of formula 1 as further active ingredient one or more, preferably an anticholinergic 2a, optionally in combination with pharmaceutically acceptable Excipients.

In the drug combinations according to the invention the anticholinergic agent 2a is preferably selected from the group consisting from 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 the formulas 2a.7 to 2a.13.

In The above salts 2a.1 to 2a.6 represent the cations Tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and Trospium are the pharmacologically active ingredients explicit reference is made to the aforementioned cations by the names 2a.1 'to 2a.6 '. Any reference to the abovementioned salts 2a.1 to 2a.6 naturally includes a reference the corresponding cations tiotropium (2a.1 '), oxitropium (2a.2'), flutropium (2a.3 '), ipratropium (2a.4'), glycopyrronium (2a.5 '), trospium (2a.6') with a.

Under the salts 2a.1 to 2a.6 are understood according to the invention as meaning those compounds in addition to the cations tiotropium 2a.1 '), oxitropium (2a.2'), flutropium (2a.3 '), ipratropium (2a.4'), glycopyrronium (2a.5 ') and trospium (2a.6') as counterion (anion) Chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, Maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, wherein chloride, bromide, iodide, sulfate, Methanesulfonate or p-toluenesulfonate are preferred as counterions. Of all the salts are the chlorides, bromides, iodide and methanesulfonate particularly preferred.

in the In the case of the trospium salts (2a.6), the chloride is particularly preferred. The other salts 2a.1 to 2a.5 are the methanesulfonate and Bromides of particular importance. Of particular importance are drug combinations, the tiotropium salts (2a.1), oxitropium salts (2a.2) or ipratropium salts (2a.4), the particular bromides being particularly preferred according to the invention are significant. Of particular importance is the tiotropium bromide (2a.1). The abovementioned salts can be used in the medicament combinations according to the invention optionally in the form of their solvates or hydrates, preferably in Form of their hydrates are present. In the case of tiotropium bromide included the drug combinations according to the invention this is preferably in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. Will the tiotropium bromide in the drug combinations according to the invention used in anhydrous form, so preferably the anhydrous crystalline tiotropium bromide for use, which is known from WO 03/000265 is known.

Examples for preferred according to the invention Drug combinations of preferred compounds of formula 1 with the aforementioned anticholinergics 2a.1 to 2a.6 Combinations containing the compounds 1.1 and 2a.1; 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.1; 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.1; 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.1; 1.4 and 2a.2; 1.4 and 2a.3; 1.4 and 2a.4; 1.4 and 2a.5; 1.4 and 2a.6; 1.5 and 2a.1; 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.1; 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.1; 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.1; 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.1; 1.15 and 2a.2; 1.15 and 2a.3; 1.15 and 2a.4; 1.15 and 2a.5 or 1.15 and 2a.6, if appropriate in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2a, one of the compounds 2a.1, 2a.2 or 2a.4, those combinations which the Contain compound 2a.1, according to the invention are particularly significant.

Possibly For example, the aforementioned anticholinergics have chiral carbon centers on. In this case, you can the drug combinations according to the invention the anticholinergics in the form of their enantiomers, mixtures of the enantiomers or racemates, preferably enantiomerically pure anticholinergics to be used.

worin
X^– ein einfach negativ geladenes Anion, bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluolsulfonat, bedeutet
gegebenenfalls in Form ihrer Racemate, Enantiomere oder Hydrate.In a likewise preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the salts of the formula 2a.7

wherein
X ^{- is} a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p Toluenesulfonate, means
optionally in the form of their racemates, enantiomers or hydrates.

Preferred drug combinations contain salts of formula 2a.7, wherein
X ^{- is} a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, preferably bromide,
optionally in the form of their racemates, enantiomers or hydrates.

Preferred drug combinations contain salts of formula 2a.7, wherein
X ^{- is} a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide,
optionally in the form of their racemates, enantiomers or hydrates.

Especially preferred drug combinations contain the compound of Formula 2a.7 in the form of the bromide.

enthalten, worin X^– die vorstehend genannten Bedeutungen aufweisen kann.Of particular importance are those drug combinations which contain the enantiomers of formula 2a.7-en

in which X ^{- may have} the meanings given above.

Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.7 are combinations comprising the compounds 1.1 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-en; 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, respectively if in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those preferred as compound 2a, the compound 2a.7-en contain, according to the invention particularly are significant.

worin R entweder Methyl (2a.8.1) oder Ethyl (2a.8.2) bedeuten und worin X^– die vorstehend genannten Bedeutungen aufweisen kann. In einer alternativen Ausführungsform ist die Verbindung der Formel 2a.8 in Form der freien Base 2a.8-base

enthalten.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the salts of the formula 2a.8

wherein R is either methyl (2a.8.1) or ethyl (2a.8.2) and in which X ^{- may have} the meanings given above. In an alternative embodiment, the compound of formula 2a.8 is in the form of the free base 2a.8-base

contain.

The drug combinations according to the invention can the anticholinergic agent of formula 2a.8 (or 2a.8-base) in the form of its Enantiomers, mixtures of enantiomers or racemates. Preferably, the anticholinergics of the formula 2a.8 (or 2a.8-base) in the form of their R-enantiomers.

Examples for drug combinations according to the invention preferred compounds of formula 1 with the abovementioned Anticholinergics 2a.8 are combinations containing the compounds 1.1 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; 1.7 and 2a.8.1; 1.7 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, respectively optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant.

worin
A eine zweibindige Gruppe ausgewählt aus den Gruppen

X^– eine der vorstehend genannten einfach negativ geladenen Anionen, bevorzugt Chlorid, Bromid oder Methansulfonat,
R¹ und R² gleich oder verschieden eine Gruppe ausgewählt aus Methyl, Ethyl, n-Propyl und iso-Propyl, die gegebenenfalls substituiert sein kann durch Hydroxy oder Fluor, bevorzugt unsubstitutiertes Methyl;
R³, R⁴, R⁵ und R⁶, gleich oder verschieden Wasserstoff, Methyl, Ethyl, Methyloxy, Ethyloxy, Hydroxy, Fluor, Chlor, Brom, CN, CF₃ oder NO₂;
R⁷ Wasserstoff, 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, Fluor, Chlor oder Brom, bedeuten.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the Formula 2a.9

wherein
A is a divalent group selected from the groups

X ^- one of the aforementioned simply negatively charged anions, preferably chloride, bromide or methanesulfonate,
R ¹ and R ^2, identically or differently, represent a group selected from methyl, ethyl, n-propyl and isopropyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R ³ , R ⁴ , R ⁵ and R ⁶ , identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ ;
R ^{7 is} hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ - OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, - O-COEt, -O-COCF ₃ , -O-COCF ₃ , fluorine, chlorine or bromine mean.

The Compounds of formula 2a.9 are known in the art (WO 02/32899).

Preferred compounds of the formula 2a.9 in the context of the drug combinations according to the invention are those in which
X ^- bromide;
R ¹ and R ^{2 are} identical or different, methyl or ethyl, preferably methyl;
R ³ , R ⁴ , R ⁵ and R ⁶ , same or different, represent hydrogen, methyl, methyloxy, chlorine or fluorine;
R ^{7 is} hydrogen, methyl or fluorine.

Of particular importance are drug combinations containing those compounds of formula 2a.9 in which
A is a divalent group selected from

• – 2,2-Diphenylpropionsäuretropenolester-methobromid (2a.9.1),
• – 2,2-Diphenylpropionsäurescopinester-methobromid (2a.9.2),
• – 2-Fluor-2,2-Diphenylessigsäurescopinester-methobromid (2a.9.3),
• – 2-Fluor-2,2-Diphenylessigsäuretropenolester-methobromid (2a.9.4),;

Of particular importance are those drug combinations which, in addition to a compound of the formula 1, contain one of the following compounds of the formula 2a.9:

• 2,2-diphenylpropionic acid tropol ester methobromide (2a.9.1),
• 2,2-diphenylpropionic acid copinester methobromide (2a.9.2),
• 2-fluoro-2,2-diphenylacetic acid-co-ester methobromide (2a.9.3),
• 2-fluoro-2,2-diphenylacetic acid tropol ester methobromide (2a.9.4);

The Compounds of the formula 2a.9 can optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or Solvates be included.

Examples for drug combinations according to the invention preferred compounds of formula 1 with the abovementioned Anticholinergics 2a.9 are combinations containing the compounds 1.1 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 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; 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, each optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which are preferred as compound 2a.9 one of the compounds 2a.9.1 or 2a.9.2, where those combinations that the Contain compound 2a.9.2, according to the invention are particularly significant.

worin
A, X^–, R¹ und R² die vorstehend genannten Bedeutungen haben können und worin
R⁷, R⁸, R⁹, R¹⁰, R¹¹ und R¹², gleich oder verschieden, Wasserstoff, Methyl, Ethyl, Methyloxy, Ethyloxy, Hydroxy, Fluor, Chlor, Brom, CN, CF₃ oder NO₂, bedeuten, wobei zumindest eine der Gruppen R⁷, R⁸, R⁹, R¹⁰, R¹¹ und R¹² nicht Wasserstoff sein kann.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.10

wherein
A, X ^- , R ¹ and R ² may have the meanings given above and in which
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ , wherein at least one of R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² can not be hydrogen.

The Compounds of formula 2a.10 are known in the art (WO 02/32898).

X^– Bromid;
R¹ und R² gleich oder verschieden, Methyl oder Ethyl, bevorzugt Methyl;
R⁷, R⁸, R⁹, R¹⁰, R¹¹ und R¹², gleich oder verschieden Wasserstoff, Fluor, Chlor oder Brom, bevorzugt Fluor, bedeuten, wobei zumindest eine der Gruppen R⁷, R⁸, R⁹, R¹⁰, R¹¹ und R¹² nicht Wasserstoff sein kann.In the context of the drug combinations according to the invention preferred compounds of formula 2a.10 are those in which
A is a divalent group selected from

X ^- bromide;
R ¹ and R ^{2 are} identical or different, methyl or ethyl, preferably methyl;
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , identical or different, denote hydrogen, fluorine, chlorine or bromine, preferably fluorine, where at least one of the groups R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² can not be hydrogen.

• – 3,3',4,4'-Tetrafluorbenzilsäuretropenolester-Methobromid (2a.10.1),
• – 3,3',4,4'-Tetrafluorbenzilsäurescopinester-Methobromid 2a.10.2),
• – 4,4'-Difluorbenzilsäuretropenolester-Methobromid (2a.10.3),
• – 4,4'-Difluorbenzilsäurescopinester-Methobromid (2a.10.4),
• – 3,3'-Difluorbenzilsäuretropenolester-Methobromid (2a.10.5),
• – 3,3'-Difluorbenzilsäurescopinester-Methobromid (2a.10.6);

Of particular importance are those drug combinations which, in addition to a compound of the formula 1, contain one of the following compounds of the formula 2a.10:

• 3,3 ', 4,4'-tetrafluorobenzylic acid tropol ester methobromide (2a.10.1),
• 3,3 ', 4,4'-tetrafluorobenzilatecopine ester methobromide 2a.10.2),
• 4,4'-difluorobenzilic acid-tropol ester-methobromide (2a.10.3),
• 4,4'-difluorobenzilic acid copoprene methobromide (2a.10.4),
• 3,3'-difluorobenzilic acid-tropol ester-methobromide (2a.10.5),
• 3,3'-difluorobenzilic acid copoprene methobromide (2a.10.6);

The Compounds of formula 2a.10 can optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or Solvates be included.

Examples for drug combinations according to the invention preferred compounds of formula 1 with the abovementioned Anticholinergics 2a.10 are combinations containing the compounds 1.1 and 2a.10.1; 1.1 and 2a.10.2; 1.1 and 2a.10.3; 1.1 and 2a.10.4; 1.1 and 2a.10.5; 1.1 and 2a.10.6; 1.2 and 2a.10.1; 1.2 and 2a.10.2; 1.2 and 2a.10.3; 1.2 and 2a.10.4; 1.2 and 2a.10.5; 1.2 and 2a.10.6; 1.3 and 2a.10.1; 1.3 and 2a.10.2; 1.3 and 2a.10.3; 1.3 and 2a.10.4; 1.3 and 2a.10.5; 1.3 and 2a.10.6; 1.4 and 2a.10.1; 1.4 and 2a.10.2; 1.4 and 2a.10.3; 1.4 and 2a.10.4; 1.4 and 2a.10.5; 1.4 and 2a.10.6; 1.5 and 2a.10.1; 1.5 and 2a.10.2; 1.5 and 2a.10.3; 1.5 and 2a.10.4; 1.5 and 2a.10.5; 1.5 and 2a.10.6; 1.6 and 2a.10.1; 1.6 and 2a.10.2; 1.6 and 2a.10.3; 1.6 and 2a.10.4; 1.6 and 2a.10.5; 1.6 and 2a.10.6; 1.7 and 2a.10.1; 1.7 and 2a.10.2; 1.7 and 2a.10.3; 1.7 and 2a.10.4; 1.7 and 2a.10.5; 1.7 and 2a.10.6; 1.12 and 2a.10.1; 1.12 and 2a.10.2; 1.12 and 2a.10.3; 1.12 and 2a.10.4; 1.12 and 2a.10.5; 1.12 and 2a.10.6; 1.14 and 2a.10.1; 1.14 and 2a.10.2; 1.14 and 2a.10.3; 1.14 and 2a.10.4; 1.14 and 2a.10.5; 1.14 and 2a.10.6; 1.15 and 2a.10.1; 1.15 and 2a.10.2; 1.15 and 2a.10.3; 1.15 and 2a.10.4; 1.15 and 2a.10.5; 1.15 and 2a.10.6, each optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2a.10, are one of the compounds 2a.10.1, 2a.10.2, 2a.10.3 or 2a.10.4, where those combinations, which contain the compounds 2a.10.1 or 2a.10.2, according to the invention particularly are significant.

worin
A und X^– die vorstehend genannten Bedeutungen haben können und worin
R¹⁵ Wasserstoff, Hydroxy, Methyl, Ethyl, -CF₃, CHF₂ oder Fluor;
R^1' und R^2' gleich oder verschieden, C₁-C₅-Alkyl, welches gegebenenfalls substituiert sein kann durch C₃-C₆-Cycloalkyl, Hydroxy oder Halogen,
oder
R^1' und R^2' gemeinsam eine -C₃-C₅-Alkylenbrücke;
R¹³, R¹⁴, R^13' und R^14' gleich oder verschieden, Wasserstoff, -C₁-C₄-Alkyl, -C₁-C₄-Alkyloxy, Hydroxy, -CF₃, -CHF₂, CN, NO₂ oder Halogen,
bedeuten.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.11

wherein
A and X ^- may have the meanings given above and in which
R ^{15 is} hydrogen, hydroxy, methyl, ethyl, -CF ₃ , CHF ₂ or fluorine;
R ^{1 '} and R ^{2' are} identical or different, C ₁ -C ₅ -alkyl, which may optionally be substituted by C ₃ -C ₆ -cycloalkyl, hydroxy or halogen,
or
R ^{1 '} and R ^2' together represent a -C ₃ -C ₅ -alkylene bridge;
R ¹³ , R ¹⁴ , R ^{13 '} and R ^{14' are} identical or different, hydrogen, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen,
mean.

The Compounds of formula 2a.11 are known in the art (WO 03/064419).

Preferred compounds of the formula 2a.11 in the context of the drug combinations according to the invention are those in which
A is a divalent group selected from

X^– ein Anion ausgewählt aus Chlorid, Bromid und Methansulfonat, bevorzugt Bromid;
R¹⁵ Hydroxy, Methyl oder Fluor, bevorzugt Methyl oder Hydroxy;
R^1' und R^2' gleich oder verschieden, Methyl oder Ethyl, bevorzugt Methyl;
R¹³, R¹⁴, R^13' und R^14' gleich oder verschieden, Wasserstoff, -CF₃, -CHF₂ oder Fluor, bevorzugt Wasserstoff oder Fluor, bedeuten.

X ^- an anion selected from chloride, bromide and methanesulfonate, preferably bromide;
R ^{15 is} hydroxy, methyl or fluoro, preferably methyl or hydroxy;
R ^{1 '} and R ^{2' are} identical or different, methyl or ethyl, preferably methyl;
R ¹³ , R ¹⁴ , R ^{13 '} and R ^{14' are} identical or different and denote hydrogen, -CF ₃ , -CHF ₂ or fluorine, preferably hydrogen or fluorine.

X^– Bromid;
R¹⁵ Hydroxy oder Methyl, bevorzugt Methyl;
R^1' und R^2' gleich oder verschieden, Methyl oder Ethyl, bevorzugt Methyl;
R¹³, R¹⁴, R^13' und R^14' gleich oder verschieden, Wasserstoff oder Fluor, bedeuten.In the context of the drug combinations according to the invention particularly preferred compounds of formula 2a.11 are those in which
A is a divalent group selected from

X ^- bromide;
R ^{15 is} hydroxy or methyl, preferably methyl;
R ^{1 '} and R ^{2' are} identical or different, methyl or ethyl, preferably methyl;
R ¹³ , R ¹⁴ , R ^{13 '} and R ^{14' are} identical or different, hydrogen or fluorine.

• – 9-Hydroxy-fluoren-9-carbonsäuretropenolester -Methobromid (2a.11.1);
• – 9-Fluor-fluoren-9-carbonsäuretropenolester -Methobromid (2a.11.2);
• – 9-Hydroxy-fluoren-9-carbonsäurescopinester -Methobromid (2a.11.3);
• – 9-Fluor-fluoren-9-carbonsäurescopinester Methobromid (2a.11.4);
• – 9-Methyl-fluoren-9-carbonsäuretropenolester Methobromid (2a.11.5);
• – 9-Methyl-fluoren-9-carbonsäurescopinester Methobromid (2a.11.6);

Of particular importance are those drug combinations which, in addition to a compound of the formula 1, contain one of the following compounds of the formula 2a.11:

• 9-hydroxyfluorene-9-carboxylic acid tropol ester methobromide (2a.11.1);
• 9-fluoro-fluoren-9-carboxylic acid tropol ester methobromide (2a.11.2);
• 9-Hydroxy-fluorene-9-carboxylic acid copinester -methobromide (2a.11.3);
• 9-fluoro-fluorene-9-carboxylic acid copoprene methobromide (2a.11.4);
• 9-methyl-fluorene-9-carboxylic acid-tropol ester methobromide (2a.11.5);
• 9-methyl-fluorene-9-carboxylic acid copoprene methobromide (2a.11.6);

The Compounds of the formula 2a.11 can optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or Solvates be included.

Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.11 are combinations comprising the compounds 1.1 and 2a.11.1; 1.1 and 2a.11.2; 1.1 and 2a.11.3; 1.1 and 2a.11.4; 1.1 and 2a.11.5; 1.1 and 2a.11.6; 1.2 and 2a.11.1; 1.2 and 2a.11.2; 1.2 and 2a.11.3; 1.2 and 2a.11.4; 1.2 and 2a.11.5; 1.2 and 2a.11.6; 1.3 and 2a.11.1; 1.3 and 2a.11.2; 1.3 and 2a.11.3; 1.3 and 2a.11.4; 1.3 and 2a.11.5; 1.3 and 2a.11.6; 1.4 and 2a.11.1; 1.4 and 2a.11.2; 1.4 and 2a.11.3; 1.4 and 2a.11.4; 1.4 and 2a.11.5; 1.4 and 2a.11.6; 1.5 and 2a.11.1; 1.5 and 2a.11.2; 1.5 and 2a.11.3; 1.5 and 2a.11.4; 1.5 and 2a.11.5; 1.5 and 2a.11.6; 1.6 and 2a.11.1; 1.6 and 2a.11.2; 1.6 and 2a.11.3; 1.6 and 2a.11.4; 1.6 and 2a.11.5; 1.6 and 2a.11.6; 1.7 and 2a.11.1; 1.7 and 2a.11.2; 1.7 and 2a.11.3; 1.7 and 2a.11.4; 1.7 and 2a.11.5; 1.7 and 2a.11.6; 1.12 and 2a.11.1; 1.12 and 2a.11.2; 1.12 and 2a.11.3; 1.12 and 2a.11.4; 1.12 and 2a.11.5; 1.12 and 2a.11.6; 1.14 and 2a.11.1; 1.14 and 2a.11.2; 1.14 and 2a.11.3; 1.14 and 2a.11.4; 1.14 and 2a.11.5; 1.14 and 2a.11.6; 1.15 and 2a.11.1; 1.15 and 2a.11.2; 1.15 and 2a.11.3; 1.15 and 2a.11.4; 1.15 and 2a.11.5; 1.15 and 2a.11.6, in each case optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, Solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2a.11, are one of the compounds 2a.11.2, 2a.11.4, 2a.11.5 or 2a.11.6, where those combinations, which contain the compounds 2a.11.5 or 2a.11.6, according to the invention particularly are significant.

worin X^– die vorstehend genannten Bedeutungen haben kann und worin
D und B gleich oder verschieden, bevorzugt gleich O, S, NH, CH₂, CH=CH oder
N(C₁-C₄-Alkyl);
R¹⁶ Wasserstoff, Hydroxy, -C₁-C₄-Alkyl, -C₁-C₄-Alkyloxy, -C₁-C₄-Alkylen-Halogen, -O-C₁-C₄-Alkylen-Halogen, -C₁-C₄-Alkylen-OH, -CF₃, CHF₂, -C₁-C₄-Alkylen-C₁-C₄-alkyloxy, -O-COC₁-C₄-Alkyl, -O-COC₁-C₄-Alkylen-halogen, -C₁-C₄-Alkylen-C₃-C₆-cycloalkyl, -O-COCF₃ oder Halogen;
R^1'' und R^2'' gleich oder verschieden, -C₁-C₅-Alkyl, das gegebenenfalls durch -C₃-C₆-Cycloalkyl, Hydroxy oder Halogen substituiert sein kann, oder
R^1'' und R^2'' gemeinsam eine -C₃-C₅-Alkylenbrücke; R¹⁷, R¹⁸, R^17' und R^18', gleich oder verschieden, Wasserstoff, -C₁-C₄-Alkyl, -C₁-C₄-Alkyloxy, Hydroxy, -CF₃, -CHF₂, CN, NO₂ oder Halogen;
R^x und R^x' gleich oder verschieden, Wasserstoff, -C₁-C₄-Alkyl, -C₁-C₄-Alkyloxy, Hydroxy, -CF₃, -CHF₂, CN, NO₂ oder Halogen, oder
R^x und R^x' gemeinsam eine Einfachbindung oder eine der zweibindigen Gruppen O, S, NH, CH₂, CH₂-CH₂, N(C₁-C₄-alkyl), CH(C₁-C₄-alkyl) und -C(C₁-C₄-alkyl)₂, bedeuten.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.12

wherein X ^- may have the meanings given above and in which
D and B are the same or different, preferably equal to O, S, NH, CH ₂ , CH = CH or
N (C ₁ -C ₄ alkyl);
R ^{16 is} hydrogen, hydroxy, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, -C ₁ -C ₄ -alkylene-halogen, -OC ₁ -C ₄ -alkylene-halogen, -C ₁ - C ₄ -alkylene-OH, -CF ₃ , CHF ₂ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ -Alkylene-halogen, -C ₁ -C ₄ -alkylene-C ₃ -C ₆ -cycloalkyl, -O-COCF ₃ or halogen;
R ^{1 ''} and R ^{2 '' are} identical or different, -C ₁ -C ₅ alkyl, which may optionally be substituted by -C ₃ -C ₆ cycloalkyl, hydroxy or halogen, or
R ^{1 "} and R ^2" together form a -C ₃ -C ₅ -alkylene bridge; R ¹⁷ , R ¹⁸ , R ^{17 '} and R ^18' , identical or different, are hydrogen, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen;
R ^x and R ^{x 'are} identical or different, hydrogen, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen, or
R ^x and R ^{x '} together represent a single bond or one of the divalent groups O, S, NH, CH ₂ , CH ₂ -CH ₂ , N (C ₁ -C ₄ -alkyl), CH (C ₁ -C ₄ -alkyl) and -C (C ₁ -C ₄ alkyl) ₂ , mean.

The Compounds of formula 2a.12 are known in the art (WO 03/064418).

Preferred compounds of the formula 2a.12 in the context of the drug combinations according to the invention are those in which
X ^- chloride, bromide or methanesulfonate, preferably bromide;
D and B are the same or different, preferably equal to O, S, NH or CH = CH;
R ^{16 is} hydrogen, hydroxy, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, -CF ₃ , -CHF ₂ , fluorine, chlorine or bromine;
R ^{1 ''} and R ^{2 '' are} identical or different, C ₁ -C ₄ -alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine, or
R ^{1 "} and R ^2" together form a -C ₃ -C ₄ -alkylene bridge;
R ¹⁷ , R ¹⁸ , R ^{17 '} and R ^18' , identical or different, are hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , Fluorine, chlorine or bromine;
R ^x and R ^{x 'are} identical or different, hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ , fluorine, chlorine or bromine, or
R ^x and R ^{x '} together represent a single bond or a divalent group selected from O, S, NH- and CH ₂ .

In the context of the drug combinations according to the invention particularly preferred compounds of formula 2a.12 are those in which
X ^- chloride, bromide, or methanesulfonate, preferably bromide;
D and B are the same or different, preferably the same, S or CH = CH;
R ^{16 is} hydrogen, hydroxy or methyl;
R ^{1 "} and R ^{2" are} identical or different, methyl or ethyl;
R ¹⁷ , R ¹⁸ , R ^{17 '} and R ^18' , identical or different, are hydrogen, -CF ₃ or fluorine, preferably hydrogen;
R ^x and R ^{x 'are} identical or different, hydrogen, -CF ₃ or fluorine, preferably hydrogen, or
R ^x and R ^{x '} together signify a single bond or -O-.

In the context of the drug combinations according to the invention particularly preferred compounds of formula 2a.12 are also those in which
X ^- bromide;
D and B are -CH = CH-;
R ^{16 is} hydrogen, hydroxy or methyl;
R ^{1 ''} and R ^{2 '' are} methyl;
R ¹⁷ , R ¹⁸ , R ^{17 '} and R ^18' , identical or different, are hydrogen or fluorine, preferably hydrogen;
R ^x and R ^{x 'are} identical or different, hydrogen or fluorine, preferably hydrogen, or
R ^x and R ^{x '} together denote a single bond or the group -O-.

• – Benzilsäurecyclopropyltropinester-Methobromid (2a.12.1);
• – 2,2-Diphenylpropionsäurecyclopropyltropinester-Methobromid (2a.12.2);
• – 9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid (2a.12.3);
• – 9-Methyl-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid (2a.12.4);
• – 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid (2a.12.5);
• – 9-Hydroxy-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid (2a.12.6);
• – 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid (2a.12.7).

Of particular importance are those drug combinations which, in addition to a compound of the formula 1, contain one of the following compounds of the formula 2a.12:

• Benzylic acid cyclopropyl tropine ester methobromide (2a.12.1);
• 2,2-diphenylpropionic acid cyclopropyltropic ester methobromide (2a.12.2);
• 9-hydroxy-xanthene-9-carboxylic acid cyclopropyltropic ester methobromide (2a.12.3);
• 9-methyl-fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide (2a.12.4);
• 9-methyl xanthene-9-carboxylic acid cyclopropyl tropine ester methobromide (2a.12.5);
• 9-hydroxyfluorene-9-carboxylic acid cyclopropyltropine ester methobromide (2a.12.6);
• - 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester methobromide (2a.12.7).

The Compounds of formula 2a.12 can optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or Solvates be included.

Examples for drug combinations according to the invention preferred compounds of formula 1 with the abovementioned Anticholinergics 2a.12 are combinations containing the compounds 1.1 and 2a.12.1; 1.1 and 2a.12.2; 1.1 and 2a.12.3; 1.1 and 2a.12.4; 1.1 and 2a.12.5; 1.1 and 2a.12.6; 1.1 and 2a.12.7; 1.2 and 2a.12.1; 1.2 and 2a.12.2; 1.2 and 2a.12.3; 1.2 and 2a.12.4; 1.2 and 2a.12.5; 1.2 and 2a.12.6; 1.2 and 2a.12.7; 1.3 and 2a.12.1; 1.3 and 2a.12.2; 1.3 and 2a.12.3; 1.3 and 2a.12.4; 1.3 and 2a.12.5; 1.3 and 2a.12.6; 1.3 and 2a.12.7; 1.4 and 2a.12.1; 1.4 and 2a.12.2; 1.4 and 2a.12.3; 1.4 and 2a.12.4; 1.4 and 2a.12.5; 1.4 and 2a.12.6; 1.4 and 2a.12.7; 1.5 and 2a.12.1; 1.5 and 2a.12.2; 1.5 and 2a.12.3; 1.5 and 2a.12.4; 1.5 and 2a.12.5; 1.5 and 2a.12.6; 1.5 and 2a.12.7; 1.6 and 2a.12.1; 1.6 and 2a.12.2; 1.6 and 2a.12.3; 1.6 and 2a.12.4; 1.6 and 2a.12.5; 1.6 and 2a.12.6; 1.6 and 2a.12.7; 1.7 and 2a.12.1; 1.7 and 2a.12.2; 1.7 and 2a.12.3; 1.7 and 2a.12.4; 1.7 and 2a.12.5; 1.7 and 2a.12.6; 1.7 and 2a.12.7; 1.12 and 2a.12.1; 1.12 and 2a.12.2; 1.12 and 2a.12.3; 1.12 and 2a.12.4; 1.12 and 2a.12.5; 1.12 and 2a.12.6; 1.12 and 2a.12.7; 1.14 and 2a.12.1; 1.14 and 2a.12.2; 1.14 and 2a.12.3; 1.14 and 2a.12.4; 1.14 and 2a.12.5; 1.14 and 2a.12.6; 1.14 and 2a.12.7; 1.15 and 2a.12.1; 1.15 and 2a.12.2; 1.15 and 2a.12.3; 1.15 and 2a.12.4; 1.15 and 2a.12.5; 1.15 and 2a.12.6; 1.15 and 2a.12.7, each optionally in form their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2a.11, are one of the compounds 2a.12.1, 2a.12.2, 2a.12.5 or 2a.12.7, where those combinations, which contain the compounds 2a.12.1 or 2a.12.2, according to the invention particularly are significant.

worin X^– die vorstehend genannten Bedeutungen haben kann und worin
A' eine zweibindige Gruppe ausgewählt aus

R¹⁹ Hydroxy, Methyl, Hydroxymethyl, Ethyl, -CF₃, CHF₂ oder Fluor;
R^1''' und R^2''' gleich oder verschieden, C₁-C₅-Alkyl, welches gegebenenfalls substituiert sein kann durch C₃-C₆-Cycloalkyl, Hydroxy oder Halogen, oder
R^1''' und R^2''' gemeinsam eine -C₃-C₅-Alkylenbrücke;
R²⁰, R²¹, R^20' und R^21' gleich oder verschieden, Wasserstoff, -C₁-C₄-Alkyl, -C₁-C₄-Alkyloxy, Hydroxy, -CF₃, -CHF₂, CN, NO₂ oder Halogen,
bedeuten.In a further preferred embodiment of the present invention, the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.13

wherein X ^- may have the meanings given above and in which
A 'is a divalent group selected from

R ^{19 is} hydroxy, methyl, hydroxymethyl, ethyl, -CF ₃ , CHF ₂ or fluorine;
R ^{1 '''} and R ^{2''' are} identical or different, C ₁ -C ₅ -alkyl, which may optionally be substituted by C ₃ -C ₆ -cycloalkyl, hydroxy or halogen, or
R ^{1 '"} and R ^2'" together form a -C ₃ -C ₅ -alkylene bridge;
R ²⁰ , R ²¹ , R ^{20 '} and R ^{21' are} identical or different, hydrogen, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen,
mean.

The Compounds of formula 2a.13 are known in the art (WO 03/064417).

X^– Chlorid, Bromid oder Methansulfnat, bevorzugt Bromid;
R¹⁹ Hydroxy oder Methyl;
R^1''' und R^2''' gleich oder verschieden, Methyl oder Ethyl, bevorzugt Methyl;
R²⁰, R²¹, R^20' und R^21' gleich oder verschieden, Wasserstoff, -CF₃, -CHF₂ oder Fluor, bevorzugt Wasserstoff oder Fluor, bedeuten.Preferred compounds of the formula 2a.13 in the context of the drug combinations according to the invention are those in which
A 'is a divalent group selected from

X ^- chloride, bromide or methanesulfonate, preferably bromide;
R ^{19 is} hydroxy or methyl;
R ^{1 '''} and R ^{2''' are} identical or different, methyl or ethyl, preferably methyl;
R ²⁰ , R ²¹ , R ^{20 '} and R ^{21' are} identical or different, hydrogen, -CF ₃ , -CHF ₂ or fluorine, preferably hydrogen or fluorine.

X^– Bromid;
R¹⁹ Hydroxy oder Methyl, bevorzugt Methyl;
R^1''' und R^2''' gleich oder verschieden, Methyl oder Ethyl, bevorzugt Methyl;
R³, R⁴, R^3' und R^4' gleich oder verschieden, Wasserstoff oder Fluor, bedeuten.In the context of the drug combinations according to the invention particularly preferred compounds of formula 2a.13 are those in which
A 'is a divalent group selected from

X ^- bromide;
R ^{19 is} hydroxy or methyl, preferably methyl;
R ^{1 '''} and R ^{2''' are} identical or different, methyl or ethyl, preferably methyl;
R ³ , R ⁴ , R ^{3 '} and R ^{4' are} identical or different, hydrogen or fluorine.

• – 9-Hydroxy-xanthen-9-carbonsäuretropenolester-Methobromid (2a.13.1);
• – 9-Hydroxy-xanthen-9-carbonsäurescopinester-Methobromid (2a.13.2);
• – 9-Methyl-xanthen-9-carbonsäuretropenolester-Methobromid (2a.13.3);
• – 9-Methyl-xanthen-9-carbonsäurescopinester-Methobromid (2 a.13.4);
• – 9-Ethyl-xanthen-9-carbonsäuretropenolester-Methobromid (2a.13.5);
• – 9-Difluormethyl-xanthen-9-carbonsäuretropenolester-Methobromid (2a.13.6);
• – 9-Hydroxymethyl-xanthen-9-carbonsäurescopinester-Methobromid (2a.13.7).

Of particular importance are those drug combinations which, in addition to a compound of the formula 1, contain one of the following compounds of the formula 2a.13:

• 9-hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide (2a.13.1);
• 9-hydroxy-xanthene-9-carboxylic acid-co-ester methobromide (2a.13.2);
• 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide (2a.13.3);
• 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide (2 a.13.4);
• 9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide (2a.13.5);
• 9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide (2a.13.6);
• 9-hydroxymethyl-xanthene-9-carboxylic acid copo-ester methobromide (2a.13.7).

The Compounds of the formula 2a.13 can optionally in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or Solvates be included.

Examples for drug combinations according to the invention preferred compounds of formula 1 with the abovementioned Anticholinergics 2a.13 are combinations containing the compounds 1.1 and 2a.13.1; 1.1 and 2a.13.2; 1.1 and 2a.13.3; 1.1 and 2a.13.4; 1.1 and 2a.13.5; 1.1 and 2a.13.6; 1.1 and 2a.13.7; 1.2 and 2a.13.1; 1.2 and 2a.13.2; 1.2 and 2a.13.3; 1.2 and 2a.13.4; 1.2 and 2a.13.5; 1.2 and 2a.13.6; 1.2 and 2a.13.7; 1.3 and 2a.13.1; 1.3 and 2a.13.2; 1.3 and 2a.13.3; 1.3 and 2a.13.4; 1.3 and 2a.13.5; 1.3 and 2a.13.6; 1.3 and 2a.13.7; 1.4 and 2a.13.1; 1.4 and 2a.13.2; 1.4 and 2a.13.3; 1.4 and 2a.13.4; 1.4 and 2a.13.5; 1.4 and 2a.13.6; 1.4 and 2a.13.7; 1.5 and 2a.13.1; 1.5 and 2a.13.2; 1.5 and 2a.13.3; 1.5 and 2a.13.4; 1.5 and 2a.13.5; 1.5 and 2a.13.6; 1.5 and 2a.13.7; 1.6 and 2a.13.1; 1.6 and 2a.13.2; 1.6 and 2a.13.3; 1.6 and 2a.13.4; 1.6 and 2a.13.5; 1.6 and 2a.13.6; 1.6 and 2a.13.7; 1.7 and 2a.13.1; 1.7 and 2a.13.2; 1.7 and 2a.13.3; 1.7 and 2a.13.4; 1.7 and 2a.13.5; 1.7 and 2a.13.6; 1.7 and 2a.13.7; 1.12 and 2a.13.1; 1.12 and 2a.13.2; 1.12 and 2a.13.3; 1.12 and 2a.13.4; 1.12 and 2a.13.5; 1.12 and 2a.13.6; 1.12 and 2a.13.7; 1.14 and 2a.13.1; 1.14 and 2a.13.2; 1.14 and 2a.13.3; 1.14 and 2a.13.4; 1.14 and 2a.13.5; 1.14 and 2a.13.6; 1.14 and 2a.13.7; 1.15 and 2a.13.1; 1.15 and 2a.13.2; 1.15 and 2a.13.3; 1.15 and 2a.13.4; 1.15 and 2a.13.5; 1.15 and 2a.13.6; 1.15 and 2a.13.7, each optionally in form their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2a.11, are one of the compounds 2a.13.2, 2a.13.3, 2a.13.4 or 2a.13.5, those combinations which contain the compounds 2a.13.3 or 2a.13.4, according to the invention particularly are significant.

In the context of the present invention, reference to anticholinergics 1 'is to be understood as referring to the pharmacologically active cations of the respective salts. These cations are tiotropium (2a.1,), oxitropium (2a.2 '), flutropium (2a.3'), ipratropium (2a.4 '), glycopyrronium (2a, 5'), trospium (2a.6 ') as well as the following cations

Further according to the invention preferred drug combinations contain, besides one or more, preferred a compound of formula 1 as further active ingredient one or more, preferably a PDE IV inhibitor 2b, optionally in combination with pharmaceutically acceptable Excipients.

In such drug combinations, the PDE IV inhibitor 2b is preferred selected from the group consisting of enprofylline, theophylline, roflumilast, Ariflo (Cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, Pumafentine, (-) p - [(4aR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridin-6 yl] -N, N-diisopropylbenzamide, (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (Cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy 4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy] 4-difluoromethoxyphenyl) cyclohexan-1-ol], (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, CDP840, Bay 198004, D-4418, PD-168787, T-440, T-2585, Arofylline, Atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4- c] -1,2,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

In particularly preferred drug combinations is the PDE IV inhibitor 2b selected from the group consisting of enprofylline (2b.1), roflumilast (2b.2), Ariflo (cilomilast) (2b.3), AWD-12-281 (GW-842470) (2b.4), N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy 3-cyclopropylmethoxybenzamide (2b.5), T-440 (2b.6), T-2585 (2b.7), arofylline (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-1-one (2b.10), cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (2b.11), PD-168787 (2b.12), atizoram (2b.13), V-11294A (2b.14), C1-1018 (2b.15), CDC-801 (2b.16), D-22888 (2b.17), YM-58997 (2b.18), Z-15370 (2b.19), 9-cyclopentyl-5,6-dihydro-7-ethyl 3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine (2b.20) and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3 -a] pyridine (2b.21), optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

In particularly preferred drug combinations is the PDE IV inhibitor 2b selected from the group consisting of roflumilast (2b.2), ariflo (cilomilast) (2b.3), AWD-12-281 (GW-842470) (2b.4), arofylline (2b.8), 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane 1-one (2b.10), cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (2b.11), atizoram (2b.13), Z-15370 (2b.19), 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3, 4-c] -1,2,4-triazolo [4,3-a) pyridine (2b.20) and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3 -a] pyridine (2b.21), wherein Roflumilast (2b.2), Z-15370 (2b.19) and AWD-12-281 (2b.4) particular importance, optionally in the form of their racemates, Enantiomers or diastereomers and optionally in the form of their pharmacological acceptable Acid addition salts, Solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids for their formation, the compounds 2b optionally in a position For example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood.

Examples of preferred drug combinations according to the invention of preferred compounds of formula 1 with the aforementioned PDE IV inhibitors 2b are combinations containing the compounds 1.1 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; 1.1 and 2b.7; 1.1 and 2b.8; 1.1 and 2b.9; 1.1 and 2b.10; 1.1 and 2b.11; 1.1 and 2b.12; 1.1 and 2b.13; 1.1 and 2b.14; 1.1 and 2b.15; 1.1 and 2b.16; 1.1 and 2b.17; 1.1 and 2b.18; 1.1 and 2b.19; 1.1 and 2b.20; 1.1 and 2b.21; 1.2 and 2b.1; 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; 1.2 and 2b.10; 1.2 and 2b.11; 1.2 and 2b.12; 1.2 and 2b.13; 1.2 and 2b.14; 1.2 and 2b.15; 1.2 and 2b.16; 1.2 and 2b.17; 1.2 and 2b.18; 1.2 and 2b.19; 1.2 and 2b.20; 1.2 and 2b.21; 1.3 and 2b.1; 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 2b.7; 1.3 and 2b.8; 1.3 and 2b.9; 1.3 and 2b.10; 1.3 and 2b.11; 1.3 and 2b.12; 1.3 and 2b.13; 1.3 and 2b.14; 1.3 and 2b.15; 1.3 and 2b.16; 1.3 and 2b.17; 1.3 and 2b.18; 1.3 and 2b.19; 1.3 and 2b.20; 1.3 and 2b.21; 1.4 and 2b.1; 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.10; 1.4 and 2b.11; 1.4 and 2b.12; 1.4 and 2b.13; 1.4 and 2b.14; 1.4 and 2b.15; 1.4 and 2b.16; 1.4 and 2b.17; 1.4 and 2b.18; 1.4 and 2b.19; 1.4 and 2b.20; 1.4 and 2b.21; 1.5 and 2b.1; 1.5 and 2b.2; 1.5 and 2b.3; 1.5 and 2b.4; 1.5 and 2b.5; 1.5 and 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.11; 1.5 and 2b.12; 1.5 and 2b.13; 1.5 and 2b.14; 1.5 and 2b.15; 1.5 and 2b.16; 1.5 and 2b.17; 1.5 and 2b.18; 1.5 and 2b.19; 1.5 and 2b.20; 1.5 and 2b.21; 1.6 and 2b.1; 1.6 and 2b.2; 1.6 and 2b.3; 1.6 and 2b.4; 1.6 and 2b.5; 1.6 and 2b.6; 1.6 and 2b.7; 1.6 and 2b.8; 1.6 and 2b.9; 1.6 and 2b.10; 1.6 and 2b.11; 1.6 and 2b.12; 1.6 and 2b.13; 1.6 and 2b.14; 1.6 and 2b.15; 1.6 and 2b.16; 1.6 and 2b.17; 1.6 and 2b.18; 1.6 and 2b.19; 1.6 and 2b.20; 1.6 and 2b.21; 1.7 and 2b.1; 1.7 and 2b.2; 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; 1.7 and 2b.10; 1.7 and 2b.11; 1.7 and 2b.12; 1.7 and 2b.13; 1.7 and 2b.14; 1.7 and 2b.15; 1.7 and 2b.16; 1.7 and 2b.17; 1.7 and 2b.18; 1.7 and 2b.19; 1.7 and 2b.20; 1.7 and 2b.21; 1.12 and 2b.1; 1.12 and 2b.2; 1.12 and 2b.3; 1.12 and 2b.4; 1.12 and 2b.5; 1.12 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.11; 1.12 and 2b.12; 1.12 and 2b.13; 1.12 and 2b.14; 1.12 and 2b.15; 1.12 and 2b.16; 1.12 and 2b.17; 1.12 and 2b.18; 1.12 and 2b.19; 1.12 and 2b.20; 1.12 and 2b.21; 1.14 and 2b.1; 1.14 and 2b.2; 1.14 and 2b.3; 1.14 and 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.10; 1.14 and 2b.11; 1.14 and 2b.12; 1.14 and 2b.13; 1.14 and 2b.14; 1.14 and 2b.15; 1.14 and 2b.16; 1.14 and 2b.17; 1.14 and 2b.18; 1.14 and 2b.19; 1.14 and 2b.20; 1.14 and 2b.21; 1.15 and 2b.1; 1.15 and 2b.2; 1.15 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.10; 1.15 and 2b.11; 1.15 and 2b.12; 1.15 and 2b.13; 1.15 and 2b.14; 1.15 and 2b.15; 1.15 and 2b.16; 1.15 and 2b.17; 1.15 and 2b.18; 1.15 and 2b.19; 1.15 and 2b.20 or 1.15 and 2b.21, in each case optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2b, one of the compounds 2b.2, 2b.3, 2b.4, 2b.8, 2b.10, 2b.11, 2b.13, 2b.19, 2b.20 or 2b.21, containing those combinations which are one of the compounds 2b.2, 2b.4 or 2b.19, according to the invention are particularly significant.

Further according to the invention preferred drug combinations contain, besides one or more, preferred a compound of formula 1 as further active ingredient one or more, preferably a steroid 2c, optionally in combination with pharmaceutical acceptable Excipients.

In such drug combinations, the steroid 2c is preferably selected from the group consisting of prednisolone (2c.1), prednisone (2c.2), butixocortepionate (2c.3), RPR-106541 (2c.4), flunisolide (2c.5), beclomethasone (2c.6), Triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), Dexamethasone (2c.14), 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothionic acid (S) fluoromethyl ester (2c.15), and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-2,4-diene-17β-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl ) ester (2c.16), optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

In particularly preferred drug combinations is the steroid 2c selected from the group consisting of flunisolide (2c.5), beclomethasone (2c.6), Triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), Dexamethasone (2c.14), 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothionic acid (S) -fluoromethylester (2c.15), and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-2,4-diene-17β-carbothionic acid (S) - (2-oxo-tetrahydro furan-3S-yl) ester (2c.16), optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their salts and derivatives, their Solvates and / or hydrates.

In particularly preferred drug combinations is the steroid 2c selected from the group consisting of budesonide (2c.8), fluticasone (2c.9), Mometasone (2c.10), ciclesonide (2c.11) and 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene -17β-carbothionic acid (S) -fluoromethyl ester (2c.15), optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Any reference to steroids 2c includes a reference to their possibly existing ones Salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids 2c may be: alkali metal salts, such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

Examples for preferred according to the invention Drug combinations of preferred compounds of formula 1 with the aforementioned steroids 2c are combinations containing the compounds 1.1 and 2c.1; 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.10; 1.1 and 2c.11; 1.1 and 2c.12; 1.1 and 2c.13; 1.1 and 2c.14; 1.1 and 2c.15; 1.1 and 2c.16; 1.2 and 2c.1; 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 and 2c.10; 1.2 and 2c.11; 1.2 and 2c.12; 1.2 and 2c.13; 1.2 and 2c.14; 1.2 and 2c.15; 1.2 and 2c.16; 1.3 and 2c.1; 1.3 and 2c.2; 1.3 and 2c.3; 1.3 and 2c.4; 1.3 and 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.10; 1.3 and 2c.11; 1.3 and 2c.12; 1.3 and 2c.13; 1.3 and 2c.14; 1.3 and 2c.15; 1.3 and 2c.16; 1.4 and 2c.1; 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.11; 1.4 and 2c.12; 1.4 and 2c.13; 1.4 and 2c.14; 1.4 and 2c.15; 1.4 and 2c.16; 1.5 and 2c.1; 1.5 and 2c.2; 1.5 and 2c.3; 1.5 and 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.10; 1.5 and 2c.11; 1.5 and 2c.12; 1.5 and 2c.13; 1.5 and 2c.14; 1.5 and 2c.15; 1.5 and 2c.16; 1.6 and 2c.1; 1.6 and 2c.2; 1.6 and 2c.3; 1.6 and 2c.4; 1.6 and 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.10; 1.6 and 2c.11; 1.6 and 2c.12; 1.6 and 2c.13; 1.6 and 2c.14; 1.6 and 2c.15; 1.6 and 2c.16; 1.7 and 2c.1; 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.10; 1.7 and 2c.11; 1.7 and 2c.12; 1.7 and 2c.13; 1.7 and 2c.14; 1.7 and 2c.15; 1.7 and 2c.16; 1.12 and 2c.1; 1.12 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.10; 1.12 and 2c.11; 1.12 and 2c.12; 1.12 and 2c.13; 1.12 and 2c.14; 1.12 and 2c.15; 1.12 and 2c.16; 1.14 and 2c.1; 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 2.c.9; 1.14 and 2c.10; 1.14 and 2c.11; 1.14 and 2c.12; 1.14 and 2c.13; 1.14 and 2c.14; 1.14 and 2c.15; 1.14 and 2c.16; 1.15 and 2c.1; 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.10; 1.15 and 2c.11; 1.15 and 2c.12; 1.15 and 2c.13; 1.15 and 2c.14; 1.15 and 2c.15 or 1.15 and 2c.16 each optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2c, are one of the compounds 2c.5, 2c.6, 2c.7, 2c.8, 2c.9, 2c.10, 2c.11, 2c.12, 2c.13, 2c.14, 2c.15 or 2c.16, where those combinations that have a contain the compounds 2c.8, 2c.9, 2c.10, 2c.11 or 2c.15, particularly according to the invention are significant.

Further according to the invention preferred drug combinations contain, besides one or more, preferred a compound of formula 1 as further active ingredient one or more, prefers a LTD4 antagonist 2d, optionally in combination with pharmaceutically acceptable Excipients.

In For such drug combinations, the LTD4 antagonist 2d is preferred selected from the group consisting of montelukast (2d.1), 1 - (((R) - (3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2- hydroxy-2-propyl) phenyl) thio) methylcyclopropaneacetic acid (2d.2), 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridine-5) -yl) - (E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid (2d.3), Pranlukast (2d.4), zafirlukast (2d.5), [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzo [uranyl] oxymethyl] phenyl] acetic acid (2d.6), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8), MEN-91507 (LM-1507) (2d.9), VUF-5078 (2d.10), VUF-K-8707 (2d.11) and L-733321 (2d.12), optionally in the form their racemates, enantiomers or diastereomers, optionally in Form of their pharmacologically acceptable Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

In preferred drug combinations is the LTD4 antagonist 2d selected from the group consisting of Montelukast (2d.1), Pranlukast (2d.4), Zafirlukast (2d.5), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8), MEN-91507 (LM-1507) (2d.9), VUF-5078 (2d.10), VUF-K-8707 (2d.11) and L-733321 (2d.12), optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmakoligisch compatible acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

In particularly preferred drug combinations is the LTD4 antagonist 2d selected from the group consisting of Montelukast (2d.1), Pranlukast (2d.4), Zafirlukast (2d.5), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8) and MEN-91507 (LM-1507) (2d.9), whereby montelukast (2d.1), prranlukast (2d.4) and zafirlukast (2d.5) particularly preferred, optionally in the form of their racemates, Enantiomers or diastereomers, optionally in the form of their pharmacokinetic acceptable Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids optionally forming compounds 2d in their position For example, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydronitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood.

Under Salts or derivatives for their formation, the compounds 2d optionally are capable of being understood, for example, as alkali metal salts, such as sodium or Potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, Acetates, Propionates, Dihydrogen Phosphates, Palmitates, Pivalates or Also Furoate.

Examples for preferred according to the invention Drug combinations of preferred compounds of formula 1 with the aforementioned LTD4 antagonists 2d are combinations containing the compounds 1.1 and 2d.1; 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.10; 1.1 and 2d.11; 1.1 and 2d.12; 1.2 and 2d.1; 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.10; 1.2 and 2d.11; 1.2 and 2d.12; 1.3 and 2d.1; 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 2d.7; 1.3 and 2d.8; 1.3 and 2d.9; 1.3 and 2d.10; 1.3 and 2d.11; 1.3 and 2d.12; 1.4 and 2d.1; 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; 1.4 and 2d.8; 1.4 and 2d.9; 1.4 and 2d.10; 1.4 and 2d.11; 1.4 and 2d.12; 1.5 and 2d.1; 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; 1.5 and 2d.9; 1.5 and 2d.10; 1.5 and 2d.11; 1.5 and 2d.12; 1.6 and 2d.1; 1.6 and 2d.2; 1.6 and 2d.3; 1.6 and 2d.4; 1.6 and 2d.5; 1.6 and 2d.6; 1.6 and 2d.7; 1.6 and 2d.8; 1.6 and 2d.9; 1.6 and 2d.10; 1.6 and 2d.11; 1.6 and 2d.12; 1.7 and 2d.1; 1.7 and 2d.2; 1.7 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; 1.7 and 2d.10; 1.7 and 2d.11; 1.7 and 2d.12; 1.12 and 2d.1; 1.12 and 2d.2; 1.12 and 2d.3; 1.12 and 2d.4; 1.12 and 2d.5; 1.12 and 2d.6; 1.12 and 2d.7; 1.12 and 2d.8; 1.12 and 2d.9; 1.12 and 2d.10; 1.12 and 2d.11; 1.12 and 2d.12; 1.14 and 2d.1; 1.14 and 2d.2; 1.14 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.10; 1.14 and 2d.11; 1.14 and 2d.12; 1.15 and 2d.1; 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.10; 1.15 and 2d.11 or 1.15 and 2d.12, each optionally in the form of their racemates, enantiomers or Diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which are preferred as compound 2d one of the compounds 2d.1, 2d.4, 2d.5, 2d.7, 2d.8, 2d.9, 2d.10, 2d.11 or 2d.12, those combinations which are one of the compounds 2d.1, 2d.4, 2d.5, 2d.7, 2d.8 or 2d.9, according to the invention particularly are significant, with those combinations that one of the compounds 2d.1, 2d.4 or 2d.5, is also important.

Further according to the invention preferred drug combinations contain, besides one or more, preferred a compound of formula 1 as further active ingredient one or more, preferably an EGFR inhibitor 2e, optionally in combination with pharmaceutically acceptable Excipients.

For example, in such drug combinations, the EGFR inhibitor 2e is selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo -2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl] 2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cycl o-propylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo -2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[ 4 - ((R) -2-methoxymethyl-6-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3 chloro-4-fluorophenyl) amino] -6 - ({4- [of N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7- cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- cyclopentyloxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) - N-ethylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4 - [N- (2-methoxy-ethyl) -N-methyl-amine o] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran -4-yl) - N -methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline, 4 - [(3 chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy ) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene -1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo -2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo -2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[ 4- (N, N -dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3 ethinyl-phen yl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy ] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3- d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino } -7-ethoxy-quinoline, 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} - furan-2-yl) quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl] 1-oxo-2-buten-1-yl] amino} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) 1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({ 4- [N, N-bis- (2-methoxy-ethyl) -amino] -1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2 '') 2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4 - [(3-chloro-4-fluoro phenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-aminocyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3 chloro-4-fluoro-phenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-ylo xy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4 -yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4- [ (3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -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) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-) yloxy) -7- (2 -acetylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(piperidin-1-yl) carbonyl] piperidin-4-ylo xy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane 1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] - N -methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexane-1 yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro -phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- (cis-4-acetylamino-cyc lohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline , 4 - [(3-Ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- ( cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- (cis-4- {N - [(4-methyl-piperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) -carbonyl-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- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-Ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1 -methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [( 3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1 -methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] cyclohexane-1-yloxy} -7-methoxy- quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- [1- ( 2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidine 4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-ch inazoline, 4 - [(3-chloro-4-fluoro-phenyl-amino] -6- {1 - [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl ) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl -amino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [ (3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-ylo xy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7 -methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

In such drug combinations, the EGFR inhibitor 2e is more preferably selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -but-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo -2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl] 2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) oxo-2-1-butene -1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- ((R) -2-methoxymethyl-6-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4 -fluorophenyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy- quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) amino] -1-oxo-2-butene 1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N- ethyl-amino] -1-oxo-2-buten-1-yl} -amino) -7-cyclopropyl-methoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} ami no) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] - 1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) - 1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [[ 4- (N, N -dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4 fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline , 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl] -amino} -7 -cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo -2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis- (2-met hoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro) 4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - {[3-chloro 4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-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-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6- { [4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morp holin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholine 4-yl) -ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4- fluorophenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- (trans-4-aminocyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino) cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6-tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl) -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2 -acetylamino-ethyl) -piperidin-4-yloxy) -7-methoxyquinazoline, 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-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans- 4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholine) 4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholine-4- yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-yl) acetylamino-ethoxy) -chi nazoline, 4 - ((3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4 -fluorophenyl) amino] -6- {1- [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (1-aminocarbonylmethyl-piperidin-4-ylo xy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] -N-methyl -amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholine-4- yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-{ N - [(morpholin-4-yl) sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidine-4- yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- [1- (tert.-butyloxycarbonyl) -Pip eridin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro) 4-fluoro-phenyl) amino] -6- (cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(4-methyl-piperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane 1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-1 -yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethyl] -piperidine-4 -yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} - 7- (2-methoxy-ethoxy) quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3 Ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methanesulfonylpiperidine) 4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-f Luoro-phenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] - cyclohexan-1-yloxy} -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl) phenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1- [ (morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2 , 6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [ (2-methyl-morpholin-4-yl) carbonyl] -piperidine = 4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [ (S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) carbonyl ] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino ) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7- methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(2-methoxyethyl) carbonyl] piperidin-4-yloxy} -7-methoxy quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexane-1-y loxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl -amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo) morpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1 -methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy quinazoline, and cetuximab, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

The EGFR inhibitors 2a which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholine-4-] are particularly preferably used in the context of the medicament combinations according to the invention. yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholine) 4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (4-yl) (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-morpholin-4-yl) -ethoxy] -7- methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N- methyl-amino] = 1-oxo-2-buten-1-yl} amino) -7-c ylpropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene -1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene -1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxy -ethoxy) quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-butene 1-yl] amino} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene] 1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2- oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4 - (2-oxo-morpholin-4-yl) piperidin-1-yl] -ethoxy} - 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-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] - piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro -phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholine) 4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-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- (cis-4- {N - [(morpholin-4-yl ) carbonyl] -N-methyl-amino} -cyclohexa n-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3 Ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N- [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(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-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidine 4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3 ethynyl-phenyl) amino] -6- (1-methanesulfonic yl-piperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-yl) methoxyethoxy) quinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) carbonyl] piperidin-4-yloxy} -7-methoxy-quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- [cis-4- (N-acetyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- ( N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino) cyclohexane-1-yloxy) -7-methoxy-chinazo lin, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 -yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidine-4- yloxy) -7-methoxy-quinazoline, 4 - ((3-chloro-4-fluoro-phenyl) -amino] -6- (1-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 their racemates, enantiomers or diastereomers optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin (2e.1),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-rriorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin (2e.2),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)ethoxy]-7-methoxy-chinazolin (2e.3),
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin (2e.4),
• – 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin (2e.5),
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin (2e.6),
• – 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazolin (2e.7),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin (2e.8),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin (2e.9),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-{1-[(morpholin-4-yl)carbonyl)-piperidin-4-yloxy}-7-methoxy-chinazolin (2e.10),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin (2e.11),
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin (2e.12),
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin (2e.13),
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin 2(e.14),
• – 4-[(3-Ethinyl-phenyl)amino)-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin (2e.15),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl)-piperidin-4-yloxy}-7-methoxy-chinazolin (2e.16),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazolin 2e.17),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazolin (2e.18),
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin (2e.19),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazolin (2e.20),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin (2e.21),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin (2e.22),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin (2e.23),
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin (2e.24) und
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-chinazolin (2e.25),

gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.According to the invention particularly preferred drug combinations containing as EGFR inhibitor 2e those compounds which are selected from the group consisting of

• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline (2e.1),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-rioriorolin-4-yl) -1-oxo-2-ol buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline (2e.2),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (2e.3),
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxyquinazoline (2e.4),
• - 4 - [(3-ethynyl-phenyl) -amino] -6,7-bis (2-methoxy-ethoxy) -quinazoline (2e.5),
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran -2-yl) methoxy] quinazoline (2e.6),
• - 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -quinazoline (2e.7),
• 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulphonylamino-cyclohexan-1-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-yloxy} -7-methoxy-quinazoline (2e.10 )
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline (2e.11)
• - 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline (2e.12),
• - 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline (2e.13),
• - 4 - [(3-ethynylphenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline 2 (e.14),
• - 4 - [(3-ethynyl-phenyl) -amino) -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline (2e.15),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl) -piperidin-4-yloxy} -7-methoxy-quinazoline (2e.16),
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline 2e .17)
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino) -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline ( 2e.18)
• 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline (2e.19),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino) -6- [trans-4- (N-methanesulfonyl-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-methyl-amino} -cyclohexane-1 yloxy) -7-methoxy-quinazoline (2e.22),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino) -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline (2e.23),
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino) -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline (2e.24) and
• 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline (2e.25),

optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Under Acid addition salts with pharmacologically acceptable acids optionally forming compounds 2e For example, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, Hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate Understood.

Examples of preferred pharmaceutical combinations according to the invention of preferred compounds of the formula 1 with the abovementioned steroids 2e are combinations comprising the compounds 1.1 and 2e.1; 1.1 and 2e.2; 1.1 and 2e.3; 1.1 and 2e.4; 1.1 and 2e.5; 1.1 and 2e.6; 1.1 and 2e.7; 1.1 and 2e.8; 1.1 and 2e.9; 1.1 and 2e.10; 1.1 and 2e.11; 1.1 and 2e.12; 1.1 and 2e.13; 1.1 and 2e.14; 1.1 and 2e.15; 1.1 and 2e.16; 1.1 and 2e.17; 1.1 and 2e.18; 1.1 and 2e.19; 1.1 and 2e.20; 1.1 and 2e.21; 1.1 and 2e.22; 1.1 and 2e.23; 1.1 and 2e.24; 1.1 and 2e.25; 1.2 and 2e.1; 1.2 and 2e.2; 1.2 and 2e.3; 1.2 and 2e.4; 1.2 and 2e.5; 1.2 and 2e.6; 1.2 and 2e.7; 1.2 and 2e.8; 1.2 and 2e.9; 1.2 and 2e.10; 1.2 and 2e.11; 1.2 and 2e.12; 1.2 and 2e.13; 1.2 and 2e.14; 1.2 and 2e.15; 1.2 and 2e.16; 1.2 and 2e.17; 1.2 and 2e.18; 1.2 and 2e1.9; 1.2 and 2e.20; 1.2 and 2e.21; 1.2 and 2e.22; 1.2 and 2e.23; 1.2 and 2e.24; 1.2 and 2e.25; 1.3 and 2e.1; 1.3 and 2e.2; 1.3 and 2e.3; 1.3 and 2e.4; 1.3 and 2e.5; 1.3 and 2e.6; 1.3 and 2e.7; 1.3 and 2e.8; 1.3 and 2e.9; 1.3 and 2e.10; 1.3 and 2e.11; 1.3 and 2e.12; 1.3 and 2e.13; 1.3 and 2e.14; 1.3 and 2e.15; 1.3 and 2e.16; 1.3 and 2e.17; 1.3 and 2e.18; 1.3 and 2e.19; 1.3 and 2e.20; 1.3 and 2e.21; 1.3 and 2e.22; 1.3 and 2e.23; 1.3 and 2e.24; 1.3 and 2e.25; 1.4 and 2e.1; 1.4 and 2e.2; 1.4 and 2e.3; 1.4 and 2e.4; 1.4 and 2e.5; 1.4 and 2e.6; 1.4 and 2e.7; 1.4 and 2e.8; 1.4 and 2e.9; 1.4 and 2e.10; 1.4 and 2e.11; 1.4 and 2e.12; 1.4 and 2e.13; 1.4 and 2e.14; 1.4 and 2e.15; 1.4 and 2e.16; 1.4 and 2e.17; 1.4 and 2e.18; 1.4 and 2e.19; 1.4 and 2e.20; 1.4 and 2e.21; 1.4 and 2e.22; 1.4 and 2e.23; 1.4 and 2e.24; 1.4 and 2e.25; 1.5 and 2e.1; 1.5 and 2e.2; 1.5 and 2e.3; 1.5 and 2e.4; 1.5 and 2e.5; 1.5 and 2e.6; 1.5 and 2e.7; 1.5 and 2e.8; 1.5 and 2e.9; 1.5 and 2e.10; 1.5 and 2e.11; 1.5 and 2e.12; 1.5 and 2e.13; 1.5 and 2e.14; 1.5 and 2e.15; 1.5 and 2e.16; 1.5 and 2e.17; 1.5 and 2e.18; 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.1; 1.6 and 2e.2; 1.6 and 2e.3; 1.6 and 2e.4; 1.6 and 2e.5; 1.6 and 2e.6; 1.6 and 2e.7; 1.6 and 2e.8; 1.6 and 2e.9; 1.6 and 2e.10; 1.6 and 2e.11; 1.6 and 2e.12; 1.6 and 2e.13; 1.6 and 2e.14; 1.6 and 2e.15; 1.6 and 2e.16; 1.6 and 2e.17; 1.6 and 2e.18; 1.6 and 2e.19; 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.1; 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.10; 1.7 and 2e.11; 1.7 and 2e.12; 1.7 and 2e.13; 1.7 and 2e.14; 1.7 and 2e.15; 1.7 and 2e.16; 1.7 and 2e.17; 1.7 and 2e.18; 1.7 and 2e.19; 1.7 and 2e.20; 1.7 and 2e.21; 1.7 and 2e.22; 1.7 and 2e.23; 1.7 and 2e.24; 1.7 and 2e.25; 1.12 and 2e.1; 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.10; 1.12 and 2e.11; 1.12 and 2e.12; 1.12 and 2e.13; 1.12 and 2e.14; 1.12 and 2e.15; 1.12 and 2e.16; 1.12 and 2e.17; 1.12 and 2e.18; 1.12 and 2e.19; 1.12 and 2e.20; 1.12 and 2e.21; 1.12 and 2e.22; 1.12 and 2e.23; 1.12 and 2e.24; 1.12 and 2e.25; 1.14 and 2e.1; 1.14 and 2e.2; 1.14 and 2e.3; 1.14 and 2e.4; 1.14 and 2e.5; 1.14 and 2e.6; 1.14 and 2e.7; 1.14 and 2e.8; 1.14 and 2e.9; 1.14 and 2.e.10; 1.14 and 2e.11; 1.14 and 2e.12; 1.14 and 2e.13; 1.14 and 2.e.14; 1.14 and 2.e.15; 1.14 and 2e.16; 1.14 and 2e.17; 1.14 and 2.e.18; 1.14 and 2.e.19; 1.14 and 2e.20; 1.14 and 2e.21; 1.14 and 2.e.22; 1.14 and 2e.23; 1.14 and 2.e.24; 1.14 and 2e.25; 1.15 and 2e.1; 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 2e.8; 1.15 and 2e.9; 1.15 and 2e.10; 1.15 and 2e.11; 1.15 and 2e.12; 1.15 and 2e.13; 1.15 and 2e.14; 1.15 and 2e.15; 1.15 and 2e.16, 1.15 and 2e.17; 1.15 and 2e.18; 1.15 and 2e.19; 1.15 and 2e.20; 1.15 and 2e.21; 1.15 and 2e.22; 1.15 and 2e.23; 1.15 and 2.e.24 or 1.15 and 2.e.25, in each case optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

From The above combinations are according to the invention those preferably, as the compound of formula 1 one of the compounds 1.1, 1.5, 1.6, or 1.12, where those combinations, the one of the compounds 1.1 or 1.12, according to the invention particularly are significant. Of the above combinations are further according to the invention those which, as compound 2e, are one of the compounds 2e.1, 2e.2, 2e.3, 2e.4, 2e.10, 2e.11, 2e.14, 2e.16, 2e.17, 2e.18, 2e.19, 2e.20, 2e.21, 2e.22, 2e.23, 2e.24 or 2e.25, where those combinations which are one of the compounds 2e.2, 2e.3 or 2e.4 contain, according to the invention particularly are significant.

The drug combinations according to the invention from compounds of the formula 1 with at least one further active ingredient 2 are not limited on binary drug combinations. The above partly exemplary mentioned combinations, in addition to a compound of formula 1 contain a further active ingredient 2, can furthermore a third or fourth, preferably a third active substance Also included in the aforementioned group of Anticholinergics (2a), PDEIV inhibitors (2b), steroids (2c), LTD4 antagonists (2d) and EGFR inhibitors (2e).

When Alkyl groups are, unless stated otherwise, branched and denotes unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. to Designation of the groups methyl, ethyl, propyl or butyl where appropriate, the abbreviations Me, Et, Prop or Bu used. Unless otherwise stated, The definitions propyl and butyl include all conceivable isomers Shapes of the respective radicals. For example, propyl includes n-propyl and iso-propyl, Butyl includes iso-butyl, sec-butyl and tert-butyl, etc.

When Cycloalkyl groups are, unless stated otherwise, alicyclic Groups with 3 to 6 Kohelnstoffatomen understood. This acts these are the groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to the invention of special Meaning is in the context of the present invention cyclopropyl.

Unless otherwise stated, the alkylene groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms. For example: methylene, ethylene, Propylene or butylene.

When Alkylene-halogen groups are branched unless stated otherwise and unbranched divalent alkyl bridges of 1 to 4 carbon atoms denotes the one, two or three times, preferably twice by a halogen are substituted. Accordingly, as alkylene-OH groups, Unless otherwise stated, branched and unbranched dodecahedra alkyl bridges with 1 to 4 carbon atoms, which are one, two or three times, preferably simply substituted by a hydroxy.

When Alkyloxy groups are branched unless otherwise specified and denotes unbranched alkyl groups having 1 to 4 carbon atoms, the above linked to an oxygen atom are. For example: methylox, ethyloxy, propyloxy or butyloxy. To designate the groups methyloxy, ethyloxy, propyloxy or also butyloxy are optionally also the abbreviations MeO, EtO, PropO or BuO- used. Unless otherwise stated, the definitions include propyloxy and butyloxy all conceivable isomeric forms of the respective radicals. So covered for example, propyloxy n-propyloxy and iso-propyloxy, butyloxy comprises iso-butyloxy, sec. butyloxy and tert-butyloxy etc. Optionally is used in the context of the present invention instead of the name Alkyloxy also used the name alkoxy. To name the groups methyloxy, ethyloxy, propyloxy or butyloxy reach accordingly, if appropriate, the terms methoxy, ethoxy, propoxy or butoxy for use.

When Alkylene-alkyloxy groups are, unless stated otherwise, branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms denotes the one, two or three times, preferably simply by an alkyloxy group are substituted.

Unless otherwise stated, -O-CO-alkyl groups denote branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an ester group. The alkyl groups are bonded directly to the carbonyl carbon of the ester group. In an analogous manner, the term -O-CO-alkyl-halogen group is to be understood. The group -O-CO-CF ₃ stands for trifluoroacetate.

halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless indicated to the contrary, fluorine and bromine are preferred Halogens. The group CO denotes a carbonyl group.

in the Framework of the present invention is under drug combination Components 1 and 2 the common application of both agents in a single dosage form or formulation or the separate Applications of the two active ingredients in separate dosage forms Understood. Be the active ingredients 1 and 2 in separate dosage forms Applied, this separate application can be done simultaneously or in time graded, that is take place in succession.

One Aspect of the present invention relates to above-mentioned drug combinations, which in addition to therapeutically effective amounts of 1 and 2 is a pharmaceutical acceptable excipient contain. One aspect of the present invention relates to above mentioned drugs, which in addition to therapeutically effective amounts of 1 and 2 contain no pharmaceutically acceptable carrier.

The The present invention further relates to the use of therapeutically effective amounts of the active ingredients 1 for producing a further one or more, preferably a drug 2 containing drug for the treatment of inflammatory and obstructive pulmonary diseases, to inhibit premature use Labor in obstetrics (tocolysis), to restore the Sinus rhythm in the heart in atrio-ventricular block, to repair bradykaler Arrhythmia (Antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase the cardiac output) as well as for the treatment of itching and inflammations of the skin.

One preferred aspect of the present invention relates to the use therapeutically effective amounts of the active ingredients 1 for the production a further one or more, preferably a drug 2 containing Drug for the treatment of respiratory diseases selected from the group consisting of obstructive lung diseases different Genesis, pulmonary emphysema of different origin, restrictive lung disease, Interstitial lung diseases, cystic fibrosis, bronchitis different genesis, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.

Preferred is the aforementioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of obstructive pulmonary diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis and COPD (chronic obstructive pulmonary disease), the use for the manufacture of a medicament for Treatment of asthma bronchial and COPD is particularly preferred according to the invention.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of pulmonary emphysema that have their origin in COPD or α1-proteinase inhibitor deficiency.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of restrictive drugs Pulmonary diseases selected are from the group consisting of allergic alveolitis, by triggered professional noxious restrictive lung diseases such as asbestosis or silicosis and restriction due to lung tumors, such as lymphangiosis carcinomatosa, bronchoalveolar Carcinoma and lymphomas.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of interstitials Pulmonary diseases selected are from the group consisting of infectious pneumonia, such as for example due to infection with viruses, bacteria, fungi, Protozoa, helminths or other pathogens, pneumonitis due different causes, such as aspiration and left ventricular failure, Radiation-induced pneumonitis or fibrosis, collagenosis, like For example, lupus erythematosus, sytemische scleroderma or Sarcoidosis, granulomatosis, such as, for example, Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of cystic Fibrosis or cystic fibrosis.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of bronchitis, such as bronchitis due to bacterial or viral Infection, Allergic Bronchitis and Toxic Bronchitis.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of bronchiectasis.

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of ARDS (adult respiratory distress syndrome).

Prefers is also the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.

Especially Preferably, the above-mentioned use of the drug combinations according to the invention relates for the manufacture of a medicament for the treatment of asthma or COPD. Of particular importance is also the aforementioned Use of the drug combinations according to the invention for the manufacture of a medicament for once daily treatment of inflammatory and obstructive airways diseases, especially preferred once daily Treatment of asthma or COPD.

The The present invention further relates to the use of therapeutically effective amounts of an active ingredient of the formula 1 in combination with therapeutically effective amounts of an active ingredient 2 for the preparation of a medicament for the treatment of any of the above Diseases.

The The present invention further relates to a method of treatment one of the aforementioned diseases, which is characterized that, therapeutically effective amounts of an active ingredient of the formula 1 in combination with therapeutically effective amounts of an active ingredient 2 are applied.

Within the scope of the drug combinations according to the invention, for example, 0.1 to 1000 μg of a compound of the formula 1 can be administered per single administration. Preferably, 1 to 500 .mu.g, more preferably 3 to 100 .mu.g of the compound of the formula 1 are administered per single administration, a dosage range from 5 to 75 μg, preferably from 7 to 50 μg, is preferred according to the invention. The medicaments according to the invention are particularly preferably applied in such an amount that 9 to 40 μg, more preferably 11 to 30 μg, furthermore preferably 12 to 25 μg of the compound of formula 1 are administered per single administration. For example, and without limiting the scope of the present invention, 5μg, 7.5μg, 10μg, 12.5μg, 15μg, 17.5μg, 20μg, 22.5μg, 25μg, 27.5μg, 30μg, 32.5μg may be used per single dose , 35μg, 37.5μg, 40μg, 42.5μg, 45μg, 47.5μg, 50μg, 52.5μg, 55μg, 57.5μg, 60μg, 62.5μg, 65μg, 67.5μg, 70μg, 72.5μg or 75μg a compound of formula 1 are applied.

The The above dosages refer to the compounds Formula 1 in the form of its free base. Be the connections of formula 1 in the form of their pharmaceutically acceptable acid addition salts, are the corresponding from the above dose ranges Dose ranges for the Acid addition salts considering The molecular weight of the acids used for the expert easily calculable. Particularly preferred, the compounds of formula 1 are at o.g. Dose ranges in the form of enantiomerically pure compounds, especially preferably applied in the form of their R-enantiomers.

Become the compounds of formula 1 in combination with an anticholinergic 2a, the amount of anticholinergic agent used varies strongly dependent from the choice of the active ingredient.

Without To limit the scope of the invention can be in the case of tiotropium 2a.1 'such quantities to anticholinergic (2a.1 ') be administered, that per single dose 0.1 - 80μg, preferably 0.5 - 60μg, especially preferably about 1 - 50μg 2a.1 'are included. For example and without the subject matter of the present invention to limit it to can per single dose 2.5μg, 5μg, 10μg, 18μg, 20μg, 36μg or 40μg 2a.1 'are applied. The respective amount of salt used 2a.1 or, if appropriate, the use of hydrates or solvates are for the skilled person depending on the choice of anion easily calculable. Is used as According to the invention preferred Tiotropium salt 2a.1, for example tiotropium bromide used correspond the one mentioned above exemplarily applied per single dose Amounts of active ingredient of 2a.1 'the following amounts of 2a.1: 3μg, 6μg, 12μg, 21.7μg, 24.1μg, 43.3μg and 48.1μg 2a.1 applied per single dose. in the Trapped tiotropium 2a.1 'takes place the application of the above dosages preferably once or twice a day, being the once-a-day Application according to the invention particularly is preferred.

Without The scope of the invention may be limited to, in the case of the cation 2a.2 'such amounts Anticholinergic (2a.2 ') be applied, that per single dose 1 - 500μg, preferably 5 - 300μg, especially preferably 15-200μg 2a.2 'are included. For example and without the subject matter of the present invention to limit it to can per single dose 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg or 200 μg 2a.2 '. The respective amount of salt used 2a.2 or, if appropriate, the use of hydrates or solvates are for the skilled person depending on the choice of anion easily calculable. In the event of of oxitropium 2a.2 'takes place the application of the above dosages preferably one to four times a day, taking the two to three times daily Application according to the invention particularly is preferred.

Without The scope of the invention may be limited to, in the case of cation 2a.3 'such amounts Anticholinergic (2a.3 ') be applied, that per single dose 1 - 500μg, preferably 5 - 300μg, especially preferably 15-200μg 2a.3 'are included. For example and without the subject matter of the present invention to limit it to can per single dose 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg or 200 μg 2a.3 '. The respective amount of salt used 2a.3 or, if appropriate, the use of hydrates or solvates are for the skilled person depending on the choice of anion easily calculable. In the event of of the flutropium 2a.3 'takes place the application of the above dosages preferably one to four times a day, taking the two to three times daily Application according to the invention particularly is preferred.

Without limiting the scope of the invention to this, in the case of the cation 2a.4 'such amounts of anticholinergic (2a.4') can be applied that for each single dose 1-500μg, preferably 5 - 300μg, more preferably 20 - 200μg 2a. 4 'are included. For example, and without limiting the subject matter of the present invention, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg or 200μg 2a.4 'are applied. The respective corresponding amount of the used salt 2a.4 or, if appropriate, the use of hydrates or solvates are readily calculable by the person skilled in the art, depending on the choice of anion. In the case of ipratropium 2a.4 ', the dosages mentioned above are preferably administered one to four times daily, with the application of two to three times, particularly preferably three times a day, being particularly preferred according to the invention.

Without To limit the scope of the invention, in the case of the cation 2a.5 'can such amounts Anticholinergic (2a.5 ') be applied, that per single dose 1 - 500μg, preferably 5 - 300μg, especially preferably 15-200 μg are. For example and without the subject matter of the present invention to limit it to can per single dose 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg or 200 μg 2a.5 '. The respective amount of salt used 2a.5 or, if appropriate, the use of hydrates or solvates are for the skilled person depending on the choice of anion easily calculable. In the event of of glycopyrronium 2a.5 ' the application of the above dosages preferably one to four times a day, being the two- to three times a day Application according to the invention particularly is preferred.

Without To limit the scope of the invention thereto, in the case of the cation 2a.6 'such amounts Anticholinergic (2a.6 ') be administered, that per single dose 1000 - 6500μg, preferably 2000 - 6000μg, especially preferably 3000-5500μg, especially preferably 4000 - 5000μg 2a.6 'are included. For example and without the subject matter of the present invention to limit it to can per single dose 3500μg, 3750μg, 4000μg, 4250μg, 4500μg, 4750μg, or 5000μg 2a.6 'applied become. The respective amount of the used Saline 2a.6 or optionally used Hydrates or Solvates are for the skilled person depending on the choice of anion easily calculable. In the event of Trospium 2a.6 'takes place the application of the above dosages preferably one to four times a day, being the two- to three times a day Application according to the invention particularly is preferred.

Without to limit the scope of the invention in the case of the cation 2a.7 'such quantities Anticholinergic (2a.7 ') be administered, that per single dose 50 - 1000μg, preferably 100 - 800μg, especially preferably 200 - 700μg, especially preferably 300 - 600μg 2a.7 'are included. For example and without the subject matter of the present invention to limit it to can 300μg, 350μg, 400μg, 450μg, 500μg, 550μg, or 600μg 2a.7 'are administered per single administration. The respective amount of salt used 2a.7 or, if appropriate, the use of hydrates or solvates for the Expert easily calculable depending on the choice of anion. In the case of Cations 2a.7 'takes place the application of the above dosages preferably one to three times a day, where once to twice, more preferably once daily application particularly according to the invention is preferred.

Without to limit the scope of the invention, in the case of cations 2a.9 'and 2a.10' such quantities Anticholinergic 2a.9 'or 2a.10 ') applied be that per single dose 1 - 500μg, preferably 5 - 300μg, especially preferably 15-200μg 2a.9 'or 2a.10' are included. For example and without the subject matter of the present invention to limit it to can per single dose 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg or 200 μg 2a.9 'or 2a.10'. The respective amount of salt used 2a.9 'or 2a.10' or optionally the use of hydrates or solvates are obvious to those skilled in the art easily calculable depending on the choice of anion. In the case of cations 2a.9 'or 2a.10' the application is carried out the above dosages preferably one to three times Every day, where once to twice, more preferably once daily application particularly according to the invention is preferred.

Without limiting the scope of the invention, in the case of cations 2a.11 'to 2a.13', such amounts of anticholinergic agent (2a.11 ', 2a.12' or 2a.13 ') are applied that 500μg, preferably 5 - 300μg, more preferably 10 - 200μg 2a.11 ', 2a.12' or 2a.13 'are included. For example, and without limiting the scope of the present invention to 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg , 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg or 200 μg 2a.11 ', 2a.12 'or 2a.13' are applied. The ever The amount of salt 2a.11, 2a.12 or 2a.13 used or, if appropriate, the amount of hydrates or solvates used can easily be calculated by the person skilled in the art, depending on the choice of anion.

in the In the case of cations 2a.11, 2a.12 or 2a.13, the application is carried out the above dosages preferably one to three times Every day, where once to twice, more preferably once daily application particularly according to the invention is preferred.

Become the compounds of formula 1 in combination with a PDE IV inhibitor 2b applied, preferably about 1 - 10000μg 2b applied per single dose. Preferably, such amounts of 2b are administered that per single dose 10 - 5000μg, preferred 50 - 2500μg, especially preferably 100-1000 μg 2b are. For example and without the subject matter of the present invention to limit it to can per Single dose 100μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490 μg, 495 μg, 500 μg, 505 μg, 510 μg, 515 μg, 520 μg, 525 μg, 530 μg, 535 μg, 540 μg, 545 μg, 550 μg, 555 μg, 560 μg, 565 μg 615 μg, 620 μg, 625 μg, 630 μg, 635 μg, 640 μg, 645 μg, 650 μg, 655 μg, 660 μg, 665 μg, 670 μg, 675 μg, 680 μg, 685 μg, 690 μg, 695 μg, 700 μg, 705 μg, 710 μg, 715 μg, 720 μg, 725 μg, 730 μg, 735 μg.740 μg, 745 μg, 750 μg, 755 μg, 760 μg, 765 μg, 770 μg, 775 μg, 780 μg, 785 μg, 790 μg, 795 μg, 800 μg, 805 μg, 810 μg, 815 μg, 820 μg, 825 μg, 830 μg, 835 μg, 840 μg, 845 μg, 850μg, 855μg, 860μg, 865μg, 870μg, 875μg, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 930μg, 935μg, 940μg, 945μg, 950μg, 955μg, 960μg, 965μg, 970μg, 975μg, 980μg, 985μg, 990μg, 995μg or 1000μg 2b applied become. For optionally used acid addition salts 2b is the corresponding amount of salt used for the Specialist depending on the choice of acid easily calculable from above values.

Become the compounds of formula 1 in combination with a steroid 2c applied, preferably about 1 - 10000μg 2c are applied per single dose. Preferably, such amounts of 2c are administered that per single dose 5 - 5000μg, preferred 5 - 2500μg, especially preferably 10 - 1000μg contain 2c are. For example and without the subject matter of the present invention to limit it to can per single dose 10μg, 15g, 20g, 25g, 30g, 35g, 40g, 45g, 50g, 55g, 60g, 65g 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 515μg, 520μg, 525 μg, 530 μg, 535 μg, 540 μg, 545 μg, 550 μg, 555 μg, 560 μg, 565 μg, 570 μg, 575 μg, 580 μg, 585 μg, 590 μg, 595 μg, 600 μg, 605 μg, 610 μg, 615 μg, 620 μg, 650μg, 655μg, 6 60 μg, 665 μg, 670 μg, 675 μg, 680 μg, 685 μg, 690 μg, 695 μg, 700 μg, 705 μg, 710 μg, 715 μg, 720 μg, 725 μg, 730 μg, 735 μg, 740 μg, 745 μg, 750 μg, 755 μg, 760 μg, 765 μg, 770 μg 785 μg, 790 μg, 795 μg, 800 μg, 805 μg, 810 μg, 815 μg, 820 μg, 825 μg, 830 μg, 835 μg, 840 μg, 845 μg, 850 μg, 855 μg, 860 μg, 865 μg, 870 μg, 875 μg, 880 μg, 885 μg, 890 μg, 895 μg, 900 μg, 905 μg 910 μg, 915 μg, 920 μg, 925 μg, 930 μg, 935 μg, 940 μg, 945 μg, 950 μg, 955 μg, 960 μg, 965 μg, 970 μg, 975 μg, 980 μg, 985 μg, 990 μg, 995 μg or 1000 μg 2c. For any salts or derivatives that may be used of 2c is the corresponding amount of salt / derivative used for the Professional depending on the choice of salt / derivative from the above values easy to calculate.

Become the compounds of formula 1 in combination with a LTD4 antagonist 2d, preferably about 0.01-500mg 2d per single dose are applied. Preferably, such amounts of 2d are administered that per single dose 0.1 - 250mg, preferably 0.5-100 mg, particularly preferably 1-50 mg 2d are included. For example and without the subject matter of the present To limit the invention to this can be per Single dose lmg, 2.5mg, 5mg, 5.5mg, 7mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg or 50mg 2d are applied. If necessary used acid addition salts, Salts or derivatives of 2d is the corresponding amount of the Use of arriving salt / derivative for the expert depending on your choice of the salt / derivative from above values easily calculable.

Become the compounds of formula 1 in combination with an EGFR inhibitor 2e applied, preferably about 100 - 15000μg 2e are applied per single dose. Preferably, such amounts of 2e are administered that per single dose 500 - 10000μg, preferred 750 - 8000μg, especially preferably 1000 - 7000μg 2e included are. For example and without the subject matter of the present invention to limit it to can per single dose 1000μg, 1150μg, 1200μg, 1250μg, 1300μg, 1350μg, 1400μg, 1450μg, 1500μg, 1550μg, 1600μg, 1650μg, 1700μg, 1750μg, 1800μg, 1850μg, 1900μg, 1950μg, 2000μg, 2050μg, 2100μg, 2150μg, 2200μg, 2250μg, 2300μg, 2350μg, 2400μg, 2450μg, 2500μg, 2550μg, 2600μg, 2650μg, 2700μg, 2750μg, 2800μg, 2850μg, 2900μg, 2950μg, 3000μg, 3050μg, 3100μg, 3150μg, 3200μg, 3250μg, 3300μg, 3350μg, 3400μg, 3450μg, 3500μg, 3550μg, 3600μg, 3650μg, 3700μg, 3750μg, 3800μg, 3850μg, 3900μg, 3950μg, 4000μg, 4050μg, 4100μg, 4150μg, 4200μg, 4250μg, 4300μg, 4350μg, 4400μg, 4450μg, 4500μg, 4550μg, 4600μg, 4650μg, 4700μg, 4750μg, 4800μg, 4850μg, 4900μg, 4950μg, 5000μg, 5050μg, 5100μg, 5150μg, 5200μg, 5250μg 5300μg 5350μg 5400μg 5450μg 5500μg 5550μg 5600μg 5650μg 5700μg 5750μg 5800μg 5850μg 5900μg 5950μg 6000μg 6050μg 6100μg 6150μg 6200μg 6250μg 6300μg 6350μg 6400μg 6450μg 6500μg, 6550μg, 6600μg, 6650μg, 6700μg, 6750μg, 6800μg, 6850μg, 6900μg, 6950μg, or 7000 g 2e applied become. For optionally used acid addition salts of 2e is the corresponding amount of salt used for the Specialist depending on the choice of acid easily calculable from above values.

The Both active ingredient components 1 and 2 can - together or spatially separated - each in a conventional manner by inhalation, orally, parenterally or on other ways in as far as possible Formulations such as tablets, dragees, pills, granules, Aerosols, syrups, emulsions, suspensions, powders and solutions, using inert, non-toxic, pharmaceutically acceptable Carriers or Solvent, be applied.

suitable Application forms for the application of the compounds of the formula 1 and 2 are, for example, tablets, capsules, suppositories, solutions, powders, etc. The proportion the pharmaceutically active compounds) should each be in the range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the total composition lie. Corresponding tablets, for example, by mixing the active ingredient (s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, like cornstarch or alginic acid, Binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or Means for achieving the depot effect, such as carboxymethylcellulose, Cellulose acetate phthalate, or polyvinyl acetate. The Tablets can too consist of several layers.

Corresponding can Dragees by coating of cores produced analogously to the tablets with usually used in dragee coatings Agents, such as Kollidon or shellac, gum arabic, Talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities the core also consist of several layers. Likewise also the dragee cover to obtain a depot effect of several layers, using the excipients mentioned above for the tablets can be.

Juices of active ingredients according to the invention or combinations of active substances may additionally contain a sweetener, such as saccharin, cyclamate, glycerine or sugar as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. she can Furthermore Suspending adjuvants or thickening agents, such as sodium carboxymethylcellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents such as p-hydroxybenzoates.

Solutions will be in usual Way, e.g. with the addition of isotonizing agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, for example, when using water as a diluent optionally organic solvents as a solubilizer or Hilflösungsmittel can be used produced and in injection bottles or ampoules or infusion bottles bottled.

The one or more active substances or combinations of active substances containing capsules For example, be prepared by using the active ingredients inert carriers, like lactose or sorbitol, mixed and encapsulated in gelatine capsules.

suitable suppository can be, for example, by mixing with designated Carriers, such as neutral fats or polyethylene glycol or its derivatives.

When Excipients are, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g., petroleum fractions), vegetable oils Origin (for example, peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerine), excipients such as. natural Minerals (e.g., kaolins, clays, talc, chalk) synthetic Minerals (e.g., fumed silica and silicates), sugars (e.g. Pipe, milk and dextrose) Emulsifying agents (for example lignin, Methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, Talc, stearic acid and sodium lauryl sulfate).

in the Case of oral use can the tablets of course except the said carriers also additives, such as. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants, such as magnesium stearate, Sodium lauryl sulfate and talc are used for tableting. In the case of aqueous suspensions can the active ingredients except the abovementioned excipients with different flavor enhancers or dyes are added.

Preferably is also in separate application of the two components 1 and 2 at least the component 1 is administered by inhalation. Will the component 1 administered by inhalation, component 2 may be administered separately the two active ingredients, for example, orally or parenterally based on the prior art more common Formulations such as tablets, dragees, pills, granules, aerosols, Syrups, emulsions, suspensions, powders and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents, be applied.

Preferably are the drug combinations of the invention however, by inhalation by means of a single, both active ingredients 1 and 2 or by means of separate, in each case only one of Active ingredients 1 and 2 containing, for inhalation use applied to appropriate dosage forms.

When inhalable dosage forms come inhalation powder, propellant-containing Metered aerosols or propellant-free inhalable solutions into consideration. Inventive inhalable powders containing the active ingredient combination of 1 and 2 alone from the named active substances or from a mixture of the named active substances with physiologically compatible Excipients exist. In the context of the present invention are of the term propellant-free inhalable solutions also concentrates or sterile, ready-to-use inhalation solutions. The dosage forms according to the invention can the drug combination of 1 and 2 either together in one or in two separate presentations. This in the frame Be used in the present invention dosage forms in the following part of the description described in detail.

A) containing inhalation powder the active compound combinations according to the invention:

The inhalable powder according to the invention can 1 and 2 either alone or in admixture with appropriate physiological safe excipients included.

are the active compounds 1 and 2 in a mixture with physiologically acceptable May contain adjuvants to illustrate these inhalable powders of the invention, the following Physiologically acceptable excipients are used: Monosaccharides (e.g., glucose or arabinose), disaccharides (e.g. Lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (e.g., dextrans), polyalcohols (e.g., sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate) or mixtures of these excipients together. Preferably mono- or disaccharides are used, wherein the use of lactose, trehalose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred.

Within the scope of the inhalable powders according to the invention, the auxiliaries have a maximum mean particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If appropriate, it may appear appropriate to add finer excipient fractions having a mean particle size of 1 to 9 μm to the auxiliaries mentioned above. The latter finer excipients are also selected from the aforementioned group of usable excipients. Finally, micronized active compound 1 and 2, preferably having an average particle size of 0.5 to 10 .mu.m, more preferably 1 to 6 .mu.m, are admixed with the adjuvant or excipient mixture to produce the inhalable powders according to the invention. Methods for producing the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art. The inhalable powders according to the invention may be either in the form of a single powder mixture containing both 1 and 2 or in the form of separate inhalable powders containing only 1 and 2 2 included and applied.

The inhalable powder according to the invention can applied by inhalers known from the prior art become.

Inhalable powders according to the invention, which in addition to 1 and 2 also contain a physiologically acceptable excipient, can be administered, for example, by means of inhalers which deliver a single dose from a supply by means of a measuring chamber as described in US Pat US 4570630A or other apparatus as described in the DE 36 25 685 A be described, dose. The inhalable powders according to the invention which contain 1 and 2 optionally in conjunction with a physiologically acceptable excipient, for example, by means of the known by the name Turbuhaler ^® inhaler or using inhalers as described for example in the EP 237507 A be disclosed, applied. Preferably, the inhalable powders according to the invention, which in addition to 1 and 2 contain physiologically acceptable excipient, but filled into capsules (called inhalers), which are used in inhalers as described for example in WO 94/28958, used.

A particularly preferred inhaler for use of the drug combination according to the invention in inhalants is 1 refer to.

This inhaler (Handihaler ^® ) for the inhalation of powdered medicines from capsules is characterized by a housing 1, comprising two windows 2, a deck 3, in which there are air inlet openings and which is provided with a sieve 5 attached via a screen 4, one with Deck 3 connected inhalation chamber 6, on which a provided with two ground needles 7, is provided against a spring 8 movable pusher 9, and a hinged via an axis 10 with the housing 1, the deck 3 and a cap 11 mouthpiece 12, and Air passage holes 13 for adjusting the flow resistance.

Should the inhalable powders according to the invention in the sense of the above-mentioned preferred use in capsules bottled can be filled from 1 to 30mg per capsule. These contain according to the invention either together or in each case the doses already mentioned above for 1 and 2 per single dose.

B) Propellant-containing inhalation aerosols containing the active compound combinations according to the invention:

Propellant gas-containing according to the invention Inhalation aerosols can 1 and 2 dissolved in the propellant gas or in dispersed form. Here can 1 and 2 in separate Dosage forms or in a common dosage form included where 1 and 2 are either both dissolved, both dispersed or only one component solved and the other may be dispersed.

The can be used for the preparation of the inhalable aerosols according to the invention Propellant gases are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halocarbons as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can thereby used alone or in mixtures thereof. Especially preferred propellants are halogenated alkane derivatives selected from TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, wherein the propellants TG134a, TG227 and Mixtures thereof are preferred.

The according to the invention propellant gas Inhalation aerosols can further components such as cosolvents, stabilizers, surface-active Agents (surfactants), antioxidants, lubricants and agents for Adjustment of pH included. All these ingredients are known in the art.

The propellant gas-containing according to the invention Inhalation aerosols can up to 5% by weight of active ingredient 1 and / or 2. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 up to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1% by weight to drug 1 and / or 2.

Lie the active compounds 1 and / or 2 in dispersed form before have the Active substance particles preferably have a mean particle size of up to to 10 μm, preferably from 0.1 to 6 μm, more preferably from 1 to 5 microns on.

The abovementioned propellant gas-containing inhalation aerosols according to the invention can by inhalers known in the art (MDIs = metered dose inhalers). Accordingly, another concerns Aspect of the present invention Drugs in the form of as above described propellant-containing aerosols in conjunction with a or more inhalers suitable for administering these aerosols. Furthermore, the present invention relates to inhalers, characterized in that they propellant-containing aerosols according to the invention described above contain.

The The present invention further relates to cartridges equipped with a suitable valve in a suitable inhaler for use can reach and the one of the abovementioned propellant gas-containing according to the invention Inhalation aerosols. Suitable cartridges and methods for bottling of these cartridges with the propellant-containing inhalation aerosols according to the invention are known from the prior art.

C) LPG-free inhalation solutions or Suspensions containing the active compound combinations according to the invention:

According to propellant-free inhalation solutions contain, for example, aqueous or alcoholic, preferably ethanolic, optionally ethanolic in a mixture with aqueous Solvents. In the case of aqueous / ethanolic Solvent mixtures the relative proportion of ethanol to water is not limited, however, the maximum limit is preferably up to 70% by volume, especially up to 60% ethanol by volume. The remaining Volume percentages are filled up with water. The 1 and 2 are separated or jointly containing solutions or suspensions are treated with appropriate acids to a pH of 2 to 7, preferably set from 2 to 5. To set this pH can acids selected find use of inorganic or organic acids. Examples for special suitable inorganic acids are hydrochloric acid, hydrobromic, Nitric acid, sulfuric acid and / or phosphoric acid. examples for particularly suitable organic acids are: ascorbic acid, Citric, malic, tartaric, maleic, succinic, fumaric, acetic, formic and / or propionic and other. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It can also the acids Already used with one of the active ingredients an acid addition salt form. Among the organic acids are ascorbic acid, fumaric acid and citric acid prefers. If necessary, you can also mixtures of the acids mentioned be used, in particular in cases of acids, in addition to their Säuerungseigenschaften also other properties, e.g. as flavorings, antioxidants or complexing agents, such as citric acid or Ascorbic acid. Particularly according to the invention hydrochloric acid is preferred used to adjust the pH.

According to the invention, in of the present formulation on the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agents are dispensed with.

Other embodiments include this compound (s).

In Such a preferred embodiment the content based on sodium edetate is below 100 mg / 100 ml, preferred below 50mg / 100ml, more preferably below 20mg / 100ml. As a general rule are such inhalation solutions preferred in which the content of sodium edetate at 0 to 10mg / 100ml lies.

The propellant-free according to the invention inhalation solutions can Co-solvents and / or other auxiliaries are added.

preferred Co-solvents are those containing hydroxyl groups or other polar ones Contain groups, for example alcohols - especially isopropyl alcohol, Glycols - in particular Propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, Glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

By auxiliaries and additives is meant in this context any pharmacologically acceptable substance which is not an active ingredient but which can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, Vi Tamine and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.

To counting the preferred excipients Antioxidants, such as ascorbic acid, if not already for the setting of the pH used, vitamin A, vitamin E, tocopherols and the like in the human organism occurring vitamins or provitamins.

preservatives can Be used to the formulation before contamination with germs too protect. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or Benzoates such as sodium benzoate in the well-known in the art Concentration. The above-mentioned preservatives are preferably in concentrations of up to 50mg / 100ml, more preferably between 5 and 20mg / 100ml.

preferred Formulations include except the solvent Water and the drug combination of 1 and 2 only benzalkonium chloride and sodium edetate. In another preferred embodiment dispensed with sodium edetate.

to Application of propellant-free invention inhalation solutions Especially those inhalers that contain a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutic inhalation can aerosolize suitable aerosol. Within the scope of the present invention, such nebulizers are preferred. where already an amount of less than 100μL, preferably less than 50μL, especially preferably between 10 and 30μL drug solution with preferably a stroke to an aerosol with an average Particle size of less than 20μm, preferably less than 10 μm, be so fogged that the inhalable portion of the aerosol already the therapeutically effective Quantity corresponds.

Such a device for propellant-free administration of a metered amount of a liquid medicament for inhalation use, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (there in particular 6a and 6b ) described in detail. The nebulisers (devices) described therein are also known by the name Respimat ^®.

The The aforementioned representatives of the active ingredients 2 are in the state of Technique known. On the other hand, the compounds of the formula 1 are still not known in the art. The synthesis examples described below serve the illustration of possible synthetic access to the new compounds of formula 1. However, they are only as exemplary procedures for further explanation to understand the invention without selbige on the examples below limited to the subject matter described.

Example 1.1: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine-3 -one

a) 8- {2- [1,1-dimethyl-2- (4-methoxyphenyl) ethylamino] -1-hydroxy-ethyl} -6-benzyloxy-4H-benzo [1,4] oxazine-3- on

To a solution of 3.6 g of 1,1-dimethyl-2- (4-methoxyphenyl) ethylamine in 100 ml of ethanol at 70 ° C., 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one ) -glyoxalhydrat and allowed to stir for 15 minutes. Subsequently, 1 g of sodium borohydride are added within 30 minutes at 10 to 20 ° C. It is stirred for one hour, mixed with 10 ml of acetone and stirred for a further 30 minutes. The reaction mixture is diluted with 150 mL of ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 ml of methanol and 100 ml of ethyl acetate and treated with conc. Hydrochloric acid acidified. After addition of 100 ml of diethyl ether, the product precipitates. The crystals are filtered off, washed and recrystallized in 50 ml of ethanol.
Yield: 7 g (68%, hydrochloride); Mp = 232-234 ° C.

b) 8- {2- [1,1-dimethyl-2- (4-methoxyphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 on

6.8 g of the benzyl compound obtained above are hydrogenated in 125 ml of methanol with the addition of 1 g of palladium on carbon (5% strength) at room temperature and atmospheric pressure. The catalyst is filtered off and the filtrate is freed from the solvent. After recrystallization of the residue in 50 ml of acetone and a little 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 can be prepared from the racemate, for example by chiral HPLC (e.g., column: Chirobiotic T of the company Astec, 250 × 22.1 mm, 5 μm). As a mobile phase methanol can be used with 0.05% triethylamine and 0.05% acetic acid be used. The retention times of the R- and S-enantiomers are depending on the river between 35 and 65 minutes with the R-enantiomer eluting first. The two Enantiomers are prepared by this method in the form of the free bases receive. According to the invention of outstanding Meaning is the R-enantiomer of Example 1.1.

Example 1.2: 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine one 3-

a) 8- {2- [1,1] -dimethyl-2- (4-phenoxy-acetic acid ethyl ester) -ethylamino] -1-hydroxy-ethyl} -6-benzyloxy-4H-benzo [1,4] oxazine-3 -one

Analogously to the procedure described under Example 1.1a), from 15 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one) -glyoxalhydrat and 11.8 g of 1,1-dimethyl-2- (4-phenoxy ethyl acetate) -ethylamine hydrochloride, the title compound.
Yield: 16.5 g (69%, hydrochloride); Mp = 212-214 ° C.

b) 8- {2- [1,1-dimethyl-2- (4-phenoxy-acetic acid ethyl ester) -ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3- on

8 g of the benzyl alcohol obtained above are dissolved in 100 ml of ethanol, 100 ml of methanol and 10 ml of water and hydrogenated in the presence of 1 g of palladium on carbon (5% strength). After taking up the theoretically calculated amount of hydrogen, the catalyst is filtered off and the filtrate is concentrated. The crystallizing out on distilling off the solvent product is filtered off with suction and washed.
Yield: 5.5 g (81%, hydrochloride); M.p. = 137-140 ° C.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.3: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine-3 -one

11 g of 8- {2- [1,1-dimethyl-2- (4-phenoxyacetic acid ethyl ester) ethylamino] -1-hydroxyethyl} -6-benzyloxy xy-4H-benzo [1,4] oxazin-3-one hydrochloride (Example 4a) are dissolved in 125 ml of methanol and hydrogenated in the presence of 1 g of palladium on carbon (5% strength). After taking up the theoretically calculated amount of hydrogen, the catalyst is filtered off. 2.6 g of sodium hydroxide dissolved in 20 ml of water are added to the filtrate. The mixture is allowed to reflux for 30 minutes, the methanol is distilled off and mixed with 10 ml of water, 20 ml of n-butanol and 3.9 ml of acetic acid. The precipitated solid is filtered off with suction and washed with diethyl ether.
Yield: 7 g (87%). By recrystallization from 0.5 molar hydrochloric acid, the hydrochloride is obtained. M.p. = 152 ° C.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.4: 8- {2- [1,1-Dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one

a) 1- (6-Benzyloxy-4H-benzo [1,4-oxazin-3-one) -2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylimino] -ethanone

7.2 g (6-Benzyloxy-4H-benzo [1,4] oxazin-3-one) -glyoxalhydrate and 3.6 g 1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamine are heated to 70 ° C in 100 ml of ethanol for one hour. After cooling, the precipitated crystals and filtered with ethanol and diethyl ether washed. Yield: 8.6 g (94%); M.p. = 175 ° C.

b) 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -1-hydroxy-ethyl} -6-benzyloxy-4H-benzo [1,4] oxazine one 3-

8.6 g of Schiff's base obtained according to procedure 1.4a) are dissolved in 100 ml of ethanol and 20 ml of THF, treated within 30 min at 10-20 ° C with 0.7 g of sodium borohydride and stirred for one hour. After addition of 10 ml of acetone is stirred for 30 minutes and then diluted with ethyl acetate and water. The acidification with conc. Hydrochloric acid crystallizing product is filtered off and washed.
Yield: 7.4 g (80%, hydrochloride); Mp = 235 ° C (decomposition).

c) 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine one 3-

7.4 g of the benzyl compound obtained in step b) are dissolved in 125 ml Methanol with the addition of 1 g of palladium on carbon (5%) at room temperature and normal pressure hydrogenated. Subsequently, the catalyst is filtered off and the filtrate concentrated. The crystallizing out with the addition of acetone Product is filtered off with suction and washed with acetone and diethyl ether. Yield: 5 g (78%, hydrochloride); Mp. 160 ° C (decomposition).

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.5: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine-3 -one

a) 8- {2- [1,1-dimethyl-2- (4-hydroxyphenyl) -ethylamino] -1-hydroxy-ethyl} -6-benzyloxy-4H-benzo [1,4] oxazine-3 on

The title compound is prepared from 10 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one) -glyoxalhydrat and 4.6 g of 1,1-dimethyl-2- (4-hydroxy-phenyl) -ethylamine analogous to the procedure for example 1.1a).
Yield: 9.0 g (64%, hydrochloride); M.p. = 255-258 ° C.

b) 8- {2- [1,1-Dimethyl-2- (4-hydroxyphenyl) -ethylamino] -1-hydroxy-ethyl} -hydroxy-4H-benzo [1,4] oxazin-3-one

5.7 g of the coupling product obtained above are in the presence of 0.6 g of palladium on carbon (5%) in 100 mL of methanol. After taking up the theoretically calculated amount of hydrogen the catalyst is filtered off and the filtrate from the solvent freed. The residue is under warming in Ethanol dissolved and then treated with diethyl ether. The failing product will filtered off and recrystallized once in water. Yield: 3.6 g (72%, hydrochloride); M.p. = 159-162 ° C.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.6: 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one

a) 1- (4-Isopropyl-phenyl) -2-methyl-propan-2-ol

Reaction of a Grignard compound prepared from 20 g (119 mmol) of 4-isopropylbenzyl chloride with 11.4 ml (155 mmol) of acetone affords the title compound as a colorless oil. Yield: 13.0 g (57%); Mass spectrometry: [M + H] ⁺ = 193.

b) N- [2- (4-Isopropyl-phenyl) -1,1-dimethyl-ethyl] -acetamide

A Ritter reaction is carried out with 10.2 g (53 mmol) of 1- (4-isopropyl-phenyl) -2-methyl-propan-2-ol in the manner described for example 1.7b). The reaction mixture is poured into ice-water and made alkaline with sodium hydroxide solution, whereby a solid precipitates. This is sucked off and dried. Yield: 9.90 g (80%); Mass spectrometry: [M + H] ⁺ = 234.

c) 2- (4-Isopropylphenyl) -1,1-dimethyl-ethylamine

implementation of 9.80 g (42 mmol) of N- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethyl] -acetamide in analogy to the regulation for Example 1.7c). Yield: 7.00 g (71%, hydrochloride); Mp 202-206 ° C.

d) 6-Benzyloxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazine-3- on

2.18 g (6.1 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 1.1 g (5.8 mmol) of 2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamine be one hour at 50-80 ° C stirred in 40 mL of ethanol. After cooling At room temperature, 0.24 g (6.3 mmol) of sodium borohydride are added. One lets one Stirring hour, dilute with 5 mL acetone and leaves more Stir for 30 minutes. The reaction mixture is acidified with hydrochloric acid, with 100 mL of water and 80 mL ethyl acetate and made alkaline with ammonia. The organic phase is separated, dried with sodium sulfate and of the solvent freed. The residue is dissolved in 20 mL of ethyl acetate and 10 mL of water, acidified with conc. Hydrochloric acid sour and diluted with diethyl ether. After addition of a crystallization aid the precipitated solid is filtered off with suction and washed. White solid. Yield: 1.7 g (52%, hydrochloride); Mp. 220-222 ° C.

e) 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one

1.6 g (3.0 mmol) of 6-benzyloxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one are dissolved in methanol and hydrogenated with palladium on carbon catalyst at normal pressure and room temperature. The catalyst is filtered off with suction, the solvent is distilled off and the residue is crystallized out in isopropanol. White solid. Yield: 1.1 g (85%, hydrochloride); Mp 248-250 ° C; Mass spectrometry: [M + H] ⁺ = 399.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.7: 8- {2- [2- (4-Ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} 1-6-hydroxy-4H-benzo [1,4] oxazine-3-one on

a) 1- (4-ethyl-phenyl-2-methyl-propan-2-ol

To 39 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether are added with cooling 14.8 g (90 mmol) of 1- (4-ethyl-phenyl) -propan-2-one, dissolved in diethyl ether, added dropwise so that the temperature does not rise above 30 ° C. After the end of the addition you leave the reaction mixture reflux for 1.5 hours and then hydrolyzed with 10% Ammnoniumchlorid solution. After separation of the organic phase, the aqueous phase with diethyl ether extracted. The combined ether phases are washed with water, dried with sodium sulfate and concentrated. The oil thus obtained becomes direct implemented further. Yield: 15.5 g (90%).

b) N- [2- (4-ethyl-phenyl) -1,1-dimethyl-ethyl] -acetamide

To 15.5 g (87 mmol) of 1- (4-ethyl-phenyl) -2-methyl-propan-2-ol in 4.8 mL (91 mmol) acetonitrile and 15 mL glacial acetic acid are dissolved within 15 minutes 6.2 mL conc. Sulfuric acid added dropwise, with the temperature up 65 ° C increases. Subsequently stir for an hour, diluted with ice water and with conc. Sodium hydroxide solution made alkaline. After further stirring for 30 minutes the precipitated solid is filtered off with suction and washed with water. The crude product is dissolved in ethyl acetate, dried with sodium sulfate and concentrated. The remaining oil is added with petroleum ether, whereby a solid precipitates, which is filtered off and dried. Yield: 16.3 g (85%); M.p. 90-92 ° C.

c) 22- (4-ethylphenyl) -1,1-dimethyl-ethylamine

16.3 g (74 mmol) of N- [2- (4-ethyl-phenyl) -1,1-dimethyl-ethyl] -acetamide and 8.0 g of potassium hydroxide are over Refluxed in 60 mL of ethylene glycol for 15 hours. The reaction mixture is added with ice-water and extracted three times with diethyl ether. The combined organic phases are washed with water, dried with sodium sulfate and freed from the solvent. For the production of the hydrochloride, the crude product is dissolved in acetonitrile and successively with ethereal hydrochloric acid and diethyl ether. The precipitated solid is sucked off and dried. Yield: 11.0 g (69%, hydrochloride); M.p. 165-167 ° C.

d) 6-Benzyloxy-8- {2- [2- (4-ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [1,4] oxazin-3-one

The Target compound is in analogy to the procedure for Example 1.6d) from 2.14 g (6.0 mmol) 6-Benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 1.0 g (5.6 mmol) of 2- (4-ethyl-phenyl) -1,1-dimethyl-ethylamine. white Solid. Yield: 1.7 g (54%, hydrochloride); Mp 210-214 ° C.

e) 8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3-one on

Hydrogenolysis of 1.45 g (2.75 mmol) of 6-benzyloxy-8- {2- [2- (4-ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [1 , 4] Oxazin-3-one according to the procedure for Example 1.6e) gives the target compound in the form of a white solid. Yield: 1.07 g (92%, hydrochloride); Mp 266-269 ° C; Mass spectrometry: [M + H] ⁺ = 385.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.8: 8- {2- [2- (4-Fluoro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one

a) 1-Fluoro-2-methyl-4- (2-methyl-propenyl) -benzene

100 mL of a 0.5 molar solution of 4-fluoro-3-methyl-phenylmagnesium bromide in THF are within of 30 minutes with 4.7 mL (50 mmol) of isopropyl aldehyde, where the temperature at 45 ° C increases. It is stirred for 30 minutes, Refluxed for 1 hour and then hydrolyzed with 10% ammonium chloride solution. After separation of the organic phase extracted with diethyl ether. The organic phases are combined, dried and concentrated. The alcohol thus obtained is dissolved in 100 ml of toluene, with 1 g of p-toluenesulfonic acid Monohydrate added and heated for three hours on a water at reflux. The Reaction mixture is poured onto water and treated with conc. caustic soda alkaline. After separation of the organic phase, this becomes washed with water, dried with sodium sulfate and freed from the solvent. Fractional distillation of the residue yields the product in the form of a colorless liquid (bp. 80-85 ° C / 10 mbar). Yield: 4.1 g (50%).

b) N- [2- (4-fluoro-3-methyl-phenyl) -1,1-dimethyl-ethyl] -formamide

To 1.5 g (31 mmol) of sodium cyanide in 5 mL of glacial acetic acid are added at 5-15 ° C 4.9 mL conc. Sulfuric acid added dropwise. Subsequently The mixture is treated with 3.9 g (24 mmol) of 1-fluoro-2-methyl-4- (2-methyl-propenyl) -benzen, dissolved in 10 mL glacial acetic acid, mixed and stirred for 1 hour at 50-60 ° C. The reaction mixture is diluted with ice water, with conc.

caustic soda made alkaline and extracted with dichloromethane. The organic Phase is dried with sodium sulfate and in vacuo from the solvents freed. The slightly yellow oil thus obtained is reacted further directly. Yield: 4.3 g (87%).

c) 2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamine

4.3 g (20.6 mmol) N- [2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethyl] -formamide, 20 mL conc. hydrochloric acid and 20 mL of water are over Heated under reflux for 2 hours. you dilute the reaction mixture with water, with conc. Caustic soda alkaline and extracted with dichloromethane. The organic phases become dried with sodium sulfate and concentrated. The residue is dissolved in ethyl acetate, with ethereal hydrochloric acid offset and cooled. The precipitated crystals are filtered off with suction and diethyl ether washed and dried. white Solid. Yield: 3.9 g (87%, hydrochloride), mp 196-198 ° C.

d) 6-Benzyloxy-8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [1,4] oxazin-3-one

1.10 g (3.1 mmol) benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -4 H -benzo [1,4] oxazin-3-one and 0.50 g (2.8 mmol) of 2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamine be log on to the regulation for Example 1.6d) implemented and worked up. White solid. Yield: 0.75 g (47%, hydrochloride); Mp 228-230 ° C.

e) 8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

The hydrogenation of 0.70 g (1.4 mmol) of 6-benzyloxy-8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4H benzo [1,4] oxazin-3-one provides the target compound as a white solid. Yield: 0.50 g (87%, hydrochloride); Mp 278-280 ° C; Mass spectroscopy: [M + H] ⁺ = 389.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.9: 8- {2- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one

a) Acetic acid 1- (4-fluoro-2-methyl-phenyl) -2-methyl-propyl ester

500 mL of a 0.5 molar solution of 4-fluoro-6-methylphenylmagnesium bromide and 23.2 mL (260 mmol) Isopropyl aldehyde are reacted analogously to Example 1.8a). After hydrolysis with 10% ammonium chloride solution becomes the watery Phase separated and extracted with diethyl ether. The United organic phases are dried with sodium sulfate and concentrated. The alcohol thus obtained is then dissolved in 50 ml of acetic anhydride, with 1 mL conc. sulfuric acid added and stirred for three hours under reflux. Then the reaction mixture poured onto water, stirred for a further hour and made alkaline. It is extracted with dichloromethane, the organic phases are dried with sodium sulfate and distilling off the solvents. A fractional Distillation of the residue delivers the product in the form of a colorless liquid (bp 105-110 ° C / 8 mbar). Yield 29.0 g (52%).

b) N- [2- (4-Fluoro-2-methyl-phenyl) -1,1-dimethyl-ethyl] -formamide

29.0 g (130 mmol) acetic acid 1- (4-fluoro-2-methyl-phenyl) -2-methyl-propyl esters are reacted analogously to the procedure for Example 1.8b) and worked up. Yellow oil. Yield: 27.0 g (99%).

c) 2- (4-Fluoro-2-methylphenyl) -1,1-dimethyl-ethylamine

to Preparation of the amine are 27.0 g (130 mmol) of N- [2- (4-fluoro-2-methyl-phenyl) -1,1-dimethyl-ethyl] -formamide as in the regulation for Example 1.8c). White solid. Yield: 15.5 g (55%, hydrochloride); Mp 277-280 ° C.

d) 6-Benzyloxy-8- {2- [2- [4-fluoro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [1,4] oxazin-3-one

presentation in analogy to the regulation for Example 1.6d) from 0.95 g (2.66 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -4H-benzo [1,4] oxazin-3-one and 0.43 g (2.37 mmol) of 2- (4-fluoro-2-methylphenyl) -1,1-dimethyl-ethylamine. Yield: 0.75 g (55%, hydrochloride); Mp 233-236 ° C.

e) 8- {2- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

Debenzylation of 0.70 g (1.36 mmol) of 6-benzyloxy-8- {2- [2- [4-fluoro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4H benzo [1,4] oxazine-3-one provides the target compound as a white solid. Yield: 0.50 g (87%, hydrochloride); Mp 278-280 ° C; Mass spectroscopy: [M + H] ⁺ = 389.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.10: 8- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one

a) 1- (2,4-difluoro-phenyl) -2-methyl-propan-2-ol

To a solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromide in diethyl ether Within 20 minutes add 11.0 mL of acetone, diluted with 50 mL diethyl ether, added dropwise. Then 1.5 hours under Stirred and refluxed then hydrolyzed with 10% ammonium chloride solution. The ether phase is separated, washed with water, dried with sodium sulfate and concentrated. The fractional distillation of the residue provides the alcohol as a colorless liquid (Bp 70-73 ° C / 2 mmbar). Yield: 20.0 g (86%).

b) N- [2- (2,4-difluoro-phenyl] -1,1-dimethyl-ethyl] -formamide

Ritter reaction with 20 g (110 mmol) of 1- (2,4-difluoro-phenyl) -2-methyl-propan-2-ol after the for Example 1.8b). Yellow oil. Yield: 22.0 g (94%).

c) 2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamine

implementation of 22.0 g (100 mmol) of N- [2- (2,4-difluoro-phenyl] -1,1-dimethyl-ethyl] -formamide in analogy to Regulation for Example 1.8c). Yield: 16.0 g (72%, hydrochloride); Mp 201-203 ° C.

d) 6-Benzyloxy-8- {2- [2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4 H -benzo [1,4] oxazine one 3-

implementation of 0.89 g (2.49 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 0.40 g (2.16 mmol) of 2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamine in the for example 1.6d) described manner. Yield: 0.80 g (62%, hydrochloride); Mp 245-247 ° C.

e) 8- {2- [2- (2,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine one 3-

Hydrogenolysis of 0.70 g (1.35 mmol) of 6-benzyloxy-8- {2- [2- (2,4-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4 H -benzo [1,4] oxazine-3-one provides the target compound as a white solid. Yield: 0.48 g (83%, hydrochloride); Mp 279-280 ° C; Mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.11: 8- {2- [2- (3,5-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one

a) 1- (3,5-difluoro-phenyl) -2-methyl-propan-2-ol

The Target compound is prepared by reacting a Grignard compound from 25.0 g (121 mmol) of 3,5-difluorobenzylbromide, with 12.6 mL (171 mmol) of acetone. Yellow oil. Yield: 13.5 g (60%).

b) 2- (3,5-difluoro-phenyl) -1,1-dimethyl-ethylamine

The Ritter reaction of 5.5 g (29.5 mmol) of 1- (3,5-difluoro-phenyl) -2-methyl-propan-2-ol and 1.8 g of sodium cyanide provides 7.0 g of formamide for cleavage the formyl group with hydrochloric acid is treated. Light yellow oil. Yield: 4.6 g (75%).

c) 6-Benzyloxy-8- {2- [2- (3,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4 H -benzo [1,4] oxazine one 3-

presentation from 1.73 g (4.84 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 0.80 g (4.32 mmol) of 2- (3,5-difluoro-phenyl) -1,1-dimethyl-ethylamine in the usual Wise. Yield: 1.50 g (58%, hydrochloride); Mp 240-244 ° C.

d) 8- {2- [2- (3,5-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine one 3-

Hydrogenolysis of 1.30 g (2.43 mmol) of 6-benzyloxy-8- {2- [2- (3,5-difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [ 1,4] oxazin-3-one provides the target compound as a white solid. Yield: 0.90 g (86%, hydrochloride); Mp 150-158 ° C; Mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.12: 8- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

a) [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethyl] -carbamic acid benzyl ester

15.0 g (50 mmol) of [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethyl] -carbamic acid benzyl esters are mixed with 7.5 mL (92 mmol) ethyl iodide and 21 g (150 mmol) Potassium carbonate over 10 hours at 90-100 ° C touched. The reaction mixture is treated with ethyl acetate, washed twice with Washed water and dried with sodium sulfate. After distilling off the solvent stays a yellow oil (15.0 g, 92%) back, which will be implemented directly.

b) 2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamine

A solution of 15.0 g (49 mmol) of [2- (4-ethoxy-phenyl) -1,1-dimethyl-ethyl] -carbamic acid benzyl ester in 100 mL glacial acetic acid is treated with 2 g palladium on charcoal (10%) offset and then at 5 bar and 40 to 50 ° C hydrogenated. The catalyst is filtered off and the filtrate from the solvent freed. The residue is dissolved in a little water, with conc. Sodium hydroxide solution made alkaline and extracted with ethyl acetate. The organic phase is washed with water, with sodium sulfate dried and concentrated. The crude product is dissolved in acetonitrile and washed with ethereal hydrochloric acid acidified. The precipitated after addition of diethyl ether solid is filtered off with suction and dried. Yield: 8.8 g (hydrochloride, 84%); Mp 198-200 ° C.

c) 6-Benzyloxy-8- {2- [2- (4-ethoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4 H -benzo [1,4] oxazine-3- on

2.14 g (6.0 mmol) 6-Benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 1.0 g (5.2 mmol) 2- (4-ethoxy-phenyl) -1,1-dimethyl-ethylamine are stirred in 40 mL of ethanol for one hour at 50-80 ° C. After cooling up Room temperature, 0.23 g (6.0 mmol) of sodium borohydride are added and one leaves over one stir for another hour. The reaction mixture is mixed with 5 ml of acetone, 30 minutes touched, acidified with glacial acetic acid and concentrated. The residue is combined with water and ethyl acetate and made alkaline. The organic phase is separated, washed with water, with Dried sodium sulfate and freed from the solvent in vacuo. The residue is redissolved in ethyl acetate and water, with conc. Hydrochloric acid added and diluted with diethyl ether. The precipitated solid is filtered off with suction and washed with diethyl ether. white Solid. Yield: 2.0 g (61%, hydrochloride); Mp 214-216 ° C.

d) 8- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3- on

1.5 g (2.8 mmol) of 6-benzyloxy-8- {2- [2- (4-ethoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -4 H -benzo [1,4] oxazin-3-one in 80 mL methanol are hydrogenated with 250 mg palladium on carbon (10%) as a catalyst at room temperature and atmospheric pressure. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is dissolved in 5 ml of ethanol by heating, seeded and diluted with ethyl acetate. The precipitated solid is filtered off and washed. White solid. Yield 1.0 g (83%, hydrochloride); Mp 232-235 ° C; Mass spectrometry: [M + H] ⁺ = 401.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.13: 8- {2- [2- (3,5-Dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

a) 1- (3,5-dimethylphenyl) -2-methyl-2-propanol

Receive from the reaction of (3,5-dimethyl-phenyl) -acetic acid ethyl ester with methylmagnesium bromide.

b) 2- (3,5-dimethylphenyl) -1,1-dimethyl-ethylamine

By reacting 6.00 g (34 mmol) of 1- (3,5-dimethylphenyl) -2-methyl-2-propanol and 2.00 g (41 mmol) of sodium cyanide in a Ritter reaction, 2.40 g of 2- (3 , 5-dimethyl-phenyl) -1,1-dimethyl-ethylformamide (35% yield). To release the amine, the formamide (2.40 g, 11.7 mmol) is treated with hydrochloric acid. The procedure and work-up are analogous to the procedure for Example 1.8c). Oil. Yield: 1.70 g (82%); Mass spectroscopy: [M + H] ⁺ = 178.

c) 6-Benzyloxy-8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4 H -benzo [1,4] oxazine one 3-

presentation in analogy to the regulation for Example 1.6d) from 1.47 g (4.1 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -4H-benzo [1,4] oxazin-3-one and 0.65 g (3.7 mmol) of 2- (3,5-dimethylphenyl) -1,1-dimethyl-ethylamine. Yield: 1.1 g (51%, hydrochloride); Mp. 220-222 ° C.

d) 8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine one 3-

The target compound was synthesized after hydrogenolysis of 0.90 g (1.71 mmol) of 6-benzyloxy-8- {2- [2- (3,5-dime ethyl-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -4H-benzo [1,4] oxazin-3-one and recrystallization of the crude product from isopropanol. White solid. Yield: 0.50 g (69%, hydrochloride); Mp 235-238 ° C; Mass spectroscopy: [M + H] ⁺ = 385.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.14: 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl-propyl} -phenoxy) -butyric acid

a) 4- [4- (2-amino-2-methyl-propyl) -phenoxy] -butyric acid ethyl ester

4.5 g (15.0 mmol) of [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethyl] -carbamic acid benzyl ester, 2.3 mL (16.0 mmol) of 4-bromo-butyric acid, 2.3 g (16.6 mmol) of potassium carbonate and 0.3 g (1.8 mmol) of potassium iodide in 20 ml of dimethylformamide be 13 h hours at 120 ° C heated. The reaction mixture is diluted with ethyl acetate and washed successively with water, Sodium hydroxide solution and water washed. The organic phase is washed with sodium sulfate dried and concentrated. The residue it is purified by chromatography (eluent: cyclohexane / ethyl acetate = 9: 1). It is 5.0 g of a yellow oil isolated, which is dissolved in 50 mL of acetic acid and with 1.0 g of palladium on carbon as a catalyst at 40 ° C and 3 bar is hydrogenated. The catalyst is filtered off and the filtrate from Lösungsmitttel freed. The residue is dissolved in diethyl ether and with ethereal hydrochloric acid added. The precipitated solid is filtered off with suction and dried. Yield: 2.9 g (66% over two Stages, hydrochloride); Mp = 103-105 ° C.

b) 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) -butyric acid ethyl ester

1.20 g (3.36 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 0.90 g (3.22 mmol) of 4- [4- (2-amino-2-methyl-propyl) -phenoxy] -butyric acid, ethyl ester be in the for Example 1.6d) described manner implemented. The crude product is dissolved in 10 mL of ethyl acetate and 10 mL of water, stirring with oxalic acid added. The solution dilute with diethyl ether and the precipitated solid is filtered off with suction and washed with diethyl ether. Yield: 1.20 g (54%, oxalate); Mp 223-227 ° C.

c) 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) -butyric acid

A solution of 1.00 g (1.73 mmol) of 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) -butyric acid ethyl ester in 25 mL of methanol, add 2.5 mL of 1 N sodium hydroxide solution, Refluxed for 30 minutes and then neutralized with 1 N hydrochloric acid. The solution will be concentrated and the remaining oil through Heat dissolved in 5 mL n-butanol. After addition of a crystallization aid precipitates a solid which filtered off with suction and washed with acetone and diethyl ether. Yield: 0.75 g (79%); Mp. 216-218 ° C.

d) 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] - 2-methyl-propyl} -phenoxy) -butyric acid

0.70 g (1.28 mmol) of 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) -butyric acid are dissolved in 25 mL of methanol and 2 mL of acetic acid and hydrogenated in the presence of 150 mg of palladium on carbon (10%) at room temperature and atmospheric pressure. The catalyst is filtered off and the filtrate is freed from the solvent. The product is obtained by crystallization from a methanol / acetone mixture. Yield: 0.40 g (68%); Mp 201-204 ° C; Mass spectroscopy: [M + H] ⁺ = 459.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.15: 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one

a) 1- (3,4-Difluoro-phenyl) -2-methyl-propan-2-ol

From 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide a Grignard is prepared, which is then reacted with 11.6 mL (158 mmol) of acetone. Light yellow oil. Yield: 9.7 g (47%); R _f value: 0.55 (ethyl acetate / petroleum ether = 1: 3).

b) N- [2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethyl] -formamide

The target compound is obtained via a Ritter reaction with 4.0 g (21.5 mmol) of 1- (3,4-difluoro-phenyl) -2-methyl-propan-2-ol. Light yellow oil. Yield: 4.0 g (87%); Mass spectrometry: [M + H] ⁺ = 214.

c) 2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethylamine

4.00 g (18.5 mmol) of N- [2- (3,4-difluoro-phenyl) -1,1-dimethyl-ethyl] -formamide are dissolved in ethanol, treated with conc. Hydrochloric acid and heated overnight under reflux. The reaction solution is poured onto ice water, made alkaline with sodium hydroxide and extracted with tert-butyl methyl ether. The organic phases are washed with water, dried with sodium sulfate and concentrated. Yellow oil. Yield: 3.2 g (92%); Mass spectrometry: [M + H] ⁺ = 186.

d) 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine one 3-

357 mg (1 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4 H -benzo [1,4] oxazin-3-one and 185 mg (1 mmol) of 2- (3,4-difluoro -phenyl) -1,1-dimethyl-ethylamine are stirred for 30 minutes in 5 ml of tetrahydrofuran at room temperature. It is cooled to 0 ° C and added dropwise under argon atmosphere 1.5 mL of a 2 molar solution of lithium borohydride in tetrahydrofuran. It is stirred for 30 min at room temperature, treated 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 the solvent. The residue is dissolved in methanol and hydrogenated with palladium on carbon (10% strength) as catalyst at 2.5 bar and room temperature. Subsequently, the catalyst is separated off and the crude product is purified by chromatography. White solid. Yield: 31 mg (6%, trifluoroethyl acetate); Mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.16: 8- {2- [2- (2-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one

a) 1- (2-Chloro-4-fluoro-phenyl) -2-methyl-propan-2-ol

manufacturing from 20 g (97 mmol) of (2-chloro-4-fluoro-phenyl) -acetic acid methyl ester and 98 mL of a 3 molar solution of methylmagnesium bromide in analogy to the procedure for example 1.6a).

N- [2- (2-chloro-4-fluoro-phenyl) -1,1-dimethyl-ethyl] -formamide

7.5 g (37 mmol) of 1- (2-chloro-4-fluorophenyl) -2-methyl-propan-2-ol were reacted and worked up according to the procedure described for example 1.8b). The resulting oil was chromatographed on a short silica gel column for further purification (petroleum ether / ethyl acetate = 9: 1). Oil. Yield 7.4 g (87%); Mass spectrometry: [M + H] ⁺ = 230/232.

c) 2- (2-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamine

Reaction of 7.4 g (32 mmol) of N- [2- (2-chloro-4-fluoro-phenyl) -1,1-dimethyl-ethyl] -formamide as described in the instructions for Example 1.15c). Brown oil. Yield: 5.14 g (79%); Mass spectrometry: [M + H] ⁺ = 202/204.

d) 8- {2- [2- (2-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

357 mg (1 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxy-acetyl) -4 H -benzo [1,4] oxazin-3-one and 202 mg (1 mmol) of 2- (2-chloro-4 -fluor-phenyl) -1,1-dimethyl-ethylamine are reacted in analogy to the procedure for Example 1.8d) with lithium borohydride. For debenzylation of the ethanolamine thus obtained, this is dissolved in 3 mL dichloromethane and cooled to -78 ° C. At this temperature is added dropwise 2 ml of a 1 molar solution of boron tribromide in dichloromethane and allowed to slowly warm to room temperature. The reaction mixture is combined with 10 mL dichloromethane and 3 mL of water and filtered through Extrelut ^®. The eluate is freed from the solvent and the residue is purified by chromatography. White solid. Yield: 70 mg (13%, trifluoroethyl acetate); Mass spectroscopy: [M + H] ⁺ = 409/11.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.17: 8- {2- [2- (4-Chloro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

A solution of 300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxy-acetyl) -4 H -benzo [1,4] oxazin-3-one and 200 mg (1.09 mmol) of 2- (4-chlorophenyl) -1,1-dimethyl-ethylamine in 3 mL Ethanol was mixed with molecular sieve and stirred at 80 ° C for 90 minutes.

Allow to cool to room temperature, add 35mg (0.91 mmol) of sodium borohydride and stir for 1 hour. Subsequently, the reaction mixture was mixed with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were freed from the solvent and the residue was chromatographed (eluent: hexane / ethyl acetate / methanol), whereby 305 mg ethanolamine could be recovered. This was dissolved in 3 mL dichloromethane and cooled to -78 ° C under an argon atmosphere. 3 mL of a 1 molar solution of boron tribromide in dichloromethane were added dropwise and the mixture was allowed to stir for one hour at -78 ° C. and for 20 minutes at room temperature. Then, at -78 ° C., 3 ml of conc. Ammonia solution and allowed to stir for 5 minutes. The reaction mixture was added with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were concentrated and the residue was chromatographed for further purification (silica gel, eluent: dichloromethane / methanol + 1% ammonia). Beige solid: 93mg (26%); Mass spectrometry: [M + H] ⁺ = 391.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.18: 8- {2- [2- (4-Bromo-n-nyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

The ethanolamine preparation and debenzylation were carried out in the manner described for Example 1.17 from 300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxy-acetyl) -4 H -benzo [1,4] oxazin-3-one and 250 mg ( 1.09) mmol) 2- (4-Bromo-phenyl) -1,1-dimethyl-ethylamine. Beige solid. Yield: 54mg (14%); Mass spectrometry: [M + H] ⁺ = 435, 437.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

Example 1.19: 8- {2- [2- (4-Fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one

300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxy-acetyl) -4 H -benzo [1,4] oxazin-3-one and 183 mg (1.09 mmol) of 2- (4-fluorophenyl) - 1,1-dimethyl-ethylamine was dissolved in 3 ml of ethanol. Molsieb was added and heated to 80 ° C for 30 minutes. After cooling to room temperature, 35 mg (0.91 mmol) of sodium borohydride were added. The mixture was stirred for 1 hour at room temperature, then to the reaction mixture was added sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were concentrated and the residue was chromatographed (eluent: hexane / ethyl acetate / methanol). The resulting ethanolamine (223 mg) was dissolved in methanol to cleave the benzyl protecting group and hydrogenated with 150 mg of palladium hydroxide as a catalyst at room temperature and atmospheric pressure. The catalyst was removed by filtration through Celite ^®, the filtrate was freed from solvent and the residue chromatographed (silica gel; eluent: dichloromethane / methanol). Beige solid. Yield: 76mg (22%); Mass spectrometry: [M + H] ⁺ = 375.

The (R) and (S) enantiomers of this embodiment can be obtained by Separation of the racemate in analogy to conventional, in the prior art obtained known methods.

In analogy to the synthesis examples described above, the following compounds according to the invention of formula 1 can furthermore be obtained:
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-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1 , 4] oxazin-3-one;
Example 1.22: 8- {2- [2- (4-Chloro-2-methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-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) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one;
Example 1.25: 8- {2- [2- (3-Chloro-4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -b-hydroxy-4H-benzo [1,4 ] oxazin-3-one;
Example 1.26: 8- {2- [2- (2,6-Difluoro-4-methoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1 , 4] oxazin-3-one;
Example 1.27: 8- {2- [2- (2,5-Difluoro-4-methoxyphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1 , 4] oxazin-3-one;
Example 1.28: 8- {2- [2- (4-Fluoro-3,5-dimethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1 , 4] oxazin-3-one;
Example 1.29: 8- {2- [2- (3,5-dichloro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one;
Example 1.30: 8- {2- [2- (4-Chloro-3-methylphenyl) -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-trifluorophenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one;
Example 1.32: 8- {2- [2- (3-Methylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one;
Example 1.33: 8- {2- [2- (3,4-dichloro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one.

Claims (43)

Medicament combinations, in addition to one or more compounds of the general formula 1

wherein n is 1 or 2; R ^{1 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl; R ^{2 is} hydrogen, halogen, C ₁ -C ₄ -alkyl or -OC ₁ -C ₄ -alkyl; R ^{3 is} C ₁ -C ₄ -alkyl, OH, halogen, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH, -OC ₁ -C ₄ -alkylene-CO-OC ₁ -C ₄ -Alkyl, containing at least one further active ingredient 2. Medicament combinations according to claim 1, in addition to one or several compounds of formula 1 as another active ingredient 2 a or more compounds selected from the classes of Anticholinergics (2a), PDEIV inhibitors (2b), steroids (2c), LTD4 antagonists (2d) and EGFR inhibitors (2e). Pharmaceutical combinations according to claim 1 or 2, containing one or more compounds of general formula 1, wherein n is 1 or 2; R ^{1 is} hydrogen, fluorine, chlorine, methyl or methoxy; R ^{2 is} hydrogen, fluorine, chlorine, methyl or methoxy; R ^{3 is} C ₁ -C ₄ -alkyl, OH, fluorine, chlorine, bromine, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH, -OC ₁ -C ₄ -alkylene-CO-OC C ₁ -C ₄ alkyl. Pharmaceutical combinations according to claim 1, 2 or 3, containing one or more compounds of general formula 1, wherein n 1; R ^{1 is} hydrogen or C ₁ -C ₄ -alkyl; R ^{2 is} hydrogen or C ₁ -C ₄ -alkyl; R ^{3 is} C ₁ -C ₄ -alkyl, OH, -OC ₁ -C ₄ -alkyl, -OC ₁ -C ₄ -alkylene-COOH or -OC ₁ -C ₄ -alkylene-CO-OC ₁ -C ₄ -alkyl . mean. Medicament combinations according to one of claims 1 to 4, which contains one or more compounds of general formula 1 in Form of the individual optical isomers, mixtures of the individual Enantiomers or racemates included. Medicament combinations according to one of claims 1 to 5, which contains one or more compounds of general formula 1 in Form of acid addition salts with pharmacologically acceptable acids and optionally in Form of solvates and / or hydrates included. Medicament combinations according to one of claims 1 to 6, in addition to one or more compounds of the general formula 1 as further active ingredient 2 an anticholinergic (2a) included. Medicament combinations according to claim 7, in addition to one or several compounds of general formula 1 an anticholinergic (2a) selected from the group consisting of tiotropium salts (2a.1), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), trospium salts (2a.6). Medicament combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.7

in which X ^{- is} a singly negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, Benzoate and p-toluenesulfonate, optionally in the form of their racemates, enantiomers or hydrates. Medicament combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.8

in which R is either methyl (2a.8.1) or ethyl (2a.8.2) and in which X ^{- may have} the meanings given in claim 9. Medicament combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.9

wherein A is a divalent group selected from the groups

X ^- one of the claim 9 simply negatively charged anions; R ¹ and R ^2, identically or differently, represent a group selected from methyl, ethyl, n-propyl and isopropyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl; R ³ , R ⁴ , R ⁵ and R ⁶ , identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ ; R ^{7 is} hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH ₂ -F, -CH ₂ -CH ₂ -F, -O-CH ₂ -F, -O-CH ₂ -CH ₂ -F, -CH ₂ - OH, -CH ₂ -CH ₂ -OH, CF ₃ , -CH ₂ -OMe, -CH ₂ -CH ₂ -OMe, -CH ₂ -OEt, -CH ₂ -CH ₂ -OEt, -O-COMe, - O-COEt, -O-COCF ₃ , -O-COCF ₃ , fluorine, chlorine or bromine, optionally in the form of their racemates, enantiomers or hydrates. Medicament combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.10

in which A, X ^- , R ¹ and R ² can have the meanings given in claim 11 and in which R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , identical or different, represent hydrogen, methyl, ethyl , Methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF ₃ or NO ₂ , where at least one of the groups R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² can not be hydrogen, optionally in the form of their racemates, enantiomers or hydrates. Pharmaceutical combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.11

wherein A and X ^- may have the meanings given in claim 11 and wherein R ^{15 is} hydrogen, hydroxy, methyl, ethyl, -CF ₃ , CHF ₂ or fluorine; R ^{1 '} and R ^{2' are} identical or different, C ₁ -C ₅ -alkyl, which may optionally be substituted by C ₃ -C ₆ -cycloalkyl, hydroxy or halogen, or R ^{1 '} and R ^2' together are a -C ₃ -C ₅ -alkylene bridge; R ¹³ , R ¹⁴ , R ^{13 '} and R ^{14' are} identical or different, hydrogen, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen, optionally in the form of their racemates, enantiomers or hydrates. Medicament combinations according to claim 7, which in addition to one or more compounds of general formula 1, an anticholinergic formula 2a.12

wherein X ^- may have the meanings given in claim 11 and wherein D and B are the same or different, preferably the same, O, S, NH, CH ₂ , CH = CH or N (C ₁ -C ₄ alkyl); R ^{16 is} hydrogen, hydroxyC ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, -C ₁ -C ₄ -alkylene-halogen, -OC ₁ -C ₄ -alkylene-halogen, -C ₁ -C ₄ -alkylene-OH, -CF ₃ , CHF ₂ , -C ₁ -C ₄ -alkylene-C ₁ -C ₄ -alkyloxy, -O-COC ₁ -C ₄ -alkyl, -O-COC ₁ -C ₄ - Alkylene-halo, -C ₁ -C ₄ -alkylene-C ₃ -C ₆ -cycloalkyl, -O-COCF ₃ or halogen; R ^{1 ''} and R ^{2 '' are} identical or different, -C ₁ -C ₅ -alkyl, which may optionally be substituted by -C ₃ -C ₆ -cycloalkyl, hydroxy or halogen, or R ^{1 ''} and R ^{2 ''} together a -C ₃ -C ₅ -alkylene bridge; R ¹⁷ , R ¹⁸ , R ^{17 '} and R ^18' , identical or different, are hydrogen, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen; R ^x and R ^{x 'are} identical or different, hydrogen, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen, or R ^x and R ^{x '} together form a single bond or one of the divalent groups O, S, NH, CH ₂ , CH ₂ -CH ₂ , N (C ₁ -C ₄ -alkyl), CH (C ₁ -C ₄ -alkyl) and C (C ₁ -C ₄ alkyl) ₂ , optionally in the form of their racemates, enantiomers or hydrates. Medicament combinations according to claim 7, which in addition to one or more compounds of the general my Formula 1 an anticholinergic formula 2a.13

in which X ^- may have the meanings mentioned in claim 11 and wherein A 'is a divalent group selected from

R ^{19 is} hydroxy, methyl, hydroxymethyl, ethyl, -CF ₃ , CHF ₂ or fluorine; R ^{1 '''} and R ^2''' , the same or different, C ₁ -C ₅ alkyl, which may optionally be substituted by C ₃ -C ₆ cycloalkyl, hydroxy or halogen, or R ^{1 '''} and R ^{2 '"} together form a -C ₃ -C ₅ -alkylene bridge; R ²⁰ , R ²¹ , R ^{20 '} and R ^{21' are} identical or different, hydrogen, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyloxy, hydroxy, -CF ₃ , -CHF ₂ , CN, NO ₂ or halogen, optionally in the form of their racemates, enantiomers or hydrates. Medicament combinations according to one of claims 1 to 6, in addition to one or more compounds of the general formula 1 as further active ingredient 2 a PDE IV inhibitor (2b). Drug combinations according to claim 16, in which the PDE IV inhibitor 2b selected from the group consisting of enprofylline, theophylline, roflumilast, Ariflo (Cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-) p - [(4aR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1 , 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (Cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy 4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy] 4-difluoromethoxyphenyl) cyclohexan-1-ol], (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, Arofylline, Atizoram, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a ] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, Solvates and / or hydrates. Medicament combinations according to one of claims 1 to 6, in addition to one or more compounds of the general formula 1 as further active ingredient 2 a steroid (2c) included. Drug combinations according to claim 18, in which the steroid 2c is selected from the group consisting of prednisolone (2c.1), prednisone (2c.2), butixocortepionate (2c.3), RPR-106541 2c.4), flunisolide 2c.5) , Beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), dexamethasone (2c.14), 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11, β-hydroxy-16α-methyl-3-oxo-androsta-1 , 4-diene-17β-carbothionic acid (S) -fluoromethyl ester (2c.15), and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothionic acid (S) - (2-oxo-tetrahydro -furan-3S-yl) esters (2c.16), optionally in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Medicament combinations according to one of claims 1 to 6, in addition to one or more compounds of the general formula 1 as further active ingredient 2 a LTD4 antagonist (2d) included. Drug combinations according to claim 20, in which the LTD4 antagonist 2d selected from the group consisting of montelukast (2d.1), 1 - (((R) - (3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2- hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid (2d.2), 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridine -5-yl) - (E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid (2d.3), Pranlukast (2d.4), zafirlukast (2d.5), [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzo [uranyl] oxymethyl] phenyl] acetic acid (2d.6), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8), MEN-91507 (LM-1507) (2d.9), VUF-5078 (2d.10), VUF-K-8707 (2d.11) and L-733321 (2d.12), optionally in the form their racemates, enantiomers or diastereomers, optionally in Form of their pharmacologically acceptable Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Medicament combinations according to one of claims 1 to 6, in addition to one or more compounds of the general formula 1 as further active ingredient 2 an EGFR inhibitor (2e) included. Medicament combinations according to Claim 22, in which EGFR inhibitors 2e are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1- oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl 2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran 3-yl) oxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-] yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-C chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3 chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl} amino) -7 -cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 -cyclopentyloxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({ 4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1 -Phenyl-ethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -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) -c hinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - (( S) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] 1-oxo-2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N- methyl-amino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl ) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] - quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (morpholin-4-yl) propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl ) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo -2-buten-1 -yl] amino} -7-ethoxy-quinoline, 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino ] methyl} -furan-2-yl) quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholine] 4-yl) -1-oxo-2-buten-1-yl] amino} -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholine) 4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] - 6 - ({4- [N, N-bis- (2-methoxy-ethyl) -amino] -1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy ] -quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxo-morpho lin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2 -dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-) dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [4- (2-oxo-morpholin-4-yl) piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-yl) 4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-china zoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino] ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans-4- [ (dimethylamino) sulfonylamino] -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) -sulfonylamino ] cyclohexane-1-yloxy } -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4- [ (3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran- 4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4 - {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- (cis-4- {N - [(morpholin-4-yl) sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (1-methanesulfonyl-p iperidin-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy -ethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy- ethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3 Ethynylphenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran- 4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N - methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4- methyl-piperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [2- (2-oxopyrrolidin-1-yl) ethyl] -piperidine 4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxyethoxy) quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-acetylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [( 3-ethynyl-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidine 4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxyethoxy ) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4 fluorophenyl) amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- { cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy quinazoline, 4 - [(3-ethynyl-phe nyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- {1 - [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) carbonyl] piperidin-4-yloxy} -7- methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane-1-yloxy] -7-methoxy-chi nazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) -amino no] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- ( N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino) cyclohexan-1-yloxy) -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4- {N - [(morpholin-4-yl) carbonyl] - N -methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl- 6-oxo-morpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) 7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates. Medicament combinations according to one of claims 1 to 23, characterized in that in addition to therapeutically effective Amounts of 1 and 2 contain a pharmaceutically acceptable carrier. Medicament combinations according to one of claims 1 to 23, characterized in that in addition to therapeutically effective Quantities of 1 and 2 contain no pharmaceutically acceptable carrier. Medicament combination according to one of Claims 1 to 25, characterized that they are in the form of a for the inhalation suitable dosage form is present. Medicament combination according to Claim 26, characterized that it is a pharmaceutical form selected from the group of inhalable powders, propellant-containing metered dose inhalers and propellant-free inhalable solutions or suspensions. Medicament combination according to Claim 27, characterized that the dosage form is an inhalable powder, which is 1 and 2 in admixture with suitable physiologically acceptable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and Polysaccharides, polyalcohols, salts, or mixtures of these excipients contains each other. Medicament combination according to Claim 27, characterized that the dosage form is a propellant-containing inhalation aerosol is which 1 and 2 in dissolved or dispersed form. Medicament combination according to claim 29, characterized in that that the inhalation aerosol as propellant hydrocarbons such n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, Butane, cyclopropane or cyclobutane. Medicament combination according to claim 30, characterized in that that the propellant is TG11, TG12, TG134a, TG227 or mixtures thereof, preferably TG134a, TG227 or a mixture thereof. Medicament combination according to Claim 27, characterized that the dosage form is a propellant-free inhalable solution or suspension acts as a solvent Water, ethanol or a mixture of water and ethanol. Use of a drug combination according to any one of claims 1 to 32 for the manufacture of a medicament for the treatment of inflammatory and obstructive pulmonary diseases, to inhibit premature use Labor in obstetrics (tocolysis), to restore the Sinus rhythm in the heart in atrio-ventricular block, to repair bradykaler Arrhythmia (Antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase the cardiac output) as well as for the treatment of itching and inflammations of the skin. Use according to claim 33, for the preparation of a medicament for the treatment of respiratory diseases selected from the group consisting of obstructive lung diseases different Genesis, pulmonary emphysema of different origin, restrictive lung disease, Interstitial lung diseases, cystic fibrosis, bronchitis different genesis, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema. Use according to claim 34, for the manufacture of a medicament for the treatment of obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric Asthma, severe asthma, acute asthma attack, chronic bronchitis and COPD (chronic obstructive pulmonary disease), the use for the manufacture of a medicament for the treatment of bronchial asthma and COPD being particularly preferred according to the invention. Use according to claim 34, for the preparation of a medicament for the treatment of pulmonary emphysema originating in COPD or α1-proteinase inhibitor deficiency. Use according to claim 34, for the preparation of a medicament for the treatment of restrictive lung diseases, which are selected from the group consisting of allergic alveolitis, by occupational Noxen triggered restrictive lung diseases such as asbestosis or silicosis and restriction due to lung tumors, such as lymphangiosis carcinomatosa, bronchoalveolar Carcinoma and lymphomas. Use according to claim 34, for the preparation of a medicament for the treatment of interstitial lung diseases, which are selected from the group consisting of infectious pneumonia, as for example due to infection with viruses, bacteria, fungi, protozoa, Helminths or other pathogens, pneumonitis due to different Genesis, such as aspiration and left ventricular failure, Radiation-induced pneumonitis or fibrosis, collagenosis, like For example, lupus erythematosus, sytemische scleroderma or Sarcoidosis, granulomatosis, such as, for example, Boeck's disease, idiopathic interstitial Pneumonia or idiopathic pulmonary fibrosis (IPF). Use according to claim 34, for the preparation of a medicament for the treatment of cystic fibrosis or cystic fibrosis. Use according to claim 34, for the preparation of a medicament for the treatment of bronchitis, such as bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis. Use according to claim 34, for the preparation of a medicament for the treatment of bronchiectasis. Use according to claim 34, for the preparation of a medicament for the treatment of ARDS (adult respiratory distress syndrome). Use according to claim 34, for the preparation of a medicament for the treatment of pulmonary edema.