Note: Descriptions are shown in the official language in which they were submitted.
CA 02559700 2012-07-17
2 57 7 1-12 4 0
1
BENZOXAZINE FOR TREATING RESPIRATORY TRACT DISEASES
The present invention relates to the use of the compounds of general formula 1
OH
R2
Me Me
HN n ISR 1 R3
OH
0 1
wherein the groups R1, R2 and R3 may have the meanings given herein,
for preparing a pharmaceutical composition for the treatment of respiratory
complaints.
Background to the invention
--
Betamimetics (13-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.
The aim of the present invention is therefore to provide betamimetics 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. A particular
aim of the
CA 02559700 2006-09-12
WO 2005/102350 2 PCT/EP2005/004075
invention is to prepare betamimetics which, by virtue of their long-lasting
effect, can be
used to prepare a drug for administration once a day for treating asthma. A
further
objective of the invention, apart from those mentioned above, is to prepare
new
betamimetics which are not only exceptionally potent but are also
characterised by a high
degree of selectivity with respect to the 13-adrenoceptor.
Detailed description of the invention
It has been found that, surprisingly, the above-mentioned problems are solved
by
compounds of general formula 1.
Accordingly, the present invention relates to the use of one or more,
preferably one,
compound of general formula 1
OH
R2 R3
Me Me
HN 410
R
0 OH 1
wherein
denotes 1 or 2, preferably 1;
RI denotes hydrogen, halogen, CI-C4-alkyl or -0-C1-C4-alkyl;
R2 denotes hydrogen, halogen, Ci-C4-alkyl or -0-C1-C4-alkyl;
R3 denotes CI-C4-alkyl, OH, halogen, -0-Ci-C4-alkyl, -0-Ci-C4-alkylene-COOH,
-0-Ci-C4-alkylene-00-0-CI-C4-alkyl,
with the proviso that if Ri and R2 each denote ortho-methyl, R3 cannot
simultaneously be
OH, 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 of various
origins,
bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of
pulmonary
oedema.
WO 2005/102350 CA 02559700 2006-09-123
PCT/EP2005/004075
Preferably, the compounds of general formula 1 used as specified above are
those wherein
denotes 1 or 2, preferably 1;
RI denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R2 denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R3 denotes Ci-C4-alkyl, OH, fluorine, chlorine, bromine, -0-C1-
C4-alkyl,
-0-C1-C4-alkylene-COOH, -0-C1-C4-alkylene-00-0-Ci-C4-alkyl,
with the proviso that if RI and R2 each denote ortho-methyl, R3 cannot
simultaneously be
OH.
Preferably, the compounds of general formula 1 used as specified above are
those wherein
denotes 1;
RI denotes hydrogen or Ci-C4-alkyl;
R2 denotes hydrogen or CI-C4-alkyl;
R3 denotes Ci-C4-alkyl, OH, -0-C1-C4-alkyl, -0-C1-C4-alkylene-
COOH or
-0-C1-C4- alkylene-00-0-Ci-C4-alkyl,
with the proviso that if RI and R2 each denote ortho-methyl, R3 cannot
simultaneously be
OH.
Preferably, the compounds of general formula 1 used as specified above are
those wherein
n denotes 1;
RI denotes hydrogen, methyl or ethyl;
R2 denotes hydrogen, methyl or ethyl;
R3 denotes methyl, ethyl, OH, methoxy, ethoxy, -0-CH2-COOH,
-0-CH2-COOmethyl or -0-CH2-COOethyl,
with the proviso that if RI and R2 each denote ortho-methyl, R3 cannot
simultaneously be
OH.
Preferably, the compounds of general formula 1 used as specified above are
those wherein
denotes 1;
RI denotes hydrogen or methyl;
R2 denotes hydrogen or methyl;
R3 denotes methyl, OH, methoxy, -0-CH2-COOH or -0-CH2-COOethyl,
with the proviso that if RI and R2 each denote ortho-methyl, R3 cannot
simultaneously be
OH.
CA 02559700 2006-09-12
W02005/102350 4 PCT/EP2005/004075
Preferably, according to the invention, the compounds of general formula 1
used as
specified above are those wherein
R3 denotes methoxy, ethoxy, -0-CH2-COOH, -0-CH2-COOmethyl or
-0-CH2-COOethyl,
and RI, R2 and n may have the meanings given above.
The present invention further relates to the above-mentioned use of compounds
of general
formula 1
wherein
n denotes 1;
RI denotes halogen, Ci-C4-alkyl or -0-C i-C4-alkyl;
R2 denotes halogen, Ci-C4-alkyl or -0-Ci-C4-alkyl;
R3 denotes halogen, CI-C4-alkyl or -0-Ci-C4-alkyl.
The present invention further relates to the above-mentioned use of compounds
of general
formula 1
wherein
denotes 1;
RI denotes fluorine, chlorine, methyl or methoxy;
R2 denotes fluorine, chlorine, methyl or methoxy;
R3 denotes fluorine, chlorine, methyl or methoxy.
According to another preferred aspect of the present invention the compounds
of general
formula 1 used as specified above are those wherein
n denotesl;
RI denotes hydrogen;
R2 denotes hydrogen, fluorine, chlorine or methyl;
R3 denotes methyl, ethyl, iso-propyl, tert.-butyl, OH, fluorine, chlorine,
bromine,
methoxy, ethoxy, -0-CH2-COOH, -0-CH2-CH2-COOH, -0-CH2-CH2-CH2-
COOH, -0-CH2-COOmethyl, -0-CH2-COOethyl, -0-CH2-CH2-COOmethyl,
-0-CH2-CH2-COOethyl, -0-CH2-CH2-CH2-COOmethyl or -0-CH2-CH2-CH2-
COOethyl.
Particularly preferably, the compounds of general formula! used as specified
above are
those wherein
CA 02559700 2006-09-12
WO 2005/102350 5 PCT/EP2005/004075
denotes 1;
R1 denotes hydrogen;
R2 denotes hydrogen, fluorine, chlorine or methyl;
R3 denotes OH, fluorine, chlorine, methyl, methoxy, ethoxy or -0-CH2-COOH.
Moreover it is particularly preferable according to the invention if the
compounds of
general formula 1 according to the invention used as specified above are those
wherein
denotes 1;
RI denotes hydrogen;
R2 denotes halogen, CI-C4-alkyl or -0-C1-C4-alkyl,
preferably fluorine, chlorine, methoxy or methyl;
R3 denotes halogen, CI-C4-alkyl or -0-C1-C4-alkyl,
preferably fluorine, chlorine, methoxy or methyl.
In another preferred aspect of the present invention the compounds of general
formula 1
according to the invention used as specified above are those wherein n = 1 ,
RI and R2
denote hydrogen and the group R3 may have the meanings given above.
In another preferred aspect of the present invention the compounds of general
formula 1
according to the invention used as specified above are those wherein
RI and R2 denote hydrogen;
R3 denotes methyl, ethyl, iso-propyl, tert.-butyl, OH, fluorine, chlorine,
bromine,
methoxy, ethoxy, -0-CH2-COOH, -0-CH2-CH2-COOH, -0-CH2-CH2-CH2-
COOH, -0-CH2-COOmethyl, -0-CH2-COOethyl, -0-CH2-CH2-COOmethyl,
-0-CH2-CH2-COOethyl, -0-CH2-CH2-CH2-COOmethyl, -0-CH2-CH2-CH2-
COOethyl.
Particularly preferably the compounds of general formula 1 according to the
invention used
as specified above are those wherein
n denotes 1;
RI and R2 denote hydrogen;
R3 denotes OH, fluorine, chlorine, methoxy, ethoxy,-0-CH2-COOH, preferably
OH, fluorine, chlorine, ethoxy or methoxy.
CA 02559700 2006-09-12
W02005/102350 6 PCT/EP2005/004075
Particularly preferably the compounds of general formula 1 according to the
invention used
as specified above are those wherein
denotes 1;
RI and R2 denote hydrogen;
R3 denote fluorine, chlorine, methoxy or ethoxy.
The present invention further relates to the above-mentioned use of compounds
of general
formula 1, wherein
denotes 1;
Ri denotes hydrogen, halogen, Ci-C4-alkyl or -0-C i-C4-alkyl;
R2 denotes hydrogen, halogen, Ci-C4-alkyl or -0-C1-C4-alkyl;
R3 denotes hydrogen.
Preferably, the compounds of general formula! used as specified above are
those wherein
n denotes 1;
RI denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R2 denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R3 denotes hydrogen.
The present invention further relates to the above-mentioned use of compounds
of general
formula 1, wherein
denotes 1;
RI denotes fluorine, chlorine, methyl or methoxy;
R2 denotes fluorine, chlorine, methyl or methoxy;
R3 denotes hydrogen.
In the compounds of formula! the groups RI and R2, if they do not represent
hydrogen,
may each be arranged in the ortho or meta position relative to the bond to the
benzylic
"-CH2" group. If none of the groups RI and R2 denotes hydrogen, preferred
compounds of
formula! for the use according to the invention are those wherein either both
groups RI
and R2 are ortho or both groups RI and R2 are in the meta configuration, while
compounds
in which both groups RI and R2 are in the ortho-configuration are of
particular importance.
In the compounds of formula! wherein one of the groups RI and R2 does not
denote
hydrogen, this group may be in the ortho or meta position relative to the bond
to the
benzylic "-CH2" group. In this case those compounds of formula! wherein the
group RI or
CA 02559700 2006-09-12
W02005/102350 7 PCT/EP2005/004075
R2 which does not denote hydrogen is in the ortho configuration are
particularly preferred
for use according to the invention.
Particularly preferably, one or more of the following compounds of general
formula! are
used for the purpose described above:
- 6-hydroxy-8-{1-hydroxy-242-(4-methoxy-pheny1)-1,1-dimethyl-ethylaminol-
ethyll-
4H-benzo[1,4]oxazin-3-one;
- 6-hydroxy-8- {1-hydroxy-2-[2-(4- ethyl-phenoxy-acetate)-1,1-dimethyl-
ethylamino]-
ethy1}-4H-benzo[1,4]oxazin-3-one;
- 6-hydroxy-8- {1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-
ethylamino]-
ethy1}-4H-benzo[1,4]oxazin-3-one;
- 8- {2-[1,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethylamino]-1-hydroxy-ethyll-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 6-hydroxy-8- {1-hydroxy-242-(4-hydroxy-pheny1)-1,1-dimethyl-
ethylaminoFethyl} -
4H-benzo[1,4]oxazin-3-one;
- 6-hydroxy-8- {1-hydroxy-242-(4-isopropyl-pheny1)-1,1dimethyl-ethylamino}-
ethyll -
4H-benzo[1,4]oxazin-3-one;
- 8- {212-(4-ethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-4H-
benzorl ,4]oxazin-3-one;
- 8- {242-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl
} -6-
hydroxy-4H-benzo [1,4]oxazin-3-one;
- 8- {212-(4-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy11-
6-
hydroxy-4H-benzo[1,41oxazin-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-ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-ethoxy-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-4H-benzo [1,4]oxazin-3-one;
- 4-(4- {242-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y1)-
ethylamino]-2-methyl-propyll-phenoxy)-butyric acid;
- 8- {24243 ,4-di fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
W02005/102350 CA 02559700 2006-09-128
PCT/EP2005/004075
- 8- {242-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl} -6-
hydroxy-4H-benzo [1,4]oxazin-3-one;
- 8- {242-(4-chloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-bromo-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl} -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one;
- 8-1242-(4-fluoro-3-methoxy-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(4-fluoro-2,6-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll -
6-hydroxy-4H-benzo[l ,4]oxazin-3-one;
- 8- {242-(4-chloro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {212-(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-ethylamino]-1-hydroxy-
ethyl} -6-
hydroxy-4H-benzo[1,4] oxazin-3-one;
- 8- {2-[2-(3-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -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-
ethyll -
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3,5-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {2-[2-(4-chloro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {2-[2-(3,4,5-trifluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl
} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
- 8- {242-(3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl} -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one and
CA 02559700 2012-07-17
25771-1240
9
- 8- (242-(3,4-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one.
A particularly preferred compound is 6-hydroxy-8-11-hydroxy-2-[2-(4-methoxy-
phenyl)-1,1-dimethyl-ethylamino]-ethyl)-4H-benzo[1,4]oxazin-3-one. The
R-enantiomer of the compound is specifically preferred.
In another aspect the present invention relates to the above-mentioned use of
the
compounds of formula 1 in the form of the individual optical isomers, or
mixtures of the
individual enantiomers or racemates. It is particularly preferable to use the
compounds of
formula! for the purpose described above in the form of the enantiomerically
pure
compounds, while the use of the R-enantiomers of the compounds of formula 1 is
of
exceptional importance according to the invention.
In another aspect the present invention relates to the above-mentioned use of
the
compounds of formula! in the form of the acid addition salts with
pharmacologically
acceptable acids as well as optionally in the form of the solvates and/or
hydrates.
The compounds of general formula! are preferably used for preparing a
pharmaceutical
composition for the treatment of obstructive pulmonary diseases selected from
among
bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks and
chronic
bronchitis, while it is particularly preferable according to the invention to
use them for
preparing a pharmaceutical composition for the treatment of bronchial asthma.
It is also preferable to use the compounds of general formula! for preparing a
pharmaceutical composition for the treatment of pulmonary emphysema which has
its
origins in COPD (chronic obstructive pulmonary disease) or al -proteinase
inhibitor
deficiency.
It is also preferable to use the compounds of general formula 1 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 compounds of general formula 1 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,
CA 02559700 2006-09-12
WO 2005/102350 10 PCT/EP2005/004075
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
sclerodermy or sarcoidosis, granulomatoses, such as for example Boeck's
disease,
idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
It is also preferable to use the compounds of general formula 1 for preparing
a
pharmaceutical composition for the treatment of cystic fibrosis or
mucoviscidosis.
It is also preferable to use the compounds of general formula 1 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 compounds of general formula 1 for preparing
a
pharmaceutical composition for the treatment of bronchiectasis.
It is also preferable to use the compounds of general formula 1 for preparing
a
pharmaceutical composition for the treatment of ARDS (adult respiratory
distress
syndrome).
It is also preferable to use the compounds of general formula 1 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.
It is particularly preferable to use the compounds detailed above for
preparing a
pharmaceutical composition for the treatment of asthma or COPD. Also of
particular
importance is the above-mentioned use of compounds of formula 1 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.
The present invention also relates to a process for the treatment of the above-
mentioned
diseases, characterised in that one or more of the above-mentioned compounds
of general
formula 1 are administered in therapeutically effective amounts. The present
invention
further relates to processes for the treatment of Asthma, characterised in
that one or more
CA 02559700 2006-09-12
WO 2005/102350 11 PCT/EP2005/004075
of the above-mentioned compounds of general formula 1 are administered once a
day in
therapeutically effective amounts.
By acid addition salts with pharmacologically acceptable acids are meant for
example salts
selected from the group comprising the hydrochloride, hydrobromide,
hydroiodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,
hydromaleate,
hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably the
hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
Of the above-mentioned acid addition salts, the salts of hydrochloric acid,
methanesulphonic acid, benzoic acid and acetic acid are particularly preferred
according to
the invention.
For use according to the invention the compounds of general formula! may
optionally be
used in the form of the individual optical isomers, mixtures of the individual
enantiomers
or racemates. If the compounds are used in enantiomerically pure form, the R-
enantiomers
are preferably used.
Unless otherwise stated, the alkyl groups are straight-chained or branched
alkyl groups
having Ito 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 groups) denotes
branched
and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an
oxygen
WO 2005/102350 CA 02559700 2006-09-1212
PCT/EP2005/004075
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
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.
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 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 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.
CA 02559700 2006-09-12
WO 2005/102350 13 PCT/EP2005/004075
Example 1: 6-hydroxy-8- 1L1-hydroxy-242-(4-methoxy-pheny1)-1,1-dimethyl-
ethylamino1-
ethyll-4H-benzo[1,4]oxazin-3-one
o OH
HN
Me Me OMe
OH
a) 8-{241,1-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
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- {241,1-dimethy1-2-(4-methoxy-pheny1)-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one
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 solvent.
After
recrystallisation of the residue from 50 mL acetone and some 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 1 may be obtained from the racemate,
for
example, by means of chiral HPLC (e.g. column: Chirobiotic T, 250 x 22.1 mm
supplied
by Messrs Astec). The mobile phase used may be methanol with 0.05 %
triethylamine and
0.05% acetic acid. Silica gel with a particle size of 5 p,m, to which the
glycoprotein
teicoplanin is covalently bound, may be used as column material.
WO 2005/102350 CA 02559700 2006-09-1214
PCT/EP2005/004075
Retention time (R-enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9
min. The
two enantiomers are obtained by this method in the form of the free bases.
Of outstanding importance according to the invention is the R-enantiomer of
Example 1.
Example 2: 6-h_ydroxy-8-{1-hydroxy-242-( ethyl 4-phenoxy-acetate)-1,1-dimethyl-
ethylaminoi-ethyll-4H-benzo[1,4]oxazin-3-one
HN OH
OH Me Me 1. 0- y 0 ,OEthyl
a) 8- {211,1-dimethy1-24 ethyl 4-phenoxy-acetate)-ethylamino]-1-hydroxy-ethy11-
6-
benzyloxy-4H-benzo[1,4]oxazin-3-one
Analogously to the method described in Example la) 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-
( ethyl 4-phenoxy-acetate)-ethylamine hydrochloride.
15 Yield: 16.5 g (69%, hydrochloride); m.p. = 212-214 C.
b) 8- {2-11,1-dimethy1-2-(4-phenoxy-acetate ethyl)-ethylamino]-1-hydroxy-
ethy11-6-
hydroxy-4H-benzo[1,4Joxazin-3-one
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 common methods known in the art.
,
CA 02559700 2006-09-12
WO 2005/102350 15 PCT/EP2005/004075
Example 3: 6-hydroxy-8- { I -hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-
ethylaminoFethyl } -4H-benzo[1,4]oxazin-3-one
C)0 OH H
HN I. N
Me Me 11101
0-.COOH
OH
11 g 8-{2-[1,1-dimethy1-2-(4-phenoxy-acetate ethyl)-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 residue 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 common methods known in the art.
Example 4: 8- {2-11,1-dimethy1-2-(2,4,6-trimethylpheny1)-ethylamino]-1-hydroxy-
ethyll -
6-hydroxy-4H-benzo[1,4]oxazin-3-one
C)0 OH H Me
Me Me 0
Me Me
OH
a) 1-(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-211,1-dimethy1-2-(2,4,6-
trimethylpheny1)-
ethyliminoi-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-trimethylpheny1)-ethylamine are heated to 70 C for one hour in 100 mL
ethanol.
, WO 2005/102350 CA 02559700 2006-09-
1216 PCT/EP2005/004075
After cooling the solid precipitated is 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)-ethylamino]-1-hydroxy-ethyll-
6-
benzylox_y-4H-benzo[1,4]oxazin-3-one
8.6 g of the Schiffs base obtained according to the prescribed method 6a) are
dissolved in
100 mL ethanol and 20 mL THF, combined within 30 min at 10-20 C with 0.7 g
sodium
borohydride 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- {241,1-dimethy1-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethy11-6-
hydroxy-
4H-benzo[1,41oxazin-3-one
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 common methods known in the art.
Example 5: 6-hydroxy-8- {1-hydroxy-242-(4-hydroxy-pheny1)-1,1-dimethyl-
ethylaminol-
ethyl} -4H-benzo[1,4]oxazin-3-one
HN 0 N OH H
OH Me Me 40 OH
CA 02559700 2006-09-12
WO 2005/102350 17 PCT/EP2005/004075
a) 8- 12-{1,1-dimethy1-2-(4-hydroxy-pheny1)-ethylamino]-1-hydroxy-ethyl} -6-
benzyloxy-
4H-benzo[1,4]oxazin-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-pheny1)-ethylamine
analogously to
the procedure laid down for Example la).
Yield: 9.0 g (64%, hydrochloride); m.p. = 255-258 C.
b) 8- {2-[1,1-dimethy1-2-(4-hydroxy-phenyl)-ethylamino]-1-hydroxy-ethyll-6-
hydroxy-
41-1-benzo[1,4]oxazin-3-one
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
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 common methods known in the art.
Example 6: 6-hydroxy-8- {1-hydroxy-2-1-2-(4-isopropyl-pheny1)-1,1dimeth_yl-
ethylaminoi-
ethyl } -4H-benzo [1,4] oxazin-3 -one
0.........---,.
0 OH
H
HN I. N
1110
OH
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+F1J+ = 193.
CA 02559700 2006-09-12
WO 2005/102350 18 PCT/EP2005/004075
b) N-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethyl]Hacetamide
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 7b). 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+1-1]+ = 234.
c) 2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamine
Reaction of 9.80 g (42 mmol) N42-(4-isopropyl-pheny1)-1,1-dimethyl-ethyll-
acetamide
analogously to the procedure laid down for Example 7c).
Yield: 7.00 g (71%, hydrochloride); m.p. = 202-206 C.
d) 6-benzyloxy-8-{1-hydroxy-242-(4-isopropyl-pheny1)-1,1-dimethyl-ethylaminol-
ethy1}-
4H-benzo[1,4]oxazin-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)
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 %, hydrochloride); m.p. = 220-222 C.
e) 6-hydroxy-8- {1-hydroxy-242-(4-isopropyl-pheny1)-1,1dimethyl-ethylaminol-
ethy11-
4H-benzoil,4]oxazin-3-one
1.6 g (3.0 mmol) 6-benzyloxy-8-11-hydroxy-242-(4-isopropyl-pheny1)-1,1-
dimethyl-
ethylamino]-ethyl}-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 distilled off and
the residue
recrystallised from isopropanol. White solid.
Yield: 1.1 g (85%, hydrochloride); m.p. = 248-250 C; mass spectrometry: [M+1-
11- = 399.
CA 02559700 2006-09-12
WO 2005/102350 19 PCT/EP2005/004075
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 7: 8- {242-(4-ethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy11-
6-
hydroxy-4H-benzo[1,4]oxazin-3-one
0 OH
HN
11101
OH
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 being cooled 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 left to reflux 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-ethyl]-acetamide
6.2 mL conc. sulphuric acid are added dropwise within 15 minutes 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, while the temperature rises to 65 C. Then the mixture is stirred
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, during
which time
a solid is precipitated, which is filtered off and dried.
Yield: 16.3 g (85%); m.p. = 90-92 C.
WO 2005/102350 CA 02559700 2006-09-1220
PCT/EP2005/004075
c) 2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamine
16.3 g (74 mmol) N-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethyll-acetamide and 8.0 g
potassium hydroxide are heated for 15 hours in 60 mL ethyleneglycol at reflux
temperature. 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.
d) 6-benzyloxy-8- {242-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -4H-
benzo[1,4Joxazin-3-one
The target compound is prepared analogously to the procedure laid down for
Example 6d)
from 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 (5.6 mmol) 2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamine. White
solid.
Yield: 1.7 g (54%, hydrochloride); m.p. 210-214 C.
e) 8- {2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl } -6-
hydroxy-4H-
benzo[1,4]oxazin-3-one
The hydrogenolysis of 1.45 g (2.75 mmol) 6-benzyloxy-8-{2-[2-(4-ethyl-pheny1)-
1,1-
dimethyl-ethylamino]-1-hydroxy-ethyll-4H-benzo[1,4]oxazin-3-one according to
the
prescribed method for Example 6e) 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+Hi+ = 385.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
CA 02559700 2006-09-12
WO 2005/102350 21 PCT/EP2005/004075
Example 8: 8- {242-(4-Fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl -6-hydroxy-4H-benzo[1,4]oxazin-3-one
O OH
HN
OH
a) 1-fluoro-2-methy1-442-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, while
the
temperature rises to 45 C . It is stirred for 30 minutes, refluxed for 1 hour
and then
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 of 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 this is
washed with
water, dried with sodium sulphate and freed from the solvent. Fractionated
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-ethyli-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. Then the mixture is 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,l-dimethyl-ethylamine
4.3 g (20.6 mmol) N-[2-(4-fluoro-3-methyl-phenyl)-1,1-dimethyl-ethyl]-
formamide, 20
mL conc. hydrochloric acid and 20 mL water are refluxed for 2 hours. The
reaction
WO 2005/102350 CA 02559700 2006-09-1222
PCT/EP2005/004075
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.
d) 6-benzyloxy-8- {242-(4-fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl } -4H-benzo[1,4]oxazin-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-phenyl)-1,1-dimethyl-ethylamine are
reacted
and worked up analogously to the procedure laid down for Example 6d). White
solid.
Yield: 0.75 g (47%, hydrochloride); m.p. 228-230 C.
e) 8- {242-(4-Fluoro-3-methyl-pheny1)-1,1-dimethyl-ethylamino1-1-hydroxy-
ethy11-6-
hydroxy-4H-benzo[1,41oxazin-3-one
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+Hr
= 389.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 9: 8- {242-(4-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl } -6-hydroxy-4H-benzo(1,4]oxazin-3-one
0 HN OH
401
OH
a) 1-(4-fluoro-2-methyl.phenyl)-2-methyl-propyl acetate
WO 2005/102350 CA 02559700 2006-09-1223
PCT/EP2005/004075
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 8a). 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
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. The mixture 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) N42-(4-fluoro-2-methyl-pheny1)-1,1-dimethyl-ethyl]-formamide
29.0 g (130 mmol) 1-(4-fluoro-2-methyl-pheny1)-2-methyl-propyl acetate
are reacted and worked up analogously to the procedure laid down for Example
8b).
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) N42-(4-fluoro-2-methyl-pheny1)-
1,1-
dimethyl-ethyl]-formamide are reacted as in the procedure laid down for
Example 8c).
White solid. Yield: 15.5 g (55%, hydrochloride); m.p. = 277-280 C.
d) 6-benzyloxy-8-124244-fluoro-2-methyl-pheny1)-1,1-dimethyl-eth_ylamino]-1-
hydroxy-
ethyll-4H-benzo[1,4]oxazin-3-one
Prepared analogously to the procedure laid down for Example 6d) 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- {242-(4-fluoro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl
-6-
hydroxy-4H-benzo[1,4]oxazin-3-one
The debenzylation of 0.70 g (1.36 mmol) 6-benzyloxy-8-124244-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]f = 389.
CA 02559700 2006-09-12
WO 2005/102350 24 PCT/EP2005/004075
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 10: 8- {242-(2,4-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl 1 -6-
hydroxy-4H-benzoj1,4Joxazin-3-one
0,.....õ,,..õ
0 OH F
H
HN 40 N
le F
OH
a) 1-(2,4-difluoro-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 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-phenyl]-1,1-dimethyl-ethyll-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 8b). Yellow oil. Yield: 22.0 g
(94%).
c) 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamine
Reaction of 22.0 g (100 mmol) N-[2-(2,4-difluoro-pheny1]-1,1-dimethyl-ethyl]-
formamide
analogously to the procedure laid down for Example 8c).
Yield: 16.0 g (72%, hydrochloride); m.p. = 201-203 C.
d) 6-benzyloxy-8- {242-(2,4-difluoro-pheny1)-1,1-dimethyl-ethylaminoi-1-
hydroxy-ethyl}-
4H-benzo[1,41oxazin-3-one
CA 02559700 2006-09-12
WO 2005/102350 25 PCT/EP2005/004075
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 6d).
Yield: 0.80 g (62%, hydrochloride); m.p. = 245-247 C.
e) 8- {242-(2,4-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
hydroxy-
4H-benzo[1,4]oxazin-3-one
The hydrogenolysis of 0.70 g (1.35 mmol) 6-benzyloxy-8-{212-(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+H]+ = 393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 11: 8- {242-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one
0
OH
H
HN le N 1 F
40
OH F
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%).
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%).
WO 2005/102350 CA 02559700 2006-09-1226
PCT/EP2005/004075
c) 6-benzyloxy-8-{2-[2-(3,5-difluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyll-
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[1,4]oxazin-3-one
Hydrogenolysis of 1.30 g (2.43 mmol) 6-benzyloxy-8- {242-(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+Hr
= 393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 12: 8- {242-(4-ethoxy-phenyl)-1, I -dimethyl-ethylaminol-l-hydroxy-
ethyl} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one
HN 0 OH
1.1OH o-\
a) benzyl [2-(4-ethoxy-phenyl)-1,1-dimethyl-ethy1]-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
WO 2005/102350 CA 02559700 2006-09-1227
PCT/EP2005/004075
A solution of 15.0 g (49 mmol) benzyl [2-(4-ethoxy-pheny1)-1,1-dimethyl-ethyl]-
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 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-{242-(4-ethoxy-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethy11-
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 dissolved again
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.
d) 8- {242-(4-ethoxy-pheny1)-1,1-dimethyl-ethyl amino] -1-hydroxy-ethy11-6-
hydroxy-4H-
benzo[1,41oxazin-3-one
1.5 g (2.8 mmol) 6-benzyloxy-8-{242-(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: [IVI+H]+
= 401.
CA 02559700 2006-09-12
WO 2005/102350 28 PCT/EP2005/004075
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art .
Example 13: 8-{2-12-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyll-
6-hydroxy-4H-benzo[1,4]oxazin-3-one
0 OH
HN
4101
OH
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-phenyl)-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-ethylformamid (35% yield) are obtained. To release the the amine the
formamide (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 8c). Oil.
Yield: 1.70 g
(82%); mass spectroscopy: [M+1-11+ = 178.
c) 6-benzyloxy-8-{242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethy1}-4H-benzo[1 ,4]oxazin-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- t242-(3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll -6-
hydroxy-
4H-benzo[1,4]oxazin-3-one
The target compound was obtained after hydrogenolysis of 0.90 g (1.71 mmol) 6-
benzyloxy-8- {21243 ,5-dimethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl -4H-
WO 2005/102350 CA 02559700 2006-09-1229
PCT/EP2005/004075
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+1-
1]+ = 385.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 14: 4-(4- {2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-
benzo[1,4]oxazin-
8-y1)-ethylamino]-2-methyl-propyl -phenoxy)-butyric acid
0 HN OH
101OH
OH 0
a) ethyl 444-(2-amino-2-methyl-propy1)-phenoxyl-butyrate
4.5 g (15.0 mmol) benzyl [2-(4-hydroxy-phenyl)-1,1-dimethyl-ethyl] -carbamate,
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 dimethylformamid are heated to 120 C for 13
hours.
The reaction mixture is diluted with ethyl acetate and washed successively
with water,
sodium hydroxide solution and water. The organic phase is dried with sodium
sulphate and
evaporated down. The residue is purified by chromatography (eluant:
cyclohexane/ethyl
acetate = 9:1). 5.0 g of a yellow oil are 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) 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 ethyl
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
WO 2005/102350
CA 02559700 2006-09-12 30
PCT/EP2005/004075
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-{212-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y1)-2-
hydroxy-
ethylamino]-2-methyl-propyll-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-propyll-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 in 5 mL n-butanol by heating. After the
addition of a
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- {2-12-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzol1,4]oxazin-8-
y1)-
ethylamino]-2-methyl-propyll-phenoxy)-butyric acid
0.70 g (1.28 mmol) 4-(4-1242-(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 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+1-1] = 459.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 15: 8- {242-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydrox_y-
ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one
O OH HN
1101
OH
WO 2005/102350 CA 02559700 2006-09-1231
PCT/EP2005/004075
a) 1-(3,4-difluoro-phenyl)-2-methyl-propan-2-ol
From 23.0 g (111 mmol) 3,4-difluorobenzylbromide a Grignard compound 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).
b) N42-(3,4-difluoro-pheny1)-1,1-dimethyl-ethyl]-formamide
The target compound is obtained by a Ritter reaction with 4.0 g (21.5 mmol)
difluoro-pheny1)-2-methyl-propan-2-ol. Light yellow oil.
Yield: 4.0 g (87%); mass spectrometry: [M+1-1]+ = 214.
c) 2-(3,4-difluoro-pheny1)-1,1-dimethyl-ethylamine
4.00 g (18.5 mmol) N12-(3,4-difluoro-pheny1)-1,1-dimethyl-ethyThformamide 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+1-1]+ = 186.
d) 8- {24243 ,4-di fluoro-phenyl)-1,1-dimethyl-ethyl amino]-1-hydroxy-ethy11-6-
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-phenyl)-1,1-dimethyl-ethylamine are
stirred for 30
minutes in 5 mL tetrahydrofiiran 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 8. 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 purified by chromatography. White solid.
Yield: 31 mg (6%, trifluorethyl acetate); mass spectroscopy: [M+f-1]- = 393.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
WO 2005/102350 CA 02559700 2006-09-1232
PCT/EP2005/004075
Example 16: 8- {242-(2-chloro-4-fluoro-pheny1)-1,1-dimeth_yl-ethylaminol-1-
hydroxy-
ethyl -6-hydroxy-4H-benzo[1,41oxazin-3-one
0 HN OH CI
401
a) 1-(2-chloro-4-fluoro-pheny1)-2-methyl-propan-2-ol OH
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 6a).
b) N-[2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethyl]-formamide
7.5 g (37 mmol) 1-(2-chloro-4-fluoro-phenyl)-2-methyl-propan-2-ol were reacted
and
worked up according to the procedure described for Example 8b). 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+FITE
= 230/232.
c) 2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamine
Reaction of 7.4 g (32 mmol) N42-(2-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethyl]-
formamide as in the procedure laid down for Example 15c) described. Brown oil.
Yield:
5.14 g (79%); mass spectrometry: [M+Hr = 202/204.
d) 8- {2-[2-(2-chloro-4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl} -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
with lithium borohydride analogously to the procedure laid down for Example
8d). For
debenzylation of the ethanolamine thus obtained the latter is dissolved in 3
mL
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
CA 02559700 2006-09-12
WO 2005/102350 33 PCT/EP2005/004075
the solvent and the residue is purified by chromatography. White solid. Yield:
70 mg
(13%, trifluorethyl acetate); mass spectroscopy: [M+II]+ = 409/11.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 17: 8- {242-(4-ch1oro-phenyl)-1,1-dimethyl-ethylaminol-1-hydroxy-
ethyll -6-
hydroxy-4H-benzo[1,4]oxazin-3-one
OH
HN ii
CI
OH
A solution of 300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-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
chromatographed (eluant: hexane/ethyl acetate /methanol), producing 305 mg
ethanolamine. This was dissolved in 3 mL dichloromethane and cooled to -78 C
under an
argon atmosphere. 3 mL of a 1 molar solution of boron tribromide in
dichloromethane
were added dropwise and the mixture was left for one hour at -78 C and 20
minutes at
ambient temperature with stirring. Then at -78 C 3 mL conc. ammonia solution
was added
dropwise and the mixture was stirred for 5 minutes. The reaction mixture was
combined
with ammonium chloride solution and extracted with ethyl acetate. The combined
organic
phases were evaporated down and the residue was chromatographed for further
purification (silica gel; eluant: dichloromethane/methanol + 1% ammonia).
Beige solid: 93
mg (26%); mass spectrometry: [M+H]+ = 391.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
WO 2005/102350 CA 02559700 2006-09-1234
PCT/EP2005/004075
Example 18: 8-{242-(4-bromo-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethy1}-
6-
hydroxy-4H-benzo[l,4]oxazin-3-one
0 HN OH
OH Br
The preparation of the ethanolamine and debenzylation were carried out as
described for
Example 17 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+H]+ = 435,
437.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
Example 19: 8- {242-(4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethy11-6-
hydroxy-4H-benzo[1,4]oxazin-3-one
0 HN OH
110
OH
300 mg (0.91 mmol) 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-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 ethanol. Molecular sieve was added and the mixture was heated to 80 C for
30
minutes. After cooling to ambient temperature, 35 mg (0.91 mmol) sodium
borohydride
were added. The mixture was stirred for 1 hour at ambient temperature, then
sodium
hydrogen carbonate solution was added to the reaction mixture and it was
extracted with
ethyl acetate. The organic phases were evaporated down and the residue was
chromatographed (eluant: hexane/ethyl acetate /methanol). The ethanolamine
thus obtained
WO 2005/102350 CA 02559700 2006-09-1235
PCT/EP2005/004075
(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 Celite ,
the filtrate
was freed from solvent and the residue was chromatographed (silica gel;
eluant:
dichloromethane/methanol). Beige solid.
Yield: 76 mg (22%); mass spectrometry: [M+H]+ = 375.
The (R)- and (S)-enantiomers of this embodiment may be obtained by separation
of the
racemate analogously to common methods known in the art.
The following compounds of formula! according to the invention may also be
obtained
analogously to the Examples of synthesis described above:
Example 20: 8- {242-(4-fluoro-3-methoxy-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 21: 8- {242-(4-fluoro-2,6-dimethyl-pheny1)-1,1-dimethyl-ethylaminoll -
hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 22: 8-1242-(4-chloro-2-methyl-phenyl)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl } -6-hydroxy-4H-benzo [1,4]oxazin-3 -one;
Example 23: 8- {2-[2-(4-chloro-3-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 24: 8-1242-(4-chloro-2-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy11-6-hydroxy-4H-benzo[1,41oxazin-3-one;
Example 25: 8- {2-[2-(3-chloro-4-fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethy1}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 26: 8- {242-(2,6-difluoro-4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;
CA 02559700 2006-09-12
WO 2005/102350 36 PCT/EP2005/004075
Example 27: 8- {242-(2,5-difluoro-4-methoxy-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl } -6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 28: 8- {242-(4-fluoro-3,5-dimethyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-ethyl1-6-hydroxy-4H-benzo[1,41oxazin-3-one;
Example 29: 8- {242-(3,5-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 30: 8- {212-(4-chloro-3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-
hydroxy-
ethyl} -6-hydroxy-4H-benzo [1,4]oxazin-3-one;
Example 31: 8- {21243,4,546 fluoro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl} -
6-hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 32: 8-1242-(3-methyl-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyll
-6-
hydroxy-4H-benzo[1,4]oxazin-3-one;
Example 33: 8-1242-(3,4-dichloro-pheny1)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -
6-hydroxy-4H-benzo[1,4]oxazin-3-one.
Suitable preparations for administering the compounds of formula 1 include for
example
tablets, capsules, suppositories, solutions, powders, etc. The content of the
pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-
%,
preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may
be obtained,
for example, by mixing the active substance(s) with known excipients, for
example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
disintegrants such as
corn starch or alginic acid, binders such as starch or gelatine, lubricants
such as magnesium
stearate or talc and/or agents for delaying release, such as carboxymethyl
cellulose,
cellulose acetate phthalate, or polyvinyl acetate. The tablets may also
comprise several
layers.
Coated tablets may be prepared accordingly by coating cores produced
analogously to the
tablets with substances normally used for tablet coatings, for example
collidone or shellac,
gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or
prevent
WO 2005/102350 CA 02559700 2006-09-1237
PCT/EP2005/004075
incompatibilities the core may also consist of a number of layers. Similarly
the tablet
coating may consist of a number of layers to achieve delayed release, possibly
using the
excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations of active
substances
according to the invention may additionally contain a sweetener such as
saccharine,
cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as
vanillin or
orange extract. They may also contain suspension adjuvants or thickeners such
as sodium
carboxymethyl cellulose, wetting agents such as, for example, condensation
products of
fatty alcohols with ethylene oxide, or preservatives such as p-
hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of isotonic
agents,
preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal
salts of
ethylenediaminetetraacetic acid, optionally using emulsifiers and/or
dispersants, while if
water is used as diluent, for example, organic solvents may optionally be used
as
solubilisers or dissolving aids, and the solutions may be transferred into
injection vials or
ampoules or infusion bottles.
Capsules containing one or more active substances or combinations of active
substances
may for example be prepared by mixing the active substances with inert
carriers such as
lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for this
purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof
Excipients which may be used include, for example, water, pharmaceutically
acceptable
organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils
(e.g. groundnut
or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol),
carriers such as
e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic
mineral powders
(e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar,
lactose and
glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose,
starch and
polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic
acid and
sodium lauryl sulphate).
For oral use the tablets may obviously contain, in addition to the carriers
specified,
additives such as sodium citrate, calcium carbonate and dicalcium phosphate
together with
CA 02559700 2006-09-12
WO 2005/102350 38 PCT/EP2005/004075
various additional substances such as starch, preferably potato starch,
gelatine and the like.
Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also
be used to
produce the tablets. In the case of aqueous suspensions the active substances
may be
combined with various flavour enhancers or colourings in addition to the
abovementioned
excipients.
In the preferred use of the compounds of formula 1 for the treatment of asthma
or COPD
according to the invention it is particularly preferred to use preparations or
pharmaceutical
formulations which are suitable for inhalation. Inhalable preparations include
inhalable
powders, propellant-containing metered-dose aerosols or propellant-free
inhalable
solutions. Within the scope of the present invention, the term propellant-free
inhalable
solutions also includes concentrates or sterile ready-to-use inhalable
solutions. The
formulations which may be used within the scope of the present invention are
described in
more detail in the next part of the specification.
The inhalable powders which may be used according to the invention may
contain! either
on its own or in admixture with suitable physiologically acceptable
excipients.
If the active substances 1 are present in admixture with physiologically
acceptable
excipients, the following physiologically acceptable excipients may be used to
prepare
these inhalable powders according to the invention: monosaccharides (e.g.
glucose or
arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and
polysaccharides
(e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.
sodium chloride,
calcium carbonate) or mixtures of these excipients. Preferably, mono- or
disaccharides are
used, while the use of lactose or glucose is preferred, particularly, but not
exclusively, in
the form of their hydrates. For the purposes of the invention, lactose is the
particularly
preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients have a
maximum average particle size of up to 250 pm, preferably between 10 and 150
pm, most
preferably between 15 and 80 pm. In some cases it may seem appropriate to add
finer
excipient fractions with an average particle size of 1 to 9 1.tm to the
excipients mentioned
above. These finer excipients are also selected from the group of possible
excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders according to
the invention,
micronised active substance 1, preferably with an average particle size of 0.5
to 10 gam,
WO 2005/102350 CA 02559700 2006-09-1239
PCT/EP2005/004075
more preferably from 1 to 5 i.tm, is added to the excipient mixture. Processes
for
producing the inhalable powders according to the invention by grinding and
micronising
and lastly mixing the ingredients together are known from the prior art.
The inhalable powders according to the invention may be administered using
inhalers
known from the prior art.
The inhalation aerosols containing propellant gas according to the invention
may contain
the compounds 1 dissolved in the propellant gas or in dispersed form. The
compounds 1
may be contained in separate formulations or in a common formulation, in which
the
compounds 1 are either both dissolved, both dispersed or in each case only one
component
is dissolved and the other is dispersed.
The propellant gases which may be used to prepare the inhalation aerosols are
known from
the prior art. Suitable propellant gases are selected from among hydrocarbons
such as
n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated
derivatives of
methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-
mentioned
propellant gases may be used on their own or mixed together. Particularly
preferred
propellant gases are halogenated alkane derivatives selected from TG134a and
TG227 and
mixtures thereof.
The propellant-driven inhalation aerosols may also contain other ingredients
such as
co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH
adjusters. All these
ingredients are known in the art.
The propellant-driven inhalation aerosols according to the invention mentioned
above may
be administered using inhalers known in the art (MDIs = metered dose
inhalers).
Moreover, the active substances 1 according to the invention may be
administered in the
form of propellant-free inhalable solutions and suspensions. The solvent used
may be an
aqueous or alcoholic, preferably an ethanolic solution. The solvent may be
water on its
own or a mixture of water and ethanol. The relative proportion of ethanol
compared with
water is not limited but the maximum is preferably up to 70 percent by volume,
more
particularly up to 60 percent by volume and most preferably up to 30 percent
by volume.
CA 02559700 2006-09-12
WO 2005/102350 40 PCT/EP2005/004075
The remainder of the volume is made up of water. The solutions or suspensions
containing
1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The
pH may be
adjusted using acids selected from inorganic or organic acids. Examples of
particularly
suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric
acid, sulphuric
acid and/or phosphoric acid. Examples of particularly suitable organic acids
include
ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic
acid, fumaric acid,
acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids
are
hydrochloric and sulphuric acids. It is also possible to use the acids which
have already
formed an acid addition salt with one of the active substances. Of the organic
acids,
ascorbic acid, fumaric acid and citric acid are preferred. If desired,
mixtures of the above
acids may be used, particularly in the case of acids which have other
properties in addition
to their acidifying qualities, e.g. as flavourings, antioxidants or complexing
agents, such as
citric acid or ascorbic acid, for example. According to the invention, it is
particularly
preferred to use hydrochloric acid to adjust the pH.
If desired, the addition of editic acid (EDTA) or one of the known salts
thereof, sodium
edetate, as stabiliser or complexing agent may be omitted in these
formulations. Other
embodiments may contain this compound or these compounds. In a preferred
embodiment
the content based on sodium edetate is less than 100 mg/100m1, preferably less
than
50mg/100m1, more preferably less than 20mg/100m1. Generally, inhalable
solutions in
which the content of sodium edetate is from 0 to 10mg/100m1 are preferred.
Co-solvents and/or other excipients may be added to the propellant-free
inhalable
solutions. Preferred co-solvents are those which contain hydroxyl groups or
other polar
groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly
propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether,
glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms
excipients and
additives in this context denote any pharmacologically acceptable substance
which is not
an active substance but which can be formulated with the active substance or
substances in
the physiologically suitable solvent in order to improve the qualitative
properties of the
active substance formulation. Preferably, these substances have no
pharmacological effect
or, in connection with the desired therapy, no appreciable or at least no
undesirable
pharmacological effect. The excipients and additives include, for example,
surfactants
such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants
and/or
WO 2005/102350 CA 02559700 2006-09-1241
PCT/EP2005/004075
preservatives which guarantee or prolong the shelf life of the finished
pharmaceutical
formulation, flavourings, vitamins and/or other additives known in the art.
The additives
also include pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example, provided
that it has not already been used to adjust the pH, vitamin A, vitamin E,
tocopherols and
similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with
pathogens.
Suitable preservatives are those which are known in the art, particularly
cetyl pyridinium
chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in
the concentration known from the prior art. The preservatives mentioned above
are
preferably present in concentrations of up to 50 mg/100 ml, more preferably
between 5 and
mg/100 ml.
Preferred formulations contain, in addition to the solvent water and the
active substance 1,
only benzalkonium chloride and sodium edetate. In another preferred
embodiment, no
15 sodium edetate is present.
The dosage of the compounds according to the invention is naturally highly
dependent on
the method of administration and the complaint which is being treated. When
administered
by inhalation the compounds of formula 1 are characterised by a high potency
even at
doses in the lig range. The compounds of formula 1 may also be used
effectively above the
20 jig range. The dosage may then be in the gram range, for example.
In another aspect the present invention relates to the above-mentioned
pharmaceutical
formulations as such, which are characterised in that they contain a compound
of formula
1, particularly preferably the above-mentioned pharmaceutical formulations
administered
by inhalation.
. -
WO 2005/102350 CA 02559700 2006-09-1242
PCT/EP2005/004075
The following examples of formulations illustrate the present invention
without restricting
its scope:
Examples of Pharmaceutical Formulations
5 A) Tablets
per tablet
active substance of formula 1 100 mg
lactose 140 mg
maize starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
500 mg
The finely ground active substance, lactose and some of the corn starch are
mixed together.
The mixture is screened, then moistened with a solution of
polyvinylpyrrolidone in water,
kneaded, wet-granulated and dried. The granules, the remaining corn starch and
the
magnesium stearate are screened and mixed together. The mixture is compressed
to
produce tablets of suitable shape and size.
B) Tablets per
tablet
active substance of formula 1 80 mg
lactose 55 mg
maize starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 mg
WO 2005/102350 CA 02559700 2006-09-1243
PCT/EP2005/004075
The finely ground active substance, some of the corn starch, lactose,
microcrystalline
cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened
and worked
with the remaining corn starch and water to form a granulate which is dried
and screened.
The sodium carboxymethyl starch and the magnesium stearate are added and mixed
in and
the mixture is compressed to form tablets of a suitable size.
C) Ampoule solution
active substance of formula 1 50 mg
sodium chloride 50 mg
water for inj. 5m1
The active substance is dissolved in water at its own pH or optionally at pH
5.5 to 6.5 and
sodium chloride is added to make it isotonic. The solution obtained is
filtered free from
pyrogens and the filtrate is transferred under aseptic conditions into
ampoules which are
then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50
mg of
active substance.
D) Metered-dose aerosol
active substance of formula 1 0.005
sorbitolan trioleate 0.1
monofluorotrichloromethane and
TG134a : TG227 2:1 ad 100
The suspension is transferred into a conventional aerosol container with a
metering
valve. Preferably, 50 ill of suspension are delivered per spray. The active
substance may
also be metered in higher doses if desired (e.g. 0.02 % by weight).
CA 02559700 2006-11-22
25771-1240
44
E) Solutions (in mg/100m1)
active substance 1 333.3 mg
benzalkonium chloride 10.0 mg
EDTA 50.0 mg
HC1 (1n) ad pH 3.4
This solution may be prepared in the usual way.
F) Powder for inhalation
active substance of formula 1 12 lag
lactose monohydrate ad 25 mg
The powder for inhalation is produced in the usual way by mixing the
individual
ingredients together.
