New medicaments for the treatment of chronic obstructive pulmonary disease

• US 20040147513A1
• Filed: 11/10/2003
• Published: 07/29/2004
• 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, Konetzki, Ingo, Hoenke, Christoph, Rudolf, Klaus, Bouyssou, Thierry, Heine, Claudia, Pestel, Sabine, Buettner, Frank, Schnapp, Andreas, Schromm, Kurt, Schollenberger, Hermann
• Granted Patent: US 7,056,916 B2
• Time in Patent Office: Days
• 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 1

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

R¹ is hydrogen, halogen or C₁-C₄-alkyl;

R² is hydrogen, halogen, or C₁-C₄-alkyl; and

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.

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

R¹ is hydrogen, fluorine, chlorine, or methyl;

R² is hydrogen, fluorine, chlorine, or methyl; and

R³ is hydrogen, C₁-C₄-alkyl, OH, fluorine, chlorine, bromine, —

O—

C₁-C₄-alkyl, —

O—

C₁-C₄-alkylene-COOH, or —

O—

C₁-C₄-alkylene-CO—

O—

C₁-C₄-alkyl.

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

R¹ is hydrogen, methyl, or ethyl;

R² is hydrogen, methyl, or ethyl; and

R³ is hydrogen, methyl, ethyl, OH, methoxy, ethoxy, —

O—

CH₂—

COOH, —

O—

CH₂—

CO—

O-methyl, or —

O—

CH₂—

COOethyl.

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

R¹ is hydrogen or methyl;

R² is hydrogen or methyl; and

R³ is hydrogen, methyl, OH, methoxy, —

O—

CH₂—

COOH, or —

O—

CH₂—

COOethyl.

6. A compound of formula 1

7. The compound of formula 1 according to claim 6, 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, or a solvate or hydrate thereof.

8. The compound of formula 1 according to claim 6, wherein:

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

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

R³ is C₁-C₄-alkyl, OH, 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, or a solvate or hydrate thereof.

9. The compound of formula 1 according to claim 8, 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, or a solvate or hydrate thereof.

10. The compound of formula ! according to claim 6, wherein:

R¹ is hydrogen or C₁-C₄-alkyl;

R² is hydrogen or C₁-C₄-alkyl; and

R³ is C₁-C₄-alkyl, OH, —

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.

11. The compound of formula 1 according to claim 10, 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, or a solvate or hydrate thereof.

12. The compound of formula 1 according to claim 6, wherein:

R¹ is hydrogen, methyl, or ethyl;

R² is hydrogen, methyl, or ethyl;

R³ is methyl, ethyl, OH, methoxy, ethoxy, —

O—

CH₂—

COOH, —

O—

CH2—

COOmethyl or —

O—

CH₂—

COOethyl,

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

13. The compound of formula 1 according to claim 12, 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, or a solvate or hydrate thereof.

14. The compound of formula 1 according to claim 6, 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, or a solvate or hydrate thereof.

15. The compound of formula 1 according to claim 14, 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, or a solvate or hydrate thereof.

16. The compound of formula 1 according to claim 6, wherein:

R¹ is hydrogen;

R² is hydrogen, fluorine, chlorine, or methyl; and

R³ is methyl, ethyl, isopropyl, tert-butyl, OH, 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, or a solvate or hydrate thereof.

17. The compound of formula 1 according to claim 16, wherein:

R¹ is hydrogen;

R² is hydrogen, fluorine, chlorine, or methyl; and

R³ 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.

18. The compound of formula 1 according to claim 6, wherein:

R¹ and R² are each hydrogen; and

R³ is methyl, ethyl, isopropyl, tert-butyl, OH, 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, or a solvate or hydrate thereof.

19. The compound of formula 1 according to claim 18, wherein R³ is OH, fluorine, chlorine, methoxy, ethoxy, —

O—

CH₂—

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

20. The compound of formula 1 according to claim 19, wherein R³ is OH, fluorine, chlorine, methoxy, or ethoxy, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.

21. The compound of formula ! according to claim 6, wherein:

R¹ is hydrogen, halogen, C₁-C₄-alkyl, or —

O—

C₁-C₄-alkyl;

R² is hydrogen, halogen, C₁-C₄-alkyl, or —

O—

C₁-C₄-alkyl; and

R³ is hydrogen,

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

22. The compound of formula 1 according to claim 21, 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, or a solvate or hydrate thereof.

24. A pharmaceutical composition comprising a compound of formula 1 according to one of claims 6 to 23, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof, and a pharmaceutically acceptable excipient or carrier.

25. The pharmaceutical composition according to claim 24, wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.

23. A compound of formula 1 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, or a solvate or hydrate thereof.