Claims for Patent: 7,056,916

Summary for Patent: 7,056,916

Title:	Medicaments for the treatment of chronic obstructive pulmonary disease
Abstract:	A pharmaceutical composition comprising a compound of formula 1 wherein: n is 1 or 2; R1 is hydrogen, C1–C4-alkyl, halogen, OH, or —O—C1–C4-alkyl; R2 is hydrogen, C1–C4-alkyl, halogen, OH, or —O—C1–C4-alkyl; R3 is hydrogen, C1–C4-alkyl, OH, halogen, —O—C1–C4-alkyl, —O—C1–C4-alkylene-COOH, or —O—C1–C4-alkylene-CO—O—C1–C4-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):	Ingo Konetzki, Kurt Schromm, Hermann Schollenberger, Sabine Pestel, Andreas Schnapp, Thierry Bouyssou, Frank Buettner, Claudia Heine, Philipp Lustenberger, Christoph Hoenke, Klaus Rudolf
Assignee:	Boehringer Ingelheim Pharma GmbH and Co KG
Application Number:	US10/705,012
Patent Claims:	1. A compound of formula 1 wherein: n is 1; R1 is hydrogen, halogen, C1–C4-alkyl, or —O—C1–C4-alkyl; R2 is hydrogen, halogen, C1–C4-alkyl or —O—C1–C4-alkyl; R3 is C1–C4-alkyl, halogen, —O—C1–C4-alkyl, —O—C1–C4-alkylene-COOH, or —O—C1–C4-alkylene-CO—O—C1–C4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 2. The compound of formula 1 according to claim 1, wherein R3 is methoxy, ethoxy, —O—CH2—COOH, —O—CH2—COOmethyl, or —O—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 3. The compound of formula 1 according to claim 1, wherein: R1 is hydrogen, fluorine, chlorine, methyl, or methoxy; R2 is hydrogen, fluorine, chlorine, methyl, or methoxy; R3 is C1–C4-alkyl, fluorine, chlorine, bromine, —O—C1–C4-alkyl, —O—C1–C4-alkylene-COOH, or —O—C1–C4-alkylene-CO—O—C1–C4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 4. The compound of formula 1 according to claim 3, wherein R3 is methoxy, ethoxy, —O—CH2—COOH, —O—CH2—COOmethyl, or —O—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 5. The compound of formula 1 according to claim 1, wherein: R1 is hydrogen or C1–C4-alkyl; R2 is hydrogen or C1–C4-alkyl; and R3 is C1–C4-alkyl, —O—C1–C4-alkyl, —O—C1–C4-alkylene-COOH, or —O—C1–C4-alkylene-CO—O—C1–C4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 6. The compound of formula 1 according to claim 5, wherein R3 is methoxy, ethoxy, —O—CH2—COOH, —O—CH2—COOmethyl, or —O—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 7. The compound of formula 1 according to claim 1, wherein: R1 is hydrogen, methyl, or ethyl; R2 is hydrogen, methyl, or ethyl; R3 is methyl, ethyl, methoxy, ethoxy, —O—CH2—COOH, —O—CH2—COOmethyl or —O—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 8. The compound of formula 1 according to claim 7, wherein R3 is methoxy, ethoxy, —O—CH2—COOH, —O—CH2—COOmethyl, or —O—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 9. The compound of formula 1 according to claim 1, wherein: R1 is halogen, C1–C4-alkyl, or —O—C1–C4-alkyl; R2 is halogen, C1–C4-alkyl, or —O—C1–C4-alkyl; and R3 is halogen, C1–C4-alkyl, or —O—C1–C4-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 10. The compound of formula 1 according to claim 9, wherein: R1 is fluorine, chlorine, methyl, or methoxy; R2 is fluorine, chlorine, methyl, or methoxy; and R3 is fluorine, chlorine, methyl, or methoxy, or an acid addition salt thereof with a pharmacologically acceptable acid. 11. The compound of formula 1 according to claim 1, wherein: R1 is hydrogen; R2 is hydrogen, fluorine, chlorine, or methyl; and R3 is methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, methoxy, ethoxy, —O—CH2—COOH, —O—CH2—CH2—COOH, —O—CH2—CH2—CH2—COOH, —O—CH2—COOmethyl, —O—CH2—COOethyl, —O—CH2—CH2—COOmethyl, —O—CH2—CH2—COOethyl, —O—CH2—CH2—CH2—COOmethyl, or —O—CH2—CH2—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 12. The compound of formula 1 according to claim 11, wherein: R1 is hydrogen; R2 is hydrogen, fluorine, chlorine, or methyl; and R3 is fluorine, chlorine, methyl, methoxy, ethoxy, or —O—CH2—COOH, or an acid addition salt thereof with a pharmacologically acceptable acid. 13. The compound of formula 1 according to claim 1, wherein: R1 and R2 are each hydrogen; and R3 is methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine, bromine, methoxy, ethoxy, —O—CH2—COOH, —O—CH2—CH2—COOH, —O—CH2—CH2—CH2—COOH, —O—CH2—COOmethyl, —O—CH2—COOethyl, —O—CH2—CH2—COOmethyl, —O—CH2—CH2—COOethyl, —O—CH2—CH2—CH2—COOmethyl, or —O—CH2—CH2—CH2—COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid. 14. The compound of formula 1 according to claim 13, wherein R3 is OH, fluorine, chlorine, methoxy, ethoxy, or —O—CH2—COOH, or an acid addition salt thereof with a pharmacologically acceptable acid. 15. The compound of formula 1 according to claim 14, wherein R3 is fluorine, chlorine, methoxy, or ethoxy, or an acid addition salt thereof with a pharmacologically acceptable acid. 16. The compound of formula 1 according to claim 1, wherein: R1 is hydrogen, halogen, C1–C4-alkyl, or —OC1–C4-alkyl; and R2 is hydrogen, halogen, C1–C4-alkyl, or —O—C1–C4-alkyl; or an acid addition salt thereof with a pharmacologically acceptable acid. 17. The compound of formula 1 according to claim 16, wherein: R1 is hydrogen, fluorine, chlorine, methyl or methoxy; and R2 is hydrogen, fluorine, chlorine, methyl or methoxy, or an acid addition salt thereof with a pharmacologically acceptable acid. 18. A compound of formula 1 according to claim 6 selected from: (1) 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; (2) 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one; (3) 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one; (4) 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (5) 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; (6) 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1 dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; (7) 8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (8) 8-{2-[2-(4-fluoro-3-methylphenyl)-1, 1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (9) 8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (10) 8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (11) 8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (12) 8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (13) 8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (14) 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) 8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (16) 8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (17) 8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (18) 8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (19) 8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (20) 8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (21) 8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (22) 8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (23) 8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (24) 8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo-[1,4]oxazin-3-one; (25) 8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (26) 8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (27) 8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (28) 8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (29) 8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (30) 8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (31) 8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (32) 8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; and (33) 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. 19. A pharmaceutical composition comprising a compound of formula 1 according to one of claims 1 to 18, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.