MEDICAMENTS FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

• US 20090092558A1
• Filed: 10/27/2008
• Published: 04/09/2009
• Est. Priority Date: 11/15/2002
• Status: Active Grant

• 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: HOENKE, Christoph, SCHROMM, Kurt, SCHOLLENBERGER, Hermann, HEINE, Claudia, RUDOLF, Klaus, KONETZKI, Ingo, LUSTENBERGER, Philipp, BOUYSSOU, Thierry, SCHNAPP, Andreas, PESTEL, Sabine, BUETTNER, Frank
• Granted Patent: US 7,786,111 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• 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

1-25. -25. (canceled)

26. :

A pharmaceutical composition comprising a compound of formula 1A

27. :

The pharmaceutical composition according to claim 26, wherein

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

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

28. :

The pharmaceutical composition according to claim 26, wherein;

R¹ is hydrogen or C₁-C₄-alkyl; and

R² is hydrogen or C₁-C₄-alkyl.

29. :

The pharmaceutical composition according to claim 26, wherein;

R¹ is hydrogen, methyl, or ethyl; and

R² is hydrogen, methyl, or ethyl.

30. :

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.

31. :

A pharmaceutical composition comprising a compound of formula 1B

32. :

The pharmaceutical composition according to claim 31, 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.

33. :

The pharmaceutical composition according to claim 31, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

34. :

A pharmaceutical composition comprising a compound of formula 1C

35. :

The pharmaceutical composition according to claim 34,

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.

36. :

The pharmaceutical composition according to claim 34,

wherein;

R^1″

and R^2″

are each hydrogen.

37. :

The pharmaceutical composition according to claim 36,

wherein

R^3″

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

O—

CH₂—

COOH.

38. :

The pharmaceutical composition according to claim 37, wherein;

R^3″

is OH, fluorine, chlorine, methoxy or ethoxy.

39. :

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.

40. :

A pharmaceutical composition comprising acompound 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.

41. :

The pharmaceutical composition according to claim 40, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

42. :

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.

43. :

The pharmaceutical composition according to claim 42 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.

44. :

The pharmaceutical composition according to claim 42, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

45. :

The pharmaceutical composition according to claim 43, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

46. :

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.

47. :

The pharmaceutical composition according to claim 46 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.

48. :

The pharmaceutical composition according to claim 46, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

49. :

The pharmaceutical composition according to claim 47, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

55. :

The pharmaceutical composition according to claim 49 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.

57. :

The pharmaceutical composition according to claim 55, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

50. :

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.

51. :

The pharmaceutical composition according to claim 50 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.

52. :

The pharmaceutical composition according to claim 50, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

53. :

The pharmaceutical composition according to claim 51, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

54. :

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.

56. :

The pharmaceutical composition according to claim 54, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

58. :

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.

59. :

The pharmaceutical composition according to claim 58 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.

60. :

The pharmaceutical composition according to claim 58, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

61. :

The pharmaceutical composition according to claim 59, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.