Medicaments for the Treatment of Chronic Obstructive Pulmonary Disease

• US 20070155741A1
• Filed: 02/21/2007
• Published: 07/05/2007
• 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: Lustenberger, Philipp, Hoenke, Christoph, KONETZKI, Ingo, Rudolf, Klaus, Bouyssou, Thierry, Heine, Claudia, Pestel, Sabine, Buettner, Frank, Schnapp, Andreas, Schromm, Kurt, Schollenberger, Hermann
• Granted Patent: US 7,727,984 B2
• Time in Patent Office: Days
• US Class Current: 514/230.500
• 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 compound of formula 1A

27. The compound of formula 1A according to claim 26,

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, or a solvate or hydrate thereof.

28. The compound of formula 1A according to claim 26, wherein:

R¹ is hydrogen or C₁-C₄-alkyl; and

R² is hydrogen or C₁-C₄-alkyl;

or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

29. The compound of formula 1A according to claim 26, wherein:

R¹ is hydrogen, methyl, or ethyl; and

R² is hydrogen, methyl, or ethyl;

or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

30. A compound of formula 1B

31. The compound of formula 1B according to claim 30, 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,

or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

32. a compound of formula 1C

33. The compound of formula 1C according to claim 32,

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,

or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

34. The compound of formula 1C according to claim 32,

wherein,

R^1″

and R^2″

are each hydrogen,

or an acid addition salt thereof with a pharmacologically, acceptable acid, or a solvate or a hydrate thereof.

35. The compound of formula 1C according to claim 34,

wherein,

R^3″

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

O—

CH₂—

COOH;

or an acid addition salt thereof with a pharmacologically, acceptable acid, or a solvate or a hydrate thereof.

36. The compound of formula 1C according to claim 35,

wherein,

R^3″

is OH, fluorine, chlorine, methoxy or ethoxy.

or an acid addition salt thereof with a pharmacologically, acceptable acid, or a solvate or a hydrate thereof.

37. 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)-1,1 dimethylethylamino]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;

or

(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, or a solvate or hydrate thereof.

38. R-6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

39. R-8-{2-[2-(2,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

40. R-8-{2-[2-(3,5-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

41. R-8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

42. R-8-{2-[2-(4-Fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.