Details for Patent: 7,786,111

Title:	Medicaments for the treatment of chronic obstructive pulmonary disease
Abstract:	A pharmaceutical composition comprising a compound of formula 1 ##STR00001## wherein: n is 1 or 2; R.sup.1 is hydrogen, C.sub.1-C.sub.4-alkyl, halogen, OH, or --O--C.sub.1-C.sub.4-alkyl; R.sup.2 is hydrogen, C.sub.1-C.sub.4-alkyl, halogen, OH, or --O--C.sub.1-C.sub.4-alkyl; R.sup.3 is hydrogen, C.sub.1-C.sub.4-alkyl, OH, halogen, --O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkylene-COOH, or --O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof; and a pharmaceutically acceptable excipient or carrier, and methods for using the pharmaceutical formulation in the treatment of chronic obstructive pulmonary disease (COPD).
Inventor(s):	Konetzki; Ingo (Warthausen, DE), Schromm; Kurt (Ingelheim, DE), Schollenberger; Hermann (Ingelheim, DE), Pestel; Sabine (Attenweiler, DE), Schnapp; Andreas (Biberach, DE), Bouyssou; Thierry (Warthausen, DE), Buettner; Frank (Attenweiler, DE), Heine; Claudia (Biberach, DE), Rudolf; Klaus (Warthausen, DE), Lustenberger; Philipp (Basel, CH), Hoenke; Christoph (Ingelheim, DE)
Assignee:	Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim, DE)
Filing Date:	Oct 27, 2008
Application Number:	12/258,830
Claims:	1. A pharmaceutical composition comprising a compound of formula 1A ##STR00026## wherein: R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl; R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.4-alkyl or --O--C.sub.1-C.sub.4-alkyl; and R.sup.3 is methoxy, ethoxy, --O--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl, or --O--CH.sub.2--COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 2. The pharmaceutical composition according to claim 1, wherein R.sup.1 is hydrogen, fluorine, chlorine, methyl, or methoxy; and R.sup.2 is hydrogen, fluorine, chlorine, methyl, or methoxy. 3. The pharmaceutical composition according to claim 1, wherein: R.sup.1 is hydrogen or C.sub.1-C.sub.4-alkyl; and R.sup.2 is hydrogen or C.sub.1-C.sub.4-alkyl. 4. The pharmaceutical composition according to claim 1, wherein: R.sup.1 is hydrogen, methyl, or ethyl; and R.sup.2 is hydrogen, methyl, or ethyl. 5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 6. A pharmaceutical composition comprising a compound of formula 1B ##STR00027## wherein: R.sup.1' is halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl; R.sup.2' is halogen, C.sub.1-C.sub.4-alkyl or --O--C.sub.1-C.sub.4-alkyl; R.sup.3' is C.sub.1-C.sub.4-alkyl, halogen, or --O--C.sub.1-C.sub.4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 7. The pharmaceutical composition according to claim 6, wherein: R.sup.1' is fluorine, chlorine, methyl, or methoxy; R.sup.2' is fluorine, chlorine, methyl, or methoxy, and R.sup.3' is fluorine, chlorine, methyl, or methoxy. 8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 9. A pharmaceutical composition comprising a compound of formula 1C ##STR00028## wherein: R.sup.1'' hydrogen, R.sup.2'' is hydrogen, fluorine, chlorine, or methyl; and R.sup.3'' is methyl, ethyl, isopropyl, tert-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, --O--CH.sub.2--COOH, --O--CH.sub.2--CH.sub.2--COOH, --O--CH.sub.2--CH.sub.2--CH.sub.2--COOH, --O--CH.sub.2--COO methyl, --O--CH.sub.2--COOethyl, --O--CH.sub.2--CH.sub.2--COO methyl, --O--CH.sub.2--CH.sub.2--COO ethyl, --O--CH.sub.2--CH.sub.2--CH.sub.2COO methyl, --O--CH.sub.2--CH.sub.2--CH.sub.2COO ethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 10. The pharmaceutical composition according to claim 9, wherein: R.sup.1'' is hydrogen; R.sup.2'' is hydrogen, fluorine, chlorine, or methyl; and R.sup.3'' is OH, fluorine, chlorine, methyl, methoxy, ethoxy or O--CH.sub.2--COOH. 11. The pharmaceutical composition according to claim 9, wherein: R.sup.1'' and R.sup.2'' are each hydrogen. 12. The pharmaceutical composition according to claim 11, wherein R.sup.3'' is OH, fluorine, chlorine, methoxy, ethoxy or --O--CH.sub.2--COOH. 13. The pharmaceutical composition according to claim 12, wherein: R.sup.3'' is OH, fluorine, chlorine, methoxy or ethoxy. 14. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 15. A pharmaceutical composition comprising a compound selected from the group consisting of: (1) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]et- hyl}-4H-benzo[1,4]oxazin-3-one; (2) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylam- ino]-ethyl}-4H-benzo[1,4]oxazin-3-one; (3) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one; (4) R-8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}- -6-hydroxy-4H-benzo[1,4]oxazin-3-one; (5) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]et- hyl}-4H-benzo[1,4]oxazin-3-one; (6) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1dimethylethylamino]e- thyl}-4H-benzo[1,4]oxazin-3-one; (7) R-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydro- xy-4H-benzo[1,4]oxazin-3-one; (8) R-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (9) R-8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (10) R-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one; (11) R-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one; (12) R-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr- oxy-4H-benzo[1,4]oxazin-3-one; (13) R-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one; (14) R-4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8- -yl)-ethylamino]-2-methylpropyl}phenoxy)butyric acid; (15) R-8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one; (16) R-8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (17) R-8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr- oxy-4H-benzo[1,4]oxazin-3-one; (18) R-8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydro- xy-4H-benzo[1,4]oxazin-3-one; (19) R-8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr- oxy-4H-benzo[1,4]oxazin-3-one; (20) R-8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyeth- yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (21) R-8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxy- ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (22) R-8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (23) R-8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (24) R-8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (25) R-8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (26) R-8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydrox- yethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (27) R-8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydrox- yethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (28) R-8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxy- ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (29) R-8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one; (30) R-8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy- l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (31) R-8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}- -6-hydroxy-4H-benzo[1,4]oxazin-3-one; (32) R-8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr- oxy-4H-benzo[1,4]oxazin-3-one; and (33) R-8-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-- hydroxy-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 17. A pharmaceutical composition comprising R-6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]- -ethyl}-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 18. The pharmaceutical composition according to claim 17 comprising an acid addition salt of R-6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]- -ethyl}-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 19. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 20. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 21. A pharmaceutical composition comprising R-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-- 6-hydroxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 22. The pharmaceutical composition according to claim 21 comprising an acid addition salt of R-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-- 6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 23. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 24. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 25. A pharmaceutical composition comprising R-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-- 6-hydroxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 26. The pharmaceutical composition according to claim 25 comprising an acid addition salt of the compound of R-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-- 6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 27. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 28. The pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 29. A pharmaceutical composition comprising R-8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-h- ydroxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 30. The pharmaceutical composition according to claim 29, comprising an acid addition salt of the compound of R-8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-h- ydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 31. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 32. The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 33. A pharmaceutical composition comprising R-8-{2-[2-(4-fluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hy- droxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 34. The pharmaceutical composition according to claim 33 comprising an acid addition salt of R-8-{2-[2-(4-fluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hy- droxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 35. The pharmaceutical composition according to claim 33, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 36. The pharmaceutical composition according to claim 34, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.