Classifications

• • 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
  • A61K31/536—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 ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • 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
  • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • 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
  • A61P17/04—Antipruritics
• • 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
  • 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
  • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
• 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.
• the present invention relates to drug combinations which, in addition to one or more, preferably a compound of general formula 1
• R 1 and R 2 alkylene independently H, halogen or C 4 alkyl or together d- 6;
• H H, halogen, OH, d -4 alkyl, or O-Ci -4 alkyl; optionally, in the form of their pharmaceutically acceptable acid addition salts, hydrates or solvates, contain at least one further active ingredient 2.
• the present invention preferably relates to medicament combinations which, in addition to one or more, preferably one compound of formula 1, as further active ingredient 2 contain one or more compounds selected from the classes of the anticholinergics (2a), PDE-IV inhibitors (2b), Steroids (2c), LTD4 antagonists (2d) and EGFR inhibitors (2e).
• R 3 is hydrogen, fluorine, chlorine, OH, methyl, ethyl, methoxy, or ethoxy
• R 1 and R 2 are identical or different, hydrogen, methyl, ethyl, propyl or together -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -;
• R 3 is hydrogen, fluorine, OH, methyl or methoxy;
• R 3 is hydrogen, fluorine, OH, methyl or methoxy
• R 3 is hydrogen, fluorine, OH or methoxy
• 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.
• Particular preference is given here to compounds of the formula 1 in the form of the enantiomerically pure compounds, the R enantiomers of the compounds of the formula 1 being of outstanding importance in accordance with the invention.
• the R-enantiomers of the compounds of the formula 1 can be represented by the general formula I-1
• drugs combinations which, in addition to one or more, preferably a compound of general formula 1, selected from the compounds 1.1: N- (5- ⁇ 2- [1,1-dimethyl-3- (4-methyl-2-oxo -4H-benzo [d] [1,3] oxazin-1-yl) propylamino] -1-hydroxyethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide 1.2: N- (5- ⁇ 2- [1, 1-Dimethyl-3- (2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] -1-hydroxyethyl ⁇ -2-hydroxy-phenyl) -methanesulfonamide
• drugs combinations which, in addition to one or more, preferably one compound of the general formula 1 selected from the compounds 1.7: N- (5- ⁇ 2- [1, 1-dimethyl-3- (2-oxo-4,4 -dipropyl-4H-benzo [d] [1,3-oxazin-1-yl) propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide 1.8: N- [5- (2- ⁇ 1, 1-Dimethyl-3- [spiro (cyclohexane-1, 4'-2H-3 ', 1'-benzoxazine) -2'-oxo-1-yl] propylamino ⁇ -1-hydroxy-ethyl) -2 hydroxy-phenyl] -methanesulfonamide
• 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 1 ), 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 containing chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate as counterions are preferred.
• 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 tiotropium bromide is 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.
• the tiotropium bromide is employed in anhydrous form in the medicament combinations according to the invention, the anhydrous crystalline tiotropium bromide is preferably used, 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 1.4 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; 1.7 and 2a.1; 1.7 and 2a.2; 1.7 and 2a.3;
• 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 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
• 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
• 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 1.4 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; 1.8 and 2a.7; 1.8 and 2a.7-en; 1.9 and 2a.7; 1.9 and 2a.7-en; 1.10 and 2a.7; 1.10 and 2a.7-en; 1.11 and 2a.7; 1.11 and 2a.7-en; 1.12 and 2a.7; 1.12 and 2a.7-en; 1.13 and 2a.7; 1.13 and 2a.7-en; 1.14 and 2a.7 or 1.14 and 2a.7-en; each optionally in the form of their racemates, enantiomers or diastereo
• 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 containing the compounds 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; 1.8 and 2a.8.1; 1.8 and 2a.8.2; 1.9 and 2a.8.1; 1.9 and 2a.8.2; 1.10 and 2a.8.1; 1.10 and 2a.8.2; 1.11 and 2a.8.1; 1.11 and 2a.8.2; 1.12 and 2a.8.1; 1.12 and 2a.8.2; 1.13 and 2a.8.1; 1.13 and 2a.8.2; 1.14 and 2a.8.1 or 1.14 and 2a.8.2; each optionally in the form of their racemates, enantiomers or diastereo
• 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, 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,
• Preferred compounds of the formula 2a.9 in the context of the drug combinations according to the invention are those in which
• 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.
• 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 1.4 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; 1.8 and 2a.9.1; 1.8 and 2a.9.2; 1.8 and 2a.9.3; 1.8 and 2a.9.4; 1.9 and 2a.9.1; 1.9 and 2a.9.2; 1.9 and 2a.9.3; 1.9 and 2a.9.4; 1.10 and 2a
• 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 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 the same 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.
• 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 1.4 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; 1.6 and 2a.10.6; 1.7 and 2a.10.1; 1.7 and 2
• the anticholinergics 2a contained in the drug combinations according to the invention are selected from the compounds of the formula 2a.11
• 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;
• RR 1 '' aanndd RR 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 13 , R 14 , R 13 ' and R 14' are identical or different, hydrogen, -C r C 4 alkyl, -C r C 4 alkyloxy, hydroxy, -CF 3 , -CHF 2 , CN, NO 2 or Halogen, mean.
• 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, 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, 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 1.4 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; 1.6 and 2a.11.6; 1.7 and 2a.11.1
• 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, -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 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 , CH 2 -CH 2 , N (dC 4 alkyl), CH (C r C 4 alkyl) and -C (C r C 4 alkyl) 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 ,
• 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 a -C 3 -C 4 -alkylene;
• R 17, R 18, R 17 'and R 18' are hydrogen, C r C 4 alkyl, dC 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 .
• X is chloride, bromide, or methanesulfonate, preferably bromide
• 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 hydrogen;
• 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 1.4 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; 1.6 and 2a.12.2; 1.6 and 2a.12.3; 1.6 and 2a.12.4
• 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 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 20, R 21, R 20 'and R 21' are identical or different are hydrogen, C r C 4 alkyl, -dC mean 4 -alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen ,
• 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, 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 mean.
• 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, methyl or ethyl, preferably methyl, R 3 , R 4 , R 3 and R 4 are identical or different and denote 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 formula 1 with the abovementioned anticholinergics 2a.13 are combinations comprising the compounds 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 2
• anticholinergics 2 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 1 ), flutropium (2a.3'), Ipratropium (2a.4 '), glycopyrronium (2a.5'), trospium (2a.6 '), and 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-oxopyridine-1-yl) -difluoromethoxy-S-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-) p - [(4aR * , 10oS * ) -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- (3
• 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) 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.2O
• salts with pharmacologically acceptable acids for the formation of the compounds 2b 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, hydroxalate, 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 1.4 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.1O; 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.2O; 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
• 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) -
• 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.
• Enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates preference is given according to the invention to those which contain, as compound of the formula 1, one of the compounds 1.7, 1.8, 1.9, 1.10, 1.11, 1.12, 1.13, or 1.14.
• 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-) 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-tert-butoxy-2-but
• 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 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 1.4 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.1O; 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.1O; 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
• 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-diethylamino) -1-oxo-2 -but-1-yl] amino ⁇ -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophen
• 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 -butene-1-yl] amino ⁇ -7-cyclopropylmethoxyquinazoline, 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-yl-amino-cyclopropylmethoxy-quinazoline, 4 - [(R)
• 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.
• Hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, 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 1.4 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.1O; 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.2O; 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
• 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).
• G a compound of formula 1, a PDEIV inhibitor (2b), an EGFR inhibitor (2e); H) a compound of formula 1, a steroid (2c), a LTD4 antagonist (2d); I) a compound of formula 1, a steroid (2c), an EGFR inhibitor (2e);
• the combined application of both active substances in a single administration form or formulation, or the separate applications of the two is the combination of drugs of components 1 and 2
• 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.
• 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, Pr 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 cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Of particular importance in the context of the present invention is cyclopropyl.
• the alkylene groups are branched and unbranched divalent alkyl bridges having 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.
• the 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. Accordingly, as 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. For example, mention may be made of: methyloxy, ethyloxy, propyloxy or butyloxy.
• the abbreviations MeO, EtO, PrO or BuO are also optionally used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
• the definitions 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 in an analogous way is the Denote -O-CO-alkyl-halogen group.
• 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.
• Examples of acid addition salts with pharmacologically acceptable acids of the compounds 1 include salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, 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.
• the salts of hydrochloric acid the salts of hydrochloric acid
• Methanesulfonic acid, benzoic acid and acetic acid according to the invention particularly preferred.
• the present invention further relates to the use of therapeutically effective amounts of the active compounds 1 for the preparation of a 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, to repair 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 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, to repair 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.
• 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.
• obstructive pulmonary diseases which are 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 preparation 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 lung diseases caused 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 pneumonia, 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, collagen, such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatous diseases such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
• infectious pneumonia 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, collagen, such as lupus erythematosus, systemic scleroderma or sarcoidosis,
• 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 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 one of the abovementioned disorders.
• 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 the Formula 1 at the above 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 applied by way of example given above by way of example corresponds to quantities of 2a.
• V The following amounts of 2a.1: 3 ⁇ g, 6 ⁇ g, 12 ⁇ g, 21, 7 ⁇ g, 24.1 ⁇ g, 43.3 ⁇ g and 48.1 ⁇ g 2a.1 applied per single dose.
• 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 1 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 1 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 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 1 are included.
• 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 are applied 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 ug 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.
• such amounts of anticholinergic agent (2a.5') can be administered that for each single dose 1 to 500 ⁇ g, preferably 5 to 300 ⁇ g, more preferably 15 to 200 ⁇ g are contained.
• 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 per single dose 1000-6500 ⁇ g, preferably 2000-6000 ⁇ g, more preferably 3000-5500 ⁇ g, especially preferably 4000 - 5000 ⁇ g 2a.6 'are included.
• 3500 .mu.g, 3750 .mu.g, 4000 .mu.g, 4250 .mu.g, 4500 .mu.g, 4750 .mu.g, or 5000 .mu.g 2a.6 ' can be administered per single administration.
• such amounts of anticholinergic agent (2a.7') can be administered that 50 to 1000 ⁇ g, preferably 100 to 800 ⁇ g, particularly preferably 200 to 700 ⁇ g, are preferred for each single dose preferably 300-600 ⁇ g 2a. T 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 particular appropriate amount of used salt 2a.7 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 three times daily, wherein the once to twice, more preferably once daily application according to the invention is particularly preferred.
• such amounts of anticholinergic agent (2a.9 'or 2a.10') can be applied that for each single dose 1-500 ⁇ g, preferably 5 300 ⁇ g, more preferably 15-200 ⁇ g 2a.9 1 or 2a.10 'are contained.
• 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.
• the dosages mentioned above are preferably administered once to three times daily, the one to twice, particularly preferably once daily, application being particularly preferred according to the invention.
• the administration of the abovementioned dosages is preferably carried out one to three times a day, whereby the one to two times, particularly preferably once daily application is 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.
• acid addition salts, salts or derivatives of 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.
• 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 excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• 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, as well as a taste-improving agent, e.g. 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, optionally with the use of 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, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or
• 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.
• auxiliaries for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk), ground synthetic minerals (eg fumed silica and silicates), sugars (eg, cane, milk and dextrose), emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, Stearic acid and sodium lauryl sulfate).
• paraffins eg petroleum fractions
• oils of vegetable origin eg peanut or sesame oil
• mono- or polyfunctional alcohols eg ethanol or glycerol
• excipients such as natural minerals (eg kaolin, Clays, talc, chalk),
• the tablets may also contain additives other than those mentioned.
• Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like.
• 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 medicament combinations according to the invention are administered by inhalation by means of a single dosage form containing both active compounds 1 and 2 or containing them by separate, in each case only one of the active compounds 1 and 2, suitable for administration by inhalation.
• Suitable inhalable dosage forms are inhalable powders, propellant-containing metered dose inhalers or propellant-free inhalable solutions.
• 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.
• 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 eg sorbitol, mannitol, xylitol
• salts eg sodium chloride, calcium carbonate
• 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, particularly preferably from 1 to 6 .mu.m, the excipient or excipient mixture added.
• 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 optionally in association with a physiologically acceptable excipient 1 and 2 237507 A may be disclosed, for example, by the known by the name Turbuhaler ® inhaler or using inhalers as described for example in EP be 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
• fill quantities of from 1 to 30 mg per capsule are suitable. These contain, according to the invention either together or separately in each case the doses already mentioned above for 1 and 2 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 abovementioned 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. If the active compounds 1 and / or 2 are present in dispersed form, 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.
• MDIs metered dose inhalers
• another aspect of the present invention relates to pharmaceutical compositions in the form of propellant-containing aerosols as described above in association with one or more inhalers suitable for administering these aerosols.
• the present invention relates to inhalers, characterized in that they contain the propellant-containing aerosols according to the invention described above.
• the present invention further relates to cartridges which can be equipped with a suitable valve in a suitable inhaler and which contain one of the abovementioned propellant-containing inhalation aerosols according to the invention.
• Suitable cartridges and methods for filling these cartridges with the propellant-containing inhalation aerosols according to the invention are known from the prior art.
• 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. To adjust this pH, acids selected from inorganic or organic acids can be used.
• Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
• Examples of 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.
• the 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.
• EDTA editic acid
• sodium edetate sodium edetate
• 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 include, for example, surfactants, such as soybean lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives, the useful life of the finished drug formulation ensure or extend flavorings, 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 for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (there in particular Figures 6a and 6b) described in detail.
• the nebulizer described therein (devices) are also known by the name Respimat ®.
• Example 1 N- (5- ⁇ 2- [1,1-Dimethyl-3- (4-methyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] - 1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• the compound is known from EP 43940.
• the individual diastereomers of this embodiment can be obtained by conventional methods known in the art.
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the compound is known from EP 43940.
• the individual diastereomers of this embodiment can be obtained by conventional methods known in the art.
• Example 5 N- (2-Hydroxy-5- ⁇ 1-hydroxy-2- [3- (6-hydroxy-4,4-dimethyl-2-oxo-4H-benzo [d] [1,3] oxazine) 1 -yl) -1, 1-dimethyl-propylamino] -ethyl ⁇ -phenyl) -methanesulfonamide
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the compound is known from EP 43940.
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• Example 7 N- (5- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-4,4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• N- (5- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-4,4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] 1-hydroxyethyl ⁇ -2-hydroxy-phenyl) -methanesulfonamide 260 mg (0.386 mmol) of N- (2-benzyloxy-5- ⁇ 2- [1, 1-dimethyl-3- (2-oxo-4 , 4-dipropyl-4H-benzo [d] [1,3-oxazin-1-yl) propylamino] -1-hydroxy-ethyl ⁇ -phenyl) -methanesulfonamide hydrochloride in 8 mL of methanol are obtained in the presence of 26 mg of palladium Charcoal (10%) hydrogenated at room temperature.
• Example 8 N- [5- (2- ⁇ 1,1-Dimethyl-3-spiro (cyclohexane-1,4'-2H-3 ', 1'-benzoxazine) -2'-oxo-1-yl] -propylamino ⁇ -1-hydroxy-ethyl) -2-hydroxyphenyl] -methanesulfonamide
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• Example 10 N- (5- ⁇ 2- [3- (4,4-Diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1,1-dimethylpropylamino ] -1-hydroxyethyl ⁇ -2-hydroxy-phenyl) -methanesulfonamide:
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• the rotation of (R) -N- (5- ⁇ 2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1 -dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide hydrochloride (cocrystallized with one molecule of acetone) is -28.8 ° (c 1%, in methanol at 20 0 C).
• Example 11 N- (5- ⁇ 2- [3- (4,4-Diethyl-6-fluoro-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1 - dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• Example 12 N - (5- ⁇ 2- [3- (4,4-Diethyl-7-fluoro-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1 - dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• Example 13 N- (5- ⁇ 2- [3- (4,4-Diethyl-8-methoxy-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1,1 -dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.
• Example 14 N- (5- ⁇ 2- [3- (4,4-Diethyl-6-methoxy-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1,1 -dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide
• the (R) and (S) enantiomers of this embodiment can be obtained by conventional methods known in the art.
• the (R) -enantiomer of this embodiment is of particular importance in the present invention.

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