EP2057152A1 - Nouveaux agonistes beta énantiomériquement purs, procédés pour leur préparation et leur utilisation comme médicament - Google Patents

Nouveaux agonistes beta énantiomériquement purs, procédés pour leur préparation et leur utilisation comme médicament

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Publication number
EP2057152A1
EP2057152A1 EP07788189A EP07788189A EP2057152A1 EP 2057152 A1 EP2057152 A1 EP 2057152A1 EP 07788189 A EP07788189 A EP 07788189A EP 07788189 A EP07788189 A EP 07788189A EP 2057152 A1 EP2057152 A1 EP 2057152A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
methyl
ethyl
benzo
dimethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07788189A
Other languages
German (de)
English (en)
Inventor
Ingo Konetzki
Peter Sieger
Marco Santagostino
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP07788189A priority Critical patent/EP2057152A1/fr
Publication of EP2057152A1 publication Critical patent/EP2057152A1/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to enantiomerically pure compounds of the formula 1
  • radicals n, A, R 1 , R 2 , R 3 , m and Y 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 can be therapeutically useful by a single application per day (single dose) can be used.
  • a once a day application 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.
  • betamimetics which are useful because of their physicochemical properties in a special way for the preparation of particularly suitable for inhalation administration drug formulations.
  • betamimetics which, in addition to the abovementioned properties, have particular suitability for the preparation of inhalable powders and suspension aerosols.
  • the present invention relates to enantiomerically pure compounds of the formula 1
  • n 1, 2, 3 or 4;
  • A is a divalent group selected from the group consisting of O, S,
  • R 1 is Ci-6-alkyl
  • R 2 and R 3 are identical or different and are H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • R 4 is H or C 1-6 -alkyl
  • R 5 is H or d -6- alkyl
  • R 6 is H or C 1-6 -alkyl
  • Y m an m-fold negatively charged anion, preferably selected from the
  • 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;
  • A is a divalent group selected from the group consisting of
  • CR 4 R 5 -O, CH CH or CH 2 -CH 2 , preferably CR 4 R 5 -O;
  • R 2 and R 3 are identical or different and are H, d- C4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl,
  • Ci -4 haloalkyl C 3 - 6 cycloalkyl, Ci -4 haloalkyl, O-Ci -4 haloalkyl, halogen, OH, CN, NO 2, C 2-4 alkyl-OH, O-Ci -4 alkyl, COOH or COO -Ci -4 alkyl, or
  • R 4 is H or d -4 -alkyl
  • R 5 is H or C 1-4 alkyl
  • R 6 is H or C 1-4 alkyl
  • Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride,
  • R 4 is H, methyl, ethyl, preferably H or methyl, more preferably H;
  • R 5 is H, methyl, ethyl, preferably H or methyl, more preferably H;
  • Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride,
  • n is 1 or 2; in which n, R 1 , R 2 , R 3 and R 6 may each have one of the meanings given above or below, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
  • R 1 is methyl, ethyl or propyl, preferably methyl or ethyl, particularly preferably methyl and wherein n, A, R 2 , R 3 , R 4 , R 5 , R 6 , m and Y each may have any of the meanings given above or below, optionally in the form of their Ta utomere, mixtures of tautomers, hydrates or solvates.
  • R 2 is H, methyl, ethyl, propyl, vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, CH 2 Cl, CHCl 2 , CCI 3 , CH 2 F, CHF 2 , CF 3 , CH 2 -CH 2 Cl, CH 2 -CHCl 2 ,
  • CH 2 -CCI 3 CH 2 -CH 2 F, CH 2 -CHF 2 , CH 2 -CF 3 , CH 2 -CH 2 OH, fluorine, chlorine, bromine, OH, CN, NO 2 , methoxy, ethoxy, propoxy , COOH, COO-methyl, COO-ethyl, COO-propyl or COO-butyl;
  • R 3 is methyl, ethyl, propyl, vinyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, CH 2 Cl, CHCl 2 , CCI 3 , CH 2 F, CHF 2 , CF 3 , CH 2 -CH 2 Cl, CH 2 - CHCI 2 ,
  • CH 2 -CCI 3 CH 2 -CH 2 F, CH 2 -CHF 2 , CH 2 -CF 3 , CH 2 -CH 2 OH, fluorine, chlorine, bromine, OH, CN, NO 2 , methoxy, ethoxy, propoxy , COOH, COO-methyl, COO-ethyl, COO-propyl or COO-butyl, or
  • R 4 is H, methyl, ethyl, preferably H or methyl, more preferably H;
  • R 5 is H, methyl, ethyl, preferably H or methyl, more preferably H;
  • R 6 is H, methyl, ethyl, preferably H or methyl, particularly preferably H;
  • Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride,
  • R 2 is H, methyl, ethyl, CF 3 , CH 2 -CF 3 , fluorine, chlorine, OH, methoxy, ethoxy, COOH or COO-methyl;
  • R 3 is methyl, ethyl, propyl, vinyl, allyl, cyclopropyl, cyclopentyl, cyclohexyl, CH 2 F, CHF 2 , CF 3 , CH 2 -CH 2 F, CH 2 -CHF 2 , CH 2 -CF 3 , CH 2 - CH 2 OH, fluorine,
  • 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, malate, lactate , Salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m is 1 or 2, and in which n, A and R 1 may each have one of the meanings given above or below, optionally in the form of their tautomers,
  • R 2 is H, methyl, ethyl, CF 3 , fluorine, chlorine, OH or methoxy;
  • R 3 is methyl, ethyl, cyclopropyl, cyclohexyl, CF 3 , fluorine, chlorine, OH, CN,
  • n is 1 or 2; in which n, A and R 1 may each have one of the meanings given above or below, optionally in the form of their Ta utomere, mixtures of tautomers, hydrates or solvates.
  • R 2 is H, methyl, fluorine, chlorine, OH or methoxy
  • R 3 is methyl, ethyl, CF 3 , fluorine, chlorine, OH, methoxy, ethoxy, COOH,
  • R 2 and R 3 together form a 2-membered group selected from O-CH 2 -O or
  • Y m is an M-fold negatively charged anion, preferably an M-fold negatively charged anion selected from the group consisting of chloride,
  • n is 1 or 2; in which n, A and R 1 may each have one of the meanings given above or below, optionally in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
  • COO-methyl or COO-butyl preferably methyl, CF 3 , fluorine, chlorine, OH, methoxy, COOH or COO-methyl, more preferably methyl, CF 3 , fluorine, chlorine, methoxy or COOH;
  • 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, methanesulfonate, maleate, acetate, benzoate, citrate, malate, lactate, salicylate, fumarate , Tartrate and oxalate;
  • m is 1 or 2; and wherein n, A, R 1 and R 2 are each one of those mentioned above or below
  • a preferred aspect of the present invention relates to compounds of general formula 1.1 wherein n, R 1 , R 2 , R 3 , m and Y may have the meanings given above. Particularly preferred are the R-enantiomers of the compounds of formula 1.1.
  • a preferred aspect of the present invention relates to compounds of general formula 1.2 wherein n, R 1 , R 2 , R 3 , m and Y may have the meanings given above. Particularly preferred are the R-enantiomers of the compounds of formula 1.2.
  • a preferred aspect of the present invention relates to compounds of general formula 1.3 wherein n, R 1 , R 2 , R 3 , m and Y may have the meanings given above. Particularly preferred are the R-enantiomers of the compounds of formula 1.3.
  • a preferred aspect of the present invention relates to compounds of general formula 1.4 wherein n, R 1 , R 2 , R 3 , m and Y may have the meanings given above. Particularly preferred are the R-enantiomers of the compounds of formula 1.4.
  • 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, malate, lactate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate, m 1 or 2 optionally in the form of their tautomers, mixtures of tautomers, hydrates or
  • 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, malate, lactate , Salicylate, trifluoroacetate, fumarate, tartrate,
  • Y m denotes " chloride, bromide, malate (salts of malic acid), maleate or lactate, if appropriate in the form of their tautomers, mixtures of tautomers, hydrates or solvates.
  • 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.
  • Particularly preferred here are 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 only in a single crystal modifications.
  • single crystal modification is meant crystalline compounds of the formula 1 which do not represent a mixture of optionally existing crystal modifications.
  • 6 -alkyl Ci The term (including those which are part of other groups) branched be and unbranched alkyl groups having 1 to 6 carbon atoms and by the term “C 4 alkyl” are meant branched and unbranched alkyl groups with 1 to 4 Understood carbon atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-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 te / f-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 are preferred. 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. For example, 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) branched be 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. Preferred are alkynyl groups having 2 to 4 carbon atoms. Examples include: ethynyl, propynyl, butynyl, pentynyl or hexynyl.
  • propynyl includes 1-propynyl and 2-propynyl
  • butynyl includes 1, 2 and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.
  • C 5-6 -cycloalkyl means cyclic alkyl groups having 5 or 6 carbon atoms. Examples include: cyclopentyl or cyclohexyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • C 1-6 -haloalkyl (including those which are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms which are substituted by one or more halogen atoms.
  • C M haloalkyl are meant branched and unbranched alkyl groups having 1 to 4 carbon atoms are understood, which are substituted with one or more halogen atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. preferred
  • Halogen atoms are fluorine, chlorine, more preferably fluorine.
  • Halogen is in the context of the present invention for 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
  • 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.
  • obstructive pulmonary diseases selected from the group consisting of COPD (chronic obstructive pulmonary disease), bronchial asthma, pediatric asthma, severe asthma, acute
  • compounds of general formula 1 for the preparation of a medicament for the treatment of pulmonary emphysema which have their origin in COPD (chronic obstructive pulmonary disease) or ⁇ i-proteinase inhibitor deficiency.
  • compounds of general formula 1 for the preparation of a medicament for the treatment of 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
  • compounds of general formula 1 for the manufacture of a medicament for the treatment of bronchitis, such as, for example, bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.
  • Preference is further the use of compounds of general formula 1 to Production 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
  • a method for the treatment of asthma or COPD characterized in that one or more of the aforementioned compounds of general formula 1 are administered in therapeutically effective amounts once a day.
  • DMPU dimethyl methacrylate
  • 3-chloro-1, 1-dimethyl-propyl) -carbamic acid tert-butyl ester 1.87 g (5 mmol) of tetrabutylammonium iodide are added and it is overnight at room temperature and then for 2 hours at 80 0th C stirred. It is mixed with water and ethyl acetate, the aqueous phase is separated off and extracted with ethyl acetate.
  • Salt precursor 1 8- (2- ⁇ 3- [3- (4-fluoro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ -1 -hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Salt precursor 2 8- ⁇ 2- [1,1-dimethyl-3- (5-methyl-3-p-tolyl- [1,2,4] triazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ - 6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Salt precursor 4 8- (2- ⁇ 3- [3- (3,5-difluorophenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ 1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Salt precursor 8 6-hydroxy-8- (1-hydroxy-2- ⁇ 3- [3- (4-methoxyphenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino-ethyl) -4H-benzo [1,4] oxazin-3-one
  • Benzo [1,3] dioxol-5-yl-5-methyl- [1,2,4] triazol-1-yl) -1,1-dimethyl-propylamine are stirred in 8 ml of ethanol at 80 ° C. for 90 minutes. After cooling to room temperature, 19 mg (0.5 mmol) of sodium borohydride are added and the mixture is allowed to stir at room temperature for 2 hours. It is acidified with 1 N hydrochloric acid, stirred for 10 minutes and then made alkaline with potassium carbonate solution. It is diluted with ethyl acetate and filtered through diatomaceous earth. The remaining organic phase is concentrated and the residue is purified by chromatography.
  • the benzyl ether thus obtained is dissolved in ethanol and hydrogenated with palladium on carbon (10% strength) as catalyst at 2.5 bar and room temperature.
  • the catalyst is then separated off and the crude product is purified by chromatography (reverse phase, acetonitrile / water gradient at 0.1%).
  • N- (3-Acetyl-5-benzyloxy-2-hydroxy-phenyl) -2-bromo-2-methyl-propionamide To a solution of 5.15 g (20 mmol) of 1- (3-amino-5-benzyloxy -2-hydroxy-phenyl) -ethanone in 20 ml of pyridine at 5-20 0 C 4.64 g (25 mmol) of 2-bromo-2-methyl-propionyl chloride dropwise. After completion of the addition, stirred for 15 minutes, treated with ice water and 10O mL of ethyl acetate and acidified with conc. Hydrochloric acid acidified. The organic phase is separated, washed with water and dried with sodium sulfate. After distilling off the solvent, the residue is crystallized from a diethyl ether / petroleum ether mixture. Yield: 6.8 g (84%); Melting range: 88-90 0 C.
  • racemates described above can be separated into the individual enantiomers in a manner known per se.
  • Example 1 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one benzoate - To a refluxing solution of 500 mg (1.03 mmol) 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy 4H-benzo [1,4] oxazin-3-one in 3 ml acetonitrile is added a solution of 125 mg (1.03 mmol) benzoic acid in 3 ml acetonitrile.
  • Figure 1.1 X-ray powder diagram of the benzoate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl] - 1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Figure 1.2 DSC / TG - diagram of the benzoate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazole-1 -yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 1 X-ray reflections (up to 30 ° 2 ⁇ ) with intensities (normalized) of the benzoate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1 ! 2,4] triazol-1-yl] -1, 1-dimethylpropylamino ⁇ -1-hydroxyethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 2 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one acetate - 300 mg
  • Figure 2.2 DSC / TG - Chart of the acetate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazole-1 -yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 2 X-ray reflections (up to 30 ° 2 ⁇ ) with intensities (normalized) of the acetate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1, 2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 3 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one L-lactate - To 300 mg (0.62 mmol) of 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H benzo [1,4] oxazin-3-one in 2 ml of 2-propanol are added at room temperature 56 mg (0.62 mmol) L (+) - lactic acid and allowed to stir for 2 hours.
  • Figure 3.2 DSC / TG diagram of the L-lactate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazole 1 -yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxyethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 3 X-ray reflections (up to 30 ° 2 ⁇ ) with intensities (normalized) of the L-lactate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- 1 ! 2,4] triazol-1-yl] -1, 1-dimethylpropylamino ⁇ -1-hydroxyethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 4 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxyethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one maleate - 300 mg
  • Figure 4.1 X-ray powder diagram of the maleate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl] - 1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Figure 4.2 DSC / TG - diagram of the maleate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl ] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 4 X-ray reflexes (up to 30 ° 2 ⁇ ) with intensities (normalized) of the maleate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1 , 2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 5 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one malate -
  • 8 - ((R) -2- ⁇ 3- [3 - (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1, 4] oxazin-3-one in 2 ml_ 2-propanol are added 83 mg (0.62 mmol) L (-) - malic acid, whereupon a precipitate precipitates.
  • Figure 5.1 X-ray powder diagram of the malate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Figure 5.2 DSC / TG - diagram of the malate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1,2,4] triazole-1 -yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 5 X-ray reflections (to 30 ° 2 ⁇ ) with intensities (normalized) of the malate salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1, 2,4] triazol-1-yl] -1, 1-dimethylpropylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 6 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one hydrobromide dihydrate -
  • Figure 6.1 X-ray powder diagram of the bromide salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl] - 1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Figure 6.2 DSC / TG - diagram of the bromide salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl ] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 6 X-ray reflexes (to 30 ° 2 ⁇ ) with intensities (normalized) of the bromide salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1 , 2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Example 7 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1,1-dimethyl propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one hydrochloride dihydrate - To a solution of 250 mg (0.51 mmol) 8 - ((R) -2- ⁇ 3- [3- (4-Chloro-phenyl) -5-methyl- [1,2,4] triazol-1-yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy -4H-benzo [1,4] oxazin-3-one in 2 ml of 2-propanol are added at 65 ° C.
  • Figure 7.1 X-ray powder diagram of the chloride salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazol-1-yl] - 1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Figure 7.2 DSC / TG - Diagram of the chloride salt of 8 - ((R) -2- ⁇ 3- [3- (4-chlorophenyl) -5-methyl- [1,2,4] triazole-1 -yl] -1, 1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • Table 7 X-ray reflections (to 30 ° 2 ⁇ ) with intensities (normalized) of the chloride salt of 8 - ((R) -2- ⁇ 3- [3- (4-chloro-phenyl) -5-methyl- [1, 2,4] triazol-1-yl] -1,1-dimethyl-propylamino ⁇ -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazin-3-one
  • the compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1. If necessary, the
  • W is a pharmacologically active substance 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 substance 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 substance and is (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, Dopamine agonists, H1 antihistamines
  • W represents a betamimetic combined with an anticholinergic, corticosteroid, PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist;
  • W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
  • W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, 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 ,
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine.
  • 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-toluenesulfonate, 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,
  • AC-1 -en contain, wherein X ⁇ can have the meanings given above.
  • Further preferred anticholinergics are selected from the salts of the formula AC-2
  • 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
  • any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates.
  • 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.
  • Preferred PDE4 inhibitors here 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 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, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
  • Examples of salts or derivatives which the LTD4-antagonists are capable of forming are understood to be: alkali salts, for example 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 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -yl] -amino ⁇ -7-cyclopropylmethoxy-quinazoline
  • 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 dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, 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.
  • H 1 -Antihistaminika here are preferably compounds used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, 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 preferably 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 preferably 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 for obtaining the depot effect such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate are obtained.
  • the tablets can also consist of several layers. Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the
  • 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.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • 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 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.
  • 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.
  • 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 having a mean particle size of 0.5 to
  • 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,
  • the dosage of the compounds according to the invention is naturally highly dependent on the mode of administration and the disease to be treated. In case of inhalation
  • the compounds of the formula are already characterized at doses in the ⁇ g range by a high efficacy. 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 rest of the cornstarch 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 part of the corn starch, lactose, microcrystalline
  • Cellulose and polyvinylpyrrolidone are mixed together, the mixture screened 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.
  • Distilled water is heated to 70 0 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.

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Abstract

La présente invention concerne des composés énantiomériquement purs de la formule 1, dans laquelle les restes n, A, R1, R2, R3, m et Y peuvent avoir les significations indiquées dans les revendications et dans la description, des procédés pour leur préparation, ainsi que leur utilisation comme médicament, en particulier comme médicament pour le traitement des maladies des voies respiratoires.
EP07788189A 2006-08-07 2007-08-03 Nouveaux agonistes beta énantiomériquement purs, procédés pour leur préparation et leur utilisation comme médicament Withdrawn EP2057152A1 (fr)

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