Medicaments for the treatment of chronic obstructive pulmonary disease

• US 7,786,111 B2
• Filed: 10/27/2008
• Issued: 08/31/2010
• Est. Priority Date: 11/15/2002
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Schromm, Kurt, Schollenberger, Hermann, Lustenberger, Philipp, Konetzki, Ingo, Hoenke, Christoph, Rudolf, Klaus, Bouyssou, Thierry, Heine, Claudia, Pestel, Sabine, Buettner, Frank, Schnapp, Andreas
• Primary Examiner(s): HABTE, KAHSAY
• Application Number:
  US12/258,830
• Publication Number:
  US 20090092558A1
• Time in Patent Office: 673 Days
• Field of Search: 514/230.5
• US Class Current: 514/230.5
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: C07D 265/36 condensed with one six-membered ring

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).

Claims

1. A pharmaceutical composition comprising a compound of formula 1A

2. The pharmaceutical composition according to claim 1, wherein

R¹ is hydrogen, fluorine, chlorine, methyl, or methoxy;

and

R² is hydrogen, fluorine, chlorine, methyl, or methoxy.

3. The pharmaceutical composition according to claim 1, wherein:

R¹ is hydrogen or C₁-C₄-alkyl; and

R² is hydrogen or C₁-C₄-alkyl.

4. The pharmaceutical composition according to claim 1, wherein:

R¹ is hydrogen, methyl, or ethyl; and

R² 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

7. The pharmaceutical composition according to claim 6, wherein:

R^1′

is fluorine, chlorine, methyl, or methoxy;

R^2′

is fluorine, chlorine, methyl, or methoxy, and

R^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

10. The pharmaceutical composition according to claim 9, wherein:

R^1″

is hydrogen;

R^2″

is hydrogen, fluorine, chlorine, or methyl; and

R^3″

is OH, fluorine, chlorine, methyl, methoxy, ethoxy or O—

CH₂—

COOH.

11. The pharmaceutical composition according to claim 9, wherein:

R^1″

and R^2″

are each hydrogen.

12. The pharmaceutical composition according to claim 11, wherein

R^3″

is OH, fluorine, chlorine, methoxy, ethoxy or —

O—

CH₂—

COOH.

13. The pharmaceutical composition according to claim 12, wherein:

R^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]ethyl}-4H-benzo[1,4]oxazin-3-one;

(2) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]-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]ethyl}-4H-benzo[1,4]oxazin-3-one;

(6) R-6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;

(7) R-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(8) R-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(9) R-8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-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-hydroxy-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-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(17) R-8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(18) R-8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(19) R-8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(20) R-8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(21) R-8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(22) R-8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(23) R-8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(24) R-8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(25) R-8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(26) R-8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(27) R-8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

(28) R-8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-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-hydroxyethyl}-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-hydroxy-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-hydroxy-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-hydroxy-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-hydroxy-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-hydroxy-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.