U.S. patent application number 12/036618 was filed with the patent office on 2008-07-10 for medicaments for the treatment of chronic obstructive pulmonary disease.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Thierry Bouyssou, Frank Buettner, Claudia Heine, Christoph Hoenke, Ingo Konetzki, Philipp Lustenberger, Sabine Pestel, Klaus Rudolf, Andreas Schnapp, Hermann Schollenberger, Kurt Schromm.
Application Number | 20080167298 12/036618 |
Document ID | / |
Family ID | 32738513 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080167298 |
Kind Code |
A1 |
Konetzki; Ingo ; et
al. |
July 10, 2008 |
MEDICAMENTS FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
Abstract
A pharmaceutical composition comprising a compound of formula 1
##STR00001## wherein: n is 1 or 2; R.sup.1 is hydrogen,
C.sub.1-C.sub.4-alkyl, halogen, OH, or --O--C.sub.1-C.sub.4-alkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.4-alkyl, halogen, OH, or
--O--C.sub.1-C.sub.4-alkyl; R.sup.3 is hydrogen,
C.sub.1-C.sub.4-alkyl, OH, halogen, --O--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-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).
Inventors: |
Konetzki; Ingo; (Warthausen,
DE) ; Schromm; Kurt; (Ingelheim, DE) ;
Schollenberger; Hermann; (Ingelheim, DE) ; Pestel;
Sabine; (Attenweiler, DE) ; Schnapp; Andreas;
(Biberach, DE) ; Bouyssou; Thierry; (Warthausen,
DE) ; Buettner; Frank; (Attenweiler, DE) ;
Heine; Claudia; (Biberach, DE) ; Lustenberger;
Philipp; (Basel, CH) ; Hoenke; Christoph;
(Ingelheim, DE) ; Rudolf; Klaus; (Warthausen,
DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
32738513 |
Appl. No.: |
12/036618 |
Filed: |
February 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11677112 |
Feb 21, 2007 |
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12036618 |
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11275730 |
Jan 26, 2006 |
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11677112 |
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11132075 |
May 18, 2005 |
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11275730 |
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10705012 |
Nov 10, 2003 |
7056916 |
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11132075 |
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60434038 |
Dec 17, 2002 |
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Current U.S.
Class: |
514/230.5 |
Current CPC
Class: |
A61K 31/535 20130101;
A61P 11/00 20180101; C07D 265/36 20130101; A61K 31/538
20130101 |
Class at
Publication: |
514/230.5 |
International
Class: |
A61K 31/538 20060101
A61K031/538; A61P 11/00 20060101 A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 15, 2002 |
DE |
102 53 282 |
Claims
1-25. (canceled)
26. A pharmaceutical composition comprising a compound of formula
1A ##STR00026## wherein: R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl; R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.4-alkyl or
--O--C.sub.1-C.sub.4-alkyl; and R.sup.3 is methoxy, ethoxy,
--O--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl, or
--O--CH.sub.2--COOethyl, or an acid addition salt thereof with a
pharmacologically acceptable acid, and a pharmaceutically
acceptable excipient or carrier.
27. The pharmaceutical composition according to claim 26, wherein
R.sup.1 is hydrogen, fluorine, chlorine, methyl, or methoxy; and
R.sup.2 is hydrogen, fluorine, chlorine, methyl, or methoxy.
28. The pharmaceutical composition according to claim 26, wherein:
R.sup.1 is hydrogen or C.sub.1-C.sub.4-alkyl; and R.sup.2 is
hydrogen or C.sub.1-C.sub.4-alkyl.
29. The pharmaceutical composition according to claim 26, wherein:
R.sup.1 is hydrogen, methyl, or ethyl; and R.sup.2 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 ##STR00027## wherein: R.sup.1' is halogen,
C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl; R.sup.2' is
halogen, C.sub.1l -C.sub.4-alkyl or --O--C.sub.1-C.sub.4-alkyl;
R.sup.3' is C.sub.1-C.sub.4-alkyl, halogen, or
--O--C.sub.1-C.sub.4-alkyl, or an acid addition salt thereof with a
pharmacologically acceptable acid, and a pharmaceutically
acceptable excipient or carrier.
32. The pharmaceutical composition according to claim 31, wherein:
R.sup.1' is fluorine, chlorine, methyl, or methoxy; R.sup.2' is
fluorine, chlorine, methyl, or methoxy, and R.sup.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 ##STR00028## wherein: R.sup.1'' is hydrogen, R.sup.2'' is
hydrogen, fluorine, chlorine, or methyl; and R.sup.3'' is methyl,
ethyl, isopropyl, tert-butyl, OH, fluorine, chlorine, bromine,
methoxy, ethoxy, --O--CH.sub.2--COOH,
--O--CH.sub.2--CH.sub.2--COOH,
--O--CH.sub.2.sup.--CH.sub.2--CH.sub.2--COOH, --O--CH.sub.2--COO
methyl, --O--CH.sub.2--COOethyl, --O--CH.sub.2--CH.sub.2--COO
methyl, --O--CH.sub.2--CH.sub.2--COO ethyl,
--O--CH.sub.2--CH.sub.2--CH.sub.2COO methyl,
--O--CH.sub.2--CH.sub.2--CH.sub.2COO ethyl, or an acid addition
salt thereof with a pharmacologically acceptable acid, and a
pharmaceutically acceptable excipient or carrier.
35. The pharmaceutical composition according to claim 34, wherein:
R.sup.1'' is hydrogen; R.sup.2'' is hydrogen, fluorine, chlorine,
or methyl; and R.sup.3'' is OH, fluorine, chlorine, methyl,
methoxy, ethoxy or --O--CH.sub.2--COOH.
36. The pharmaceutical composition according to claim 34, wherein:
R.sup.1'' and R.sup.2'' are each hydrogen.
37. The pharmaceutical composition according to claim 36, wherein
R.sup.3'' is OH, fluorine, chlorine, methoxy, ethoxy or
--O--CH.sub.2--COOH.
38. The pharmaceutical composition according to claim 37, wherein:
R.sup.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 a compound selected
from the group consisting of: (1)
R-6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]et-
hyl}4H-benzo[1,4]oxazin-3-one; (2)
R-6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylam-
ino]-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-hydro-
xy-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-hydroxyethy-
l} -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-hydr-
oxy-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-hydrox-
yethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (17)
R-8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one; (18)
R-8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydro-
xy-4H-benzo[1,4]oxazin-3-one; (19)
R-8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one; (20)
R-8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (21)
R-8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (22)
R-8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy-
l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (23)
R-8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy-
l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (24)
R-8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy-
l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (25)
R-8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethy-
l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (26)
R-8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydrox-
yethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (27)
R-8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydrox-
yethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; (28)
R-8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxy-
ethyl}-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-hydroxyethy-
l}-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-hydr-
oxy-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.
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.
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-h-
ydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically
acceptable acid, 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.
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.
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-hy-
droxy-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.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
11/275,730, filed Jan. 26, 2006, which in turn is a Continuation of
U.S. Ser. No. 11/132,075, filed May 18, 2005, which in turn is a
Continuation of U.S. Ser. No. 10/705,012, filed Nov. 10, 2003,
which claims priority to U.S. Ser. No. 60/434,038, filed Dec. 17,
2002, and German Application No. 102 53 282.6 filed Nov. 15, 2003,
each of which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the use of the compounds of
general formula 1
##STR00002##
wherein the groups R.sup.1, R.sup.2, and R.sup.3 may have the
meanings given in the claims and in the specification, for
preparing a pharmaceutical composition for the treatment of chronic
obstructive pulmonary disease (COPD), as well as new compounds of
general formula 1 and processes for preparing them.
BACKGROUND OF THE INVENTION
[0003] Betamimetics (.beta.-adrenergic substances) are known from
the prior art. Reference may be made, for example, to the
disclosures of U.S. Pat. No. 4,460,581, which is hereby
incorporated by reference, which proposes betamimetics for the
treatment of a variety of complaints.
[0004] For drug treatment of diseases it is often desirable to
prepare medicaments with a longer duration of activity. As a rule,
this ensures that the concentration of the active substance in the
body needed to achieve the therapeutic effect is guaranteed for a
longer period without the need to re-administer the drug at
frequent intervals. Moreover, giving an active substance at longer
time intervals contributes to the well-being of the patient to a
high degree.
[0005] It is particularly desirable to prepare a pharmaceutical
composition which can be used therapeutically by administration
once a day (single dose). The use of a drug once a day has the
advantage that the patient can become accustomed relatively quickly
to taking the drug regularly at certain times of the day.
[0006] The aim of the present invention is therefore to provide
betamimetics which have a therapeutic benefit in the treatment of
COPD and are characterized by a longer duration of activity and can
thus be used to prepare pharmaceutical compositions with a longer
duration of activity. A particular aim of the invention is to
prepare betamimetics which, by virtue of their long-lasting effect,
can be used to prepare a drug for administration once a day for
treating COPD. In addition to the above objectives, the present
invention also sets out to provide betamimetics which are not only
exceptionally potent but are also characterized by a high degree of
selectivity with respect to the .beta..sub.2-adreno-receptor.
DETAILED DESCRIPTION OF THE INVENTION
[0007] Surprisingly it has been found that the abovementioned
problems are solved by compounds of general formula 1.
[0008] Accordingly, the present invention relates to compounds of
general formula 1
##STR00003##
wherein: [0009] n denotes 1 or 2, [0010] R.sup.1 denotes hydrogen,
C.sub.1-C.sub.4-alkyl, halogen, OH, or --O--C.sub.1-C.sub.4-alkyl;
[0011] R.sup.2 denotes hydrogen, C.sub.1-C.sub.4-alkyl, halogen,
OH, or --O--C.sub.1-C.sub.4-alkyl; and [0012] R.sup.3 denotes
hydrogen, C.sub.1-C.sub.4-alkyl, OH, halogen,
--O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0013]
for preparing a pharmaceutical composition for the treatment of
COPD.
[0014] It is preferable to use compounds of general formula 1,
wherein: [0015] n denotes 1 or 2; [0016] R.sup.1 denotes hydrogen,
halogen or C.sub.1-C.sub.4-alkyl; [0017] R.sup.2 denotes hydrogen,
halogen or C.sub.1-C.sub.4-alkyl; and [0018] R.sup.3 denotes
hydrogen, C.sub.1-C.sub.4-alkyl, OH, halogen,
--O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0019]
for preparing a pharmaceutical composition for the treatment of
COPD.
[0020] It is preferable to use compounds of general formula 1
wherein: [0021] n denotes 1 or 2; [0022] R.sup.1 denotes hydrogen,
fluorine, chlorine or methyl; [0023] R.sup.2 denotes hydrogen,
fluorine, chlorine or methyl; and [0024] R.sup.3 denotes hydrogen,
C.sub.1-C.sub.4-alkyl, OH, fluorine, chlorine, bromine,
--O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0025]
for preparing a pharmaceutical composition for the treatment of
COPD.
[0026] It is particularly preferred to use compounds of general
formula 1 wherein: [0027] n denotes 1 or 2; [0028] R.sup.1 denotes
hydrogen, methyl or ethyl; [0029] R.sup.2 denotes hydrogen, methyl
or ethyl; and [0030] R.sup.3 denotes hydrogen, methyl, ethyl, OH,
methoxy, ethoxy, --O--CH.sub.2--COOH, --O--CH.sub.2--CO--O-methyl,
or --O--CH.sub.2--COOethyl, [0031] for preparing a pharmaceutical
composition for the treatment of COPD.
[0032] It is particularly preferred to use compounds of general
formula 1 wherein: [0033] n denotes 1 or 2; [0034] R.sup.1 denotes
hydrogen or methyl; [0035] R.sup.2 denotes hydrogen or methyl; and
[0036] R.sup.3 denotes hydrogen, methyl, OH, methoxy,
--O--CH.sub.2--COOH, or --O--CH.sub.2--COOethyl, [0037] for
preparing a pharmaceutical composition for the treatment of
COPD.
[0038] Also of particular importance according to the invention is
the use of compounds of general formula 1 wherein: [0039] n denotes
1 or 2; [0040] R.sup.1 denotes hydrogen or methyl; [0041] R.sup.2
denotes hydrogen or methyl; and [0042] R.sup.3 denotes hydrogen,
OH, methoxy, or --O--CH.sub.2--COOH, [0043] for preparing a
pharmaceutical composition for the treatment of COPD.
[0044] A preferred aspect of the present invention further relates
to the use of compounds of general formula 1 wherein n is 1 and the
groups R.sup.1, R.sup.2, and R.sup.3 may have the abovementioned
meanings, for preparing a pharmaceutical composition for the
treatment of COPD.
[0045] Another preferred aspect of the present invention relates to
the use of compounds of general formula 1 wherein n is 1 or 2,
R.sup.3 denotes a group selected from among hydrogen, OH,
--O--C.sub.1-C.sub.4-alkyl, and --O--C.sub.1-C.sub.4-alkylene-COOH,
and wherein the groups R.sup.1 and R.sup.2 may have the
abovementioned meanings, for preparing a pharmaceutical composition
for the treatment of COPD.
[0046] Another preferred aspect of the present invention relates to
the use of compounds of general formula 1 wherein n is 2, R.sup.1
and R.sup.2 are each hydrogen, and the group R.sup.3 may have the
abovementioned meanings, for preparing a pharmaceutical composition
for the treatment of COPD.
[0047] In the compounds of formula 1 the groups R.sup.1 and
R.sup.2, if they do not represent hydrogen, may each be arranged in
the ortho or meta position relative to the bond to the benzylic
"--CH.sub.2" group. If neither of the groups R.sup.1 and R.sup.2
denotes hydrogen, it is preferable according to the invention to
use those compounds of formula 1 wherein the two groups R.sup.1 and
R.sup.2 are either in the ortho configuration or both groups
R.sup.1 and R.sup.2 are in the meta configuration, while the use of
those compounds wherein both groups R.sup.1 and R.sup.2 are in the
ortho configuration is particularly important.
[0048] In the compounds of formula 1 wherein one of the groups
R.sup.1 and R.sup.2 does not denote hydrogen, it may be in the
ortho or meta configuration with respect to the bond to the
benzylic "--CH.sub.2" group. In this case it is particularly
preferred according to the invention to use those compounds of
formula 1 wherein the group R.sup.1 or R.sup.2, which does not
denote hydrogen, is in the ortho configuration.
[0049] In another aspect, the present invention relates to the
abovementioned use of the compounds of formula 1 in the form of the
individual optical isomers, mixtures of the individual enantiomers,
or racemates. It is particularly preferable to use the compounds of
formula 1 as mentioned above in the form of the enantiomerically
pure compounds, while the use of the R enantiomers of the compounds
of formula 1 is of particular importance according to the
invention.
[0050] In another aspect, the present invention relates to the
abovementioned use of the compounds of formula 1 in the form of the
acid addition salts with pharmacologically acceptable acids as well
as optionally in the form of the solvates and/or hydrates
thereof.
[0051] The present invention further relates to the use of the
abovementioned compounds of general formula 1 for preparing a
pharmaceutical composition for once-a-day treatment of COPD.
[0052] Moreover, the present invention relates to a process for the
treatment of COPD, characterized in that one or more of the
abovementioned compounds of general formula 1 are administered in
therapeutically effective amounts. The present invention also
relates to processes for treating COPD, characterized in that one
or more of the abovementioned compounds of general formula 1 are
administered once a day in therapeutically effective amounts.
[0053] The compounds of general formula 1 are partly known from the
prior art. Reference is made here to the disclosure of U.S. Pat.
No. 4,460,581. In some cases, however, the compounds of general
formula 1 have not yet been disclosed in the prior art. Another
aspect of the present invention relates to these new compounds of
formula 1 as such.
[0054] Accordingly, the present invention also relates to compounds
of general formula 1
##STR00004##
wherein: [0055] n denotes 1; [0056] R.sup.1 denotes hydrogen,
halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl;
[0057] R.sup.2 denotes hydrogen, halogen, C.sub.1-C.sub.4-alkyl, or
--O--C.sub.1-C.sub.4-alkyl; and [0058] R.sup.3 denotes
C.sub.1-C.sub.4-alkyl, OH, halogen, --O--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0059]
with the proviso that, if R.sup.1 and R.sup.2 each represent
ortho-methyl, R.sup.3 cannot simultaneously be OH.
[0060] Preferred compounds of general formula 1 are those wherein:
[0061] n denotes 1; [0062] R.sup.1 denotes hydrogen, fluorine,
chlorine, methyl, or methoxy; [0063] R.sup.2 denotes hydrogen,
fluorine, chlorine, methyl, or methoxy; and [0064] R.sup.3 denotes
C.sub.1-C.sub.4-alkyl, OH, fluorine, chlorine, bromine,
--O--C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0065]
with the proviso that, if R.sup.1 and R.sup.2 each represent
ortho-methyl, R.sup.3 cannot simultaneously be OH.
[0066] Preferred compounds of general formula 1 are those wherein:
[0067] n denotes 1; [0068] R.sup.1 denotes hydrogen or
C.sub.1-C.sub.4-alkyl; [0069] R.sup.2 denotes hydrogen or
C.sub.1-C.sub.4-alkyl; and [0070] R.sup.3 denotes
C.sub.1-C.sub.4-alkyl, OH, --O--C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkylene-COOH, or
--O--C.sub.1-C.sub.4-alkylene-CO--O--C.sub.1-C.sub.4-alkyl, [0071]
with the proviso that, if R.sup.1 and R.sup.2 each represent
ortho-methyl, R.sup.3 cannot simultaneously be OH.
[0072] Preferred compounds of general formula 1 are those wherein:
[0073] n denotes 1; [0074] R.sup.1 denotes hydrogen, methyl or
ethyl; [0075] R.sup.2 denotes hydrogen, methyl or ethyl; and [0076]
R.sup.3 denotes methyl, ethyl, OH, methoxy, ethoxy,
--O--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl, or
--O--CH.sub.2--COOethyl, with the proviso that, if R.sup.1 and
R.sup.2 each represent ortho-methyl, R.sup.3 cannot simultaneously
be OH.
[0077] Also preferred are the compounds of general formula 1
wherein: [0078] n denotes 1; [0079] R.sup.1 denotes hydrogen or
methyl; [0080] R.sup.2 denotes hydrogen or methyl; and [0081]
R.sup.3 denotes methyl, OH, methoxy, --O--CH.sub.2--COOH, or
--O--CH.sub.2--COOethyl, with the proviso that if R.sup.1 and
R.sup.2 each represent ortho-methyl, R.sup.3 cannot simultaneously
be OH.
[0082] Also preferred according to the invention are compounds of
general formula 1 wherein R.sup.3 denotes methoxy, ethoxy,
--O--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl, or
--O--CH.sub.2--COOethyl, and R.sup.1, R.sup.2, and n may have the
above meanings.
[0083] The present invention also relates to compounds of general
formula 1 wherein: [0084] n denotes 1; [0085] R.sup.1 denotes
halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl;
[0086] R.sup.2 denotes halogen, C.sub.1-C.sub.4-alkyl, or
--O--C.sub.1-C.sub.4-alkyl; and [0087] R.sup.3 denotes halogen,
C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl.
[0088] The present invention also relates to compounds of general
formula 1 wherein: [0089] n denotes 1; [0090] R.sup.1 denotes
fluorine, chlorine, methyl, or methoxy; [0091] R.sup.2 denotes
fluorine, chlorine, methyl, or methoxy; and [0092] R.sup.3 denotes
fluorine, chlorine, methyl, or methoxy.
[0093] In another preferred aspect the present invention relates to
the compounds of general formula 1 wherein: [0094] n denotes 1;
[0095] R.sup.1 denotes hydrogen; [0096] R.sup.2 denotes hydrogen,
fluorine, chlorine, or methyl; and [0097] R.sup.3 denotes methyl,
ethyl, isopropyl, tert-butyl, OH, fluorine, chlorine, bromine,
methoxy, ethoxy, --O--CH.sub.2--COOH,
--O--CH.sub.2--CH.sub.2--COOH,
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl,
--O--CH.sub.2--COOethyl, --O--CH.sub.2--CH.sub.2-COOmethyl,
--O--CH.sub.2--CH.sub.2-COOethyl,
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOmethyl, or
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOethyl.
[0098] Also particularly preferred are compounds of general formula
1 wherein [0099] n denotes 1; [0100] R.sup.1 denotes hydrogen;
[0101] R.sup.2 denotes hydrogen, fluorine, chlorine, or methyl; and
[0102] R.sup.3 denotes OH, fluorine, chlorine, methyl, methoxy,
ethoxy, or --O--CH.sub.2--COOH.
[0103] Other particularly preferred compounds of general formula 1
according to the invention are those wherein [0104] n denotes 1;
[0105] R.sup.1 denotes hydrogen; [0106] R.sup.2 denotes halogen,
C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl, preferably
fluorine, chlorine, methoxy, or methyl; and [0107] R.sup.3 denotes
halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl,
preferably fluorine, chlorine, methoxy, or methyl.
[0108] Another preferred aspect of the present invention relates to
the compounds of general formula 1 wherein n is 1, R.sup.1 and
R.sup.2 denote hydrogen, and the group R.sup.3 may have the
abovementioned meanings.
[0109] Another preferred aspect of the present invention relates to
the compounds of general formula 1 wherein: [0110] n denotes 1;
[0111] R.sup.1 and R.sup.2 denote hydrogen; and [0112] R.sup.3
denotes methyl, ethyl, isopropyl, tert-butyl, OH, fluorine,
chlorine, bromine, methoxy, ethoxy, --O--CH.sub.2--COOH,
--O--CH.sub.2--CH.sub.2--COOH,
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOH, --O--CH.sub.2--COOmethyl,
--O--CH.sub.2--COOethyl, --O--CH.sub.2--CH.sub.2-COOmethyl,
--O--CH.sub.2--CH.sub.2-COOethyl,
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOmethyl, or
--O--CH.sub.2--CH.sub.2--CH.sub.2--COOethyl.
[0113] Particularly preferred are compounds of general formula 1
wherein: [0114] n denotes 1; [0115] R.sup.1 and R.sup.2 denote
hydrogen; and [0116] R.sup.3 denotes OH, fluorine, chlorine,
methoxy, ethoxy, or --O--CH.sub.2--COOH, preferably OH, fluorine,
chlorine, ethoxy, or methoxy.
[0117] Particularly preferred are compounds of general formula 1
wherein: [0118] n denotes 1; [0119] R.sup.1 and R.sup.2 denote
hydrogen; and [0120] R.sup.3 denotes fluorine, chlorine, methoxy,
or ethoxy.
[0121] The present invention also relates to compounds of general
formula 1 wherein: [0122] n denotes 1; [0123] R.sup.1 denotes
hydrogen, halogen, C.sub.1-C.sub.4-alkyl, or
--O--C.sub.1-C.sub.4-alkyl; [0124] R.sup.2 denotes hydrogen,
halogen, C.sub.1-C.sub.4-alkyl, or --O--C.sub.1-C.sub.4-alkyl; and
[0125] R.sup.3 denotes hydrogen.
[0126] Also preferred are compounds of general formula 1 wherein:
[0127] n denotes 1; [0128] R.sup.1 denotes hydrogen, fluorine,
chlorine, methyl, or methoxy; [0129] R.sup.2 denotes hydrogen,
fluorine, chlorine, methyl, or methoxy; and [0130] R.sup.3 denotes
hydrogen.
[0131] The present invention also relates to compounds of general
formula 1 wherein: [0132] n denotes 1; [0133] R.sup.1 denotes
fluorine, chlorine, methyl, or methoxy; [0134] R.sup.2 denotes
fluorine, chlorine, methyl, or methoxy; and [0135] R.sup.3 denotes
hydrogen.
[0136] In the compounds of formula 1, the groups R.sup.1 and
R.sup.2, if they do not represent hydrogen, may each be arranged in
the ortho or meta position relative to the bond to the benzylic
"--CH.sub.2" group. If neither of the groups R.sup.1 and R.sup.2
denotes hydrogen, preferred compounds of formula 1 are those
wherein the two groups R.sup.1 and R.sup.2 are either in the ortho
configuration or both groups R.sup.1 and R.sup.2 are in the meta
configuration, while the use of those compounds wherein both groups
R.sup.1 and R.sup.2 are in the ortho configuration is particularly
important.
[0137] In the compounds of formula 1 wherein one of the groups
R.sup.1 and R.sup.2 does not denote hydrogen, it may be in the
ortho or meta configuration with respect to the bond to the
benzylic "--CH.sub.2" group. In this case, particularly preferred
compounds of formula 1 are those wherein the group R.sup.1 or
R.sup.2, which does not denote hydrogen, is in the ortho
configuration.
[0138] Also particularly preferred are compounds of general formula
1 which are selected from among: [0139] (1)
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethy-
l}-4H-benzo[1,4]oxazin-3-one; [0140] (2)
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamin-
o]-ethyl}-4H-benzo[1,4]oxazin-3-one; [0141] (3)
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic
acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;
[0142] (4)
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethy-
l}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0143] (5)
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethy-
l}-4H-benzo[1,4]oxazin-3-one; [0144] (6)
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1
dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; [0145] (7)
8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one; [0146] (8)
8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0147] (9)
8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0148] (10)
8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one; [0149] (11)
8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one; [0150] (12)
8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydrox-
y-4H-benzo[1,4]oxazin-3-one; [0151] (13)
8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one; [0152] (14)
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methylpropyl}phenoxy)butyric acid; [0153] (15)
8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one; [0154] (16)
8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0155] (17)
8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydrox-
y-4H-benzo[1,4]oxazin-3-one; [0156] (18)
8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one; [0157] (19)
8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydrox-
y-4H-benzo[1,4]oxazin-3-one; [0158] (20)
8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl-
}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0159] (21)
8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyet-
hyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0160] (22)
8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0161] (23)
8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0162] (24)
8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0163] (25)
8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0164] (26)
8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxye-
thyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0165] (27)
8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxye-
thyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0166] (28)
8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyet-
hyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0167] (29)
8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one; [0168] (30)
8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one; [0169] (31)
8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one; [0170] (32)
8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydrox-
y-4H-benzo[1,4]oxazin-3-one; and [0171] (33)
8-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one.
[0172] In another aspect, the present invention relates to the
abovementioned new compounds of formula 1 in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates. Particularly preferred are compounds of formula 1 in
the form of the enantiomerically pure compounds, while the
R-enantiomers of the compounds of formula 1 are of exceptional
importance according to the invention. Methods of separating
racemates into the respective enantiomers are known in the prior
art and may be used analogously to prepare the enantiomerically
pure R- and S-enantiomers of the compounds of formula 1.
[0173] In another aspect, the present invention relates to the
abovementioned compounds of formula 1 in the form of the acid
addition salts with pharmacologically acceptable acids as well as
optionally in the form of the solvates and/or hydrates thereof.
[0174] In another aspect, the present invention relates to the
abovementioned compounds of formula 1 for use as pharmaceutical
compositions. The present invention further relates to the use of
the abovementioned new compounds of general formula 1 for preparing
a pharmaceutical composition for the treatment of COPD. The present
invention further relates to the use of the abovementioned new
compounds of general formula 1 for preparing a pharmaceutical
composition for the once-a-day treatment of COPD.
[0175] Moreover, the present invention relates to a process for the
treatment of COPD, characterized in that one or more of the
abovementioned compounds of general formula 1 are administered in
therapeutically effective amounts. The present invention also
relates to processes for treating COPD, characterized in that one
or more of the abovementioned new compounds of general formula 1
are administered once a day in therapeutically effective
amounts.
[0176] By acid addition salts with pharmacologically acceptable
acids are meant, for example, the salts selected from among the
hydrochloride, hydrobromide, hydroiodide, hydrosulfate,
hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate,
hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,
hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and
hydro-p-toluenesulfonate salts, preferably the hydrochloride,
hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, and
hydromethanesulfonate salts. Of the abovementioned acid addition
salts, the salts of hydrochloric acid, methanesulfonic acid,
benzoic acid, and acetic acid are particularly preferred according
to the invention.
[0177] For use according to the invention, the compounds of general
formula 1 may optionally be used in the form of their individual
optical isomers, mixtures of the individual enantiomers or
racemates. If the compounds are used in enantiomerically pure form,
the R-enantiomers are preferred.
[0178] Unless otherwise stated, the alkyl groups are
straight-chained or branched alkyl groups having 1 to 4 carbon
atoms. The following are mentioned by way of example: methyl,
ethyl, propyl, or butyl. In some cases the abbreviations Me, Et,
Prop, or Bu are used to denote the groups methyl, ethyl, propyl, or
butyl. Unless otherwise stated, the definitions propyl and butyl
include all the possible isomeric forms of the groups in question.
Thus, for example, propyl includes n-propyl and isopropyl, butyl
includes isobutyl, sec-butyl, and tert-butyl, etc.
[0179] Unless otherwise stated, the alkylene groups are branched
and unbranched double-bonded alkyl bridges having 1 to 4 carbon
atoms. The following are mentioned by way of example: methylene,
ethylene, n-propylene, or n-butylene.
[0180] Unless otherwise stated, the term alkyloxy groups (or
--O-alkyl groups) denotes branched and unbranched alkyl groups
having 1 to 4 carbon atoms which are linked via an oxygen atom.
Examples of these include: methyloxy, ethyloxy, propyloxy, or
butyloxy. The abbreviations MeO-, EtO-, PropO-, or BuO- are used in
some cases to denote the groups methyloxy, ethyloxy, propyloxy, or
butyloxy. Unless otherwise stated, the definitions propyloxy and
butyloxy include all possible isomeric forms of the groups in
question. Thus, for example, propyloxy includes n-propyloxy and
isopropyloxy, butyloxy includes isobutyloxy, sec-butyloxy, and
tert-butyloxy, etc. In some cases, within the scope of the present
invention, the term alkoxy is used instead of the term alkyloxy.
Accordingly, the terms methoxy, ethoxy, propoxy, or butoxy may also
be used to denote the groups methyloxy, ethyloxy, propyloxy, or
butyloxy.
[0181] Halogen within the scope of the present invention denotes
fluorine, chlorine, bromine, or iodine. Unless stated otherwise,
fluorine, chlorine, and bromine are the preferred halogens.
[0182] The compounds according to the invention may be prepared
analogously to methods already known from the prior art. Suitable
methods of preparation are known for example from U.S. Pat. No.
4,460,581, to the entire contents of which reference is made at
this point.
[0183] The examples of synthesis described below serve to
illustrate compounds known from the prior art, which may
surprisingly be used according to the present invention for the
treatment of COPD.
EXAMPLE 1
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-2,6-dimethylphenyl)-1,1-dimethyl-et-
hylamino]ethyl}-4H-benzo[1,4]oxazin-3-one
##STR00005##
[0185] The compound is known from U.S. Pat. No. 4,460,581.
EXAMPLE 2
8-{2-[1,1-dimethyl-3-phenylpropylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo-
[1,4]oxazin-3-one
##STR00006##
[0187] The compound is known from U.S. Pat. No. 4,460,581.
[0188] The examples of synthesis described below serve to
illustrate new compounds according to the invention more fully.
They are intended only as examples of procedure to illustrate the
invention without restricting it to the subject matter described
hereinafter.
EXAMPLE 3
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1'-dimethylethylamino]-eth-
yl}-4H-benzo[1,4]oxazin-3-one
##STR00007##
[0189] (a)
8-{2-[1,1-dimethyl-2-(4-methoxyphenyl)ethylamino]-1-hydroxyethy-
l}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one
[0190] 7.5 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxal
hydrate is added at 70.degree. C. to a solution of 3.6 g of
1,1-dimethyl-2-(4-methoxyphenyl)ethylamine in 100 mL ethanol and
stirred for 15 minutes. Then 1 g of sodium borohydride is added
within 30 minutes at 10.degree. C. to 20.degree. C. The mixture is
stirred for one hour, combined with 10 mL acetone, and stirred for
a further 30 minutes. The reaction mixture is diluted with 150 mL
ethyl acetate, washed with water, dried with sodium sulfate, and
evaporated down. The residue is dissolved in 50 mL methanol and 100
mL ethyl acetate and acidified with concentrated hydrochloric acid.
After the addition of 100 mL diethyl ether, the product
precipitates out. The crystals are filtered off, washed, and
recrystallized in 50 mL ethanol. Yield: 7 g (68%; hydrochloride);
melting point: 232.degree. C.-234.degree. C.
(b)
8-{2-[1,1-dimethyl-2-(4-methoxyphenyl)ethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one
[0191] 6.8 g of the benzyl compound obtained above are hydrogenated
in 125 mL methanol with the addition of 1 g palladium on charcoal
(5%) at ambient temperature and under normal pressure. The catalyst
is filtered off and the filtrate is freed from solvent. After
recrystallization of the residue in 50 mL acetone and some water, a
solid is obtained, which is filtered off and washed. Yield: 5.0 g
(89%; hydrochloride); melting point: 155.degree. C.-160.degree.
C.
[0192] The (R)- and (S)-enantiomers of Example 3 may be obtained
from the racemate, for example, by chiral HPLC (e.g., column:
Chirobiotic T, 250.times.22.1 mm made by Messrs Astec). The mobile
phase may be methanol with 0.05% triethylamine and 0.05% acetic
acid. Silica gel with a particle size of 5 .mu.m, to which the
glycoprotein Teicoplanin is covalently bound, can be used as the
column material. Retention time (R-enantiomer): 40.1 minutes;
retention time (S-enantiomer): 45.9 minutes. Both enantiomers are
obtained according to this method in the form of their free base.
The R-enantiomer of Example 3 is of exceptional importance
according to the invention.
EXAMPLE 4
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethyl
acetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one
##STR00008##
[0193] (a) 8-{2-[1,1-dimethyl-2-(4-phenoxyethyl
acetate)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one
[0194] The title compound is obtained analogously to the method
described in Example 3(a) from 15 g of
(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxal hydrate and 11.8 g
of 1,1-dimethyl-2-(4-phenoxyethyl acetate)ethylamine hydrochloride.
Yield: 16.5 g (69%, hydrochloride); melting point: 212.degree.
C.-214.degree. C.
(b) 8-{2-[1,1-dimethyl-2-(4-phenoxyethyl
acetate)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one
[0195] 8 g of the benzyl alcohol obtained above is dissolved in 100
mL ethanol, 100 mL methanol, and 10 mL water and hydrogenated in
the presence of 1 g palladium on charcoal (5%). After the
theoretically calculated amount of hydrogen has been taken up, the
catalyst is filtered off and the filtrate is evaporated down. The
product which crystallizes out when the solvent is distilled off is
suction filtered and washed. Yield: 5.5 g (81%; hydrochloride);
melting point: 137.degree. C.-140.degree. C.
[0196] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 5
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic
acid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one
##STR00009##
[0198] 11 g of
8-{2-[1,1-dimethyl-2-(4-phenoxyethylacetate)ethylamino]-1-hydroxyethyl}-6-
-benzyloxy-4H-benzo[1,4]oxazin-3-one hydrochloride (Example 4(a))
is dissolved in 125 mL methanol and hydrogenated in the presence of
1 g palladium on charcoal (5%). After the theoretically calculated
amount of hydrogen has been taken up, the catalyst is filtered off.
2.6 g of sodium hydroxide dissolved in 20 mL water is added to the
filtrate. The mixture is refluxed for 30 minutes, the methanol is
distilled off and combined with 10 mL water, 20 mL n-butanol, and
3.9 mL acetic acid. The solid precipitated is suction filtered and
washed with diethyl ether. Yield: 7 g (87%). The hydrochloride is
obtained by recrystallization from 0.5 molar hydrochloric acid.
Melting point: 152.degree. C.
[0199] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 6
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6--
hydroxy-4H-benzo[1,4]oxazin-3-one
##STR00010##
[0200] (a)
1-(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-2-[11'-dimethyl-2-(2,-
4,6-trimethylphenyl)ethylimino]ethanone
[0201] 7.2 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxal
hydrate and 3.6 g of
1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamine are heated to
70.degree. C. for one hour in 100 mL ethanol. After cooling, the
crystals precipitated are filtered off and washed with ethanol and
diethyl ether. Yield: 8.6 g (94%); melting point: 175.degree.
C.
(b)
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl-
}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one
[0202] 8.6 g of the Schiff base obtained according to Example 6(a)
is dissolved in 100 mL ethanol and 20 mL THF, combined with 0.7 g
sodium borohydride within 30 minutes at 10.degree. C.-20.degree.
C., and stirred for one hour. After the addition of 10 mL acetone,
the mixture is stirred for 30 minutes and then diluted with ethyl
acetate and water. The product which crystallizes out on
acidification with concentrated hydrochloric acid is filtered off
and washed. Yield: 7.4 g (80%, hydrochloride); melting point:
235.degree. C. (decomposition).
c)
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one
[0203] 7.4 g of the benzyl compound obtained according to Example
6(b) is hydrogenated in 125 mL methanol with the addition of 1 g
palladium on charcoal (5%) at ambient temperature under normal
pressure. Then the catalyst is filtered off and the filtrate is
evaporated down. The product which crystallizes out when acetone is
added is suction filtered and washed with acetone and diethyl
ether. Yield: 5 g (78%, hydrochloride); melting point 160.degree.
C. (decomposition).
[0204] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 7
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-ethy-
l}-4H-benzo[1,4]oxazin-3-one
##STR00011##
[0205] (a)
8-{2-[1,1-dimethyl-2-(4-hydroxyphenyl)ethylamino]-1-hydroxyethy-
l}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one
[0206] The title compound is prepared from 10 g of
(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxal hydrate and 4.6 g
of 1,1-dimethyl-2-(4-hydroxyphenyl)ethylamine analogously to the
method for Example 3(a). Yield: 9.0 g (64%, hydrochloride); melting
point: 255.degree. C.-258.degree. C.
(b)
8-{2-[1,1-dimethyl-2-(4-hydroxyphenyl)ethylamino]-1-hydroxyethyl}-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one
[0207] 5.7 g of the coupling product obtained above are
hydrogenated in the presence of 0.6 g palladium on charcoal (5%) in
100 mL methanol. After the theoretically calculated amount of
hydrogen has been taken up, the catalyst is filtered off and the
filtrate is freed from solvent. The residue is dissolved in ethanol
with heating and then combined with diethyl ether. The product
precipitated is suction filtered and recrystallized once in water.
Yield: 3.6 g (72%, hydrochloride); melting point: 159.degree.
C.-162.degree. C.
[0208] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 8
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]-et-
hyl}-4H-benzo[1,4]oxazin-3-one
##STR00012##
[0209] (a) 1-(4-isopropylphenyl)-2-methylpropan-2-ol
[0210] The reaction of a Grignard compound, prepared from 20 g (119
mmol) 4-isopropylbenzyl chloride, with 11.4 mL (155 mmol) acetone
yields the target compound as a colorless oil. Yield: 13.0 g (57%);
mass spectrometry: [M+H].sup.+=193.
(b) N-[2-(4-isopropylphenyl)-1,1-dimethylethyl]acetamide
[0211] A Ritter reaction is carried out with 10.2 g (53 mmol) of
1-(4-isopropylphenyl)-2-methylpropan-2-ol in the manner described
for Example 9(b). The reaction mixture is poured onto ice water and
made alkaline with sodium hydroxide solution, whereupon a solid is
precipitated. This is suction filtered and dried. Yield: 9.90 g
(80%); mass spectrometry: [M+H].sup.+=234.
(c) 2-(4-isopropylphenyl)-1,1-dimethylethylamine
[0212] Reaction of 9.80 g (42 mmol) of
N-[2-(4-isopropylphenyl)-1,1-dimethylethyl]acetamide analogously to
the method for Example 9(c). Yield: 7.00 g (71%, hydrochloride);
melting point 202.degree. C.-206.degree. C.
(d)
6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylami-
no]ethyl}-4H-benzo[1,4]oxazin-3-one
[0213] 2.18 g (6.1 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 1.1 g (5.8 mmol) of
2-(4-isopropylphenyl)-1,1-dimethylethylamine are stirred in 40 mL
ethanol at 50.degree. C.-80.degree. C. for one hour. After cooling
to ambient temperature, 0.24 g (6.3 mmol) sodium borohydride is
added. The mixture is stirred for one hour, diluted with 5 mL
acetone, and stirred for a further 30 minutes. The reaction mixture
is acidified with hydrochloric acid, combined with 100 mL water and
80 mL ethyl acetate, and made alkaline with ammonia. The organic
phase is separated off, dried with sodium sulfate, and freed from
solvent. The residue is dissolved in 20 mL ethyl acetate and 10 mL
water, acidified with concentrated hydrochloric acid and diluted
with diethyl ether. After the addition of a crystallization aid,
the solid precipitate is suction filtered and washed. White solid.
Yield: 1.7 g (52%, hydrochloride); melting point: 220.degree.
C.-222.degree. C.
(e) 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1
dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one
[0214] 1.6 g (3.0 mmol) of
6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]-
ethyl}-4H-benzo[1,4]oxazin-3-one is dissolved in methanol and
hydrogenated with palladium on charcoal as catalyst at normal
pressure and ambient temperature. The catalyst is suction filtered,
the solvent distilled off, and the residue recrystallized from
isopropanol. White solid. Yield: 1.1 g (85%, hydrochloride);
melting point 248.degree. C.-250.degree. C.; mass spectrometry:
[M+H].sup.+=399.
[0215] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 9
8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy--
4H-benzo[1,4]oxazin-3-one
##STR00013##
[0216] (a) 1-(4-ethylphenyl)-2-methylpropan-2-ol
[0217] 14.8 g (90 mmol) of 1-(4-ethylphenyl)propan-2-one dissolved
in diethyl ether is added dropwise to 39 mL of a 3 molar solution
of methylmagnesium bromide in diethyl ether while being cooled with
an ice bath in such a way that the temperature does not exceed
30.degree. C. After the addition has ended, the reaction mixture is
refluxed for 1.5 hours and then hydrolyzed with 10% ammonium
chloride solution. After the removal of the organic phase, the
aqueous phase is extracted with diethyl ether. The combined ether
phases are washed with water, dried with sodium sulfate, and
evaporated down. The oil thus obtained is further reacted directly.
Yield: 15.5 g (90%).
(b) N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide
[0218] 6.2 mL of concentrated sulfuric acid is added dropwise to
15.5 g (87 mmol) of 1-(4-ethylphenyl)-2-methylpropan-2-ol in 4.8 mL
(91 mmol) acetonitrile and 15 mL glacial acetic acid within 15
minutes, during which time the temperature rises to 65.degree. C.
It is then stirred for one hour, diluted with ice water, and made
alkaline with concentrated sodium hydroxide solution. After another
30 minutes' stirring, the solid precipitated is suction filtered
and washed with water. The crude product is dissolved in ethyl
acetate, dried with sodium sulfate, and evaporated down. The oil
remaining is combined with petroleum ether, whereupon a solid is
precipitated which is filtered off and dried. Yield: 16.3 g (85%);
melting point 90.degree. C.-92.degree. C.
(c) 2-(4-ethylphenyl)-1,1-dimethylethylamine
[0219] 16.3 g (74 mmol) of
N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide and 8.0 g of
potassium hydroxide are refluxed for 15 hours in 60 mL ethylene
glycol. The reaction mixture is combined with ice water and
extracted three times with diethyl ether. The combined organic
phases are washed with water, dried with sodium sulfate, and freed
from solvent. To prepare the hydrochloride, the crude product is
dissolved in acetonitrile and ethereal hydrochloric acid and
diethyl ether are added successively. The solid precipitated is
suction filtered and dried. Yield: 11.0 g (69%, hydrochloride);
melting point 165.degree. C.-167.degree. C.
(d)
6-benzyloxy-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxye-
thyl}-4H-benzo[1,4]oxazin-3-one
[0220] The target compound is prepared analogously to the method
for Example 8(d) from 2.14 g (6.0 mmol) of
6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 1.0 g (5.6 mmol) of 2-(4-ethylphenyl)-1,1-dimethylethylamine.
White solid. Yield: 1.7 g (54%, hydrochloride); melting point
210.degree. C.-214.degree. C.
(e)
8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one
[0221] The hydrogenolysis of 1.45 g (2.75 mmol) of
6-benzyloxy-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethy-
l}-4H-benzo[1,4]oxazin-3-one according to the method for Example
8(e) yields the target compound in the form of a white solid.
Yield: 1.07 g (92%; hydrochloride); melting point 266.degree.
C.-269.degree. C.; mass spectrometry: [M+H].sup.+=385.
[0222] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 10
8-{2-[2-(4-Fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one
##STR00014##
[0223] (a) 1-fluoro-2-methyl-4-(2-methylpropenyl)benzene
[0224] 100 mL of a 0.5 molar solution of
4-fluoro-3-methylphenylmagnesium bromide in THF are combined with
4.7 mL (50 mmol) isopropylaldehyde within 30 minutes, while the
temperature rises to 45.degree. C. The mixture is stirred for 30
minutes, refluxed for 1 hour, and then hydrolyzed with 10% ammonium
chloride solution. After separation of the organic phase,
extraction is carried out with diethyl ether. The organic phases
are combined, dried, and evaporated down. The alcohol thus obtained
is dissolved in 100 mL toluene, combined with 1 g of
p-toluenesulfonic acid monohydrate, and refluxed for three hours
using the water separator. The reaction mixture is poured onto
water and made alkaline with concentrated sodium hydroxide
solution. After separation of the organic phase, it is washed with
water, dried with sodium sulfate, and freed from solvent.
Fractional distillation of the residue yields the product in the
form of a colorless liquid (boiling point 80.degree. C.-85.degree.
C./10 mbar). Yield: 4.1 g (50%).
(b) N-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethyl]formamide
[0225] 4.9 mL concentrated sulfuric acid are added dropwise at
5.degree. C.-15.degree. C. to 1.5 g (31 mmol) sodium cyanide in 5
mL glacial acetic acid. Then the mixture is combined with 3.9 g (24
mmol) of 1-fluoro-2-methyl-4-(2-methylpropenyl)benzene, dissolved
in 10 mL glacial acetic acid, and stirred for 1 hour at 50.degree.
C.-60.degree. C. The reaction mixture is diluted with ice water,
made alkaline with concentrated sodium hydroxide solution, and
extracted with dichloromethane. The organic phase is dried with
sodium sulfate and freed from solvents in vacuo. The slightly
yellow oil thus obtained is further reacted directly. Yield: 4.3 g
(87%).
(c) 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine
[0226] 4.3 g (20.6 mmol) of
N-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethyl]formamide, 20 mL
concentrated hydrochloric acid, and 20 mL water are refluxed for 2
hours. The reaction mixture is diluted with water, made alkaline
with concentrated sodium hydroxide solution, and extracted with
dichloromethane. The organic phases are dried with sodium sulfate
and evaporated down. The residue is dissolved in ethyl acetate,
combined with ethereal hydrochloric acid, and cooled. The crystals
precipitated are suction filtered and washed with diethyl ether and
dried. White solid. Yield: 3.9 g (87%, hydrochloride); melting
point 196.degree. C.-198.degree. C.
(d)
6-benzyloxy-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]--
1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one
[0227] 1.10 g (3.1 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.50 g (2.8 mmol) of
2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine are reacted and
worked up analogously to the method for Example 8(d). White solid.
Yield: 0.75 g (47%, hydrochloride); melting point 228.degree.
C.-230.degree. C.
(e)
8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one
[0228] The hydrogenation of 0.70 g (1.4 mmol) of
6-benzyloxy-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-h-
ydroxyethyl}-4H-benzo[1,4]oxazin-3-one yields the target compound
as a white solid. Yield: 0.50 g (87%, hydrochloride); melting point
278.degree. C.-280.degree. C.; mass spectroscopy:
[M+H].sup.+=389.
[0229] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 11
8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one
##STR00015##
[0230] (a) 1-(4-fluoro-2-methylphenyl)-2-methylpropyl acetate
[0231] 500 mL of a 0.5 molar solution of
4-fluoro-6-methylphenylmagnesium bromide and 23.2 mL (260 mmol)
isopropylaldehyde are reacted analogously to Example 10(a). After
hydrolysis with 10% ammonium chloride solution, the aqueous phase
is separated off and extracted with diethyl ether. The combined
organic phases are dried with sodium sulfate and evaporated down.
The alcohol thus obtained is then dissolved in 50 mL acetic
anhydride, combined with 1 mL concentrated sulfuric acid, and
refluxed for three hours. Then the reaction mixture is poured onto
water, stirred for a further hour, and made alkaline. It is
extracted with dichloromethane, the organic phases are dried with
sodium sulfate, and the solvents are distilled off. Fractional
distillation of the residue yields the product in the form of a
colorless liquid (boiling point: 105.degree. C.-110.degree. C./8
mbar). Yield 29.0 g (52%).
(b) N-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide
[0232] 29.0 g (130 mmol) of
1-(4-fluoro-2-methylphenyl)-2-methylpropyl acetate is reacted and
worked up analogously to the method for Example 10(b). Yellow oil.
Yield: 27.0 g (99%).
(c) 2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine
[0233] In order to prepare the amine, 27.0 g (130 mmol) of
N-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide is
reacted as described in the method for Example 10(c). White solid.
Yield: 15.5 g (55%, hydrochloride); melting point: 277.degree.
C.-280.degree. C.
(d)
6-benzyloxy-8-{2-[2-[4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]--
1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one
[0234] Prepared analogously to the method for Example 8(d) from
0.95 g (2.66 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.43 g (2.37 mmol) of
2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine. Yield: 0.75 g
(55%, hydrochloride); melting point 233.degree. C.-236.degree.
C.
(e)
8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one
[0235] The debenzylation of 0.70 g (1.36 mmol) of
6-benzyloxy-8-{2-[2-[4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-h-
ydroxyethyl}-4H-benzo[1,4]oxazin-3-one yields the target compound
in the form of a white solid. Yield: 0.50 g (87%, hydrochloride);
melting point 278.degree. C.-280.degree. C.; mass spectroscopy:
[M+H].sup.+=389.
[0236] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 12
8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
##STR00016##
[0237] (a) 1-(2,4-difluorophenyl)-2-methylpropan-2-ol
[0238] 11.0 mL acetone, diluted with 50 mL diethyl ether, is added
dropwise to a solution of 500 mL of 0.25 molar
2,4-difluorobenzylmagnesium bromide in diethyl ether within 20
minutes. Then the mixture is refluxed for 1.5 hours and then
hydrolyzed with 10% ammonium chloride solution. The ether phase is
separated off, washed with water, dried with sodium sulfate, and
evaporated down. The fractional distillation of the residue yields
the alcohol as a colorless liquid (boiling point: 70.degree.
C.-73.degree. C./2 mmbar). Yield: 20.0 g (86%).
(b) N-[2-(2,4-difluorophenyl-1,1-dimethylethyl]formamide
[0239] Ritter reaction with 20 g (110 mmol) of
1-(2,4-difluorophenyl)-2-methylpropan-2-ol according to the method
described for Example 10(b). Yellow oil. Yield: 22.0 g (94%).
(c) 2-(2,4-difluorophenyl)-1,1-dimethylethylamine
[0240] Reaction of 22.0 g (100 mmol) of
N-[2-(2,4-difluorophenyl]-1,1-dimethylethyl]formamide analogously
to the method for Example 10(c). Yield: 16.0 g (72%,
hydrochloride); melting point: 201.degree. C.-203.degree. C.
(d)
6-benzyloxy-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hyd-
roxyethyl}-4H-benzo[1,4]oxazin-3-one
[0241] Reaction of 0.89 g (2.49 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.40 g (2.16 mmol) of
2-(2,4-difluorophenyl)-1,1-dimethylethylamine in the manner
described for Example 8(d). Yield: 0.80 g (62%, hydrochloride);
melting point 245.degree. C.-247.degree. C.
(e)
8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one
[0242] The hydrogenolysis of 0.70 g (1.35 mmol) of
6-benzyloxy-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydrox-
yethyl}-4H-benzo[1,4]oxazin-3-one yields the target compound as a
white solid. Yield: 0.48 g (83%, hydrochloride); melting point
279.degree. C.-280.degree. C.; mass spectroscopy:
[M+H].sup.+=393.
[0243] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 13
8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
##STR00017##
[0244] (a) 1-(3,5-difluorophenyl)-2-methylpropan-2-ol
[0245] The target compound is obtained by reacting a Grignard
compound, prepared from 25.0 g (121 mmol) of 3,5-difluorobenzyl
bromide, with 12.6 mL (171 mmol) of acetone. Yellow oil. Yield:
13.5 g (60%).
(b) 2-(3,5-difluorophenyl)-1,1-dimethylethylamine
[0246] The Ritter reaction of 5.5 g (29.5 mmol) of
1-(3,5-difluorophenyl)-2-methylpropan-2-ol and 1.8 g of sodium
cyanide yields 7.0 g of formamide, which is treated with
hydrochloric acid to cleave the formyl group. Slightly yellow oil.
Yield: 4.6 g (75%).
(c)
6-benzyloxy-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hyd-
roxyethyl}-4H-benzo[1,4]oxazin-3-one
[0247] Prepared from 1.73 g (4.84 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.80 g (4.32 mmol) of
2-(3,5-difluorophenyl)-1,1-dimethylethylamine in the usual way.
Yield: 1.50 g (58%, hydrochloride); melting point: 240.degree.
C.-244.degree. C.
(d)
8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one
[0248] Hydrogenolysis of 1.30 g (2.43 mmol) of
6-benzyloxy-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydrox-
yethyl}-4H-benzo[1,4]oxazin-3-one yields the target compound as a
white solid. Yield: 0.90 g (86%, hydrochloride); melting point
150.degree. C.-158.degree. C.; mass spectroscopy:
[M+H].sup.+=393.
[0249] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 14
8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00018##
[0250] (a) benzyl
[2-(4-ethoxyphenyl)-1,1-dimethylethyl]carbaminate
[0251] 15.0 g (50 mmol) of benzyl
[2-(4-hydroxyphenyl)-1,1-dimethylethyl]carbaminate is stirred with
7.5 mL (92 mmol) ethyl iodide and 21 g (150 mmol) potassium
carbonate for 10 hours at 90.degree. C.-100.degree. C. The reaction
mixture is combined with ethyl acetate, washed twice with water,
and dried with sodium sulfate. After the solvents have been
distilled off, a yellow oil remains (15.0 g, 92%), which is further
reacted directly.
(b) 2-(4-ethoxyphenyl)-1,1-dimethylethylamine
[0252] A solution of 15.0 g (49 mmol) benzyl
[2-(4-ethoxyphenyl)-1,1-dimethylethyl]-carbaminate in 100 mL
glacial acetic acid is combined with 2 g palladium on charcoal
(10%) and then hydrogenated at 5 bar and 40.degree. C. to
50.degree. C. The catalyst is filtered off and the filtrate is
freed from solvent. The residue is dissolved in a little water,
made alkaline with concentrated sodium hydroxide solution, and
extracted with ethyl acetate. The organic phase is washed with
water, dried with sodium sulfate, and evaporated down. The crude
product is dissolved in acetonitrile and acidified with ethereal
hydrochloric acid. The solid precipitated after the addition of
diethyl ether is suction filtered and dried. Yield: 8.8 g
(hydrochloride, 84%); melting point 198.degree. C.-200.degree.
C.
(c)
6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxy-
ethyl}-4H-benzo[1,4]oxazin-3-one
[0253] 2.14 g (6.0 mmol) of
6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 1.0 g (5.2 mmol) of 2-(4-ethoxyphenyl)-1,1-dimethylethylamine
are stirred in 40 mL ethanol for one hour at 50.degree.
C.-80.degree. C. After cooling to ambient temperature, 0.23 g (6.0
mmol) of sodium borohydride are added and the mixture is stirred
for a further hour. The reaction mixture is combined with 5 mL
acetone, stirred for 30 minutes, acidified with glacial acetic
acid, and evaporated down. The residue is combined with water and
ethyl acetate and made alkaline. The organic phase is separated
off, washed with water, dried with sodium sulfate, and freed from
solvent in vacuo. The residue is dissolved again in ethyl acetate
and water, combined with concentrated hydrochloric acid, and
diluted with diethyl ether. The solid precipitated is suction
filtered and washed with diethyl ether. White solid. Yield: 2.0 g
(61%, hydrochloride); melting point: 214.degree. C.-216.degree.
C.
(d)
8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
[0254] 1.5 g (2.8 mmol) of
6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-4H-benzo[1,4]oxazin-3-one in 80 mL methanol are hydrogenated
with 250 mg palladium on charcoal (10%) as catalyst at ambient
temperature and normal pressure. The catalyst is suction filtered
and the filtrate is evaporated down. The residue is dissolved in 5
mL ethanol by heating, seeded, and diluted with ethyl acetate. The
solid precipitated is filtered off and washed. White solid. Yield
1.0 g (83%, hydrochloride); melting point: 232.degree.
C.-235.degree. C.; mass spectrometry: [M+H].sup.+=401.
[0255] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 15
8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
##STR00019##
[0256] (a) 1-(3,5-dimethylphenyl)-2-methylpropanol-2-ol
[0257] Obtained by reacting ethyl (3,5-dimethylphenyl)acetate with
methylmagnesium bromide.
(b) 2-(3,5-dimethylphenyl)-1,1-dimethylethylamine
[0258] By reacting 6.00 g (34 mmol) of
1-(3,5-dimethylphenyl)-2-methylpropanol-2-ol and 2.00 g (41 mmol)
of sodium cyanide in a Ritter reaction, 2.40 g of
2-(3,5-dimethylphenyl)-1,1-dimethylethylformamide (35% yield) is
obtained. To liberate the amine, the formamide (2.40 g, 11.7 mmol)
is treated with hydrochloric acid. The method and working up are
analogous to the method for Example 10(c). Oil. Yield: 1.70 g
(82%); mass spectroscopy: [M+H].sup.+=178.
(c)
6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hyd-
roxyethyl}-4H-benzo[1,4]oxazin-3-one
[0259] Prepared analogously to the method for Example 8(d) from
1.47 g (4.1 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.65 g (3.7 mmol) of
2-(3,5-dimethylphenyl)-1,1-dimethylethylamine. Yield: 1.1 g (51%,
hydrochloride); melting point: 220.degree. C.-222.degree. C.
(d)
8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one
[0260] The target compound was obtained after hydrogenolysis of
0.90 g (1.71 mmol) of
6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydrox-
yethyl}-4H-benzo[1,4]oxazin-3-one and recrystallization of the
crude product from isopropanol. White solid. Yield: 0.50 g (69%,
hydrochloride); melting point: 235.degree. C.-238.degree. C.; mass
spectroscopy: [M+H].sup.+=385.
[0261] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 16
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
##STR00020##
[0262] (a) ethyl
4-[4-(2-amino-2-methylpropyl)-phenoxy]-butyrate
[0263] 4.5 g (15.0 mmol) of benzyl
[2-(4-hydroxyphenyl)-1,1-dimethylethyl]carbaminate, 2.3 mL (16.0
mmol) of ethyl 4-bromobutyrate, 2.3 g (16.6 mmol) of potassium
carbonate, and 0.3 g (1.8 mmol) of potassium iodide in 20 mL
dimethylformamide are heated to 120.degree. C. for 13 hours. The
reaction mixture is diluted with ethyl acetate and washed
successively with water, sodium hydroxide solution, and water. The
organic phase is dried with sodium sulfate and evaporated down. The
residue is purified by chromatography (eluent: cyclohexane-ethyl
acetate (9:1)). 5.0 g of a yellow oil is isolated which is
dissolved in 50 mL acetic acid and hydrogenated with 1.0 g
palladium on charcoal as catalyst at 40.degree. C. and 3 bar. The
catalyst is filtered off and the filtrate is freed from solvent.
The residue is dissolved in diethyl ether and combined with
ethereal hydrochloric acid. The solid precipitated is suction
filtered and dried. Yield: 2.9 g (66% in two stages,
hydrochloride); melting point: 103.degree. C.-105.degree. C.
(b) ethyl
4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8--
yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyrate
[0264] 1.20 g (3.36 mmol) of
benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 0.90 g (3.22 mmol) of ethyl
4-[4-(2-amino-2-methylpropyl)phenoxy]butyrate are reacted in the
manner described for Example 8(d). The crude product is dissolved
in 10 mL ethyl acetate and 10 mL water and combined with oxalic
acid with stirring. The solution is diluted with diethyl ether and
the solid precipitated is suction filtered and washed with diethyl
ether. Yield: 1.20 g (54%, oxalate); melting point 223.degree.
C.-227.degree. C.
(c)
4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2--
hydroxyethylamino]-2-methylpropyl}phenoxy)butyric acid
[0265] A solution of 1.00 g (1.73 mmol) of ethyl
4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hyd-
roxyethylamino]-2-methylpropyl}phenoxy)butyrate in 25 mL methanol
is combined with 2.5 mL of 1 N sodium hydroxide solution, refluxed
for 30 minutes, and then neutralized with 1 N hydrochloric acid.
The solution is evaporated down and the residual oil is dissolved
by heating in 5 mL of n-butanol. After the addition of a
crystallization aid, a solid is precipitated out which is suction
filtered and washed with acetone and diethyl ether. Yield: 0.75 g
(79%); melting point: 216.degree. C.-218.degree. C.
(d)
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
[0266] 0.70 g (1.28 mmol) of
4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hyd-
roxyethylamino]-2-methylpropyl}phenoxy)butyric acid is dissolved in
25 mL methanol and 2 mL acetic acid and hydrogenated in the
presence of 150 mg palladium on charcoal (10%) at ambient
temperature and normal pressure. The catalyst is filtered off and
the filtrate is freed from solvent. The product is obtained by
crystallization from a methanol-acetone mixture. Yield: 0.40 g
(68%); melting point: 201.degree. C.-204.degree. C.; mass
spectroscopy: [M+H].sup.+=459.
[0267] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 17
8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
##STR00021##
[0268] (a) 1-(3,4-difluorophenyl)-2-methylpropan-2-ol
[0269] From 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide a
Grignard is prepared, which is then reacted with 11.6 mL (158 mmol)
of acetone. Slightly yellow oil. Yield: 9.7 g (47%); R.sub.f value:
0.55 (ethyl acetate-petroleum ether (1:3)).
(b) N-[2-(3,4-difluorophenyl)-1,1-dimethylethyl]formamide
[0270] The target compound is obtained by a Ritter reaction with
4.0 g (21.5 mmol) of 1-(3,4-difluorophenyl)-2-methylpropan-2-ol.
Slightly yellow oil. Yield: 4.0 g (87%); mass spectrometry:
[M+H].sup.+=214.
(c) 2-(3,4-difluorophenyl)-1,1-dimethylethylamine
[0271] 4.00 g (18.5 mmol) of
N-[2-(3,4-difluorophenyl)-1,1-dimethylethyl]formamide is dissolved
in ethanol, combined with concentrated hydrochloric acid, and
refluxed overnight. The reaction solution is poured onto ice water,
made alkaline with sodium hydroxide, and extracted with
tert-butylmethyl ether. The organic phases are washed with water,
dried with sodium sulfate, and evaporated down. Yellow oil. Yield:
3.2 g (92%); mass spectrometry: [M+H].sup.+=186.
(d)
8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one
[0272] 357 mg (1 mmol) of
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 185 mg (1 mmol) of
2-(3,4-difluorophenyl)-1,1-dimethylethylamine are stirred for 30
minutes in 5 mL tetrahydrofuran at ambient temperature. It is
cooled to 0.degree. C. and, under an argon atmosphere, 1.5 mL of a
2 molar solution of lithium borohydride in tetrahydrofuran is added
dropwise. The mixture is stirred for 30 minutes at ambient
temperature, combined with 10 mL dichloromethane, and 3 mL water,
stirred for a further hour and then filtered through an
EXTRELUT.RTM. column. The eluate containing the ethanol amine is
freed from solvent. The residue is dissolved in methanol and
hydrogenated with palladium on charcoal (10%) as catalyst at 2.5
bar and ambient temperature. Then the catalyst is separated off and
the crude product is purified by chromatography. White solid.
Yield: 31 mg (6%, trifluoroethyl acetate); mass spectroscopy:
[M+H].sup.+=393.
[0273] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 18
8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one
##STR00022##
[0274] (a) 1-(2-chloro-4-fluorophenyl)-2-methylpropan-2-ol
[0275] Prepared from 20 g (97 mmol) of methyl
(2-chloro-4-fluorophenyl)acetate and 98 mL of a 3 molar solution of
methylmagnesium bromide analogously to the method for Example
8(a).
(b) N-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethyl]formamide
[0276] 7.5 g (37 mmol) of
1-(2-chloro-4-fluorophenyl)-2-methylpropan-2-ol was reacted and
worked up according to the method described for Example 10(b). The
oil thus obtained was chromatographed for further purification on a
short silica gel column (petroleum ether-ethyl acetate (9:1)). Oil.
Yield 7.4 g (87%); mass spectrometry: [M+H].sup.+=230/232.
(c) 2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamine
[0277] Reaction of 7.4 g (32 mmol) of
N-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethyl]-formamide as
described in the method for Example 17(c). Brown oil. Yield: 5.14 g
(79%); mass spectrometry: [M+H].sup.+=202/204.
(d)
8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one
[0278] 357 mg (1 mmol) of
6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one
and 202 mg (1 mmol) of
2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamine are reacted with
lithium borohydride analogously to the method for Example 10(d). To
debenzylate the ethanolamine thus obtained, it is dissolved in 3 mL
of dichloromethane and cooled to -78.degree. C. At this
temperature, 2 mL of a 1 molar solution of boron tribromide in
dichloromethane is added and the mixture is slowly allowed to come
up to ambient temperature. The reaction mixture is combined with 10
mL dichloromethane and 3 mL water and filtered through an
EXTRELUT.RTM. column. The eluate is freed from solvent and the
residue is purified by chromatography. White solid. Yield: 70 mg
(13%, trifluoroethyl acetate); mass spectroscopy:
[M+H].sup.+=409/11.
[0279] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 19
8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00023##
[0281] A solution of 300 mg (0.91 mmol) of
6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
200 mg (1.09 mmol) of 2-(4-chlorophenyl)-1,1-dimethylethylamine in
3 mL ethanol was combined with molecular sieve and stirred for 90
minutes at 80.degree. C. It was allowed to cool to ambient
temperature, 35 mg (0.91 mmol) of sodium borohydride was added, and
the mixture was stirred for 1 hour. Then the reaction mixture was
combined with sodium hydrogen carbonate solution and extracted with
ethyl acetate. The combined organic phases were freed from solvent
and the residue was chromatographed (eluent: hexane-ethyl
acetate-methanol), yielding 305 mg of ethanolamine. This was
dissolved in 3 mL dichloromethane and cooled to -78.degree. C.
under an argon atmosphere. 3 mL of a 1 molar solution of boron
tribromide in dichloromethane were added dropwise and the mixture
was stirred for one hour at -78.degree. C. and for 20 minutes at
ambient temperature. Then at -78.degree. C., 3 mL of concentrated
ammonia solution was added dropwise and the mixture was stirred for
5 minutes. The reaction mixture was combined with ammonium chloride
solution and extracted with ethyl acetate. The combined organic
phases were evaporated down and the residue was further purified by
chromatography (silica gel; eluent: dichloromethane-methanol+1%
ammonia). Beige-colored solid: 93 mg (26%); mass spectrometry:
[M+H].sup.+=391.
[0282] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 20
8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy--
4H-benzo[1,4]oxazin-3-one
##STR00024##
[0284] The preparation of the ethanolamine and debenzylation were
carried out as described in Example 19 from 300 mg (0.91 mmol) of
6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
250 mg (1.09 mmol) of 2-(4-bromophenyl)-1,1-dimethylethylamine.
Beige solid. Yield: 54 mg (14%); mass spectrometry:
[M+H].sup.+=435, 437.
[0285] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
EXAMPLE 21
8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00025##
[0286] 300 mg (0.91 mmol) of
6-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and
183 mg (1.09 mmol) of 2-(4-fluorophenyl)-1,1-dimethylethylamine
were dissolved in 3 mL of ethanol. Molecular sieve was added and
the mixture was heated to 80.degree. C. for 30 minutes. After
cooling to ambient temperature, 35 mg (0.91 mmol) of sodium
borohydride was added. The mixture was stirred for 1 hour at
ambient temperature, then sodium hydrogen carbonate solution was
added to the reaction mixture and it was extracted with ethyl
acetate. The organic phases were evaporated down and the residue
was chromatographed (eluent: hexane-ethyl acetate-methanol). The
ethanolamine thus obtained (223 mg) was dissolved in methanol to
cleave the benzyl protecting group and hydrogenated with 150 mg
palladium hydroxide as catalyst at ambient temperature and normal
pressure. The catalyst was separated off by filtering through
CELITE.RTM. filter agent, the filtrate was freed from solvent and
the residue was chromatographed (silica gel; eluent:
dichloromethane-methanol). Beige solid. Yield: 76 mg (22%); mass
spectrometry: [M+H].sup.+=375.
[0287] The (R)- and (S)-enantiomers of this example can be obtained
by separating the racemate analogously to current methods of
racemate cleaving known in the prior art.
[0288] The following compounds of Formula 1 according to the
invention may be obtained analogously to the synthesis examples
described above:
EXAMPLE 22
8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 23
8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 24
8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 25
8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 26
8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 27
8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 28
8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyet-
hyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 29
8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyet-
hyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 30
8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyeth-
yl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 31
8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 32
8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}--
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 33
8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6--
hydroxy-4H-benzo[1,4]oxazin-3-one;
EXAMPLE 34
8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one; and
EXAMPLE 35
8-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one
[0289] The compounds of general formula 1 may be used on their own
or combined with other active substances of formula 1 according to
the invention. The compounds of general formula 1 may optionally
also be combined with other pharmacologically active substances.
These include, in particular, anticholinergics, optionally other
betamimetics, antiallergic agents, PDE-IV inhibitors,
PAF-antagonists, leukotriene-antagonists, and corticosteroids and
combinations of these active substances.
[0290] Examples of preferred anticholinergics which may be
mentioned include ipratropium, oxitropium, and tiotropium salts.
Pharmaceutical combinations which contain the abovementioned salts,
in addition to the compounds of formula 1 according to the
invention, preferably contain those salts of ipratropium,
oxitropium, or tiotropium wherein the anion is selected from among
the chloride, bromide, iodide, sulfate, phosphate,
methanesulfonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate,
optionally in the form of one of the solvates or hydrates
thereof.
[0291] Within the scope of the present invention, the
corticosteroids which may optionally be used in conjunction with
the compounds of formula 1 may be compounds selected from among
flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, and
dexamethasone. In some cases, within the scope of the present
patent application, the term steroids is used on its own instead of
the word corticosteroids. Any reference to steroids within the
scope of the present invention includes a reference to salts or
derivatives which may be formed from the steroids. Examples of
possible salts or derivatives include: sodium salts,
sulfobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates, or furoates. In some
cases, the corticosteroids may also occur in the form of their
hydrates.
[0292] Within the scope of the present invention, the term dopamine
agonists, which may optionally be used in conjunction with the
compounds of formula 1, denotes compounds selected from among
bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride,
pergolide, pramipexol, roxindole, ropinirole, talipexole,
terguride, and viozan. Any reference to the abovementioned dopamine
agonists also includes, within the scope of the present invention,
a reference to any pharmacologically acceptable acid addition salts
and hydrates thereof which may exist. By the physiologically
acceptable acid addition salts thereof which may be formed by the
abovementioned dopamine agonists are meant, for example,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, acetic acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid, and maleic acid.
Examples of antiallergic agents which may be used according to the
invention as a combination with the compound of formula 1 include
epinastine, cetirizine, azelastine, fexofenadine, levocabastine,
loratadine, mizolastine, ketotifene, emedastine, dimetindene,
clemastine, bamipine, hexachloropheniramine, pheniramine,
doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,
promethazine, ebastine, desloratadine, and meclizine. Any reference
to the abovementioned antiallergic agents also includes, within the
scope of the present invention, a reference to any
pharmacologically acceptable acid addition salts thereof which may
exist.
[0293] Examples of PDE-IV inhibitors which may be used according to
the invention as a combination with the compound of formula 1
include compounds selected from among enprofylline, roflumilast,
ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591),
V-11294A, and AWD-12-281. Any reference to the abovementioned
PDE-IV inhibitors also includes, within the scope of the present
invention, a reference to any pharmacologically acceptable acid
addition salts thereof which may exist. By the physiologically
acceptable acid addition salts which may be formed by the
abovementioned PDE-IV inhibitors are meant, for example,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, acetic acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid, and maleic acid.
According to the invention, the salts selected from among the
acetate, hydrochloride, hydrobromide, sulfate, phosphate, and
methanesulfonate are preferred in this context.
[0294] Suitable preparations for administering the compounds of
formula 1 include, for example, tablets, capsules, suppositories,
solutions, powders, etc. The content of the pharmaceutically active
compound(s) should be in the range from 0.05 to 90 wt.-%,
preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable
tablets may be obtained, for example, by mixing the active
substance(s) with known excipients, for example inert diluents such
as calcium carbonate, calcium phosphate, or lactose, disintegrants
such as corn starch or alginic acid, binders such as starch or
gelatine, lubricants such as magnesium stearate or talc and/or
agents for delaying release, such as carboxymethyl cellulose,
cellulose acetate phthalate, or polyvinyl acetate. The tablets may
also comprise several layers.
[0295] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example, collidone or shellac, gum arabic,
talc, titanium dioxide, or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number or
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0296] Syrups or elixirs containing the active substances or
combinations thereof according to the invention may additionally
contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavor enhancer, e.g., a flavoring such as vanillin or
orange extract. They may also contain suspension adjuvants or
thickeners such as sodium carboxymethyl cellulose, wetting agents
such as, for example, condensation products of fatty alcohols with
ethylene oxide, or preservatives such as p-hydroxybenzoates.
[0297] Solutions are prepared in the usual way, e.g. with the
addition of isotonic agents, preservatives such as
p-hydroxybenzoates or stabilizers such as alkali metal salts of
ethylenediaminetetraacetic acid, optionally using emulsifiers
and/or dispersants, while if water is used as diluent, for example,
organic solvents may optionally be used as solubilizers or
dissolving aids, and the solutions may be transferred into
injection vials or ampoules or infusion bottles.
[0298] Capsules containing one or more active substances or
combinations of active substances may, for example, be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0299] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0300] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g., petroleum fractions), vegetable oils (e.g., groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or
glycerol), carriers such as, e.g., natural mineral powders (e.g.,
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.,
highly dispersed silicic acid and silicates), sugars (e.g., cane
sugar, lactose and glucose), emulsifiers (e.g., lignin, spent
sulfite liquors, methylcellulose, starch, and polyvinylpyrrolidone)
and lubricants (e.g., magnesium stearate, talc, stearic acid, and
sodium lauryl sulfate).
[0301] For oral use, the tablets may obviously contain, in addition
to the carriers specified, additives such as sodium citrate,
calcium carbonate, and dicalcium phosphate together with various
additional substances such as starch, preferably potato starch,
gelatin, and the like. Lubricants such as magnesium stearate,
sodium lauryl sulfate, and talc may also be used to produce the
tablets. In the case of aqueous suspensions, the active substances
may be combined with various flavor enhancers or colorings in
addition to the abovementioned excipients.
[0302] For administering the compounds of formula 1 for the
treatment of COPD, it is particularly preferred according to the
invention to use preparations or pharmaceutical formulations which
are suitable for inhalation. Inhalable preparations include
inhalable powders, propellant-containing metered-dose aerosols, or
propellant-free inhalable solutions. Within the scope of the
present invention, the term propellant-free inhalable solutions
also includes concentrates or sterile inhalable solutions ready for
use. The formulations which may be used within the scope of the
present invention are described in more detail in the next part of
the specification.
[0303] The inhalable powders which may be used according to the
invention may contain 1 either on its own or in admixture with
suitable physiologically acceptable excipients.
[0304] If the active substances 1 are present in admixture with
physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare these
inhalable powders according to the invention: monosaccharides
(e.g., glucose or arabinose), disaccharides (e.g., lactose,
saccharose, or maltose), oligo- and polysaccharides (e.g.,
dextrans), polyalcohols (e.g., sorbitol, mannitol, or xylitol),
salts (e.g., sodium chloride or calcium carbonate) or mixtures of
these excipients. Preferably, mono- or disaccharides are used,
while the use of lactose or glucose is preferred, particularly, but
not exclusively, in the form of their hydrates. For the purposes of
the invention, lactose is the particularly preferred excipient,
while lactose monohydrate is most particularly preferred.
[0305] Within the scope of the inhalable powders according to the
invention the excipients have a maximum average particle size of up
to 250 .mu.m, preferably between 10 .mu.m and 150 .mu.m, most
preferably between 15 .mu.m and 80 .mu.m. It may sometimes seem
appropriate to add finer excipient fractions with an average
particle size of 1 .mu.m to 9 .mu.m to the excipient mentioned
above. These finer excipients are also selected from the group of
possible excipients listed hereinbefore. Finally, in order to
prepare the inhalable powders according to the invention,
micronised active substance 1, preferably with an average particle
size of 0.5 .mu.m to 10 .mu.m, more preferably from 1 .mu.m to 5
.mu.m, is added to the excipient mixture. Processes for producing
the inhalable powders according to the invention by grinding and
micronizing and finally mixing the ingredients together are known
from the prior art.
[0306] The inhalable powders according to the invention may be
administered using inhalers known from the prior art.
[0307] The inhalation aerosols containing propellant gas according
to the invention may contain the compounds 1 dissolved in the
propellant gas or in dispersed form. The compounds 1 may be
contained in separate formulations or in a common formulation, in
which the compounds 1 are either both dissolved, both dispersed or
in each case only one component is dissolved and the other is
dispersed. The propellant gases which may be used to prepare the
inhalation aerosols are known from the prior art. Suitable
propellant gases are selected from among hydrocarbons such as
n-propane, n-butane, or isobutane and halohydrocarbons such as
fluorinated derivatives of methane, ethane, propane, butane,
cyclopropane, or cyclobutane. The abovementioned propellant gases
may be used on their own or mixed together. Particularly preferred
propellant gases are halogenated alkane derivatives selected from
TG134a and TG227 and mixtures thereof.
[0308] The propellant-driven inhalation aerosols may also contain
other ingredients such as co-solvents, stabilizers, surfactants,
antioxidants, lubricants, and pH adjusters. All these ingredients
are known in the art.
[0309] The propellant-driven inhalation aerosols according to the
invention mentioned above may be administered using inhalers known
in the art, such as metered dose inhalers (MDIs).
[0310] Moreover, the active substances 1 according to the invention
may be administered in the form of propellant-free inhalable
solutions and suspensions. The solvent used may be an aqueous or
alcoholic, preferably an ethanolic solution. The solvent may be
water on its own or a mixture of water and ethanol. The relative
proportion of ethanol compared with water is not limited but the
maximum is preferably up to 70 percent by volume, more particularly
up to 60 percent by volume and most preferably up to 30 percent by
volume. The remainder of the volume is made up of water. The
solutions or suspensions containing 1 are adjusted to a pH of 2 to
7, preferably 2 to 5, using suitable acids. The pH may be adjusted
using acids selected from inorganic or organic acids. Examples of
particularly suitable inorganic acids include hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric
acid. Examples of particularly suitable organic acids include
ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,
succinic acid, fumaric acid, acetic acid, formic acid, and/or
propionic acid etc. Preferred inorganic acids are hydrochloric and
sulfuric acids. It is also possible to use the acids which have
already formed an acid addition salt with one of the active
substances. Of the organic acids, ascorbic acid, fumaric acid and
citric acid are preferred. If desired, mixtures of the above acids
may be used, particularly in the case of acids which have other
properties in addition to their acidifying qualities, e.g., as
flavorings, antioxidants or complexing agents, such as citric acid
or ascorbic acid, for example. According to the invention, it is
particularly preferred to use hydrochloric acid to adjust the
pH.
[0311] If desired, the addition of edetic acid (EDTA) or one of the
known salts thereof, sodium edetate, as stabilizer or complexing
agent may be omitted in these formulations. Other embodiments may
contain this compound or these compounds. In a preferred embodiment
the content based on sodium edetate is less than 100 mg/100 mL,
preferably less than 50 mg/100 mL, more preferably less than 20
mg/100 mL. Generally, inhalable solutions in which the content of
sodium edetate is from 0 to 10 mg/100 mL are preferred.
[0312] Co-solvents and/or other excipients may be added to the
propellant-free inhalable solutions. Preferred co-solvents are
those which contain hydroxyl groups or other polar groups, e.g.,
alcohols, particularly isopropyl alcohol, glycols, particularly
propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycol
ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty
acid esters. The terms excipients and additives in this context
denote any pharmacologically acceptable substance which is not an
active substance but which can be formulated with the active
substance or substances in the physiologically suitable solvent in
order to improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilizers, complexing agents,
antioxidants and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavorings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride as isotonic agents.
[0313] The preferred excipients include antioxidants such as
ascorbic acid, for example, provided that it has not already been
used to adjust the pH, vitamin A, vitamin E, tocopherols, and
similar vitamins and provitamins occurring in the human body.
[0314] Preservatives may be used to protect the formulation from
contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride, or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art. The
preservatives mentioned above are preferably present in
concentrations of up to 50 mg/100 mL, more preferably between 5 and
20 mg/100 mL.
[0315] Preferred formulations contain, in addition to the solvent
water and the active substance 1, only benzalkonium chloride and
sodium edetate. In another preferred embodiment, no sodium edetate
is present.
[0316] The dosage of the compounds according to the invention is
naturally highly dependent on the method of administration and the
complaint which is being treated. When administered by inhalation,
the compounds of formula 1 are characterized by a high potency even
at doses in the .mu.g range. The compounds of formula 1 may also be
used effectively above the .mu.g range. The dosage may then be in
the gram range, for example.
[0317] In another aspect, the present invention relates to the
above-mentioned pharmaceutical formulations as such which are
characterized in that they contain a compound of formula 1,
particularly the above-mentioned pharmaceutical formulations which
can be administered by inhalation.
[0318] The following examples of formulations illustrate the
present invention without restricting its scope:
Examples of Pharmaceutical Formulations
TABLE-US-00001 [0319] A. Tablets per tablet active substance 1 100
mg lactose 140 mg maize starch 240 mg polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg 500 mg
[0320] The finely ground active substance, lactose, and some of the
maize starch are mixed together. The mixture is screened, then
moistened with a solution of polyvinylpyrrolidone in water,
kneaded, wet granulated, and dried. The granules, the remaining
maize starch and the magnesium stearate are screened and mixed
together. The mixture is pressed into tablets of suitable shape and
size.
TABLE-US-00002 B. Tablets per tablet active substance 1 80 mg
lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg
magnesium stearate 2 mg 400 mg
[0321] The finely ground active substance, some of the corn starch,
lactose, microcrystalline cellulose, and polyvinylpyrrolidone are
mixed together, the mixture is screened and worked with the
remaining corn starch and water to form a granulate which is dried
and screened. The sodium carboxymethyl starch and the magnesium
stearate are added and mixed in and the mixture is compressed to
form tablets of a suitable size.
TABLE-US-00003 C. Ampoule Solution active substance 1 50 mg sodium
chloride 50 mg water for inj. 5 mL
[0322] The active substance is dissolved in water at its own pH or
optionally at pH 5.5 to 6.5 and sodium chloride is added to make
the solution isotonic. The resulting solution is filtered to remove
pyrogens and the filtrate is transferred under aseptic conditions
into ampoules which are then sterilized and heat-sealed. The
ampoules contain 5 mg, 25 mg, and 50 mg of active substance.
TABLE-US-00004 D. Metering Aerosol active substance 1 0.005
sorbitan trioleate 0.1 monofluorotrichloromethane and TG134a:TG227
(2:1) to 100
[0323] The suspension is transferred into a conventional aerosol
container with metering valve. Preferably 50 .mu.l suspension are
released on each actuation. The active substance may also be
released in higher doses if desired (e.g., 0.02 wt.-%).
TABLE-US-00005 E. Solutions (in mg/100 mL) active substance 1 333.3
mg benzalkonium chloride 10.0 mg EDTA 50.0 mg HCl (1 N) to pH
3.4
[0324] This solution can be prepared in the usual way.
TABLE-US-00006 F. Inhalable Powder active substance 1 12 .mu.g
lactose monohydrate to 25 mg
[0325] The inhalable powder is prepared in the usual way by mixing
the individual ingredients.
* * * * *