AEROSOL FORMULATION FOR INHALATION OF BETA AGONISTS

FORMULATION D'AEROSOL POUR L'INHALATION DE BETA-AGONISTES

English Abstract

The invention relates to a propellant-free aerosol formulation for inhalation,
which
comprises one or more compounds of general formula (1), wherein the groups R1,
R2,
R3 and X- are defined as in the claims and in the description.

French Abstract

L'invention concerne une formulation d'aérosol sans gaz propulseur, pour inhalation, qui contient un ou plusieurs composés de formule générale (1) dans laquelle R1, R2, R3 et X- ont la signification indiquée dans les revendications et la description.

Claims

61
CLAIMS:
1. Pharmaceutical formulation containing as sole active substance one
or more
compounds of general formula 1
<IMG>
wherein
R1 denotes hydrogen, methyl, ethyl, fluorine or chlorine;
R2 denotes hydrogen, methyl, ethyl, fluorine or chlorine;
R3 denotes hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluorine,
chlorine, bromine, -O-CH2-COOH, -O-CH2-COOmethyl, -O-CH2-COOethyl, -O-CH2-
CH2COOH, -O-CH2-CH2COOmethyl, -O-CH2-CH2COOethyl, -O-CH2-CH2-CH2COOH,
-O-CH2-CH2-CH2COOmethyl or -O-CH2-CH2-CH2COOethyl;
X- denotes an anion with a single negative charge,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates or solvates, at least one pharmacologically acceptable
acid, optionally
other pharmacologically acceptable excipients and/or complexing agents and, as
solvent,
water, ethanol or a mixture of water and ethanol, and wherein the content of
the free base of 1
is about 0.75 to 200 mg per 100 ml solution.

62
2. Pharmaceutical formulation according to claim 1, which contains one or
more
compounds of formula 1, wherein
R1 denotes hydrogen or methyl;
R2 denotes hydrogen or methyl;
R3 denotes methoxy, ethoxy, fluorine, chlorine, bromine, -O-CH2-COOH,
-O-CH2-COOmethyl or -O-CH2-COOethyl;
X- denotes an anion with a single negative charge,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates or solvates.
3. Pharmaceutical formulation according to claim 1 or 2, which contains
one or
more compounds of formula 1, wherein X- denotes an anion with a single
negative charge
selected from the group consisting of chloride, bromide, iodide, sulphate,
phosphate,
methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate,
trifluoroacetate,
fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.
4. Pharmaceutical formulation according to claim 1, which contains one or
more
compounds of formula 1, wherein
R1 and R2 denote hydrogen;
R3 denotes methoxy, fluorine, chlorine or -O-CH2-COOH;
X- denotes an anion with a single negative charge selected from the group
consisting of chloride, bromide, sulphate, methanesulphonate, maleate,
acetate, benzoate,
citrate, salicylate, trifluoroacetate, fumarate, tartrate and succinate;
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates or solvates.

63
5. Pharmaceutical formulation containing as sole active substance a
compound of
formula 1a
<IMG>
wherein
HX denotes hydrochloride, hydrobromide, hydrosulphate,
hydromethanesulphonate, hydromaleate, hydroacetate, hydrobenzoate,
hydrocitrate,
hydrosalicylate, hydrotrifluoroacetate, hydrofumarate, hydrotartrate or
hydrosuccinate;
or a tautomer, enantiomer, mixtures of enantiomers, racemate or solvate, at
least one pharmacologically acceptable acid, optionally other
pharmacologically acceptable
excipients and/or complexing agents and, as solvent, water, ethanol or a
mixture of water and
ethanol, and wherein the content of the free base of 1 is about 0.75 to 200 mg
per 100 ml
solution.
6. Pharmaceutical formulation according to claim 5, wherein HX is
hydrochloride.
7. Pharmaceutical formulation according to claim 5 or 6, wherein the
compound
of formula 1a is the R-enantiomer.
8. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6 or 7,
wherein the
pharmacologically acceptable acid is selected from the inorganic acids
hydrochloric acid,
hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid or is
selected from the
organic acids ascorbic acid, citric acid, malic acid, tartaric acid, maleic
acid, succinic acid,
fumaric acid, acetic acid, formic acid and propionic acid.

64
9. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7 or 8,
having a
pH of 2.5 to 6.5.
10. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7, 8 or
9, which
contains benzalkonium chloride as excipient.
11. Pharmaceutical formulation according to claim 10, wherein the content
of
benzalkonium chloride is 1 to 50 mg per 100 ml solution.
12. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7, 8,
9, 10 or 11,
which contains a complexing agent as a further ingredient.
13. Pharmaceutical formulation according to claim 12, wherein the content
of
complexing agent is 1 to 50 mg per 100 ml solution.
14. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11,
12 or 13, which contains pure water as solvent.
15. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11,
12 or 13, which contains pure ethanol as solvent.
16. Pharmaceutical formulation according to claim 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 12
or 13, which contains a mixture of water and ethanol as solvent.
17. Pharmaceutical formulation according to claim 16, which contains as
solvent a
mixture of water and ethanol, wherein the percentage proportion of ethanol by
mass is in the
range from 5 to 99 % ethanol.
18. Pharmaceutical formulation according to claim 5, 6 or 7, which contains
citric
acid as the pharmacologically acceptable acid and purified water as the
solvent, and which
further contains benzalkonium chloride and disodium edetate dihydrate.
19. Pharmaceutical formulation containing as sole active substance a free
base of
formula 1'

65
<IMG>
wherein the groups R1, R2 and R3 may have the meanings given in claim 1, 2 or
4, optionally
in the form of a tautomer, enantiomer, mixtures of enantiomers, racemate or
solvate, at least
one pharmacologically acceptable acid, optionally other pharmacologically
acceptable
excipients and/or complexing agents and, as solvent, water, ethanol or a
mixture of water and
ethanol, and wherein the content of the free base of 1 is about 0.75 to 200 mg
per 100 ml
solution.
20. Use of a pharmaceutical formulation as defined in claim 1, 2, 3, 4, 5,
6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, for preparing a pharmaceutical
composition for the
treatment of a respiratory complaint.
21. Inhalation kit consisting of a pharmaceutical formulation as defined in
claim 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, and an
inhaler suitable for
nebulising this pharmaceutical formulation.
22. Inhalation kit according to claim 21, wherein the inhaler is a
Respimat®.

Description

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87420pct
Aerosol formulation for Inhalation of Beta Agonists
The present invention relates to a propellant-free aerosol formulation which
one or more
compounds of general formula 1
- +
Co
0 OH H H
R1
\ /
____ HN 40 N _
X
Me Me 1110
R3
R2
OH
1
wherein the groups R1, R2, R3 and X- may have the meanings given in the claims
and in
the specification, for inhalation.
Background to the invention
Betamimetics (B-adrenergic substances) are known from the prior art. For
example
reference may be made in this respect to the disclosure of US 4,460,581, which
proposes
betamimetics for the treatment of a range of diseases.
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. 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
regularly taking the drug at certain times of the day.

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The aim of the present invention is therefore to provide medicament
formulations for
inhalation which on the one hand confer a therapeutic benefit in the treatment
of
respiratory complaints and are also characterised by a longer duration of
activity and can
thus be used to prepare pharmaceutical compositions with a longer duration of
activity.
Detailed description of the invention
To solve the problems mentioned above the present invention proposes the
following
medicament formulations.
The medicament formulations according to the invention are propellant-free
medicament
formulations, containing as sole active substance one or more compounds of
general
formula 1
¨ +
0
0 OH H H
R1
\ /
HN le N _
X
Me Me R2 119
R3
OH
________________________________________________ 1
wherein
RI denotes hydrogen, CI-Ca-alkyl, Ci-Ca-alkoxy or halogen;
R2 denotes hydrogen, CI-Ca-alkyl, CI-Ca-alkoxy or halogen;
R3 denotes hydrogen, CI-Ca-alkyl, CI-Ca-alkoxy, halogen, OH,
-0-C1-Ca-alkylene-COOH or -0-C1-C4-alkylene-000-C1-C4-alkyl,
X- denotes an anion with a single negative charge, preferably an anion
with a
single negative charge selected from the group consisting of chloride,
bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,

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3
acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate,
oxalate, succinate, benzoate and p-toluenesulphonate,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates
or solvates,
at least one pharmacologically acceptable acid, optionally other
pharmacologically
acceptable excipients and/or complexing agents and, as solvent, water, ethanol
or a mixture
of water and ethanol.
Preferred are pharmaceutical formulations which contain compounds of general
formula!,
wherein
RI denotes hydrogen, methyl, ethyl, fluorine or chlorine;
R2 denotes hydrogen, methyl, ethyl, fluorine or chlorine;
R3 denotes hydrogen, methyl, ethyl, propyl, OH, methoxy, ethoxy,
fluorine, chlorine,
bromine, -0-CH2-COOH, -0-CH2-COOmethyl or -0-CH2-COOethyl, -0-CH2-
CH2COOH, -0-CH2-CH2COOmethyl or -0-CH2-CH2C0Oethyl, -0-CH2-CH2-
CH2COOH, -0-CH2-CH2-CH2COOmethyl or -0-CH2-CH2-CH2C0Oethyl;
denotes an anion with a single negative charge, preferably an anion with a
single
negative charge selected from the group consisting of chloride, bromide,
iodide,
sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate,
citrate,
salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, benzoate
and p-
toluenesulphonate,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates
or solvates.
Preferred are pharmaceutical formulations which contain compounds of general
formula!
wherein
RI denotes hydrogen or methyl, preferably hydrogen;
R2 denotes hydrogen or methyl, preferably hydrogen;
R3 denotes methyl, OH, methoxy, fluorine,.chlorine, bromine, -0-CH2-
COOH or
-0-CH2-COOethyl, preferably methoxy, fluorine, chlorine or -0-CH2-COOH;

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denotes an anion with a single negative charge selected from the group
consisting
of chloride, bromide, sulphate, methanesulphonate, maleate, acetate, benzoate,
citrate, salicylate, trifluoroacetate, fumarate, tartrate and succinate;
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates
or solvates.
Also preferred are pharmaceutical formulations which contain compounds of
general
formula 1 wherein
R3 denotes methoxy, ethoxy, fluorine, chlorine, bromine, -0-CH2-COOH,
-0-CH2-COOmethyl or -0-CH2-COOethyl;
and RI, R2 and X- may have the meanings given above,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates
or solvates.
Also preferred are pharmaceutical formulations which contain compounds of
general
formula! wherein
RI and R2 denote hydrogen;
R3 denotes OH, fluorine, chlorine, methoxy, ethoxy,-0-CH2-COOH,
preferably
OH, fluorine, chlorine, ethoxy or methoxy, and
X- may have one of the meanings given above,
optionally in the form of their tautomers, enantiomers, mixtures of
enantiomers, racemates
or solvates.
Also preferred are pharmaceutical formulations which contain compounds of
general
formula! which are selected from the following, wherein HX denotes an acid,
wherein )(-
may have one of the meanings given above:
6-hydroxy-8- {1 -hydroxy-242-(4-methoxy-pheny1)-1,1 -dimethyl -ethylamino] -
ethyl} -4H-benzo [1,4]oxazin-3-one;
6-hydroxy-8- {1-hydroxy-2-[2-(4-phenoxyethyl-acetate )-1,1-dimethyl-
ethylamino]-
ethy11-4H-benzo[1,4]oxazin-3-one;

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- 6-hydroxy-8- {1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1 ,1-dimethyl-
ethylamino]-
ethyl} -4H-benzo[1,4] oxazin-3 -one;
- 8- {2- [1,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethylamino]-1-hydrox
y-ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 6-hydroxy-8- {1-hydroxy-2-[2-(4-hydroxy-pheny1)-1,1-dimethyl-ethylamino] -
ethyl} -4H-benzo[1,4]oxazin-3-one;
- 6-hydrox y-8- {1-hydrox y-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-
ethyl amino]-
ethyl 1 -4H-benzo[1,4]oxazin-3 -one;
- 8- {242-(4-ethyl-pheny1)-1,1-dimethyl-ethylamino1-1-hydroxy-ethyl} -
6-hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(2,4-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino] -1-hydroxy-ethyl }
-6-
hydroxy-4H-benzo [1,4]oxazin-3-one;
- 8- {242-(4-ethoxy-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -
6-hydroxy-
4H-benzo[1,4]oxazin-3 -one;
- 8- {242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -6-
hydroxy-4H-benzo [1,4]oxazin-3-one;
- 4-(4- {2- [2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-b enzo
[1,4]oxazin-8-y1)-
ethylamino] -2-methyl-propyll-phenoxy)-butyric acid;
- 8- {242-(3,4-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl} -
6-
hydroxy-4H-benzo[1,4]oxazin-3 -one;
- 8- {242-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3 -one;
8- {242-(4-chloro-pheny1)-1,1-dimethyl-ethylamino] -1-hydroxy-ethy11-6-hydroxy-
4H-benzo[1,4]oxazin-3 -one;

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- 8- {242-(4-bromo-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl} -
6-hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8- {2- [2-(4-fluoro-pheny1)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethy11-6-hydroxy-
4H-benzo[1,4]oxazin-3 -one;
- 8- {242-(4-fluoro-3 -methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydrox y-
ethy1}-
6-hydroxy-4H-benzo[1,4] oxazin-3-one;
- 8- {2-[2-(4-fluoro-2 ,6-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-chloro-2-methyl-pheny1)-1,1-dimethyl-ethylamino] -1-
hydroxy-ethy11-6-
hydroxy-4H-benzo[1,41oxazin-3-one;
- 8- {2-[2-(4-chloro-3-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl) -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-chloro-2-fluoro-pheny1)-1,1-dimethyl-ethylamino1-1-
hydroxy-ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl 1 -6-
hydroxy-4H-benzo [1,4]oxazin-3 -one;
- 8- {242-(2,6-difluoro-4-methoxy-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl } -6-hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8-1242-(2,5-difluoro-4-methoxy-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl} -6-hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- (242-(4-fluoro-3 ,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl} -6-hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3,5-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl) -
6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-chloro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl) -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3,4,5-tri fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -6-
hydroxy-4H-b enzo[1,4]oxazin-3-one;
8- {242-(3-methyl-pheny1)-1,1-dimethyl-ethyl amino] -1-hydroxy-ethyl } -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one and

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7
8- {242-(3,4-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one,
in each case in the form of an acid addition salt with an acid HX, wherein X-
may have one
of the meanings given above, as well as optionally in the form of their
tautomers,
enantiomers, mixtures of enantiomers, racemates or solvates.
Each of the above formulations also contain at least one pharmacologically
acceptable
acid, optionally other pharmacologically acceptable excipients and/or
complexing agents
and, as solvent, water, ethanol or a mixture of water and ethanol, and wherein
the content
of the free base 1 is about 0.75 to 200 mg per 100 ml solution.
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 iso-propyl, butyl includes iso-
butyl, sec.butyl
and tert.-butyl, etc.
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.
Unless otherwise stated, the term alkyloxy groups (or -0-alkyl or alkoxy
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 Me0-, Et0-, Prop0- 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 iso-propyloxy,
butyloxy

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7a
includes iso-butyloxy, 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.

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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.
The medicament formulations according to the invention contain as solvent pure
water,
pure ethanol or mixtures of ethanol and water. If ethanol-water mixtures are
used, the
percentage by mass of ethanol in these mixtures is preferably in the range
between 5 and
99 % ethanol, particularly preferably in the range from 10 to 96 % ethanol.
Most
particularly preferred medicament formulations for the purposes of the present
invention
contain as solvent pure water, pure ethanol or ethanol-water mixtures
containing between
50 and 92 %, particularly preferably between 69 and 91% ethanol.
If desired, other co-solvents may be used in addition to ethanol and water.
Preferably,
however, no other solvent is used according to the invention.
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 US 4460581, to the entire contents of which reference is made at this
point.
The compounds of formula 1 may optionally be present in the medicament
formulations
according to the invention in the form of their tautomers. By tautomerism is
meant the
occurrence of isomeric compounds which are formed by the shifting of a or TE
bonds and
may be present in equilibrium. Examples of possible tautomeric forms of the
compounds
of formula 1 are
HO
0 OH H H
Ri
N
Me Me X
R3
R2
OH
Or

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0 OH
Ri
H-N
Me Me le X
R3
R2
OH
In another aspect the present invention relates to pharmaceutical formulations
which
contain the above-mentioned compounds of formula 1 in the form of the
individual optical
isomers, mixtures of individual enantiomers or racemates. Particularly
preferred are
medicament formulations which contain the above-mentioned compounds of formula
1 in
the form of the enantiomerically pure compounds, while the R-enantiomers of
the
compounds of formula 1 according to the invention are of particular
importance. These R-
enantiomers may be represented by general formula R-1
0,
0 OH H H
R
HN
Me Me X119
R3
R2
OH
wherein the groups R1, R2, R3 and X- may have the meanings given above.
In another aspect the present invention relates to the use of the
pharmaceutical
formulations according to the invention for preparing a pharmaceutical
composition for the
treatment of respiratory complaints selected from the group comprising
obstructive
pulmonary diseases of various origins, pulmonary emphysema of various origins,
restrictive pulmonary diseases, interstitial pulmonary diseases, cystic
fibrosis, bronchitis

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PCT/EP2005/005028
of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome)
and all
forms of pulmonary oedema.
Preferably the medicament formulations according to the invention are used as
specified
above for preparing a pharmaceutical composition for the treatment of
obstructive
pulmonary diseases selected from among bronchial asthma, paediatric asthma,
severe
asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive
pulmonary disease), while it is particularly preferable according to the
invention to use
them for preparing a pharmaceutical composition for the treatment of bronchial
asthma or
COPD.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of pulmonary
emphysema which
has its origins in COPD (chronic obstructive pulmonary disease) or cd-
proteinase inhibitor
deficiency.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of restrictive
pulmonary diseases
selected from among allergic alveolitis, restrictive pulmonary diseases
triggered by work-
related noxious substances, such as asbestosis or silicosis, and restriction
caused by lung
tumours, such as for example lymphangiosis carcinomatosa, bronchoalveolar
carcinoma
and lymphomas.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of interstitial
pulmonary diseases
selected from among pneumonia caused by infections, such as for example
infection by
viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis
caused by
various factors, such as for example aspiration and left heart insufficiency,
radiation-
induced pneumonitis or fibrosis, collagenoses, such as for example lupus
erythematodes,
systemic scleroderma or sarcoidosis, granulomatoses, such as for example
Boeck's disease,
idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

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It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of cystic fibrosis or
mucoviscidosis.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of bronchitis, such
as for
example bronchitis caused by bacterial or viral infection, allergic bronchitis
and toxic
bronchitis.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of bronchiectasis.
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of ARDS (adult
respiratory
distress syndrome).
It is also preferable to use the medicament formulations according to the
invention for
preparing a pharmaceutical composition for the treatment of pulmonary oedema,
for
example toxic pulmonary oedema after aspiration or inhalation of toxic
substances and
foreign substances.
Most preferably, the present invention relates to the use of the
pharmaceutical formulations
according to the invention for preparing a pharmaceutical composition for the
treatment of
asthma or COPD. Also of particular importance is the above-mentioned use for
preparing a
pharmaceutical composition for once-a-day treatment of inflammatory and
obstructive
respiratory complaints, particularly for the once-a-day treatment of asthma or
COPD.
Moreover the present invention relates to a process for the treatment of the
above-
mentioned diseases, characterised in that one or more of the above-mentioned

CA 02564379 2006-10-26
WO 2005/110421 12 PCT/EP2005/005028
medicament formulations according to the invention are administered in
therapeutically
effective amounts.
The present invention relates to liquid active substance formulations of these
compounds
which can be administered by inhalation; the liquid formulations according to
the invention
have to meet high quality standards. The formulations according to the
invention may be
inhaled by oral or nasal route. To achieve an optimum distribution of the
active substances
in the lung it makes sense to use a liquid formulation without propellant
gases administered
using suitable inhalers. A formulation of this kind may be inhaled both by
oral route and
by nasal route. Those inhalers which are capable of nebulising a small amount
of a liquid
formulation in the dosage needed for therapeutic purposes within a few seconds
into an
aerosol suitable for therapeutic inhalation are particularly suitable. Within
the scope of the
invention, preferred nebulisers are those in which an amount of less than 100
microlitres,
preferably less than 50 microlitres, most preferably less than 25 microlitres
of active
substance solution can be nebulised preferably in one puff or two puffs to
form an aerosol
having an average particle size of less than 20 microns, preferably less than
10 microns, so
that the inhalable part of the aerosol already corresponds to the
therapeutically effective
quantity.
An apparatus of this kind for the propellant-free administration of a metered
amount of a
liquid pharmaceutical composition for inhalation is described in detail for
example in
International Patent Application WO 91/14468 "Atomizing Device and Methods"
and also
in WO 97/12687, cf. Figures 6a and 6b and the accompanying description. In a
nebuliser of
this kind a pharmaceutical solution is converted by means of a high pressure
of up to 500
bar into an aerosol destined for the lungs, which is sprayed. Within the scope
of the present
specification reference is expressly made to the entire contents of the
literature mentioned
above.
In inhalers of this kind the formulations of solutions are stored in a
reservoir. It is essential
that the active substance formulations used are sufficiently stable when
stored and at the
same time are such that they can be administered directly, if possible without
any further

CA 02564379 2006-10-26
WO 2005/110421 13 PCT/EP2005/005028
handling, in accordance with their medical purpose. Moreover, they must not
contain any
ingredients which might interact with the inhaler in such a way as to damage
the inhaler or
the pharmaceutical quality of the solution or of the aerosol produced.
To nebulise the solution a special nozzle is used as described for example in
WO 94/07607
or WO 99/16530. Reference is expressly made here to both these publications.
The aim of the invention is to provide an aqueous, ethanolic or aqueous-
ethanolic
formulation of the compound of formula 1 which meets the high standards
required to
ensure optimum nebulisation of a solution using the inhalers mentioned above.
The active
substance formulations according to the invention must be of sufficiently high
pharmaceutical quality, i.e. they should be pharmaceutically stable over a
storage time of
some years, preferably at least one year, more preferably two years. These
propellant-free
formulations of solutions must also be capable of being nebulised by means of
an inhaler
under pressure, while the composition delivered in the aerosol produced is
within a
specified range.
Within the scope of the present invention, those compounds of formula 1 are
preferably
used wherein X" is selected from among the chloride, maleate, salicylate,
fumarate or
succinate, optionally in the form of the hydrates and solvates thereof.
Particularly preferred, within the scope of the present invention, are the
formulations which
contain the compound of formula 1 wherein X denotes chloride.
References to the compound of formula! always include within the scope of the
present
invention all possible amorphous and crystalline modifications of this
compound.
References to the compound of formula 1 also include within the scope of the
present
invention all the possible solvates and hydrates which may be formed from this
compound.
Any reference to the compound l' within the scope of the present invention is
to be
regarded as a reference to the pharmacologically active free base of the
following formula

CA 02564379 2012-08-07
25771-1261
14
C)0 OH
R1
HN
Me Me 1110
R3
R2
OH 1',
contained in the salts 1 wherein the groups RI, R2 and R3 may have the
meanings given
above.
In another aspect the present invention relates to medicament formulations
containing as
the sole active substance a free base of formula 1' wherein the groups RI, R2
and R3
may have the meanings given above, optionally in the form of their tautomers,
enantiomers, mixtures of enantiomers, racemates or solvates, at least one
pharmacologically acceptable acid, optionally other pharmacologically
acceptable
excipients and/or complexing agents and, as solvent, water, ethanol or a
mixture of water
and ethanol, and wherein the content of the free base of! is about 0.75 to 200
mg
per 100 ml solution.
According to the invention the formulation preferably contains only one
compound of
formula 1. However, the formulation may also contain a mixture of different
salts of
formula 1. If the medicament formulations according to the invention contain
different
salts of formula 1 the preferred formulations according to the invention are
those wherein
the various salts denote different salts of the same free base of formula 1'.
Formulations
which contain active substances other than those of formula 1 are not included
in the
invention.
The concentration of the compound of formula 1 based on the proportion of
pharmacologically active free base l' in the pharmaceutical preparation
according to the
invention is about 0.1 to 1600 mg per 100 ml, according to the invention,
preferably about
0.5 to 1000 mg per 100 ml, particularly preferably 0.75 to 200 mg per 100 ml.

CA 02564379 2006-10-26
WO 2005/110421 15 PCT/EP2005/005028
Particularly preferably, 100 ml of the formulations according to the invention
contain
about 1 to about 100 mg of 1'.
The pH of the formulation according to the invention is preferably between 2.0
and 6.5,
preferably between 2.2 and 5.0, more preferably between about 3.0 and 4.5.
The pH is adjusted by the addition of pharmacologically acceptable acids.
Pharmacologically acceptable inorganic acids or organic acids may be used for
this
purpose. Examples of preferred inorganic acids are selected from the group
consisting of
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and
phosphoric acid.
Examples of particularly suitable organic acids are selected from the group
consisting of
ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic
acid, fumaric acid,
acetic acid, formic acid and propionic acid. Preferred inorganic acids are
hydrochloric acid
and sulphuric acid, of which hydrochloric acid is particularly preferred
according to the
invention. Of the organic acids, ascorbic acid, fumaric acid and citric acid
are preferred. If
desired, mixtures of the abovementioned acids may also be used, particularly
in the case of
acids which have other properties in addition to their acidifying properties,
e.g. those
which act as flavourings or antioxidants, such as for example citric acid or
ascorbic acid.
If desired, pharmacologically acceptable bases may be used to titrate the pH
precisely.
Suitable bases include for example alkali metal hydroxides and alkali metal
carbonates.
The preferred alkali metal ion is sodium. If bases of this kind are used, care
must be taken
to ensure that the resulting salts, which are then contained in the finished
pharmaceutical
formulation, are pharmacologically compatible with the abovementioned acid.
The formulations according to the invention may contain complexing agents as
other
ingredients. By complexing agents are meant within the scope of the present
invention
molecules which are capable of entering into complex bonds. Preferably, these
compounds
should have the effect of complexing cations, most preferably metal cations.
The
formulations according to the invention preferably contain editic acid (EDTA)
or one of
the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium

CA 02564379 2006-10-26
WO 2005/110421 16 PCT/EP2005/005028
edetate), as complexing agent. Preferably, sodium edetate is used, optionally
in the form
of its hydrates, more preferably in the form of its dihydrate. If complexing
agents are used
within the formulations according to the invention, their content is
preferably in the range
from 1 to 50 mg per 100 ml, more preferably in the range from 2 to 15 mg per
100 ml of
the formulation according to the invention. Preferably, the formulations
according to the
invention contain a complexing agent in an amount of about 4 to 12 mg per 100
ml, more
preferably about 10 mg per 100 ml of the formulation according to the
invention.
The remarks made concerning sodium edetate also apply analogously to other
possible
additives which are comparable to EDTA or the salts thereof, which have
complexing
properties and can be used instead of them, such as for example
nitrilotriacetic acid and the
salts thereof.
Other pharmacologically acceptable excipients may also be added to the
formulation
according to the invention. By adjuvants and additives are meant, in this
context, any
pharmacologically acceptable and therapeutically useful substance which is not
an active
substance, but can be formulated together with the active substance in the
pharmacologically suitable solvent, in order to improve the qualities of the
active
substance formulation. Preferably, these substances have no pharmacological
effects or no
appreciable or at least no undesirable pharmacological effects in the context
of the desired
therapy. The adjuvants and additives include, for example, stabilisers,
antioxidants and/or
preservatives which prolong the shelf life of the finished pharmaceutical
formulation, as
well as flavourings, vitamins and/or other additives known in the art. The
additives also
include pharmacologically acceptable salts such as sodium chloride, for
example.
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 or provitamins occurring in the human body.
Preservatives can be added to protect the formulation from contamination with
pathogenic
bacteria. Suitable preservatives are those known from the prior art,
particularly

CA 02564379 2006-10-26
WO 2005/110421 17
PCT/EP2005/005028
benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in
the
concentration known from the prior art. Preferably, benzalkonium chloride is
added to the
formulation according to the invention. The amount of benzalkonium chloride is
between 1
mg and 50 mg per 100 ml of formulation, preferably about 2 to 15 mg per 100
ml, more
preferably about 3 to 12 mg per 100 ml of the formulation according to the
invention,
most preferably about 4 to 10 mg per 100 ml of the formulation according to
the invention.
Benzalkonium chloride may also be used according to the invention in admixture
with
other preservatives.
Preferred formulations contain only benzalkonium chloride, sodium edetate and
the acid
needed to adjust the pH, in addition to the solvent water and the compounds of
formulal.
The pharmaceutical formulations according to the invention containing
compounds of
formula 1 are preferably used in an inhaler of the kind described hereinbefore
in order to
produce the propellant-free aerosols according to the invention. At this point
we should
once again expressly mention the patent documents described hereinbefore, to
which
reference is hereby made.
As described at the beginning, a further developed embodiment of the preferred
inhaler is
disclosed in WO 97/12687 (cf. in particular Figures 6a and 6b and the
associated passages
of description). This nebuliser (Respimat ) can advantageously be used to
produce the
inhalable aerosols according to the invention containing a tiotropium salt as
active
substance. Because of its cylindrical shape and handy size of less than 9 to
15 cm long and
2 to 4 cm wide, the device can be carried anywhere by the patient. The
nebuliser sprays a
defined volume of the pharmaceutical formulation out through small nozzles at
high
pressures, so as to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
housing, a
nozzle, a locking clamp, a spring housing, a spring and a storage container,
characterised
by

CA 02564379 2006-10-26
WO 2005/110421 18 PCT/EP2005/005028
a pump housing fixed in the upper housing part and carrying at one end a
nozzle
body with the nozzle or nozzle arrangement,
a hollow piston with valve body,
a power take-off flange in which the hollow body is fixed and which is located
in
the upper housing part,
a locking clamping mechanism located in the upper housing part,
a spring housing with the spring located therein, which is rotatably mounted
on the
upper housing part by means of a rotary bearing,
a lower housing part which is fitted onto the spring housing in the axial
direction.
The hollow piston with valve body corresponds to a device disclosed in WO
97/12687. It
projects partially into the cylinder of the pump housing and is disposed to be
axially
movable in the cylinder. Reference is made particularly to Figures 1-4 -
especially Figure 3
- and the associated passages of description in the abovementioned
International Patent
Application. At the moment of release of the spring the hollow piston with
valve body
exerts, at its high pressure end, a pressure of 5 to 60 Mpa (about 50 to 600
bar), preferably
10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of
active substance
solution. Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20
microlitres
are more preferable, whilst a volume of 10 to 15 microlitres per actuation is
particularly
preferred.
The valve body is preferably mounted at the end of the hollow piston which
faces the
nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by
micro-
engineering. Microstructured nozzle bodies are disclosed for example in WO-
99/16530;
reference is hereby made to the contents of this specification, especially
Figure 1 and the
associated description.
The nozzle body consists for example of two sheets of glass and/or silicon
securely fixed
together, at least one of which has one or more microstructured channels which
connect the
nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is
at least one round

CA 02564379 2006-10-26
WO 2005/110421 19
PCT/EP2005/005028
or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth
preferably
being 4.5 to 6.5 microns and the length being 7 to 9 microns.
If there is a plurality of nozzle openings, preferably two, the directions of
spraying of the
nozzles in the nozzle body may run parallel to each other or may be inclined
relative to one
another in the direction of the nozzle opening. In the case of a nozzle body
having at least
two nozzle openings at the outlet end, the directions of spraying may be
inclined relative to
one another at an angle of 20 degrees to 160 degrees, preferably at an angle
of 60 to 150
degrees, most preferably 80 to 1000
.
The nozzle openings are preferably arranged at a spacing of 10 to 200 microns,
more
preferably at a spacing of 10 to 100 microns, still more preferably 30 to 70
microns. A
spacing of 50 microns is most preferred.
The directions of spraying therefore meet in the region of the nozzle
openings.
As already mentioned, the liquid pharmaceutical preparation hits the nozzle
body at an
entry pressure of up to 600 bar, preferably 200 to 300 bar and is atomised
through the
nozzle openings into an inhalable aerosol. The preferred particle sizes of the
aerosol are up
to 20 microns, preferably 3 to 10 microns.
The locking clamping mechanism contains a spring, preferably a cylindrical
helical
compression spring as a store for the mechanical energy. The spring acts on
the power
take-off flange as a spring member the movement of which is determined by the
position
of a locking member. The travel of the power take-off flange is precisely
limited by an
upper stop and a lower stop. The spring is preferably tensioned via a stepping-
up gear, e.g.
a helical sliding gear, by an external torque which is generated when the
upper housing
part is turned relative to the spring housing in the lower housing part. In
this case, the
upper housing part and the power take-off flange contain a single- or multi-
speed spline
gear.
The locking member with the engaging locking surfaces is arranged in an
annular
configuration around the power take-off flange. It consists for example of a
ring of plastics
or metal which is inherently radially elastically deformable. The ring is
arranged in a plane

CA 02564379 2006-10-26
WO 2005/110421 20 PCT/EP2005/005028
perpendicular to the axis of the atomiser. After the locking of the spring,
the locking
surfaces of the locking member slide into the path of the power take-off
flange and prevent
the spring from being released. The locking member is actuated by means of a
button. The
actuating button is connected or coupled to the locking member. In order to
actuate the
locking clamping mechanism the actuating button is moved parallel to the
annular plane,
preferably into the atomiser, and the deformable ring is thereby deformed in
the annular
plane. Details of the construction of the locking clamping mechanism are
described in WO
97/20590.
The lower housing part is pushed axially over the spring housing and covers
the bearing,
the drive for the spindle and the storage container for the fluid.
When the atomiser is operated, the upper part of the housing is rotated
relative to the lower
part, the lower part taking the spring housing with it. The spring meanwhile
is compressed
and biased by means of the helical sliding gear, and the clamping mechanism
engages
automatically. The angle of rotation is preferably a whole-number fraction of
360 degrees,
e.g. 180 degrees. At the same time as the spring is tensioned, the power take-
off
component in the upper housing part is moved along by a given amount, the
hollow piston
is pulled back inside the cylinder in the pump housing, as a result of which
some of the
fluid from the storage container is sucked into the high pressure chamber in
front of the
nozzle.
If desired, a plurality of replaceable storage containers containing the fluid
to be atomised
can be inserted in the atomiser one after another and then used. The storage
container
contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by gently pressing the actuating button.
The clamping
mechanism then opens the way for the power take-off component. The biased
spring
pushes the piston into the cylinder in the pump housing. The fluid emerges
from the nozzle
of the atomiser in the form of a spray.

CA 02564379 2006-10-26
WO 2005/110421 21 PCT/EP2005/005028
Further details of the construction are disclosed in PCT applications WO
97/12683 and
WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material suitable for
their
function. The housing of the atomiser and ¨ if the function allows ¨ other
parts as well are
preferably made of plastics, e.g. by injection moulding. For medical
applications,
physiologically acceptable materials are used.
Figures 6a/b of WO 97/12687 show the Respimat nebuliser with which the
aqueous
aerosol preparations according to the invention can advantageously be inhaled.
Figure 6a
shows a longitudinal section through the atomiser with the spring under
tension, Figure 6b
shows a longitudinal section through the atomiser with the spring released.
The upper housing part (51) contains the pump housing (52), on the end of
which is
mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle
body (54) and a
filter (55). The hollow piston (57) fixed in the power take-off flange (56) of
the locking
clamping mechanism projects partly into the cylinder of the pump housing. At
its end the
hollow piston carries the valve body (58). The hollow piston is sealed off by
the gasket
(59). Inside the upper housing part is the stop (60) on which the power take-
off flange rests
when the spring is relaxed. Located on the power take-off flange is the stop
(61) on which
the power take-off flange rests when the spring is under tension. After the
tensioning of the
spring, the locking member (62) slides between the stop (61) and a support
(63) in the
upper housing part. The actuating button (64) is connected to the locking
member. The
upper housing part ends in the mouthpiece (65) and is closed off by the
removable
protective cap (66).
The spring housing (67) with compression spring (68) is rotatably mounted on
the upper
housing part by means of the snap-fit lugs (69) and rotary bearings. The lower
housing part
(70) is pushed over the spring housing. Inside the spring housing is the
replaceable storage
container (71) for the fluid (72) which is to be atomised. The storage
container is closed off

CA 02564379 2006-10-26
WO 2005/H0421 22 PCT/EP2005/005028
by the stopper (73), through which the hollow piston projects into the storage
container and
dips its end into the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted on the outside of the
spring
housing. The drive pinion (75) is located at the end of the spindle facing the
upper housing
part. On the spindle is the slider (76).
The nebuliser described above is suitable for nebulising the aerosol
preparations according
to the invention to form an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method
described
above (Respimat()), the mass expelled, in at least 97%, preferably at least
98% of all the
actuations of the inhaler (puffs), should correspond to a defined quantity
with a range of
tolerance of not more than 25%, preferably 20% of this quantity. Preferably,
between 5 and
30 mg, more preferably between 5 and 20 mg of formulation are delivered as a
defined
mass per puff.
However, the formulation according to the invention can also be nebulised
using inhalers
other than those described above, for example jet-stream inhalers.
The present invention also relates to an inhalation kit consisting of one of
the
pharmaceutical preparations according to the invention described above and an
inhaler
suitable for nebulising this pharmaceutical preparation. The present invention
preferably
relates to an inhalation kit consisting of one of the pharmaceutical
preparations according
to the invention described above and the Respimat inhaler described above.

CA 02564379 2006-10-26
WO 2005/110421 23 PCT/EP2005/005028
The examples of formulations given below serve as illustrations without
restricting the
subject matter of the present invention to the compositions shown by way of
example.
I. Preparation of the compounds of formula 1
Example 1: 6-hydroxy-8- {1-hydroxy-242-(4-hydroxy-2,6-dimethyl-pheny1)-1,1-
dimethyl-
ethylamino]-ethyl) -4H-benzo[1,4]oxazin-3-one-methanesulphonate
0 OH
H Me
HN 0 N
Me Me le
Me OH
OH
x CH3S03H
The compound is known from US 4460581.
The examples of synthesis described below serve to illustrate new compounds
according to
the invention in more detail. However, they are intended only as examples of
procedures
to illustrate the invention without restricting it to the subject matter
described in an
exemplifying capacity hereinafter.
Example 2: 8- {2-12-(4-fluoro-pheny1)-1,1-dimethyl-ethylaminol-1-hydroxy-
ethyll-6-
h_ydroxy-4H-benzo[1,4]oxazin-3-one acid addition salt
Oy" '......,
0 OH
H
HN
lig N
lei F
OH
x HX
300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-414-benzo[1,4]oxazin-3-
one
and 183 mg (1.09 mmol) 2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamine were
dissolved in 3
ml of ethanol. Molecular sieve was added and the mixture was heated for 30
minutes to

CA 02564379 2006-10-26
WO 2005/110421 24
PCT/EP2005/005028
80 C. After cooling to ambient temperature 35 mg (0.91 mmol) sodium
borohydride were
added. The mixture was stirred for 1 hour at ambient temperature, sodium
hydrogen
carbonate solution was then added to the reaction mixture and it was extracted
with ethyl
acetate. The organic phases were evaporated down and the residue was
chromatographed
(eluant: hexane/ethyl acetate/methanol). The ethanolamine thus obtained (223
mg) was
dissolved in methanol in order 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 filtration through Celitee, the filtrate was
freed from the
solvent and the residue was chromatographed (silica gel; eluant:
dichloromethane/methanol). Beige solid. Yield: 76 mg (22%); mass spectrometry:
[M+Hr
= 375. The product may be converted into the desired acid addition salt by
reaction with
the corresponding acid HX.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racem ate analogously to current methods known in the art.
Example 3: 6-hydroxy-8-{1-hydrox_y-2-[2-(4-methoxy-pheny1)-1,1-dimethyl-
ethylamino]-
ethyll-4H-benzol1,41oxazin-3-one hydrochloride
0 OH
H
HN 001 N
Me Me 1401
OMe
OH x HCI
a) 8- {2-[1,1-dimethy1-2-(4-methoxy-pheny1)-ethylamino]-1-hydroxy-ethyll-6-
benzyloxy-
4H-benzo[1,4]oxazin-3-one
7.5 g (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxalhydrate are added at 70 C
to a
solution of 3.6 g 1,1-dimethy1-2-(4-methoxypheny1)-ethylamine in 100 mL
ethanol and
the mixture is stirred for 15 minutes. Then within 30 minutes at 10 to 20 C 1
g sodium
borohydride is added. The mixture is stirred for one hour, combined with 10 mL
acetone

CA 02564379 2006-10-26
WO 2005/110421 25 PCT/EP2005/005028
and stirred for a further 30 minutes. The reaction mixture is diluted with 150
mL ethyl
acetate, washed with water, dried with sodium sulphate and evaporated down.
The residue
is dissolved in 50 mL methanol and 100 mL ethyl acetate and acidified with
conc.
hydrochloric acid. After the addition of 100 mL diethyl ether the product is
precipitated
out. The crystals are filtered off, washed and recrystallised from 50 mL
ethanol.
Yield: 7 g (68%; hydrochloride); m.p. = 232-234 C.
b) 8- {2-j1,1-dimethy1-244-methoxy-phenyl)-ethylaminol-1-hydroxy-ethyl}-6-
hydroxy-
4H-benzo[1,4]oxazin-3-one-hydrochloride
6.8 g of the benzyl compound obtained previously are hydrogenated in 125 mL
methanol
with the addition of 1 g palladium on charcoal (5%) at ambient temperature and
normal
pressure. The catalyst is filtered off and the filtrate is freed from the
solvent. After
recrystallisation of the residue from 50 mL acetone and a little water a solid
is obtained,
which is filtered off and washed.
Yield: 5.0 g (89 %; hydrochloride); m.p. = 155-160 C.
The (R)- and (S)-enantiomers of Example 3 may be obtained from the racemate
for
example by means of chiral HPLC (e.g. column: Chirobiotic T, 250 x 22.1 mm
obtained
from Messrs Astec). Methanol with 0.05 % triethylamine and 0.05% acetic acid
may be
used as the mobile phase. Silica gel with a particle size of 5 m, to which
the glycoprotein
teicoplanin is covalently bound may be used as the column material. Retention
time (R-
enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two
enantiomers
are obtained in the form of the free bases by this method and may be converted
into the
corresponding acid addition salts by reaction with the desired acid (e.g.
hydrochloric acid)
by the methods generally known in the prior art.
Of outstanding importance according to the invention is the R-enantiomer of
Example 3.

CA 02564379 2006-10-26
WO 2005/110421 26 PCT/EP2005/005028
Example 4: 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethyl-acetate )-1,1-dimethyl-
ethylaminol-ethy1}-4H-benzo[1,4]oxazin-3-one-hydrochloride
C)0 OH
HN
Me Me I. 00Ethyl
OH 0 x HC1
a) 8- {2-[1,1-dimethy1-2-(4-phenoxyethyl-acetate _)-ethylamino1-1-hydroxy-
ethy11-6-
benzyloxy-4H-benzo[1,41oxazin-3-one
Analogously to the method described in Example 3a) the title compound is
obtained from
g (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxalhydrate and 11.8 g 1,1-
dimethy1-2-
10 (4-phenoxy-acetate ethyl)-ethylamine hydrochloride.
Yield: 16.5 g (69%, hydrochloride); m.p. = 212-214 C.
b) 8- {2-[1,1-dimethy1-2-(4-phenoxy-acetate ethyl)-ethylaminol-l-hydroxy-
ethy11-6-
hydroxy-4H-benzo{1,4}oxazin-3-one-hydrochloride
15 8 g of the benzylalcohol obtained previously are 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 uptake of the theoretical amount of hydrogen calculated the
catalyst is filtered
off and the filtrate is evaporated down. The product that crystallises out
when the solvent is
distilled off is suction filtered and washed.
Yield: 5.5 g (81%; hydrochloride); m.p. = 137-140 C.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.

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Example 5: 6-hydroxy-8-11-hydroxy-242-(4-phenoxv-acetic acid)-1,1-dimethyl-
ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-hydrochloride
0
0 OH
H
HN 0 N
Me Me Ol
OCOOH
OH x HC1
11 g 8- {2-[1,1-dimethy1-2-(4-phenoxyethyl-acetate )-ethylamino]-1-hydroxy-
ethyl} -6-
benzyloxy-4H-benzo[1,4]oxazin-3-one hydrochloride (Example 4a) are dissolved
in 125
mL methanol and hydrogenated in the presence of 1 g palladium on charcoal
(5%). After
uptake of the theoretically calculated amount of hydrogen the catalyst is
filtered off. 2.6 g
sodium hydroxide dissolved in 20 mL water are added to the filtrate. The
mixture is
refluxed for 30 minutes, the methanol is distilled off and the remaining
mixture is
combined with 10 mL water, 20 mL n-butanol and 3.9 mL acetic acid. The
precipitated
solid is suction filtered and washed with diethyl ether.
Yield: 7 g (87%). The hydrochloride is obtained by recrystallisation from 0.5
molar
hydrochloric acid. M.p. = 152 C.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 6: 8- {2-11,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethylamino}-1-hydroxy-
ethy11-6-hydroxy-4H-benzof1,4]oxazin-3-one-hydrochloride
o0 OH H Me
HN 0 N
Me Me 401
Me Me
OH x HC1

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a) 1-(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-2-1-1,1-dimethyl-2-12,4,6-
trimethylpheny1)-
ethylimino]-ethanone
7.2 g (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxalhydrate and 3.6 g 1,1-
dimethy1-2-
(2,4,6-trimethylphenye-ethylamine are heated to 70 C for 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%); m.p. = 175 C.
b) 8- {2-[1,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethy1amino1-1-hydroxy-ethyl} -
6-
benzyloxy-4H-benzo[1,4]oxazin-3-one
8.6 g of the Schiff-base obtained according to the prescribed method 6a) are
dissolved in
100 mL ethanol and 20 mL THF, combined with 0.7 g sodium borohydride within 30
min
at 10-20 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 that
crystallises out during acidification with conc. hydrochloric acid is filtered
off and washed.
Yield: 7.4 g (80%, hydrochloride); m.p. = 235 C (decomposition).
c) 8- {2-[1,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethy1aminol-1-hydroxy-ethy11-
6-hydroxy-
4H-benzo[1,41oxazin-3-one-hydrochloride
7.4 g of the benzyl compound obtained in Step b) are hydrogenated in 125 mL
methanol
with the addition of 1 g palladium on charcoal (5%) at ambient temperature and
normal
pressure. Then the catalyst is filtered off and the filtrate is evaporated
down. The product
that crystallises out on the addition of acetone is suction filtered and
washed with acetone
and diethyl ether. Yield: 5 g (78%, hydrochloride); m.p. 160 C
(decomposition).
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.

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Example 7: 6-hydroxy-8- (1-hydrox_y-2-12-(4-hydroxy-pheny1)-1,1-dimethyl-ethyl
aminol-
ethyl} -4H-benzo[1,41oxazin-3-one-hydrochloride
o0 OH
H
HN 0 N
Me Me 401
OH
OH x HC1
a) 8- (241,1-dimethyl-2-(4-hydroxy-pheny1)-ethylaminol-1-hydroxy-ethyll-6-
benzyloxy-
4H-benzo[1,41oxazin-3-one
The title compound is prepared from 10 g (6-benzyloxy-4H-benzo[1,4]oxazin-3-
one)-
glyoxalhydrate and 4.6 g 1,1-dimethy1-2-(4-hydroxy-phenyl)-ethylamine
analogously to
the procedure laid down for Example 3a).
Yield: 9.0 g (64%, hydrochloride); m.p. = 255-258 C.
b) 8- {241 ,1-dimethy1-2-(4-hydroxy-Theny1)-ethylaminol-1-hydroxy-ethyl } -6-
hydroxy-
411-benzo[l Al oxazin-3-one-hydrochloride
5.7 g of the coupling product obtained previously are hydrogenated in the
presence of 0.6 g
palladium on charcoal (5%) in 100 mL methanol. After uptake of the
theoretically
calculated amount of hydrogen the catalyst is filtered off and the filtrate is
freed from the
solvent. The residue is dissolved in ethanol with heating and then combined
with diethyl
ether. The product precipitated is suction filtered and recrystallised once
from water. Yield:
3.6 g (72%, hydrochloride); m.p. = 159-162 C.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.

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Example 8: 6-hydroxy-8- {1-hydroxy-24244-isopropyl=pheny1)-1,1dimethyl-
ethylaminol-
ethyll-4H-benzo[1,4]oxazin-3-one-hydrochloride
(30 OH
H
HN 0 N
401
OH x HCI
a) 1-(4-isopropyl-pheny1)-2-methyl-propan-2-ol
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 colourless oil. Yield: 13.0 g (57%); mass spectrometry: [M+H1+ = 193.
b) N42-(4-isopropyl-pheny1)-1,1-dimethyl-ethyTacetamide
A Ritter reaction is carried out with 10.2 g (53 mmol) 1-(4-isopropyl-pheny1)-
2-methyl-
propan-2-ol in the manner described for Example 9b). The reaction mixture is
poured onto
ice water and made alkaline with sodium hydroxide solution, during which time
a solid is
precipitated. This is suction filtered and dried.
Yield: 9.90 g (80%); mass spectrometry: [M+H] = 234.
c) 2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamine
Reaction of 9.80 g (42 mmol) N42-(4-isopropyl-pheny1)-1,1-dimethyl-
ethylkacetamide
analogously to the procedure laid down for Example 9c).
Yield: 7.00 g (71%, hydrochloride); m.p. 202-206 C.
d) 6-benzyloxy-8- {1-hydroxy-242-14-isoprqpyl-pheny1)-1,1-dimethyl-ethylaminol-
ethyl}-
4H-benzo[1,41oxazin-3-one
2.18 g (6.1 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-
3-one
and 1.1 g (5.8 mmol) 2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamine are
stirred for one
hour at 50-80 C in 40 mL ethanol. After cooling to ambient temperature 0.24 g
(6.3 mmol)

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sodium borohydride are 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
sulphate and
freed from the solvent. The residue is dissolved in 20 mL ethyl acetate and 10
mL water,
acidified with conc. hydrochloric acid and diluted with diethyl ether. After
the addition of
a crystallisation aid the precipitated solid is suction filtered and washed.
White solid.
Yield: 1.7 g (52 A, hydrochloride); m.p. 220-222 C.
e) 6-hydroxy-8-{1-hydroxy-242-(4-isopropyl-pheny1)-1,1dimethyl-ethy1amino]-
ethyll-
4H-benzo[1,4]oxazin-3-one-hydrochloride
1.6 g (3.0 mmol) 6-benzyloxy-8-{1-hydroxy-242-(4-isopropyl-pheny1)-1,1-
dimethyl-
ethylamino]-ethy1}-4H-benzo[1,4]oxazin-3-one are dissolved in methanol and
hydrogenated with palladium on charcoal as catalyst at normal pressure and
ambient
temperature. The catalyst is suction filtered, the solvent is distilled off
and the residue is
recrystallised from isopropanol. White solid.
Yield: 1.1 g (85%, hydrochloride); m.p. 248-250 C; mass spectrometry: [M+H] =
399.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 9: 8- t242-(4-ethyl-pheny1)-1,1-dimethyl-ethylaminol-l-hydroxy-ethyll-
6-
hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
C)0 OH
H
HN 0 N
le
OH x HC1

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PCT/EP2005/005028
a) 1-(4-ethyl-pheny1)-2-methyl-propan-2-ol
14.8 g (90 mmol) 1-(4-ethyl-phenyl)-propan-2-one, dissolved in diethyl ether,
are added
dropwise to 39 mL of a 3 molar solution of methylmagnesium bromide in diethyl
ether,
while cooling with the ice bath, in such a way that the temperature does not
exceed 30 C.
After the addition has ended the reaction mixture is refluxed for 1.5 hours
and then
hydrolysed with 10% ammonium chloride solution. After separation of the
organic phase
the aqueous phase is extracted with diethyl ether. The combined ether phases
are washed
with water, dried with sodium sulphate and evaporated down. The oil thus
obtained is
further reacted directly. Yield: 15.5 g (90%).
b) N42-(4-ethyl-pheny1)-1,1-dimethyl-ethyli-acetamide
6.2 mL conc. sulphuric acid are added dropwise to 15.5 g (87 mmol) 1-(4-ethyl-
pheny1)-2-
methyl-propan-2-ol in 4.8 mL (91 mmol) acetonitrile and 15 mL glacial acetic
acid within
minutes, during which time the temperature rises to 65 C. Then the mixture is
stirred
15 for one hour, diluted with ice water and made alkaline with conc. sodium
hydroxide
solution. After further stirring for 30 minutes the precipitated solid is
suction filtered and
washed with water. The crude product is dissolved in ethyl acetate, dried with
sodium
sulphate 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%); m.p. 90-92 C.
c) 2-(4-ethyl-phenyl)-1,1-dimeth_yl-ethylamine
16.3 g (74 mmol) N-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethyl]acetamide and 8.0 g
potassium hydroxide are refluxed for 15 hours in 60 mL ethyleneglycol. 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 sulphate and
freed
from the solvent. In order to prepare the hydrochloride the crude product is
dissolved in
acetonitrile and combined successively with ethereal hydrochloric acid and
diethyl ether.
The precipitated solid is suction filtered and dried.
Yield: 11.0 g(69%, hydrochloride); m.p. 165-167 C.

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d) 6-benzyloxy-8- {2-1-2-(4-ethyl-pheny1)-1,1-dimethyl-ethylaminol-1-hydroxy-
ethy11-4H-
benzo[1,41oxazin-3-one
The target compound is prepared analogously to the procedure laid down for
Example 8d)
from 2.14 g (6.0 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acety1)-4H-
benzo[1,4]oxazin-
3-one and 1.0 g (5.6 mmol) 2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamine. White
solid.
Yield: 1.7 g (54%, hydrochloride); m.p. 210-214 C.
e) 8-{242-(4-ethyl-pheny1)-1,1-dimettal-ethylamino1-1-hydroxy-ethyl}-6-hydroxy-
4H-
benzo[1,4}oxazin-3-one-hydrochloride
The hydrogenolysis of 1.45 g (2.75 mmol) 6-benzyloxy-8-{242-(4-ethyl-pheny1)-
1,1-
dimethyl-ethylamino]-1-hydroxy-ethy1}-4H-benzo[1,4]oxazin-3-one according to
the
prescribed method for Example 8e) yields the target compound in the form of a
white
solid.
Yield: 1.07 g (92%; hydrochloride); m.p. 266-269 C; mass spectrometry: [M+Hr =
385.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 10: 8- {2-12-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino-1-1-
hydroxy-
ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
Oy"....,.
0 OH
H
HN
0 N
01
F
OH x HC1
a) 1-fluoro-2-methy1-4-(2-methyl-propeny1)-benzene
100 mL of a 0.5 molar solution of 4-fluoro-3-methyl-phenylmagnesium bromide in
THF
are combined within 30 minutes with 4.7 mL (50 mmol) isopropylaldehyde, during
which
time the temperature rises to 45 C. It is stirred for 30 minutes, refluxed for
1 hour and then

CA 02564379 2006-10-26
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hydrolysed with 10% ammonium chloride solution. After separation of the
organic phase
the mixture is extracted 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 p-toluenesulphonic acid monohydrate and refluxed for three hours
using the water
separator. The reaction mixture is poured onto water and made alkaline with
conc. sodium
hydroxide solution. After separation of the organic phase the latter is washed
with water,
dried with sodium sulphate and freed from the solvent. Fractional distillation
of the residue
yields the product in the form of a colourless liquid (b.p. 80-85 C/10 mbar).
Yield: 4.1 g (50%).
b) N42-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethyl]-formamide
4.9 mL conc. sulphuric acid are added dropwise at 5-15 C to 1.5 g (31 mmol)
sodium
cyanide in 5 mL glacial acetic acid. The mixture is then combined with 3.9 g
(24 mmol) 1-
fluoro-2-methy1-4-(2-methyl-propeny1)-benzene, dissolved in 10 mL glacial
acetic acid,
and stirred for 1 hour at 50-60 C. The reaction mixture is diluted with ice
water, made
alkaline with conc. sodium hydroxide solution and extracted with
dichloromethane. The
organic phase is dried with sodium sulphate and freed from the solvent in
vacuo. The light
yellow oil thus obtained is further reacted directly. Yield: 4.3 g (87%).
c) 2-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamine
4.3 g (20.6 mmol) N42-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylFformamide,
20
mL conc. hydrochloric acid and 20 mL water are refluxed for 2 hours. The
reaction
mixture is diluted with water, made alkaline with conc. sodium hydroxide
solution and
extracted with dichloromethane. The organic phases are dried with sodium
sulphate and
evaporated down. The residue is dissolved in ethyl acetate, combined with
ethereal
hydrochloric acid and cooled. The precipitated crystals are suction filtered
and washed
with diethyl ether and dried. White solid.
Yield: 3.9 g (87%, hydrochloride); m.p. 196-198 C.

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d) 6-benzyloxy-8- (242-(4-fluoro-3-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl -4H-benzo[1,4joxazin-3-one
1.10 g (3.1 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-
3-one
and 0.50 g (2.8 mmol) 2-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamine are
reacted
and worked up analogously to the procedure laid down for Example 8d). White
solid.
Yield: 0.75 g (47%, hydrochloride); m.p. 228-230 C.
e) 8- {242-(4-fluoro-3-methyl-Theny1)-1,1-dimethyl-ethylaminol-1-hydroxy-ethyl
} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
The hydrogenation of 0.70 g (1.4 mmol) 6-benzyloxy-8-{242-(4-fluoro-3-methyl-
pheny1)-
1,1-dimethyl-ethylamino]-1-hydroxy-ethy1}-4H-benzo[1,4]oxazin-3-one yields the
target
compound as a white solid.
Yield: 0.50 g (87%, hydrochloride); m.p. 278-280 C; mass spectroscopy: [M+H]+
= 389.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 11: 8- t2-[2-(4-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
OH
HN 411
OF
OH x HC1
a) 1-(4-fluoro-2-methyl-pheny1)-2-methyl-propyl acetate
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 10a). 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 sulphate

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and evaporated down. The alcohol thus obtained is then dissolved in 50 mL
acetic
anhydride, combined with 1 mL conc. sulphuric acid and stirred for three hours
at reflux
temperature. 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 sulphate and the solvents are distilled off. Fractional distillation of
the residue
yields the product in the form of a colourless liquid (b.p. 105-110 C/8 mbar).
Yield 29.0 g (52%).
b) N-[2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethy1]-formamide
29.0 g (130 mmol) 1-(4-fluoro-2-methyl-phenyl)-2-methyl-propyl acetate
are reacted and worked up analogously to the procedure laid down for Example
10b).
Yellow oil. Yield: 27.0 g (99%).
c) 2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamine
In order to prepare the amine 27.0 g (130 mmol) N-[2-(4-fluoro-2-methyl-
pheny1)-1,1-
dimethyl-ethyl]-formamide are reacted as described in the procedure laid down
for
Example 10c). White solid. Yield: 15.5 g (55%, hydrochloride); m.p. 277-280 C.
d) 6-benzyloxy-8- {2-1244-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl)-4H-benzo[1,4joxazin-3-one
Prepared analogously to the procedure laid down for Example 8d) from 0.95 g
(2.66
mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
0.43 g
(2.37 mmol) 2-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamine.
Yield: 0.75 g (55%, hydrochloride); m.p. 233-236 C.
e) 8- {2-{2-(4-fluoro-2-methyl-phenyl)-1,1-dimeth_yl-ethylamino]-1-hydroxy-
ethyl} -6-
hydroxy-4H-benzof 1,41oxazin-3-one-hydrochloride
The debenzylation of 0.70 g (1.36 mmol) 6-benzyloxy-8-{24244-fluoro-2-methyl-
pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy11-4H-benzo[1,4]oxazin-3-one
yields the
target compound in the form of a white solid.
Yield: 0.50 g (87%, hydrochloride); m.p. 278-280 C; mass spectroscopy: [M+I-
I]+ = 389.

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The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 12: 8- {2-{2-(2,4-difluorolpheny1)-1, I -dimethyl-ethylamino]-1-
hydroxy-ethyl} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
0 OH
HN
401
100
OH x HCI
a) 1 -(2,4-di fluoro-pheny1)-2-methyl-propan-2-ol
11.0 mL acetone, diluted with 50 mL diethyl ether, are added dropwise within
20 minutes
to a solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromide in
diethyl
ether. Then the mixture is stirred for 1.5 hours at reflux temperature and
then hydrolysed
with 10% ammonium chloride solution. The ether phase is separated off, washed
with
water, dried with sodium sulphate and evaporated down. The fractional
distillation of the
residue yields the alcohol as a colourless liquid (b.p. 70-73 C/ 2 mmbar).
Yield: 20.0 g (86%).
b) N42-(2.4-difluoro-pheny1]-1,1-dimethyl-ethyl]-formamide
Ritter reaction with 20 g (110 mmol) 1-(2,4-difluoro-phenyl)-2-methyl-propan-2-
ol
according to the process described for Example 10b). Yellow oil. Yield: 22.0 g
(94%).
c) 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamine
Reaction of 22.0 g (100 mmol) N42-(2,4-difluoro-pheny1]-1,1-dimethyl-
ethyThformamide
analogously to the procedure laid down for Example 10c).
Yield: 16.0 g (72%, hydrochloride); m.p. 201-203 C.

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d) 6-benzyloxy-8-{2-[2-(2,4-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl -
4H-benzo[1,4]oxazin-3-one
Reaction of 0.89 g (2.49 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acety1)-4H-
benzo[1,4]oxazin-3-one and 0.40 g (2.16 mmol) 2-(2,4-difluoro-pheny1)-1,1-
dimethyl-
ethylamine in the manner described for Example 8d).
Yield: 0.80 g (62%, hydrochloride); m.p. 245-247 C.
e) 8-{242-(2,4-difluoro-pheny11-1,1-dimethyl-ethylaminol-1-hydroxy-ethy11-6-
hydroxy-
4H-benzo[ 1 ,4Joxazin-3 -one-hydrochloride
The hydrogenolysis of 0.70 g (1.35 mmol) 6-benzyloxy-8-{242-(2,4-difluoro-
pheny1)-1,1-
dimethyl-ethylamino]-1-hydroxy-ethy1}-4H-benzo[1,4]oxazin-3-one yields the
target
compound as a white solid.
Yield: 0.48 g (83%, hydrochloride); m.p. 279-280 C; mass spectroscopy: [M+Hr =
393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 13: 8- [242-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino1-1-hydroxy-
ethyl} -6-
hydroxy-4H-benzo[1,41oxazin-3-one-hydrochloride
Oy¨.....
0 OH
H
HN 40 N Is F
OH F x HC1
a) 1-(3,5-difluoro-pheny1)-2-methyl-propan-2-ol
The target compound is obtained by reacting a Grignard compound, prepared from
25.0 g
(121 mmol) 3,5-difluorobenzylbromide, with 12.6 mL (171 mmol) acetone. Yellow
oil.
Yield: 13.5 g (60%).

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PCT/EP2005/005028
b) 2-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamine
The Ritter reaction of 5.5 g (29.5 mmol) 1-(3,5-difluoro-phenyl)-2-methyl-
propan-2-ol
and 1.8 g sodium cyanide yields 7.0 g formamide, which is treated with
hydrochloric acid
in order to cleave the formyl group. Light yellow oil. Yield: 4.6 g (75%).
c) 6-benzyloxy-8-{2-12-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl)-
4H-benzo[1,4]oxazin-3-one
Prepared from 1.73 g (4.84 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acety1)-4H-
benzo[1,4]oxazin-3-one and 0.80 g (4.32 mmol) 2-(3,5-difluoro-pheny1)-1,1-
dimethyl-
ethylamine in the usual way. Yield: 1.50 g (58 %, hydrochloride); m.p. 240-244
C.
d) 8-{242-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy1}-6-
hydroxy-
4H-benzo[1,4Joxazin-3-one-hydrochloride
Hydrogenolysis of 1.30 g (2.43 mmol) 6-benzyloxy-8- {2-[2-(3,5-difluoro-
pheny1)-1,1-
dimethyl-ethylamino]-1-hydroxy-ethy11-4H-benzo[1,4]oxazin-3-one yields the
target
compound as a white solid.
Yield: 0.90 g (86%, hydrochloride); m.p. 150-158 C; mass spectroscopy: [M+H] =
393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 14: 8- {242-(4-ethoxy-pheny1)-1,1-dimethyl-ethylaminol1-hydroxy-ethyl
1 -6-
hydroxy-4H-benzo[1,41oxazin-3-one-hydrochloride
Oy" \
0 OH
H
HN 0 N
lei o-
OH x HCI

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a) benzyl [2-(4-ethoxy-phenyl)-1,1-dimethyl-ethyll-carbamate
15.0 g (50 mmol) benzyl [2-(4-hydroxy-phenyl)-1,1-dimethyl-ethyl] -carbamate
are stirred with 7.5 mL (92 mmol) ethyl iodide and 21 g (150 mmol) potassium
carbonate
for 10 hours at 90-100 C. The reaction mixture is combined with ethyl acetate,
washed
twice with water and dried with sodium sulphate. After removal of the solvents
by
distillation a yellow oil remains (15.0 g, 92%), which is further reacted
directly.
b) 2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamine
A solution of 15.0 g (49 mmol) benzyl [2-(4-ethoxy-pheny1)-1,1-dimethyl-ethyll-
carbamate in 100 mL glacial acetic acid is combined with 2 g palladium on
charcoal (10%)
and then hydrogenated at 5 bar and 40 to 50 C. The catalyst is filtered off
and the filtrate is
freed from the solvent. The residue is dissolved in a little water, made
alkaline with conc.
sodium hydroxide solution and extracted with ethyl acetate. The organic phase
is washed
with water, dried with sodium sulphate 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%); m.p. 198-200 C.
c) 6-benzyloxy-8- {2-12-(4-ethoxy-pheny1)-1,1-dimethyl-ethylaminol-1-hydroxy-
ethyll -
4H-benzo[1,4]oxazin-3-one
2.14 g (6.0 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-
benzo[1,4]oxazin-3-one
and 1.0 g (5.2 mmol) 2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamine are stirred
in 40 mL
ethanol for one hour at 50-80 C. After cooling to ambient temperature 0.23 g
(6.0 mmol)
sodium borohydride are added and the mixture is stirred for another 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
sulphate and freed from the solvent in vacuo. The residue is again dissolved
in ethyl
acetate and water, combined with conc. hydrochloric acid and diluted with
diethyl ether.
The precipitated solid is suction filtered and washed with diethyl ether.
White solid.
Yield: 2.0 g (61 %, hydrochloride); m.p. 214-216 C.

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d) 8- {242-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino1-1-hydroxy-ethyll-6-
hydroxy-4H-
benzo[1,4]oxazin-3-one-hydrochloride
1.5 g (2.8 mmol) 6-benzyloxy-8- {2-[2-(4-ethoxy-pheny1)-1,1-dimethyl-
ethylamino]-1-
hydroxy-ethy11-4H-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, inoculated and diluted with ethyl acetate. The
precipitated
solid is filtered off and washed. White solid.
Yield 1.0 g (83%, hydrochloride); m.p. 232-235 C; mass spectrometry: [M+H]+ =
401.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 15: 8- {242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylaming1-1-hydroxy-
ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one-hydrochloride
Oy\
0 OH
H
HN N
1.1 01
OH x HCI
a) 1-(3,5-dimethyl-pheny1)-2-methyl-propano1-2-ol
Obtained from the reaction of ethyl (3,5-dimethyl-phenyl)-acetate with
methylmagnesium
bromide.
b) 2-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamine
By reacting 6.00 g (34 mmol) 1-(3,5-dimethyl-phenyl)-2-methyl-propano1-2-ol
and 2.00 g
(41 mmol) sodium cyanide in a Ritter reaction, 2.40 g 2-(3,5-dimethyl-pheny1)-
1,1-
dimethyl-ethylformamide (35% yield) are obtained. To release the amine the
formamide

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(2.40 g, 11.7 mmol) is treated with hydrochloric acid. The process and working
up take
place analogously to the procedure laid down for Example 10c). Oil.
Yield: 1.70 g (82%); mass spectroscopy: [M+H] = 178.
c) 6-benzyloxy-8- {242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylaminol-1-
hydroxy-
ethyl} -4H-benzo[1,41oxazin-3-one
Prepared analogously to the procedure laid down for Example 8d) from 1.47 g
(4.1 mmol)
benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 0.65 g
(3.7
mmol) 2-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamine.
Yield: 1.1 g (51 %, hydrochloride); m.p. 220-222 C.
d) 8- (242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethy1amino1-1-hydroxy-ethyl}-6-
hydroxy-
4H-benzo[1,41oxazin-3-one-hydrochloride
The target compound was obtained after hydrogenolysis of 0.90 g (1.71 mmol) 6-
benzyloxy-8- {242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethyl amino] -1-hydroxy-
ethyl } -4H-
benzo[1,4]oxazin-3-one and recrystallisation of the crude product from
isopropanol. White
solid.
Yield: 0.50 g (69%, hydrochloride); m.p. 235-238 C; mass spectroscopy: [M+H]F
= 385.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 16: Acid addition salt of 444- {242-hydroxy-2-(6-hydroxy-3-oxo-3,4-
dihydro-
2H-benzo[1,4]oxazin-8-y1)-ethylamino]-2-methyl-propy1}-Thenoxy)-butyric acid
0
OH
H
HN ilo N
OH 0 x HX

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a) ethyl 444-(2-amino-2-methyl-propy1)-phenoxy]-butyrate
4.5 g (15.0 mmol) benzyl [2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylFcarbamate,
2.3 mL
(16.0 mmol) ethyl 4-bromo-butyrate, 2.3 g (16.6 mmol) potassium carbonate and
0.3 g (1.8
mmol) potassium iodide in 20 mL dimethylformamide are heated for 13 hours at
120 C.
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
sulphate and
evaporated down. The residue is purified by chromatography (eluant:
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 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 precipitated solid is
suction filtered and
dried.
Yield: 2.9 g (66% over two steps, hydrochloride); m.p. = 103-105 C.
b) ethyl 4-(4- {242-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,41oxazin-8-y1)-2-
hydroxy-ethylamino]-2-methyl-propy11-phenoxy)-butyrate
1.20 g (3.36 mmol) benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-
3-one
and 0.90 g (3.22 mmol) ethyl 444-(2-amino-2-methyl-propy1)-phenoxy]-butyrate
are
reacted in the manner described for Example 8d). 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 precipitated solid is suction filtered and
washed with
diethyl ether. Yield: 1.20 g (54%, oxalate); m.p. 223-227 C.
c) 4-(4- {2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo11,41oxazin-8-y1)-2-
hydroxy-
ethylamino]-2-methyl-prop_ylj-phenoxy)-butyric acid
A solution of 1.00 g (1.73 mmol) ethyl 4-(4-{242-(6-benzyloxy-3-oxo-3,4-
dihydro-2H-
benzo[1,4]oxazin-8-y1)-2-hydroxy-ethylamino]-2-methyl-propy1}-phenoxy)-
butyrate in 25
mL methanol is combined with 2.5 mL 1 N sodium hydroxide solution, refluxed
for 30
minutes and then neutralised with 1 N hydrochloric acid. The solution is
evaporated down
and the oil remaining is dissolved by heating in 5 mL n-butanol. After the
addition of a

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crystallisation aid a solid is precipitated, which is suction filtered and
washed with acetone
and diethyl ether. Yield: 0.75 g (79%); m.p. 216-218 C.
d) 4-(4- {242-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzol1,4joxazin-8-y1)-
ethylamino]-2-methyl-propyll-phenoxy)-butyric acid
0.70 g (1.28 mmol) 4-(4- {242-(6-benzyloxy-3-oxo-3,4-dihydro-2H-
benzo[1,4]oxazin-8-
y1)-2-hydroxy-ethylamino]-2-methyl-propyll -phenoxy)-butyric acid are
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 the solvent. The product is obtained by
crystallisation from a
methanol/acetone mixture.
Yield: 0.40 g (68%); m.p. 201-204 C; mass spectroscopy: [M+Hr = 459.
The product may be converted into the desired acid addition salt by reaction
with the
corresponding acid HX.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 17: 8- {242-(3,4-difluoro-phenv1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethy11-6-
hydroxy-4H-benzo[1,4Joxazin-3-one-trifluoroacetate
0 OH
HN F
OH x CF3COOH
a) 1-(3,4-difluoro-pheny1)-2-methyl-propan-2-ol
From 23.0 g (111 mmol) 3,4-difluorobenzylbromide a Grignard is prepared, which
is then
reacted with 11.6 mL (158 mmol) acetone. Light yellow oil.
Yield: 9.7 g (47%); Rf value: 0.55 (ethyl acetate/petroleum ether = 1:3).

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b)_N-[2-(3 ,4-difluoro-pheny1)-1,1 -dimethyl-ethyl] -form amide
The target compound is obtained by Ritter reaction with 4.0 g (21.5 mmol) 1-
(3,4-difluoro-
pheny1)-2-methyl-propan-2-ol. Light yellow oil.
Yield: 4.0 g (87%); mass spectrometry: [M+Hr = 214.
c) 2-(3,4-difluoro-pheny1)-1,1-dimethyl-ethylamine
4.00 g (18.5 mmol) N42-(3,4-difluoro-pheny1)-1,1-dimethyl-ethyl]-formamide are
dissolved in ethanol, combined with conc. hydrochloric acid and heated
overnight at reflux
temperature. The reaction solution is poured onto ice water, made alkaline
with sodium
hydroxide and extracted with tert-butylmethylether. The organic phases are
washed with
water, dried with sodium sulphate and evaporated down. Yellow oil.
Yield: 3.2 g (92%); mass spectrometry: [M+H] = 186.
d) 8- {242-(3,4-difluoro-pheny1)-1,1-dimethyl-ethylamino1-1-hydroxy-ethylj-6-
hydroxy-
4H-benzo[1,4]oxazin-3-one
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-
3-one
and 185 mg (1 mmol) 2-(3,4-difluoro-pheny1)-1,1-dimethyl-ethylamine are
stirred for 30
minutes in 5 mL tetrahydrofuran at ambient temperature. The mixture is cooled
to 0 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 min at
ambient
temperature, combined with 10 mL dichloromethane and 3 mL water, stirred for a
further
hour and then filtered through Extrelut . The eluate containing the
ethanolamine is freed
from the 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
(acetonitrile/water/0,1% trifluoroacetic acid). White solid.
Yield: 31 mg (6%, trifluoroacetate); mass spectroscopy: [M+H]+ = 393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.

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Example 18: 8- {242-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylaminol-l-
hydroxy-
ethyl)-6-hydroxy-4H-benzo[1,41oxazin-3-one-trifluoroacetate
Clip OH CI
HN
OH x CF3COOH
a) 1-(2-chloro-4-fluoro-pheny1)-2-methyl-propan-2-ol
Prepared from 20 g (97 mmol) methyl (2-chloro-4-fluoro-phenyl)-acetate and 98
mL of a 3
molar solution of methylmagnesium bromide analogously to the procedure laid
down for
Example 8a).
b) N42-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylFformamide
7.5 g (37 mmol) 1-(2-chloro-4-fluoro-pheny1)-2-methyl-propan-2-ol were reacted
and
worked up according to the procedure described for Example 10b). 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]+
= 230/232.
c) 2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamine
Reaction of 7.4 g (32 mmol) N-[2-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-
ethy1]-
formamide as described in the procedure laid down for Example 17c). Brown oil.
Yield: 5.14 g (79%); mass spectrometry: [M+Hr = 202/204.
d) 8- {242-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethylj -6-
hydroxy-4H-benzo[1,4]oxazin-3-one
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-
3-one
and 202 mg (1 mmol) 2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamine are
reacted
analogously to the procedure laid down for Example 10d) with lithium
borohydride. In
order to debenzylate the ethanolamine thus obtained it is dissolved in 3 mL

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dichloromethane and cooled to -78 C. At this temperature 2 ml of a 1 molar
solution of
boron tribromide in dichloromethane is added dropwise and the mixture is
allowed to come
slowly up to ambient temperature. The reaction mixture is combined with 10 mL
dichloromethane and 3 mL water and filtered through Extrelut . The eluate is
freed from
the solvent and the residue is purified by chromatography
(acetonitrile/water/0,1%
trifluoroacetic acid). White solid.
Yield: 70 mg (13%, trifluoroacetate); mass spectroscopy: [M+H] = 409/11.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 19: Acid addition salt of 8-{212-(4-chloro-pheny1)-1,1-dimethyl-
ethylamino]-1-
hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one
0.,,..
0 OH
H
HN 40 N
01 CI
OH x HX
A solution of 300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acety1)-4H-
benzo[1,4]oxazin-3-one and 200 mg (1.09 mmol) 2-(4-chloro-pheny1)-1,1-dimethyl-
ethylamine in 3 mL ethanol was combined with molecular sieve and stirred for
90 minutes
at 80 C. The mixture was left to cool to ambient temperature, 35 mg (0.91
mmol) sodium
borohydride were 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 the solvent and the residue was
chromatogaphed (eluant: hexane/ethyl acetate/methanol), yielding 305 mg
ethanolamine.
This was dissolved in 3 mL dichloromethane and under an argon atmosphere
cooled to
-78 C. 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 C and for 20 minutes
at ambient

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temperature. Then at -78 C 3 mL conc. ammonia solution were 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 chromatographed for further purification
(silica gel;
eluant: dichloromethane/methanol + 1% ammonia). Beige solid: 93 mg (26%); mass
spectrometry: [M+H]+ = 391. The product may be converted into the desired acid
addition
salt by reaction with the corresponding acid HX.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.
Example 20: 8- {242-(4-bromo-pheny1)-1,1-dimethyl-ethylaminol-1-hydroxy-ethyll-
6-
hydroxy-4H-benzo[1,41oxazin-3-one acid addition salt
Oye
0 OH
HN
401 Br
OH x HX
The preparation of the ethanolamine and debenzylation were carried out as
described in
Example 19 from 300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acety1)-4H-
benzo[1,4]oxazin-3-one and 250 mg (1.09) mmol) 2-(4-bromo-pheny1)-1,1-dimethyl-
ethylamine. Beige solid.
Yield: 54 mg (14%); mass spectrometry: [M+Hr = 435, 437.
The product may be converted into the desired acid addition salt by reaction
with the
corresponding acid HX.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to current methods known in the art.

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The following compounds of formula 1 according to the invention may also be
obtained
analogously to the examples of synthesis described hereinbefore:
Example 21: Acid addition salt of 8- {242-(3-methyl-pheny1)-1,1-dimethyl-
ethylamino]-
1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 22: Acid addition salt of 8- {2-[2-(4-fluoro-3-methoxy-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 23: Acid addition salt of 8-{242-(4-fluoro-2,6-dimethyl-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 24: Acid addition salt of 8-{242-(4-chloro-2-methyl-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 25: Acid addition salt of 8-{242-(4-chloro-3-fluoro-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethyll -6-hydroxy-4H-benzo [1,4]oxazin-3 -one;
Example 26: Acid addition salt of 8- {242-(4-chloro-2-fluoro-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 27: Acid addition salt of 8- {242-(3-chloro-4-fluoro-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 28: Acid addition salt of 8-{242-(2,6-difluoro-4-methoxy-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 29: Acid addition salt of 8-{242-(2,5-difluoro-4-methoxy-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;

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Example 30: Acid addition salt of 8-{242-(4-fluoro-3,5-dimethyl-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 31: Acid addition salt of 8-{242-(3,5-dichloro-pheny1)-1,1-dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 32: Acid addition salt of 8-{2-[2-(4-chloro-3-methyl-pheny1)-1,1-
dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 33: Acid addition salt of 8-{242-(3,4,5-trifluoro-pheny1)-1,1-dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 34: Acid addition salt of -{2-[2-(3,4-dichloro-pheny1)-1,1-dimethyl-
ethylamino]-1-hydroxy-ethy11-6-hydroxy-4H-benzo[1,4]oxazin-3-one.

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II. Examples of formulations
A) The Table that follows shows examples of formulations of the R-enantiomer
of the
compound of Example 1:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (E-CH3S03H) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 3
2 1.0 15 - 5
3 100 5
4 10 - 5 3
5 1.0 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 90 5 12 3
9 10 5 10 4
2.7 10 10 3
11 0.5 15 10 2

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B) The Table that follows shows examples of formulations of the R-
enantiomer of the
compound of Example 3:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (j-HCl) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 - 3
2 1.0 15 - 5
3 100- - 5
4 10- 5 3
5 1.0- 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 90 10 10 3
9 23 10 10 3
2.7 10 10 3
11 0.5 15 10 2

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C) The
Table that follows shows examples of formulations of the R-enantiomer of the
compound of Example 7:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (-HCl) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 - 3
2 1.0 15 - 5
3 100 - - 5
4 10- 5 3
5 1.0- 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 100 5 12 3
9 10 5 10 4
2.5 10 10 3
11 0.5 15 10 2

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D) The
Table that follows shows examples of formulations of the R-enantiomer of the
compound of Example 9:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (11-HC1) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 - 3
2 1.0 15 - 5
3 100 - - 5
4 10 - 5 3
5 1.0_ 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 100 5 12 3
9 10 5 10 4
2.5 10 10 3
11 0.5 15 10 2

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E) The
Table that follows shows examples of formulations of the R-enantiomer of the
compound of Example 14:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (j.-HCl) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 - 3
2 1.0 15 - 5
3 100- - 5
4 10- 5 3
5 1.0- 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 100 5 12 3
9 10 5 10 4
2.5 10 10 3
11 0.5 15 10 2

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F) The Table that follows shows examples of formulations of the R-enantiomer
of the
compound of Example 17:
100 ml of pharmaceutical formulation contain in purified water or water for
injections:
Example 1 (L-CF3COOH) benzalkonium disodium edetate citric acid
(mg) chloride dihydrate (mg)
(mg) (mg)
1 10 10 3
2 1.0 15 - 5
3 100 5
4 10- 5 3
5 1.0 10 3
6 0.5 5 7 2
7 1000 5 15 4
8 100 5 12 3
9 10 5 10 4
2.5 10 10 3
11 0.5 15 10 2

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G) The Table that follows shows examples of formulations of the R-enantiomer
of the
compound of Example 3:
100 ml of pharmaceutical preparation contain:
Example 1 benzalkonium disodium citric acid to 100 ml with
(E-HC1) chloride edetate (mg) ethanol/water
(mg) (mg) dihydrate mixture
(mg) ( % m/m)
1 10 10 10 3 20/80
2 10 10 10 3 ' 50/50
3 1.0 5 - 3 70/30
4 100 - 10 5 70/30
5 10 - 20 2 70/30
6 1.0 - 10 3 90/10
7 0.5 - 10 2 90/10
8 1000 - - 4 90/10
9 100 - - 3 90/10
10 - - 4 95/5
11 2.5 - - 3 95/5
12 0.5 5 - 3 95/5
13 10- 5 3 100/0
14 10 5 - 3 100/0

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H) The Table that follows shows examples of formulations of the R-
enantiomer of the
compound of Examplel:
100 ml of pharmaceutical preparation contain:
Example 1 benzalkonium disodium citric acid to 100 ml with
(L-CH3S03H) chloride edetate (mg) ethanol/water
(mg) (mg) dihydrate mixture
(mg) ( % m/m)
1 10 10 10 3 20/80
2 10 10 10 - 3 50/50
3 1.0 5 - 3 70/30
4 100 - 10 5 70/30
5 10 - 20 2 70/30
6 1.0 - 10 3 90/10
7 0.5 - 10 2 90/10
8 1000 - - 4 90/10
9 100 - - 3 90/10
10 - - 4 95/5
11 2.5 - - - 3 95/5
12 0.5 5 - 3 95/5
13 10 - 5 3 100/0
14 10 5 - 3 100/0

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I) The Table that follows shows examples of formulations of the R-enantiomer
of the
compound of Example 17:
100 ml of pharmaceutical preparation contain:
Example 1 benzalkonium disodium citric acid to 100 ml with
(E-CF3COOH) chloride edetate (mg) ethanol/water
(mg) (mg) dihydrate mixture
(mg) ( % m/m)
1 10 10 10 3 20/80
2 10 10 10 3 50/50
3 1.0 5 - 3 70/30
4 100 - 10 5 70/30
5 10 - 20 2 70/30
6 1.0 - 10 3 90/10
7 0.5 - 10 2 90/10
8 1000 - - 4 90/10
9 100 - - 3 90/10
10 - - 4 95/5
11 2.5 - - 3 95/5
12 0.5 5 - 3 95/5
13 10 - 5 3 100/0
14 10 5 - ' 3 100/0

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J) The Table that follows shows examples of formulations of the R-enantiomer
of the
compound of Example 13:
100 ml of pharmaceutical preparation contain:
Example 1 benzalkonium disodium citric acid to 100 ml with
(E-HC1) chloride edetate (mg) ethanol/water
(mg) (mg) dihydrate mixture
(mg) ( % m/m)
1 10 10 10 3 20/80
2 10 10 10 3 50/50
3 1.0 5 - 3 70/30
4 100 - 10 5 70/30
5 10 - 20 2 70/30
6 1.0 - 10 3 90/10
7 0.5 - 10 2 90/10
8 1000 - - 4 90/10
9 100 - - 3 90/10
10 - - 4 95/5
11 2.5 - - 3 95/5
12 0.5 5 - 3 95/5
13 10 - 5 3 100/0
14 10 5 - - 3 100/0

Representative Drawing