Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • 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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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

Definitions

• the present invention relates to enantiomerically pure compounds of the formula 1
• radicals m, n, B, X, R 1 , m and Y m may have the meanings given in the claims and in the description, processes for their preparation, and their use as medicaments, in particular as medicaments for the treatment of respiratory diseases ,
• Betamimetics ( ⁇ -adrenergic agents) are known in the art. For example, reference may be made in this regard to the disclosure of US 4,460,581, which suggests betamimetics for the treatment of a wide variety of diseases.
• Particularly desirable is the provision of a drug which is therapeutically useful by a single application per day (single dose) used can be.
• An application once a day has the advantage that the patient can get used to the regular intake of the drug at certain times of day relatively quickly.
• betamimetics which on the one hand develop a therapeutic benefit in the treatment of respiratory diseases and are also characterized by a longer duration of action and thus can be used for the production of drugs with longer efficacy. It is in particular an object of the present invention to provide betamimetics which, because of their long-term effectiveness for the preparation of a therapy for
• Respiratory diseases once daily administered drug can be used.
• betamimetics which are particularly useful because of their physicochemical properties for the preparation of pharmaceutical formulations particularly suitable for inhalation application.
• the present invention relates to enantiomerically pure compounds of the formula 1
• n 1, 2, 3 or 4;
• X is CH 2 , CO, NR 2 , S or O;
• B is a divalent group of the formula CR D3 d ⁇ R-> 4 4 -0;
• R 1 H de-alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3 - 6 cycloalkyl, Ci -6 haloalkyl,
• R2 is H, Ci-6-alkyl, Ci-C6-io-aryl-alkylene, or Ci -4 -4 alkylene-C 3- 6 cycloalkyl, preferably H or C 6 alkyl;
• R 3 is H or C 1-6 alkyl
• R 4 is H or C 1-6 -alkyl
• ⁇ rr ⁇ - an m-fold negatively charged anion, preferably a m-fold negatively charged
• Propanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• the enantiomerically pure compound represented in formula 1 corresponds to the R-enantiomer.
• the compounds of the formula 1 consist of a singly positively charged molecule and a singly charged anion Y m " or a corresponding proportion 1 / m of an m-fold anion Y m" .
• n 1, 2 or 3; preferably 2 or 3
• X is CH 2 , CO, NR 2 , S or O;
• B is a divalent group of the formula CR 3 R 4 -O;
• R 1 H de-alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3 - 6-cycloalkyl, Ci -6 haloalkyl, O
• R is H, Ci 4 alkyl, Ci -2 -alkylene-C 3 - 6 cycloalkyl, benzyl or phenylethyl, preferably H,
• R 3 is H or Ci -4 alkyl; preferably H or methyl;
• R 4 is H or Ci -4 alkyl; preferably H or methyl; a m-fold negatively charged anion, preferably a m-fold negatively charged
• m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• X is CH 2 , CO, NR 2 , S or O;
• B is a divalent group of the formula CR 3 R 4 -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;
• R 2 is H, d-4-alkyl, Cs- ⁇ -cycloalkyl-methyl, particularly preferably H, methyl or cyclopropylmethyl;
• R 3 is H or methyl
• R 4 is H or methyl
• Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate , Fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• X is CH 2 , CO, NR 2 , S or O;
• B is a divalent group of the formula CR 3 R 4 -O;
• 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 or methyl
• R 4 is H or methyl
• Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate,
• m is 1 or 2 optionally, in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• X is CH 2 , CO, NR 2 , S or O;
• B is a divalent group of the formula CH 2 -O;
• 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
• Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate , Fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• X is NR 2 or O
• B is a divalent group of the formula CH 2 -O;
• 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;
• Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate , Fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates. Preference is given to enantiomerically pure compounds of the formula 1 in which n is 2
• B is a divalent group of the formula CH 2 -O; R 1 is H, methyl or CF 3,
• Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate , Fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• Preferred are enantiomerically pure compounds of formula 1, wherein n 2 and X, B, R 1 , R 2 , m and Y m "may have the abovementioned meaning, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• Preferred are enantiomerically pure compounds of formula 1, wherein X NH and n, X, B, R 1 , m and Y m "may have the abovementioned meaning, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
• enantiomerically pure compounds of formula 1 wherein B is a divalent group of the formula CH 2 -O and n, X, R 1 , R 2 , m and Y m "may have the abovementioned meaning, optionally in the form of their tautomers, mixtures the tautomers, hydrates or solvates. Particular preference is furthermore given to compounds of the above formula 1 which are selected from the group consisting of
• the above enantiomerically pure compounds of general formula 1 in crystalline form optionally in the form of their crystalline tautomers, crystalline hydrates or crystalline solvates.
• the above enantiomerically pure, crystalline compounds of general formula 1 optionally in the form of their crystalline tautomers, crystalline hydrates or crystalline solvates, which are further characterized in that they are crystalline compounds which are present in only a single crystal modifications.
• single crystal modification crystalline compounds of the formula 1 which do not represent a mixture of optionally existing crystal modifications.
• the compounds of formula 1 according to the invention are distinguished by a variety of possible uses in the therapeutic field. Particularly noteworthy in accordance with the invention are those possible applications for which the compounds of the formula 1 according to the invention can preferably be used as betamimetics because of their pharmaceutical activity.
• a further aspect of the present invention accordingly relates to the abovementioned enantiomerically pure compounds of the formula 1 as medicaments.
• the present invention further relates to the use of the aforementioned compounds of general formula 1 for the preparation of a medicament for the treatment of respiratory diseases.
• the present invention preferably relates to the use of the abovementioned compounds of the general formula 1 for the preparation of a medicament for the treatment of respiratory diseases, which are selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, Bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
• respiratory diseases which are selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, Bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
• COPD chronic obstructive pulmonary disease
• bronchial asthma pediatric asthma
• severe asthma acute asthma attack
• chronic bronchitis chronic bronchitis
• compounds of general formula 1 for the preparation of a medicament for the treatment of pulmonary emphysema, which originate in COPD (chronic obstructive pulmonary disease) or ⁇ 1-proteinase inhibitor deficiency.
• restrictive lung diseases which are selected from the group consisting of allergic alveolitis, induced by occupational Noxen restrictive lung diseases such as asbestosis or silicosis and restriction due to lung tumors, such as Lymphangiotic carcinomatosa, bronchoalveolar carcinoma and lymphomas.
• interstitial lung diseases which are selected from the group consisting of infectious pneumonia, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or others Pathogens, pneumonitis due to differential causes, such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis, such as, for example, Boeck's disease, idiopathic interstitial pneumonia, or idiopathic pulmonary fibrosis (IPF).
• infectious pneumonia such as due to infection with viruses, bacteria, fungi, protozoa, helminths or others Pathogens
• pneumonitis due to differential causes such as aspiration and left ventricular failure
• radiation-induced pneumonitis or fibrosis such as lupus erythematosus, systemic scleroderma or sarco
• Preference is further the use of compounds of general formula 1 to Preparation of a medicament for the treatment of bronchiectasis.
• compounds of general formula 1 for the preparation of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
• the present invention relates to the use of the compounds of formula 1 for the manufacture of a medicament for the treatment of asthma or COPD.
• the compounds of formula 1 for the manufacture of a medicament for the once-daily treatment of inflammatory and obstructive airway diseases, particularly preferably for the once-daily treatment of asthma or COPD.
• the present invention relates to a method for the treatment of the abovementioned disorders, characterized in that one or more of the abovementioned compounds of general formula 1 are administered in therapeutically effective amounts.
• the present invention preferably relates to methods for the treatment of asthma or COPD, characterized in that one or more of the abovementioned compounds of general formula 1 are administered once a day in therapeutically effective amounts.
• C 1-6 -alkyl (including those which are part of other groups) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 10 by the term "C 1-4 -alkyl” 4 carbon atoms understood. Preferred are alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, / so-propyl, n- Butyl, / so-butyl, sec-butyl, terf-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl.
• the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
• the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals.
• propyl includes n-propyl and / so-propyl
• butyl includes / so-butyl, sec-butyl and terf-butyl, etc.
• C 2 - 6 alkenyl (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 6 carbon atoms and the term “C 2 - 4 alkenyl” branched and unbranched alkenyl groups having 2 to 4 Carbon atoms understood, as far as they have at least one double bond.
• alkenyl groups having 2 to 4 carbon atoms examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals.
• propenyl includes 1-propenyl and 2-propenyl
• butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.
• C 2 - 6 -alkynyl (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C 2-4 alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 Carbon atoms understood as far as they have at least one triple bond.
• alkynyl groups having 2 to 4 carbon atoms examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl.
• propynyl includes 1-propynyl and 2-propynyl
• butinyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.
• C 3-6 -cycloalkyl means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with a or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, terf-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
• C haloalkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups having 1 to 6 carbon atoms which are substituted with one or more halogen atoms.
• C 1-4 -alkyl is meant branched and unbranched alkyl groups having from 1 to 4 carbon atoms which are substituted by one or more halogen atoms.
• alkyl groups having 1 to 4 carbon atoms For example: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 .
• aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
• Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
• enantiomerically pure describes in the context of the present invention compounds of the formula 1 which are present in an enantiomeric purity of at least 85% ee, preferably of at least 90% ee, particularly preferably of> 95% ee.
• ee enantiomeric excess
• i-or-4-methyl-nitro-pentane To 26.0 g (177 mmol) of 1-methyl-4-nitro-pentan-1-ol and 52.8 g (352 mmol) of sodium iodide in 350 ml_ acetonitrile is a solution of 44.7 ml_ (352 mmol) of chlorotrimethylsilane and 50 ml of acetonitrile were added dropwise. The mixture is then heated for 4 hours at 50 ° C, then the solvent is distilled off and the residue is mixed with 500 ml of diethyl ether. It is washed successively with water, sodium thiosulfate solution and sodium chloride solution. The organic phase is dried with sodium sulfate and concentrated. Yield: 34.2 g.
• 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.
• Salt precursor 1 8- ⁇ 2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6 -hydroxy-4H-benzo [1,4] oxazin-3-one
• Salt precursor 2 8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6 -hydroxy-4H-benzo [1,4] oxazin-3-one
• Salt precursor 3 8- ⁇ 2- [1,1-dimethyl-4- (2-oxo-benzooxazol-3-yl) -butylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4 ] oxazin-3-one
• Salt precursor 4 8- ⁇ 2- [1,1-dimethyl-3- (3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6 -hydroxy-4H-benzo [1,4] oxazin-3-one
• Salt precursor 5 8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H benzo [1,4] oxazin-3-one
• Salt precursor 6 8- ⁇ 2- [1,1-dimethyl-4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -butyl-amino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H benzo [1,4] oxazin-3-one
• Salt precursor 7 8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-benzooxazol-3-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1, 4 ] oxazin-3-one
• Salt precursor 8 6-hydroxy-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
• the R-enantiomer according to the invention can be obtained from the racemate according to methods known per se in the prior art.
• the compounds of formula 1 can generally be prepared according to the following procedure.
• L - (+) - tartrate 35.2 mmol of one of the compounds of salt precursors 1-11 are dissolved at room temperature in 150 ml of ethanol. The solution is heated to 60 ° C and treated dropwise with a solution of 5.3 g (35.2 mmol) of L - (+) - tartaric acid in 40 ml of ethanol. The mixture is cooled to room temperature over 6 hours and the resulting solid filtered. The isolated solid is washed with 40 ml of ethanol and dried at 45 ° C for 12 hours. Yield: about 65-75% of theory, the stoichiometry cation to anion is 1: 1.
• Hemi-ethanedisulfonate 3.52 mmol of one of the compounds of salt precursors 1-11 are dissolved in 15 ml of boiling ethanol and admixed with 0.67 g (3.52 mmol) of ethanedisulfonic acid. The mixture is refluxed for 1 hour and then cooled to room temperature. After 12 hours at room temperature, the solid formed is filtered off, washed with 10 ml of ethanol and dried at 45 ° C for 12 hours. Yield: about 40-50% of theory, the stoichiometry cation to anion is 2: 1.
• Example 1 R-8- ⁇ 2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleinate
• Example 2 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2,3 -dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleinate
• Example 3 R-8- ⁇ 2- [1 , 1-Dimethyl-4- (2-oxo-benzooxazol-3-yl) -butylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• Example 4 R-8- ⁇ 2- [1,1-dimethyl-3- (3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleinate
• Example 5 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazole 1-yl) propylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleinate.
• Example 7 R-8- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-benzooxazol-3-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1 , 4] oxazin-3-one maleinate
• Example 8 R-6-hydroxy-8- ⁇ 1-hydroxy-2- [4- (4-methoxy-2-oxo-2,3-dihydrobenzoimidazol-1-yl ) -1, 1-dimethyl-butylamino] -ethyl ⁇ -4 H -benzo [1,4] oxazin-3-one maleinate.
• Example 9 R-6-hydroxy-8- ⁇ 1-hydroxy-2- [4- ( 5-methoxy-3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethylbutylamino] ethyl ⁇ -4 H -benzo [1,4] oxazin-3-one maleinate
• Example 10 R-8- ⁇ 2- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethyl-butylamino] -1 -hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleinate
• Example 11 R-8- ⁇ 2- [4- (7-Fluoro-3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethyl-butylamino] -1 - hydroxyeth
• Example 12 R-8- ⁇ 2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ 6-hydroxy-4H-benzo [1,4] oxazin-3-one tartrate
• Example 13 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one tartrate
• Example 14 R-8- ⁇ 2- [1,1-dimethyl-4- (2-oxo-benzooxazol-3-yl) - butylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one tartrate
• Example 15 R-8- ⁇ 2- [1,1-dimethyl-3- (3- Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• Example 16 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H- benzo [1,4] oxazin-3-one tartrate
• Example 17 R-8- ⁇ 2- [1,1-Dimethyl-4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -butylamino ] - 1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one tartrate
• Example 18 R-8- ⁇ 2- [1,1-Dimethyl-3- (2-oxo-benzooxazol-3-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1 4] oxazin-3-one tartrate
• Example 19 R-6-Hydroxy-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 tartrate
• Example 20 R-6-hydroxy-8- ⁇ 1-hydroxy-2- [4- (5-methoxy-3-methyl-2 -oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethylbutylamino] ethyl ⁇ -4 H -benzo [1,4] oxazin-3-one tartrate
• Example 21 R-8- 2- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1-dimethylbutylamino] -1-hydroxyethyl ⁇
• Example 23 R-8- ⁇ 2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• Example 24 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2 , 3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• Example 25 R-8- ⁇ 2- [1,1-dimethyl-4- (2-oxo-benzooxazol-3-yl) -butylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1 , 4] Oxazin-3-one hemi-ethanedisulfonate
• Example 26 R-8- ⁇ 2- [1,1-dimethyl-3- (3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• Example 27 R-8- ⁇ 2- [1,1-dimethyl-3- (2-oxo-2,3-dihydro benzoimidazol-1-yl) propylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,
• Example 31 R-6-hydroxy-8- ⁇ 1-hydroxy-2- [4- (5-methoxy-3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -1, 1 -dimethyl-butylamino] -ethyl ⁇ -4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• Example 32 R-8- ⁇ 2- [4- (6-fluoro-3-methyl-2-oxo -2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethylbutylamino] -1-hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• Example 33 R-8- ⁇ 2- [4- (7-Fluoro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -1, 1-dimethylbutylamino] -1 - hydroxyethyl ⁇ -6-hydroxy-4H-benzo [1,4] oxazin-3-one hemi-ethanedisulfonate
• the following table shows the characteristic X-ray reflexes with intensities (normalized, up to 40 ° 2 ⁇ ) for the example mentioned. As is known to those skilled in the art, the intensities of the reflections may vary due to the sample preparation. The following These intensities were found in a measurement of the above example and can not be transferred to any further measurement.
• the following table shows the characteristic X-ray reflexes with intensities (normalized, up to 40 ° 2 ⁇ ) for the example mentioned. As is known to those skilled in the art, the intensities of the reflections may vary due to the sample preparation. The following intensities were found in a measurement of the above example and can not be transferred to any further measurement.
• the intensities of the reflections may vary due to the sample preparation. The following intensities were found in a measurement of the above example and can not be transferred to any further measurement.
• the compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1.
• the compounds of Formula 1 may also be used in combination with W wherein W is a pharmacologically active agent and is (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR Inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors.
• W is a pharmacologically active agent and is (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR Inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors.
• W represents a betamimetic, combined with an anticholinergic, corticosteroid, PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
• W represents an anticholinergic, combined with a betamimetic, corticosteroid, PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
• W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
• W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4
• W represents an EGFR inhibitor combined with a LTD4 antagonist.
• Preferred betamimetics are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenalines, levosalbutamol, mabuterol, meluadrins, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
• anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the
• the cations are the pharmacologically active ingredients.
• the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
• the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
• anticholinergics are selected from the salts of the formula AC-1
• 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-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates.
• anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate
• R is either methyl or ethyl and in which X ⁇ may have the abovementioned meanings.
• the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.
• Preferred corticosteroids are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS -126, ST-26 and
• Examples of possible salts and derivatives of the steroids may be: alkali metal salts, for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
• alkali metal salts for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
• Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 1 1294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
• Preferred LTD4 antagonists here are compounds which are selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, Hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate.
• understood alkali salts such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• Preferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
• the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydroxides citrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
• Betamimetics selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate.
• H1 -Antihistaminika here are preferably compounds used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• Preferred PAF antagonists here are compounds which are selected from the group consisting of
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
• Suitable application forms for the application of the compounds of the formula 1 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% by weight 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 to obtain 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 to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example iner
• 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.
• 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, such as flavorings, such as vanillin or orange extract included. 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.
• a sweetener such as saccharin, cyclamate, glycerol or Sugar
• a taste-improving agent such as flavorings, such as vanillin or orange extract included.
• 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 compounds of formula 1 containing capsules according to the invention can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulated in gelatin 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, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting be used. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
• inhalable dosage forms are inhalable powders, propellant-containing metered dose inhalers or propellant-free inhalable solutions.
• propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
• the compounds of the formula 1 which are particularly preferably used in crystalline form according to the invention are preferably used for the preparation of inhalable powders.
• Inhalable powders which can be used according to the invention can contain the crystalline compounds of the formula 1 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), oligo- and polysaccharides (eg Dextran), 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
• oligo- and polysaccharides eg Dextran
• polyalcohols eg sorbitol, mannitol, xylitol
• salts eg sodium chloride, calcium carbonate
• Lactose most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
• 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 ingredient preferably with an average particle size of 0.5 to 10 .mu.m, particularly preferably from 1 to 5 .mu.m, admixed to the excipient mixture.
• 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.
• inhalable powders according to the invention can be applied by means of inhalers known from the prior art.
• Propellant gas-containing inhalation aerosols according to the invention can be dissolved in the propellant gas or contained in dispersed form.
• the propellant gases which can be used for the preparation of the inhalation aerosols 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 fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the abovementioned propellant gases can be used alone or in mixtures thereof.
• Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
• the propellant-containing inhalation aerosols may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.
• the dosage of the compounds according to the invention is naturally highly dependent on the mode of administration and the disease to be treated.
• the compounds of the formula When administered by inhalation, the compounds of the formula are already characterized by a high efficacy at doses in the ⁇ g range. Even above the ⁇ g range, the compounds of the formula can be used meaningfully.
• the dosage can then also be in the milligram range, for example.
• a further aspect of the present invention relates to the abovementioned pharmaceutical formulations, characterized by a content of a compound of the formula 1 as such, particularly preferably the above-mentioned inhalable pharmaceutical formulations.
• the finely ground active substance, lactose and part of the corn starch are mixed together.
• the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
• the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
• the mixture is compressed into tablets of suitable shape and size.
• the finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.
• the active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water.
• the moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve.
• curved tablet cores having a diameter of 6 mm are pressed on a tableting machine.
• the coated dragee cores are coated in a known manner with a layer consisting essentially of sugar and talc.
• the finished dragees are polished with wax.
• Substance and cornstarch are mixed and moistened with water.
• the moist mass is sieved and dried.
• the dry granules are sieved and mixed with magnesium stearate.
• the final mixture is filled into hard gelatine capsules size 1.
• the active ingredient is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and treated with sodium chloride as isotonic.
• the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
• the vials contain 5 mg, 25 mg and 50 mg active ingredient.
• the hard fat is melted.
• the ground active substance is dispersed homogeneously. It is cooled to 38 ° C and poured into slightly pre-cooled suppository molds
• Distilled water is heated to 70 ° C. Herein dissolved hydroxyethyl-cellulose with stirring. After addition of sorbitol solution and glycerol is cooled to room temperature. At room temperature, sorbic acid, flavor and substance are added. To vent the suspension is evacuated with stirring, and 50 mg of active ingredient.

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