WO2007093608A1 - Arzneimittelkombinationen zur behandlung von atemwegserkrankungen - Google Patents

Arzneimittelkombinationen zur behandlung von atemwegserkrankungen Download PDF

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Publication number
WO2007093608A1
WO2007093608A1 PCT/EP2007/051408 EP2007051408W WO2007093608A1 WO 2007093608 A1 WO2007093608 A1 WO 2007093608A1 EP 2007051408 W EP2007051408 W EP 2007051408W WO 2007093608 A1 WO2007093608 A1 WO 2007093608A1
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Prior art keywords
amino
methyl
quinazoline
methoxy
chloro
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Ceased
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PCT/EP2007/051408
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German (de)
English (en)
French (fr)
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WO2007093608A8 (de
Inventor
Ingo Konetzki
Thierry Bouyssou
Sabine Pestel
Andreas Schnapp
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Priority to CA002642239A priority Critical patent/CA2642239A1/en
Priority to EP07726364A priority patent/EP1986644A1/de
Priority to JP2008554769A priority patent/JP2009526817A/ja
Publication of WO2007093608A1 publication Critical patent/WO2007093608A1/de
Publication of WO2007093608A8 publication Critical patent/WO2007093608A8/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to novel drug combinations, in addition to one or more, preferably a compound of general formula 1
  • A, B, R 1 , X, n and m may have the meanings given in the claims and in the description, at least one further active ingredient 2, processes for their preparation and their use as medicaments.
  • the present invention relates to drug combinations which, in addition to one or more, preferably a compound of general formula 1
  • X is CH 2 , CO, NR 2 , S or O;
  • A is a divalent group selected from the group consisting of CO, SO or SO 2 ;
  • R 1 H de-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, Ci -6 haloalkyl, O
  • R 3 is H or C 1-6 alkyl
  • R 4 is H or C 1-6 -alkyl
  • R 5 is H or C 1-6 alkyl; mean, at least one further active ingredient 2 included.
  • the present invention preferably relates to medicament combinations which comprise, in addition to one or more, preferably one compound of formula 1, as further active ingredient 2 one or more compounds selected from the classes of the anticholinergics (2a), PDEIV inhibitors (2b), steroids ( 2c), LTD4 antagonists (2d) and EGFR inhibitors (2e).
  • Preference is furthermore given to the above drug combinations which, in addition to one or more, preferably one compound of the general formula 1 in which A CO, contain at least one further active ingredient 2.
  • n 1, 2, 3 or 4
  • m 1, 2 or 3;
  • X is CH 2 , CO, NR 2 , S or O;
  • R 1 is H, Ci- 6 alkyl, Ci -6 haloalkyl, C 3 - 6 cycloalkyl, halogen, OH 1 CN, NO 2, O-Ci-6-alkyl, COOH or COO-Ci -4 alkyl;
  • R2 is H, Ci -4 alkyl, Ci -2 alkylene-C 3 - 6 cycloalkyl, phenylethyl or benzyl;
  • R 3 is H or C 1-6 alkyl;
  • R 4 is H or C 1-6 -alkyl;
  • R 5 is H or C 1-6 alkyl; mean, at least one further active ingredient 2 included.
  • n is 1, 2 or 3; preferably 2 or 3 m 1, 2, 3 or 4; preferably 1, 2 or 3;
  • X is CH 2 , CO, NR 2 , S or O;
  • B is a divalent group selected from the group consisting of O, S, CH 2 ,
  • R 1 is H, d-4 alkyl, Ci -4 haloalkyl, cyclopropyl, cyclohexyl, halogen, OH, O-Ci -4 alkyl, COOH or COOMe;
  • R2 is H, Ci 4 alkyl, Cs- ⁇ -cycloalkyl-methyl, particularly preferably H, methyl or cyclopropylmethyl;
  • R 3 is H or Ci -4 alkyl, preferably H or methyl;
  • R 4 is H or Ci -4 alkyl, preferably H or methyl;
  • R 5 is H or Ci -4 alkyl, preferably H or methyl; mean, at least one further active ingredient 2 included.
  • X is CH 2 , CO, NR 2 , S or O; A CO;
  • R 1 is H, methyl, ethyl, propyl, CF 3 , CH 2 F, CH 2 CF 3 , fluorine, chlorine, bromine, OH, methoxy, ethoxy, COOH or COOMe;
  • R 2 is H, methyl, ethyl or propyl;
  • R 3 is H, methyl, ethyl or propyl;
  • R 4 is H, methyl, ethyl or propyl;
  • R 5 is H, methyl, ethyl or propyl; mean, at least one further active ingredient 2 included.
  • X is CH 2 , CO, NR 2 , S or O;
  • B is a divalent group selected from the group consisting of O, S, CH 2 ,
  • R 1 is H, methyl, ethyl, propyl, CF 3 , CH 2 F, CH 2 CF 3 , fluorine, chlorine, bromine, OH, methoxy,
  • R 2 is H, methyl, ethyl or propyl
  • R 3 is H or methyl, preferably H
  • R 4 is H or methyl, preferably H;
  • R 5 is H or methyl, preferably H; mean, at least one further active ingredient 2 included.
  • X is CH 2 , CO, NR 2 , S or O; A CO;
  • R 1 is H, methyl, ethyl, propyl, CF 3 , CH 2 F, CH 2 CF 3 , fluorine, chlorine, bromine, OH, methoxy, ethoxy, COOH or COOMe;
  • R 2 is H, methyl, ethyl or propyl; mean, at least one further active ingredient 2 included.
  • X is CH 2 , CO, NR 2 , S or O; A CO;
  • R 1 is H, methyl, ethyl, propyl, CF 3 , CH 2 F or CH 2 CF 3 ;
  • R 2 is H, methyl, ethyl or propyl; 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 pharmaceutical combinations, which in addition to one or more, preferably a compound of general formula 1, wherein n is 2 or 3; m 1;
  • X is CH 2 , CO, NR 2 , S or O;
  • R 1 is H, methyl or CF 3,
  • R 2 is H or methyl; mean, at least one further active ingredient 2 included.
  • the present invention further relates to pharmaceutical combinations, which in addition to one or more, preferably a compound of general formula 1, wherein n is 2 or 3; m 1;
  • X is CH 2 , CO, NR 2 , S or O;
  • R 1 is H, methyl or CF 3,
  • R 2 is H or methyl; mean, 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 is 2 or 3; m 1;
  • R 1 is H, methyl or CF 3,
  • R 2 is H or methyl; mean, at least one further active ingredient 2 included.
  • n 2; m 1; X NH;
  • B is a divalent group CH 2 -O; R 1 is H, methyl or CF 3, containing at least one further active ingredient 2.
  • R 2 is cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl, preferably cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, more preferably cyclopropylmethyl; mean the radicals and wherein n, m, A, B and R 1 have the meanings mentioned above may contain at least one further active ingredient. 2
  • radicals n, m, A, B and R 1 may have the abovementioned meanings, contain at least one further active compound 2.
  • a preferred aspect of the present invention relates to pharmaceutical combinations which, in addition to one or more, preferably a compound of general formula 1.1, wherein n, m, X and R 1 have the meanings given above, contain at least one further active ingredient 2.
  • a preferred aspect of the present invention relates to medicament combinations which contain, in addition to one or more, preferably one compound of the general formula 1.2, in which n, m, X and R 1 have the meanings given above, at least one further active ingredient 2.
  • a preferred aspect of the present invention relates to pharmaceutical combinations which, in addition to one or more, preferably a compound of general formula 1.3, wherein n, m, X and R 1 have the meanings given above, contain at least one further active ingredient 2.
  • a preferred aspect of the present invention relates to pharmaceutical combinations which, in addition to one or more, preferably a compound of general formula 1.4, wherein n, m, X and R 1 have the meanings given above, contain at least one further active ingredient 2.
  • a preferred aspect of the present invention relates to medicament combinations which contain, in addition to one or more, preferably one compound of the general formula 1.5, in which n, m, X and R 1 have the abovementioned meanings, at least one further active ingredient 2.
  • a preferred aspect of the present invention relates to drug combinations which, in addition to one or more, preferably a compound of formula 1, which are selected from the group consisting of
  • a further aspect of the present invention relates to the abovementioned novel compounds of the formula I in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
  • radicals n, m, A, B, X and R 1 may have the abovementioned meanings. Also particularly preferred are compounds of the formula / M which are selected from the group consisting of
  • drug combinations which, in addition to one or more, preferably a compound of general formula 1, are selected from the compounds
  • a further aspect of the present invention relates to medicament combinations which comprise the abovementioned compounds of the formula I in the form of the acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates, at least one further active ingredient 2.
  • Examples of acid addition salts with pharmacologically acceptable acids of compounds 1 include 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.
  • 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, preferably one compound of formula 1 as further active ingredient one or more, preferably an anticholinergic 2a, optionally in combination with pharmaceutically acceptable excipients.
  • the anticholinergic agent 2a is preferably 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) and the compounds of the formulas 2a.7 to 2a.13.
  • the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents.
  • An explicit reference to the aforementioned cations is made by the names 2a.1 'to 2a .6 ⁇ Any reference to the aforementioned salts 2a.1 to 2a.6 naturally includes a reference to the corresponding cations tiotropium (2a.1 '), oxitropium (2a.2'), flutropium (2a.3 '), ipratropium (2a.4 '), glycopyrronium (2a.5'), trospium (2a.6 ').
  • the salts 2a.1 to 2a.6 mean those compounds which, 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 contain, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • the chloride is particularly preferred.
  • the methanesulfonates and bromides are of particular importance.
  • drug combinations containing tiotropium salts (2a.1), oxitropium salts (2a.2) or ipratropium salts (2a.4) are of particular importance.
  • the particular bromides being particularly important according to the invention.
  • the abovementioned salts can be present in the medicament combinations according to the invention optionally in the form of their solvates or hydrates, preferably in the form of their hydrates.
  • the drug combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in the medicament combinations according to the invention in an anhydrous form, this is preferred Anhydrous crystalline tiotropium bromide for use, which is known from WO 03/000265.
  • Examples of preferred drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.1 to 2a.6 are combinations comprising 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.
  • the aforementioned anticholinergics have chiral carbon centers.
  • the medicament combinations according to the invention may contain the anticholinergics in the form of their enantiomers, mixtures of the enantiomers or racemates, wherein preferably enantiomerically pure anticholinergics are used.
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the salts of the formula 2a.7
  • 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, means
  • 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,
  • 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,
  • Particularly preferred drug combinations contain the compound of formula 2a.7 in the form of the bromide. Of particular importance are those drug combinations which contain the enantiomers of formula 2a.7-en contain, wherein 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 1.2 and 2a.7; 1.2 and 2a.7-en; 1.5 and 2a.7; 1.5 and 2a.7-en; 1.8 and 2a.7; 1.8 and 2a.7-en; 1.10 and 2a.7; 1.10 and 2a.7-en; 1.12 and 2a.7; 1.12 and 2a.7-en; 1.15 and 2a.7 or 1.15 and 2a.7-en; 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.
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the salts of the formula 2a.8
  • the drug combinations according to the invention may contain the anticholinergic acid of formula 2a.8 (or 2a.8-base) in the form of their enantiomers, mixtures of enantiomers or racemates.
  • the anticholinergics of formula 2a.8 (or 2a.8-base) are included in the form of their R-enantiomers.
  • Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.8 are combinations comprising the compounds 1.2 and 2a.8.1; 1.2 and 2a.8.2; 1.5 and 2a.8.1; 1.5 and 2a.8.2; 1.8 and 2a.8.1; 1.8 and 2a.8.2; 1.10 and 2a.8.1; 1.10 and 2a.8.2; 1.12 and 2a.8.1; 1.12 and 2a.8.2; 1.15 and 2a.8.1 or 1.15 and 2a.8.2, 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.
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.9
  • A is a divalent group selected from the groups
  • X is one of the abovementioned singly negatively charged anions, preferably chloride, bromide or methanesulfonate,
  • R 1 and R 2 are the same or different and are selected from methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by
  • R 3 , R 4 , R 5 and R 6 identical or different, represent hydrogen, methyl, ethyl, methyloxy,
  • 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,
  • 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, are methyl or ethyl, preferably methyl;
  • R 3 , R 4 , R 5 and R 6 are hydrogen, methyl, methyloxy, chlorine or
  • R 7 is hydrogen, methyl or fluorine.
  • A is a divalent group selected from
  • the compounds of the formula 2a.9 may optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.9 are combinations comprising the compounds 1.1 and 2a.9.1; 1.1 and 2a.9.2; 1.1 and 2a.9.3; 1.1 and
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.10
  • A, X " , R 1 and R 2 may have the abovementioned meanings and 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 , wherein at least one of the groups R 7 , R 8 , R 9 , R 10 , R 11 and R 12 can not be hydrogen.
  • preferred compounds of formula 2a.10 are those in which A is a divalent group selected from
  • R 1 and R 2 are identical or different, are 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.
  • the compounds of the formula 2a.1O may optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.10 are combinations comprising 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.
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.11
  • 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 -QrCs-alkylene bridge;
  • R 13, R 14, R 13 'and R 14' identical or different are hydrogen, C r C 4 alkyl,
  • -C r C 4 alkyloxy, hydroxy, -CF 3 , -CHF 2 , CN, NO 2 or halogen.
  • 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 is an anion selected from chloride, bromide and methanesulfonate, preferably
  • R 15 is hydroxy, methyl or fluoro, preferably methyl or hydroxy;
  • R 1 and R 2 are identical or different, are 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.
  • particularly preferred compounds of formula 2a.11 are those in which A is a divalent group selected from
  • R 15 is hydroxy or methyl, preferably methyl
  • R 1 and R 2 are identical or different, are methyl or ethyl, preferably methyl;
  • R 13 , R 14 , R 13 ' and R 14 are identical or different, hydrogen or fluorine.
  • the compounds of the formula 2a.11 may optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • 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
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.12
  • R 16 is hydrogen, hydroxy, -C r C 4 alkyl, -C r C 4 alkyloxy,
  • R 1 and R 2 are identical or different, -CrC 5 -alkyl, optionally substituted by
  • R 17, R 18, R 17 'and R 18' are hydrogen, C r C 4 alkyl,
  • R x and R x are identical or different, hydrogen, -dC 4 -alkyl, -dC 4 -alkyloxy,
  • R x and R x together form a single bond or one of the divalent groups O, S, NH, CH 2 ,
  • Preferred compounds of the formula 2a.12 in the context of the drug combinations according to the invention are those in which
  • X is chloride, bromide or methanesulfonate, preferably bromide
  • R 16 is hydrogen, hydroxy, -C r C 4 alkyl, -C r C 4 alkyloxy, -CF 3 , -CHF 2 , fluorine, chlorine or bromine;
  • R 1 "and R 2 are the same or different, dC 4 alkyl which may optionally be substituted by hydroxyl, fluorine, chlorine or bromine, or R 1 and R 2 together denote a -C 3 -C 4 -alkylene;
  • R 17, R 18, R 17 'and R 18' are hydrogen, C r C 4 alkyl, C r C 4 -alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2, fluorine , Chlorine or bromine;
  • R x and R x are identical or different, are hydrogen, CrC 4 alkyl, dC 4 alkyloxy,
  • R x and R x ' together represent a single bond or a divalent group selected from O, S, NH- and CH 2 .
  • 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
  • R x and R x are the same or different, hydrogen, -CF 3 or fluorine, preferably
  • R x and R x together denote a single bond or -O-.
  • R 16 is hydrogen, hydroxy or methyl
  • R 1 " and R 2" are methyl;
  • R 17 , R 18 , R 17 ' and R 18 are hydrogen or fluorine, preferably
  • R x and R x are identical or different, hydrogen or fluorine, preferably hydrogen, or R x and R x together represent a single bond or the group -O-.
  • the compounds of the formula 2a.12 may optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.12 are combinations comprising 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;
  • the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.13
  • 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 the same or different, dC 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 -Cs-Cs-alkylene bridge;
  • R 20, R 21, R 20 'and R 21' are identical or different are hydrogen, C r C 4 alkyl, -CRC 4 -alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen, mean.
  • 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 is chloride, bromide or methanesulfonate, preferably bromide
  • R 19 is hydroxy or methyl;
  • R 1 and R 2 are identical or different, are 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.
  • particularly preferred compounds of formula 2a.13 are those in which A 'is a divalent group selected from
  • R 19 is hydroxy or methyl, preferably methyl
  • R 1 and R 2 are identical or different, are methyl or ethyl, preferably methyl; R 3 , R 4 , R 3 ' and R 4 are identical or different, hydrogen or fluorine.
  • the compounds of the formula 2a.13 may optionally be present in the form of their enantiomers, mixtures of their enantiomers or racemates, and optionally in the form of their hydrates and / or solvates.
  • Examples of drug combinations according to the invention of preferred compounds of the formula 1 with the abovementioned anticholinergics 2a.13 are combinations comprising 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.13.1; 1.4 and 2a.13.2;
  • 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
  • compositions according to the invention furthermore comprise, in addition to one or more, preferably one compound of formula 1, as further active ingredient one or more, preferably a PDE IV inhibitor 2b, optionally in combination with pharmaceutically acceptable excipients.
  • PDE IV inhibitor 2b is preferably 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-oxo-pyridine-1-yl) -difluoromethoxy-S-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-) p - [(4aR * , 10t »S * ) -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 -
  • the PDE IV inhibitor 2b is 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-oxopyridin-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-
  • PDE IV inhibitor 2b is 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) cyclohexan-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.2O)
  • 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 comprising 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.1O; 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.2O; 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
  • compositions according to the invention furthermore comprise, in addition to one or more, preferably one compound of formula 1, as further active ingredient one or more, preferably one steroid 2c, optionally in combination with pharmaceutically acceptable excipients.
  • 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.1O), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), dexamethasone (2c.14), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2-furanylcarbonyl) oxy] -11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1, 4-diene-17 ⁇ -carbothionic acid (S) -fluoromethyl ester (2c.15), 6 ⁇ , 9 ⁇ -difluoro-1 ⁇ -hydroxy
  • steroid 2c is selected from the group consisting of flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.1O), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), dexamethasone (2c.14), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2-furanylcarbonyl) oxy] -11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothionic acid (S) -fluoromethyl ester (2c.15), 6 ⁇ , 9 ⁇ -difluoro-1 1 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1,4-diene-17 ⁇ -carbothionic acid (S) - (2-o
  • the steroid 2c is selected from the group consisting of budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [(2-furanylcarbonyl) oxy] -1,1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothionic acid (S) -fluoromethyl ester (2c.15) and etiprednol-dichloroacetate (2c .17), 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 reference to their optional 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.
  • Further preferred drug combinations according to the invention furthermore comprise, in addition to one or more, preferably one compound of formula 1, as further active ingredient one or more, preferably a LTD4-antagonist 2d, optionally in combination with pharmaceutically acceptable excipients.
  • the LTD4 antagonist 2d is preferably 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] pyridin-5-yl) - (E) - ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid (2d.3), pranlukast (2d.4), zafirlukast (2d.5), [2 - [[2- (4- (4,7
  • the LTD4 antagonist 2d is 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.1O), 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 pharmacologically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • the LTD4 antagonist 2d is 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), with montelukast (2d.1), pranlukast (2d.4) and zafirlukast (2d.5) being particularly preferred, if appropriate in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable
  • Acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • salts with pharmacologically acceptable acids for the formation of the compounds 2d are optionally in the 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.
  • salts or derivatives which the compounds 2d are able to form are understood as meaning alkali metal salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • alkali metal salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • Examples of preferred pharmaceutical combinations according to the invention of preferred compounds of the formula 1 with the abovementioned LTD4-antagonists 2d are combinations comprising 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.1O; 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.1O; 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
  • compositions according to the invention furthermore comprise, in addition to one or more, preferably one compound of formula 1, as further active ingredient one or more, preferably an EGFR inhibitor 2e, optionally in combination with pharmaceutically acceptable excipients.
  • 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 -butene-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-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-dimethylamino) -1-oxo-2 -butene-1-ylamino] -cyclopropylmethoxy-quinazoline, 4 - [(R)
  • the EGFR inhibitor 2e is 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-y-cyclopropyl-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - ⁇ [4- (N, N-diethylamino) -1-oxo-2-butene] 1-yl] amino ⁇ -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-dimethylamino) -1-oxo-2-butene] 1 -yl] amino ⁇ -7-cyclopropylmethoxy-quinazoline
  • the EGFR inhibitors 2a which are selected are particularly preferably used in the context of the medicament combinations according to the invention from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-ylylamino] -y-cyclopropylmethoxy quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-ylamino] -y-cyclopentyloxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - ⁇ [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-one buten-1-y
  • EGFR inhibitor 2e 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] -yl] -amino ⁇ -7-cyclopropylmethoxy-quinazoline (2e.1),
  • 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 pharmaceutical combinations according to the invention of preferred compounds of the formula 1 with the abovementioned EGFR inhibitors 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.1O; 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.2O; 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;
  • the medicament combinations according to the invention of compounds of the formula 1 with at least one further active ingredient 2 are not restricted to binary active substance combinations.
  • the above-mentioned partly exemplarily named combinations which, in addition to a compound of the formula 1, contain a further active ingredient 2, may further comprise a third or fourth, preferably a third active ingredient which is likewise selected from the abovementioned group of anticholinergics (2a), PDEIV inhibitors ( 2b), steroids (2c), LTD4 antagonists (2d) and EGFR inhibitors (2e).
  • compositions listed below Particularly preferred combinations which, in addition to a compound of formula 1, contain 2 further active compounds are selected from the active substance combinations listed below.
  • drug combinations which may contain, for example: A) a compound of formula 1, an anticholinergic agent (2a), a PDEIV inhibitor (2b);
  • alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. If appropriate, the abbreviations Me, Et, Prop or Bu are also used to designate the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert. Butyl etc.
  • cycloalkyl groups are understood as meaning alicyclic groups having 3 to 6 carbon atoms. These are the groups
  • alkylene groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms.
  • Examples include: methylene, ethylene, propylene or butylene.
  • alkylene-halogen groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably doubly substituted by a halogen.
  • alkylene-OH groups unless stated otherwise, branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted by a hydroxy.
  • alkyloxy groups unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom.
  • the abbreviations MeO, EtO, PropO or BuO are also optionally used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • propoxy and butoxy include all conceivable isomeric forms of the respective radicals.
  • propyloxy includes n-propyloxy and iso-propyloxy
  • butyloxy includes iso-butyloxy, sec-butyloxy and tert.
  • alkoxy is also used.
  • methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • alkylene-alkyloxy groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms which are monosubstituted, disubstituted or trisubstituted, preferably monosubstituted by an alkyloxy group.
  • -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.
  • -O-CO-alkyl-halogen group is to be understood.
  • the group -O-CO-CF 3 stands for trifluoroacetate.
  • Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine and bromine are preferred halogens.
  • the group CO denotes a carbonyl group.
  • the combination of drugs of components 1 and 2 is understood to mean the joint application of both active ingredients in a single administration form or formulation or the separate applications of the two active substances in separate administration forms.
  • this separate application can be graded simultaneously or temporally, that is, one after the other.
  • One aspect of the present invention relates to above-mentioned drug combinations which contain, in addition to therapeutically effective amounts of 1 and 2, a pharmaceutically acceptable carrier.
  • One aspect of the present invention relates to the above-mentioned medicaments which contain, in addition to therapeutically effective amounts of 1 and 2, no pharmaceutically acceptable carrier.
  • the present invention further relates to the use of therapeutically effective amounts of the active compounds 1 for producing a further one or more, preferably an active ingredient 2-containing drug for the treatment of inflammatory and obstructive airways diseases, for the prevention of premature labor in obstetrics (tocolysis), to restore the Sinus rhythm in the heart in atrio-ventricular block, for the correction of bradykaler arrhythmias (antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase in cardiac output) and for the treatment of itching and inflammation of the skin.
  • an active ingredient 2-containing drug for the treatment of inflammatory and obstructive airways diseases, for the prevention of premature labor in obstetrics (tocolysis), to restore the Sinus rhythm in the heart in atrio-ventricular block, for the correction of bradykaler arrhythmias (antiarrhythmic), for the treatment of circulatory shock (vasodilation and increase in cardiac output) and for the treatment of itching and inflammation of the skin.
  • a preferred aspect of the present invention relates to the use of therapeutically effective amounts of the active ingredients 1 for the preparation of a medicament containing one or more, preferably an active ingredient 2, for the treatment of
  • Respiratory disorders selected from the group consisting of obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, adult respiratory distress syndrome (ARDS) and all forms of pulmonary edema.
  • Drug combinations 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), wherein the use for the production of a medicament for the treatment of bronchial asthma and COPD according to the invention is particularly preferred.
  • restrictive lung diseases which are selected from the group consisting of allergic alveolitis, restrictive pulmonary diseases induced by occupational noxae, such as asbestosis or silicosis and restriction due to lung tumors such as lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
  • interstitial lung diseases which are selected from the group consisting of infectious pneumonias, for example due to an infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens , Pneumonitis due to different causes, such as aspiration and left heart failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis, such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
  • infectious pneumonias for example due to an infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens
  • Pneumonitis due to different causes, such as aspiration and left heart failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic sclero
  • bronchitis such as, for example, bronchitis due to bacterial or viral infection, Allergic Bronchitis and Toxic Bronchitis.
  • ARDS adult respiratory distress syndrome
  • the above-mentioned use of the drug combinations according to the invention for the manufacture of a medicament for the treatment of asthma or COPD.
  • the abovementioned use of the medicament combinations according to the invention for the preparation of a medicament for the once-daily treatment of inflammatory and obstructive respiratory diseases, particularly preferably for the once-daily treatment of asthma or COPD.
  • the present invention further relates to the use of therapeutically effective amounts of a compound of formula 1 in combination with therapeutically effective
  • Amounts of an active ingredient 2 for the manufacture of a medicament for the treatment of any of the aforementioned disorders are provided.
  • the present invention further relates to a method for the treatment of one of the abovementioned disorders, which is characterized in that therapeutically effective amounts of an active compound of the formula 1 are administered in combination with therapeutically effective amounts of an active compound 2.
  • 0.1 to 1000 ⁇ g of a compound of the formula 1 can be administered per single administration.
  • 1 to 500 ⁇ g, particularly preferably 3 to 100 ⁇ g of the compound of the formula 1 are administered per single administration, a dosage range of 5 to 75 ⁇ g, preferably of 7 to 50 ⁇ g, being preferred according to the invention.
  • the medicaments according to the invention are particularly preferably applied in such an amount that 9 to 40 ⁇ g, more preferably 11 to 30 ⁇ g, furthermore preferably 12 to 25 ⁇ g of the compound of formula 1 are administered per single administration.
  • 5 ⁇ g, 7.5 ⁇ g, 10 ⁇ g, 12.5 ⁇ g, 15 ⁇ g, 17.5 ⁇ g, 20 ⁇ g, 22.5 ⁇ g, 25 ⁇ g, 27.5 ⁇ g, 30 ⁇ g, 32.5 ⁇ g may be used per single dose , 35 ⁇ g, 37.5 ⁇ g, 40 ⁇ g, 42.5 ⁇ g, 45 ⁇ g, 47.5 ⁇ g, 50 ⁇ g, 52.5 ⁇ g, 55 ⁇ g, 57.5 ⁇ g, 60 ⁇ g, 62.5 ⁇ g, 65 ⁇ g, 67.5 ⁇ g, 70 ⁇ g, 72.5 ⁇ g or 75 ⁇ g a compound of formula 1 are applied.
  • the above dosages refer to the compounds of formula 1 in the form of their free base. If the compounds of the formula 1 are administered in the form of their pharmaceutically acceptable acid addition salts, the dose ranges for the acid addition salts, taking into account the molecular weight of the acids used, are readily calculable by a person skilled in the art from the above-mentioned dose ranges. Particularly preferred, the compounds of formula 1 are at o.g. Dose ranges in the form of the enantiomerically pure compounds, particularly preferably applied in the form of their R-enantiomers.
  • the amount of anticholinergic agent used varies greatly depending on the choice of the active ingredient.
  • such amounts of anticholinergic agent (2a.V) can be applied that 0.1 to 80 ⁇ g, preferably 0.5 to 60 ⁇ g, particularly preferably about 1, are used per single dose - 50 ⁇ g 2a.1 'are included.
  • 2a.V anticholinergic agent
  • the particular appropriate amount of used salt 2a.1 or optionally used for reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion.
  • the active substance amounts of 2a.1 applied above by way of example correspond to the following amounts of 2a.1: 3 ⁇ g, 6 ⁇ g, 12 ⁇ g, 21 ⁇ g, 24 ⁇ g, administered per single administration. 43.3 ⁇ g and 48.1 ⁇ g 2a.1.
  • the dosages mentioned above are preferably applied once or twice a day, with the once daily application being particularly preferred according to the invention.
  • such amounts of anticholinergic (2a.2') can be applied that for each single dose 1 - 500 ⁇ g, preferably 5 - 300 micrograms, more preferably 15-200 micrograms 2a.2 'are included.
  • such amounts of anticholinergic agent (2a.3') can be administered that for each single dose 1 to 500 ⁇ g, preferably 5 to 300 ⁇ g, particularly preferably 15 to 200 ⁇ g 2a.3 'are included.
  • the particular appropriate amount of the used salt 2a.3 or optionally used for reaching hydrates or solvates are easily calculable for the skilled person depending on the choice of anion.
  • the application of the above dosages preferably one to four times daily, wherein the two to three times daily administration according to the invention is particularly preferred.
  • such amounts of anticholinergic agent (2a.4') can be applied that 1-150 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 20-200 ⁇ g, are administered once per single dose 2a.4 'are included.
  • 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.
  • such amounts of anticholinergic (2a.5') can be applied that for each single dose 1-500 ⁇ g, preferably 5-300 ⁇ g, particularly preferably 15-200 ⁇ g are included.
  • the dosages mentioned above are preferably applied once to four times daily, with the two to three times daily application being particularly preferred according to the invention.
  • such amounts of anticholinergic (2a.6') can be applied that for each single dose 1000-6500 ⁇ g, preferably 2000-6000 ⁇ g, more preferably 3000-5500 ⁇ g, more preferably 4000-5000 ⁇ g 2a.6 'are included.
  • such amounts of anticholinergic agent (2a.7') are administered that 50 to 1000 ⁇ g, preferably 100 to 800 ⁇ g, particularly preferably 200 to 700 ⁇ g, are particularly preferred per single administration 300 - 600 ⁇ g 2a.7 'are included.
  • 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 550 ⁇ g, or 600 ⁇ g 2a.7 ' can be administered per single administration.
  • the dosages mentioned above are preferably applied once to three times daily, the one to twice, particularly preferably the once daily application being particularly preferred according to the invention.
  • such amounts of anticholinergic (2a.9 'or 2a.10') are administered that for each single dose 1-500 ⁇ g, preferably 5% 300 ⁇ g, more preferably 15-200 ⁇ g 2a.9 'or 2a.10' are included.
  • 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g , 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g, 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g or 200 ⁇ g 2a.9 "or 2a.1O" become.
  • such amounts of anticholinergic (2a.11 1 , 2a.12' or 2a.13 ') are applied that 500 .mu.g, preferably 5-300 .mu.g, more preferably 10-200 .mu.g 2a.11 ', 2a.12' or 2a.13 'are included.
  • the dosages mentioned above are preferably administered once to three times a day, the one to twice, particularly preferably the once daily, application being particularly preferred according to the invention.
  • the compounds of the formula 1 are administered in combination with a PDE IV inhibitor 2b, it is preferable to apply about 1-10000 ⁇ g 2b per single dose. Such amounts of 2b are preferably applied so that 10 to 5000 .mu.g, preferably 50 to 2500 .mu.g, particularly preferably 100 to 1000 .mu.g, are contained per single administration.
  • the compounds of the formula 1 are administered in combination with a steroid 2c, preferably about 1-10000 ⁇ g 2c are administered per single dose.
  • Such amounts of 2c are preferably applied so that 5 to 5000 .mu.g, preferably 5 to 2500 .mu.g, more preferably 10 to 1000 .mu.g 2c are contained per single dose.
  • the compounds of the formula 1 are administered in combination with a LTD4-antagonist 2d, preferably about 0.01-500 mg 2 d are administered per single dose.
  • Such amounts of 2d are preferably applied such that 0.1 to 250 mg, preferably 0.5 to 100 mg, particularly preferably 1 to 50 mg of 2 d are contained per single dose.
  • 1 mg, 2.5 mg, 5 mg, 5.5 mg, 7 mg, 7, 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22 mg may be administered per single dose , 5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg or 50mg 2d.
  • the appropriate amount of the salt / derivative used can easily be calculated by the person skilled in the art, depending on the choice of salt / derivative from the above values.
  • the compounds of the formula 1 are administered in combination with an EGFR inhibitor 2e, preferably about 100-15,000 ⁇ g 2e are administered per single dose.
  • Such amounts of 2e are preferably applied such that 500 to 10,000 ⁇ g, preferably 750 to 8000 ⁇ g, particularly preferably 1000 to 7000 ⁇ g of 2e are contained per single administration.
  • per one-time administration 1000 .mu.g, 1 150 .mu.g, 1200 .mu.g, 1250 .mu.g, 1300 .mu.g,
  • the two active ingredient components 1 and 2 can be administered together or spatially separated in a manner known per se by inhalation, orally, parenterally or by other means in widely customary formulations such as, for example, tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, Powders and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents can 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 of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably 0 , 1 to 50 wt .-% of the total composition.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known auxiliaries, for example inert diluents, such as
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. They may also contain suspending aids 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 are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, if appropriate using emulsifiers and / or dispersants, wherein, for example, when using water as a diluent, organic solvents may optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection vials or ampoules or infusion bottles.
  • isotonic agents e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, if appropriate using emulsifiers and / or dispersants, wherein, for example, when using water as a diluent, organic solvents may optionally be used as solubilizers or auxiliary
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • water pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g.
  • paraffins e.g., petroleum fractions
  • oils of vegetable origin e.g., peanut or sesame oil
  • mono- or polyfunctional alcohols e.g., ethanol or glycerin
  • carriers such as e.g.
  • ground natural minerals eg kaolins, clays, talc, chalk
  • ground synthetic minerals eg fumed silica and silicates
  • sugars eg pipe, milk and dextrose
  • emulsifiers eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants for example, magnesium stearate, talc, stearic acid and sodium lauryl sulfate
  • the tablets may of course also contain additives such as, for example, sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • component 1 is applied by inhalation.
  • component 2 may also be more common, for example orally or else parenterally based on the prior art, given separate administration of the two active substances
  • Formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, powders and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents.
  • the drug combinations according to the invention are administered by inhalation by means of a single, both active ingredients 1 and 2 containing or by means of separate, each containing only one of the active ingredients 1 and 2, suitable for administration by inhalation appropriate dosage forms.
  • Inventive inhalable powders comprising the active ingredient combination of 1 and 2 may consist solely of the active substances mentioned or of a mixture of the active substances mentioned with physiologically acceptable excipients.
  • propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
  • the administration forms according to the invention may contain the active ingredient combination of 1 and 2 either together in one or in two separate administration forms. These administration forms which can be used in the context of the present invention are described in detail in the following part of the description.
  • the inhalable powders according to the invention may contain 1 and 2, either alone or in admixture with suitable physiologically acceptable auxiliaries. If the active compounds 1 and 2 are mixed with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose, trehalose), oligo - And polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose, trehalose
  • oligo - And polysaccharides eg dextrans
  • polyalcohols e
  • the auxiliaries have a maximum mean particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may seem appropriate to add finer excipient fractions having a mean particle size of 1 to 9 .mu.m to the abovementioned excipients. The latter finer excipients are also selected from the aforementioned group of usable excipients.
  • 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 of the invention may be provided and applied 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.
  • the inhalable powders according to the invention can be applied by means of inhalers known from the prior art.
  • 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 comprising a single dose from a supply by means of a measuring chamber as described in US 4570630A or other apparatus such as be described in DE 36 25 685 A, dosing.
  • the inhalable powders according to the invention which contain 1 and 2 optionally in combination with a physiologically acceptable excipient, can For example, by means of the known under the name Turbuhaler ® inhaler or with inhalers as they are disclosed for example in EP 237507 A, are applied.
  • the inhalable powders according to the invention, which in addition to 1 and 2 contain physiologically acceptable auxiliaries are preferably filled into capsules (called inhalers) which are used in inhalers such as, for example, in WO 94/28958.
  • FIG. 1 A particularly preferred inhaler for use of the medicament combination according to the invention in inhalants is shown in FIG.
  • 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 1 1 connected mouthpiece 12, and air passage holes 13 for adjusting the flow resistance.
  • 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
  • inhalable powders according to the invention are to be filled into capsules in the sense of the abovementioned preferred application, fill quantities of from 1 to 30 mg per capsule are suitable. These contain according to the invention either together or in each case already mentioned above for 1 and 2 dosages per single dose.
  • propellant-containing inhalable aerosols according to the invention can contain 1 and 2 dissolved in the propellant gas or in dispersed form.
  • 1 and 2 may be contained in separate dosage forms or in a common dosage form, wherein 1 and 2 either dissolved both, both dispersed or dissolved only one component and the other may be contained dispersed.
  • the propellant gases which can be used for the preparation of the inhalable aerosols according to the invention 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 halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n-propane, n-butane or isobutane
  • halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the above mentioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellant gases are halogenated alkane derivatives selected from TG1 1, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof, wherein the Propellants TG134a, TG227 and mixtures thereof are preferred.
  • the propellant-containing inhalation aerosols according to the invention may also contain further constituents such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these ingredients are known in the art.
  • the propellant-containing inhalation aerosols according to the invention may contain up to 5% by weight of active compound 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 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1 % By weight of active ingredient 1 and / or 2.
  • the active substance particles preferably have an average particle size of up to 10 ⁇ m, preferably from 0.1 to 6 ⁇ m, particularly preferably from 1 to 5 ⁇ m.
  • propellant-free inhalable solutions or suspensions containing the active compound combinations according to the invention contain, for example, aqueous or alcoholic, preferably ethanolic, optionally ethanolic in admixture with aqueous solvents.
  • aqueous or alcoholic solvent mixtures the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume of ethanol. The remaining volume percentages are filled up with water.
  • the solutions containing 1 and 2 separately or together are adjusted to a pH of 2 to 7, preferably 2 to 5, with suitable acids.
  • acids selected from inorganic or organic acids can be used.
  • inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances.
  • organic acids ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of the abovementioned acids in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • editic acid or one of the known salts thereof, sodium edetate, as a stabilizer or complexing agent
  • EDTA editic acid
  • sodium edetate sodium edetate
  • Other embodiments include this compound (s).
  • the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, more preferably below 20 mg / 100 ml.
  • those inhalation solutions are preferred in which the content of sodium edetate at 0 to 10mg / 100ml lies.
  • Co-solvents and / or further auxiliaries can be added to the propellant-free inhalable solutions according to the invention.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • 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 e.g.
  • surfactants e.g. Soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, chelating agents, antioxidants and / or preservatives which assure or prolong the useful life of the finished drug formulation, flavoring agents, vitamins and / or other additives known in the art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.
  • Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism.
  • Preservatives may be used to protect the formulation from contamination by germs. 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 concentration known from the prior art. The abovementioned preservatives are preferably present in concentrations of up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml. Preferred formulations contain, apart from the solvent water and the active ingredient combination of 1 and 2, only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is dispensed with.
  • the propellant-free inhalable solutions according to the invention are particularly those inhalers that can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalant suitable aerosol.
  • Such a device for the propellant-free administration of a metered amount of a liquid medicament for inhalation use is described in detail, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (there in particular Figures 6a and 6b).
  • the nebulisers (devices) described therein are also known by the name Respimat ®.
  • N- (3-Acetyl-5-benzyloxy-2-hydroxypropyl) -2-bromo-2-methyl-propionamide To a solution of 5.15 g (20 mmol) of 1- (3-amino-5-benzyloxy 2-hydroxy-phenyl) -ethanone in 20 ml of pyridine are added dropwise at 5 to 20 ° C 4.64 g (25 mmol) of 2-bromo-2-methyl-propionyl chloride. After completion of the addition, stirred for 15 minutes, treated with ice water and 100 mL of ethyl acetate and acidified with conc. Hydrochloric acid acidified. The organic phase is separated, washed with water and dried with sodium sulfate. After distilling off the solvent, the residue is crystallized in a diethyl ether / petroleum ether mixture. Yield: 6.8 g (84%); Melting range: 88-90 ° C.
  • Trifluoromethanesulfonic acid 2-acetyl-4-benzyloxy-6-nitro-phenyl ester 92.7 ml (660 mmol) of triethylamine are added to 90 g (313 mmol) of 1- (5-benzyloxy-2-hydroxy-3-nitro-phenyl) ethanone in 940 mL dichloromethane at -10 ° C. Subsequently, a solution of 65 mL (394 mmol) trifluoromethanesulfonic anhydride and 40 mL
  • Trimethylchlorosilane added dropwise at room temperature.
  • the reaction mixture is filtered, concentrated and treated with diethyl ether.
  • the eluate is freed from the solvent and the residue, if necessary, purified by chromatography.
  • the benzyl ether thus obtained is dissolved in methanol and hydrogenated with palladium on carbon (10%) as a catalyst at 2.5 bar and room temperature. Subsequently, the catalyst is separated and the crude product purified by chromatography (reverse phase, acetonitrile / water gradient with 0.1% trifluoroacetic acid) or crystallized in acetonitrile.
  • Example 1.1 8- ⁇ 2-M-J-Dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino-1-hydroxy-ethyl) -6-hydroxypropyl 4H-benzo ⁇ 1, 4 ⁇ oxazin-3-one
  • Example 1.2 8- ⁇ 2-ri, 1-Dimethyl-3- (2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl) -propylamino1-1-hydroxy-ethyl) -6-hydroxypropyl -4H-benzo [1, 41-oxazin-3-one
  • Example 1.4 8- ⁇ 2-M J-dimethyl-S-re-methyl ⁇ -oxo ⁇ -dihydro-benzoimidazol-i-propylamino-i-hydroxy-ethylHj-hydroxy-H-benzoyl-ioxazine-S-one
  • Example 1.5 8- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino1-1-hydroxy-ethyl) -6-hydroxy-4H- benzo [1, 41oxazin-3-one
  • Example 1.8 7- ⁇ 2- [1, 1-dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino1-1 ⁇ Hydroxy-ethyl) -5-Hydroxy-3H- benzoxazol-2-one
  • Example 1.9 8- ⁇ 2-r3- (3-Benzyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1-dimethvl-propylamino-i-hydroxy-ethinyl- ⁇ -hydroxy] -dimethvMH-benzori ⁇ ioxazine-S-on
  • Example 1.10 8- ⁇ 2-r3- (3-Cyclopropylmethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethyl-propylamino1-1-hydroxy-ethyl) -6-hydroxypropyl -4H-benzo [1, 41-oxazin-3-one
  • Example 1.12 6-Hydroxy-8- ⁇ 1-hydroxy-2- [4- (4-methoxy-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethyl-butylamino-1-ethyl ) -4H-benzo [1, 41oxazin-3-one
  • 6-Hydroxy-8- ⁇ 1-hydroxy-2- [4- (4-methoxy-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethylbutylamino1-ethyl] -4H-benzo [1, 41-oxazin-3-one 130 mg (0.213 mmol) 6-benzyloxy-8- ⁇ 1-hydroxy-2- [4- (4-methoxy-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethyl- butylamino] -ethyl ⁇ -4H-benzo [1,4] oxazin-3-one hydrochloride are dissolved in methanol and hydrogenated with palladium on carbon as a catalyst at atmospheric pressure.
  • Example 1.14 8- ⁇ 2-r4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethylbutylamino1-1-hydroxyethyl) 6-hydroxy-4H-benzo [1, 41-oxazin-3-one
  • Example 1.15 8- ⁇ 2-r4- (7-Fluoro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethylbutylamino1-1-hydroxypropyl-ethyl) 6-hydroxy-4H-benzo [1, 41-oxazin-3-one

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PCT/EP2007/051408 2006-02-16 2007-02-14 Arzneimittelkombinationen zur behandlung von atemwegserkrankungen Ceased WO2007093608A1 (de)

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