Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL ENANTIOMERICALLY PURE BETA-AGONISTS, METHOD FOR THE
PRODUCTION AND THE USE THEREOF IN THE FORM OF A DRUG
The present invention relates to enantiomerically pure compounds of general
formula 1
,
O
I ~O OH H H R~
HN N R2
Me Me X
R s
OH 4
1
wherein the groups R', R2, R3, R4 and X- are described herein, processes for
preparing
them and the use thereof as pharmaceutical compositions, particularly as
pharmaceutical
compositions for the treatment of respiratory complaints.
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 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
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 respiratory complaints. A
further objective
of the invention, apart from those mentioned above, is to prepare betamimetics
which are
not only exceptionally potent but are also characterised by a high degree of
selectivity with
respect to the R2-adrenoceptor.
A further aim of the present invention is to prepare betamimetics which by
virtue of their
physicochemical properties are particularly suitable for preparing
pharmaceutical
formulations for use by inhalation. The present invention sets out in
particular to prepare
betamimetics which, in addition to the above-mentioned properties, are
particularly
suitable for preparing inhalable powders and suspension aerosols.
Detailed description of the invention
Surprisingly it has been found that these objectives are achieved with
compounds of
general formula 1.
The present invention relates to enantiomerically pure compounds of general
formula 1
O OH H H R1
HN N R
Me Me X
R 3
OH R4
wherein
R1 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy or halogen;
R2 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy or halogen;
R3 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, OH,
-O-C1-C4-alkylene-COOH or -O-C1-C4-alkylene-COO-CI-C4-alkyl;
R4 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy or halogen;
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X- denotes an anion with a single negative charge, preferably an anion with a
single negative charge selected from among 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 the tautomers, mixtures of the tautomers, hydrates
or solvates
thereof.
Preferred are enantiomerically pure compounds of general formula 1, wherein
R' denotes hydrogen or halogen;
R2 denotes hydrogen or halogen;
R3 denotes hydrogen, Ci-C4-alkoxy or halogen;
R4 denotes hydrogen or halogen;
X- denotes an anion with a single negative charge, preferably an anion with a
single negative charge selected from among 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 the tautomers, mixtures of the tautomers, hydrates
or solvates
thereof.
Preferred are enantiomerically pure compounds of general formula 1, wherein
RI denotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine;
R2 denotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine;
R3 denotes hydrogen, methoxy, ethoxy, fluorine or chlorine, preferably
hydrogen,
methoxy, ethoxy or fluorine;
R4 denotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine;
X- an anion with a single negative charge, preferably an anion with a single
negative charge selected from among 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 the tautomers, mixtures of the tautomers, hydrates
or solvates
thereof.
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Preferred are enantiomerically pure compounds of general formula 1, wherein
R' denotes hydrogen or fluorine;
R2 denotes hydrogen;
R3 denotes methoxy, ethoxy or fluorine;
R4 denotes hydrogen;
X- denotes an anion with a single negative charge selected from among
chloride,
bromide, sulphate, methanesulphonate, maleate, acetate, benzoate, citrate,
salicylate, trifluoroacetate, fumarate, tartrate and succinate;
optionally in the form of the tautomers, mixtures of the tautomers, hydrates
or solvates
thereof.
Of equal importance according to the invention are also enantiomerically pure
compounds
of general formula 1, wherein
R' denotes hydrogen;
R2 denotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine;
R3 denotes hydrogen;
R4 denotes hydrogen, fluorine or chlorine, preferably hydrogen or fluorine;
X- denotes an anion with a single negative charge selected from among
chloride,
bromide, sulphate, methanesulphonate, maleate, acetate, benzoate, citrate,
salicylate, trifluoroacetate, fumarate, tartrate and succinate;
optionally in the form of the tautomers, mixtures of the tautomers, hydrates
or solvates
thereof.
Also preferred are enantiomerically pure compounds of general formula 1,
wherein
X- denotes an anion with a single negative charge selected from among
chloride,
methanesulphonate, maleate, acetate, citrate, salicylate, trifluoroacetate,
fumarate and succinate, preferably chloride, maleate, salicylate, fumarate and
succinate, particularly preferably chloride;
and R', R2, R3 and R4 may have the meanings given above, optionally in the
form of the
tautomers, mixtures of the tautomers, hydrates or solvates thereof.
Also particularly preferred are compounds of general formula 1 which are
selected from
among
- 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethyl amino]
-
ethyl }-4H-benzo[1,4]oxazin-3-one hydrochloride;
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- 8-{(R)-2- [2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl}-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one hydrochloride;
- 8-{(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-
6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one hydrochloride;
- 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethyl amino] -1-hydroxy-ethyl}-6-
hydroxy-4H-benzo[1,4]oxazin-3-one hydrochloride;
- 8-{(R)-2- [2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-ethyl}-6-
hydroxy-4H-benzo[1,4]oxazin-3-one hydrochloride;
- 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino] -
ethyl) -4H-benzo[1,4,]oxazin-3-one maleate;
- 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino] -
ethyl }-4H-benzo[ 1,4,]oxazin-3-one salicylate;
- 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino] -
ethyl }-4H-benzo[1,4,]oxazin-3-one succinate;
- 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethyl amino]
-
ethyl }-4H-benzo[1,4,]oxazin-3-one fumarate;
- 8- {(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl
} -6-
hydroxy-4H-benzo[1,4]oxazin-3-one maleate;
- 8-{(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-
6-
hydroxy-4H-benzo[1,4]oxazin-3-one salicylate;
- 8- {(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-hydroxy-
ethyl}-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one succinate;
- 8-{(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl)-
6-
hydroxy-4H-benzo[1,4]oxazin-3-one fumarate;
- 8-{(R)-2-[ 2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl}-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one maleate;
- 8- {(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl}-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one salicylate;
- 8- {(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-hydroxy-
ethyl}-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one succinate;
- 8-{(R)-2-[ 2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-hydroxy-
ethyl }-6-
hydroxy-4H-benzo[ 1,4]oxazin-3-one fumarate;
- 8- {(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethyl amino] -1-hydroxy-ethyl } -
6-
hydroxy-4H-benzo[1,4]oxazin-3-one maleate;
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- 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one salicylate;
- 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[I,4]oxazin-3-one succinate;
- 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one fumarate;
- 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one maleate;
- 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one salicylate;
- 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one succinate and
- 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one fumarate,
optionally in the form of the tautomers, mixtures of the tautomers,
hydrates or solvates thereof.
Further provided is the enantiomerically pure compound:
O
O OH
H
HN \
Me x HX
Me
OMe
OH
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optionally in the form of a tautomer, mixture of tautomers, hydrate or solvate
thereof,
wherein
X in HX represents a chloride, bromide, sulphate, methanesuIphonate,
maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,
tartrate or succinate anion.
Also particularly preferred are enantiomerically pure compounds of
general formula 1, wherein R1, R2, R3, R4 and X- have the meanings given
above,
in crystalline form, optionally in the form of their crystalline tautomers,
crystalline hydrates or crystalline solvates. Particularly preferred are
enantiomerically pure, crystalline compounds of general formula 1 wherein R1,
R2, R3,
R4 and X" have the meanings given above, optionally in the form of their
crystalline
tautomers, crystalline hydrates or crystalline solvates, which are further
characterised
in that they are crystalline compounds which are present in only a single
crystal
modification.
By the expression "a single crystal modification" are meant
crystalline compounds of formula 1 which are not a mixture of any
polymorphic crystal modifications that may exist.
The compounds of formula 1 according to the invention are
characterised by their versatility of use in the therapeutic field. Particular
mention
should be made according to the invention of those possible applications for
which
the compounds according to the invention of formula 1 are preferably used on
account of their pharmaceutical efficacy as betamimetics.
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In another aspect the present invention therefore relates to the above-
mentioned
enantiomeri cally pure compounds of formula 1 as pharmaceutical compositions.
The
present invention also relates to the use of the above-mentioned compounds of
general
formula 1 for preparing a pharmaceutical composition for the treatment of
respiratory
complaints.
The present invention preferably relates to the use of the above-mentioned
compounds of
general formula 1 for preparing a pharmaceutical composition for the treatment
of
respiratory complaints which are selected from among 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.
It is preferable to use compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of obstructive pulmonary diseases which are
selected from
among COPD (chronic obstructive pulmonary disease), 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 compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of pulmonary emphysemas that have their origin
in COPD
(chronic obstructive pulmonary disease) or al-proteinase inhibitor deficiency.
It is also preferable to use compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of restrictive pulmonary diseases, which are
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 compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of interstitial pulmonary diseases which are
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
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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 compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use 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 compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of bronchiectasis.
It is also preferable to use 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 compounds of general formula 1 for preparing a
pharmaceutical
composition for the treatment of pulmonary oedemas, for example toxic
pulmonary
oedema after aspiration or inhalation of toxic substances and foreign
substances.
Particularly preferably, the present invention relates to the use of the
compounds of
formula 1 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
or COPD.
Moreover the present invention relates to a method of treating 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
preferably relates to methods of treating asthma or COPD, characterised in
that one or
more of the above-mentioned compounds of general formula 1 are administered
once a day
in therapeutically effective amounts.
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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 with 1 to 4 carbon atoms. Examples include: 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
atom. Examples of these include: methyloxy, ethyloxy, propyloxy or butyloxy.
The
abbreviations MeO-, EtO-, PropO- or BuO- are used in some cases to denote the
groups
methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, the
definitions
propyloxy and butyloxy include all possible isomeric forms of the groups in
question.
Thus, for example, propyloxy includes n-propyloxy and 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.
Within the scope of the present invention halogen denotes fluorine, chlorine,
bromine or
iodine. Unless otherwise stated, fluorine, chlorine and bromine are the
preferred halogens.
The term enantiomerically pure within the scope of the present invention
describes
compounds of formula 1 which are present with an enantiomeric purity of at
least 85%ee,
preferably at least 90%ee, particularly preferably > 95%ee. The term ee
(enantiomeric
excess) is known in the art and describes the optical purity of chiral
compounds.
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The preparation of the compounds according to the invention may be carried out
according
to the method outlined in Diagram 1.
OY O O~ Oz~ OH
HN Me - HN HN
OPG OPG OPG
2 3 4
R'
H2N R2
Me Me
3 OH N R`
H R H R
\ 6 R4
Me Me 3
OPG OPG R
7
LO, ~O OH H H R1
R2
HN N
c 11 Me Me 3 X
R
OH R4
5 Diagram 1:
In the compounds of formulae 2 to 5 and 7 specified in Diagram 1 the group OPG
denotes
a hydroxyl function protected by a protective group (PG). With regard to the
choice of
suitable protective groups for the hydroxyl group reference is hereby made to
the prior art
as laid out for example in Protective Groups in Organic Synthesis, T.W. Greene
and
P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999.
Preferably OPG denotes a group which is selected from among
-O-CI-C4-alkyl, -O-benzyl or -O-CO-CI-C4-alkyl, preferably
-0-methyl, -O-benzyl or -0-acetyl, particularly preferably -0-methyl or -0-
benzyl, particularly preferably -0-benzyl.
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In the compounds of formulae 3 and 4 specified in Diagram I the group L
denotes a
leaving group. Preferably L denotes a leaving group which is selected from
among
chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate and p-
toluenesulphonate, preferably chlorine or bromine, particularly preferably
chlorine.
In the compounds of formulae 6 and 7 specified in Diagram 1 the groups R1, R2,
R3 and R4
may have the meanings given above.
Starting from 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one ( ) the compounds
of
general formula 3 are prepared in the manner known in the art. The compound of
formula
3 is then enantioselectively converted, in the presence of a chiral transition
metal catalyst,
into the chiral alcohol of general formula 4, which is then reacted under
suitable conditions
to form the chiral oxiran of formula 5. Methods of carrying out the
enantioselective
synthesis of oxirans are known in the art (cf. for example Hamada et al., Org.
Letters 2002,
4, 4373-4376).
By reacting the oxirans 5 with the amines of formula 6 the compounds of
formula 7 are
obtained, which can be converted into the salts of formula I after the
protective group (PG)
has been cleaved.
In view of their central importance as intermediate products in the synthesis
of the
compounds of formula 1 according to the invention, in another aspect the
present invention
relates to the compounds of formula 5 per se
O O 0
HN
OPG 5
wherein
OPG denotes a hydroxyl function protected by a protective group PG, preferably
a
group which is selected from -O-C1-C4-alkyl, -O-benzyl or
-O-CO-C1-C4-alkyl, preferably -0-methyl, -0-benzyl or -0-acetyl, particularly
preferably -0-methyl or -0-benzyl, particularly preferably -0-benzyl.
In another aspect the present invention relates to the use of a compound of
formula 5 ,
wherein OPG may have the meanings given above, as starting compound for
preparing a
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compound of formula 1, wherein the groups R', R2, R3, R4 and X- may have the
meanings
given above. In another aspect the present invention relates to the use of a
compound of
formula 5, wherein OPG may have the meanings given above, for preparing a
compound
of formula 1, wherein the groups R', R2, R3, R4 and X may have the meanings
given
above.
In the light of their central importance as intermediate products in the
synthesis of the
compounds of formula 1 according to the invention, in another aspect the
present invention
relates to the compounds of formula 7 per se
O OH H R1
1 2
HN N R
Me Me
R s
OPG R4 7
wherein
OPG denotes a hydroxyl function protected by a protective group PG, preferably
a
group which is selected from -O-C1-C4-alkyl, -0-benzyl or -0-CO-C1-C4-alkyl,
preferably -0-methyl, -0-benzyl or -0-acetyl, particularly preferably
-0-methyl or -0-benzyl, particularly preferably -0-benzyl,
and wherein the groups R', R2, R3 and R4 may have the meanings given above.
In another aspect the present invention relates to the use of a compound of
formula 7 ,
wherein OPG, R', R2, R3 and R4 may have the meanings given above, as an
intermediate
product in the preparation of a compound of formula 1, wherein the groups R1,
R2, R3, R4
and X- may have the meanings given above. In another aspect the present
invention relates
to the use of a compound of formula 7, wherein OPG, R', R2, R3 and R4 may have
the
meanings given above, for preparing a compound of formula 1, wherein the
groups R', R2,
R3, R4 and X- may have the meanings given above.
The enantiomerically pure compounds of formula 1 may optionally also be
obtained by the
method illustrated in Diagram 2.
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O OH H R' O O OH H R'
HN N R2 HHN N R2
Me Me / / Me Me
s
R R
OPG 7 4 OH 4
- 1'
O~O OH H H R'
Z
H-X HN N R-
X
Me Me
R
OH R4
Diagram 2:
The compound of formula 7 which may be obtained according to Diagram 1 may
then
optionally be converted first of all into the free bases of formula 11, while
the groups R',
R2, R3 and R4 may have the meanings given above. The free bases of formula 1'
are
converted by reaction with a suitable acid H-X into the compounds of formula
1, which
may be obtained in crystalline form by precipitation in a suitable solvent,
for example in an
alcohol, preferably in an alcohol selected from isopropanol, ethanol or
methanol,
optionally mixtures thereof, such as for example isopropanol/methanol
mixtures.
In the light of their central importance as possible intermediate products in
the synthesis of
the compounds of formula 1 according to the invention, in another aspect the
present
invention relates to the compounds of formula P per se
Oy : OH R'
H N N R
Me Me
U H R4
wherein the groups R', R, R and R4 may have the meanings given above.
2 3
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In another aspect the present invention relates to the use of a compound of
formula 1' ,
wherein R', R2, R3 and R4 may have the meanings given above, as an
intermediate product
in the preparation of a compound of formula 1, wherein the groups R', R2, R3,
R4 and X
may have the meanings given above.
In another aspect the present invention relates to the use of a compound of
formula 1' ,
wherein R', R2, R3 and R4 may have the meanings given above, for preparing a
compound
of formula 1, wherein the groups R', R2, R3, R4 and X- may have the meanings
given
above.
The reactions carried out are described in an exemplary capacity in the
following
experimental section of this patent application. The examples of synthesis
described below
serve to illustrate new compounds according to the invention. However, they
are intended
purely as examples of methods as an illustration of the invention without
restricting it to
the subject matter described below by way of example.
Example 1: 6-hydroxy-8- {(R)- I -hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-
ethylaminol-ethyl}-4H-benzo[1,4]oxazin-3-one hydrochloride
O~O OH
HN N \ x HCI
Me Me
OMe
OH
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a) 1 -(5-benzyloxy-2-h dy roxy-3-nitro-phenyl)-ethanone
18 mL fuming nitric acid are added dropwise to a solution of 81.5 g (0.34 mol)
1-(5-
benzyloxy-2-hydroxy-phenyl)-ethanone in 700 mL acetic acid while cooling with
the ice
bath, so that the temperature does not exceed 20 C. Then the reaction mixture
is stirred for
two hours at ambient temperature, poured onto ice water and filtered. The
product is
recrystallised from isopropanol, suction filtered and washed with isopropanol
and
diisopropylether. Yield: 69.6 g (72%); mass spectroscopy [M+H]+ = 288.
b) 1-(3-amino -5-benzyloxy-2-hydroxy-phenyl -ethanone
69.5 g (242 mmol) 1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are
dissolved in
1.4 L methanol and hydrogenated in the presence of 14 g rhodium on charcoal
(10%) as
catalyst at 3 bar and ambient temperature. Then the catalyst is filtered off
and the filtrate is
evaporated down. The residue is reacted further without additional
purification.
Yield: 60.0 g (96%), Rf value = 0.45 (dichloromethane on silica gel).
c 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one
21.0 mL (258 mmol) chloroacetyl chloride are added dropwise to 60.0 g (233
mmol) 1-(3-
amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) potassium
carbonate while being cooled with the ice bath. Then the mixture is stirred
overnight at
ambient temperature and then for 6 hours at reflux temperature. The hot
reaction mixture is
filtered, then evaporated down to approx. 400 mL and combined with ice water.
The
precipitate obtained is suction filtered, dried and purified by chromatography
on a short
silica gel column (dichloromethane:methanol = 99:1). The fractions containing
the product
are evaporated down, suspended in isopropanol/diisopropylether, suction
filtered and
washed with diisopropylether. Yield: 34.6 g (50%); mass spectroscopy [M+H]+ =
298.
d) 6-benzvloxy-8-(2-chloro-acetyl) 4H-benzo[1,4]oxazin-3-one
13.8 g (46.0 mmol) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one and 35.3 g
(101.5
mmol) benzyltrimethylammonium-dichloriodate are stirred in 250 mL
dichloroethane, 84
mL glacial acetic acid and 14 mL water for 5 hours at 65 C. After cooling to
ambient
temperature the mixture is combined with 5% sodium hydrogen sulphite solution
and
stirred for 30 minutes. The precipitated solid is suction filtered, washed
with water and
diethyl ether and dried. Yield: 13.2 g (86%); mass spectroscopy [M+H]+ =
330/32.
e) 6-benzvloxy-8-((R)-2-chloro-l-hydroxy-ethyl)-4H-benzo[1,4]-oxazin-3-one
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The method is carried out analogously to a process described in the literature
(Org. Lett.
2002, 4, 4373-4376).
8 mL of a mixture of formic acid and triethylamine (molar ratio = 5:2) are
added dropwise
at -15 C to 13.15 g (39.6 mmol) 6-benzyloxy-8-(2-chloro-acetyl)-4H-
benzo[1,4]oxazin-3-
one and 25.5 mg (0.04 mmol) Cp*RhCl[(S,S)-TsDPEN] (Cp* =
pentamethylcyclopentadienyl and TsDPEN = (1S,2S)-N-p-toluenesulphonyl-l,2-
diphenylethylenediamine) in 40 mL dimethylformamide. The mixture is stirred
for 5 hours
at this temperature, then 25 mg catalyst are added and the mixture is stirred
overnight at
-15 C. The reaction mixture is combined with ice water and filtered. The
filter residue is
dissolved in dichloromethane, dried with sodium sulphate and freed from the
solvent. The
residue is chromatographed (dichloromethane/methanol gradient) and the product
recrystallised from diethyl ether/diisopropylether. Yield: 10.08 g (76%); Rf
value = 0.28
(dichloromethane:methanol = 50:1 on silica gel).
f) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[ 1,41oxazin-3 -one
10.06 g (30.1 mmol) 6-benzyloxy-8-((R)-2-chloro-l-hydroxy-ethyl)-4H-benzo[1,4]-
oxazin-3-one are dissolved in 200 mL dimethylformamide. The solution is
combined at
0 C with 40 mL of a 2 molar sodium hydroxide solution and stirred at this
temperature for
4 hours. The reaction mixture is poured onto ice water, stirred for 15 minutes
and then
filtered. The solid is washed with water and dried.
Yield: 8.60 g (96%); mass spectroscopy [M+H]+ = 298.
g) 6-benyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxv-phenyl)-1,1-dimethyl-ethyl
amino] -
ethyl } -4H-benzo [ 1,4,l oxazin-3 -one
5.25 g (17.7 mmol) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one and
6.30 g
(35.1 mmol) 2-(4-methoxy-phenyl)- 1, 1 -dimethyl- ethyl amine are combined
with 21 mL
isopropanol and stirred for 30 minutes at 135 C under microwave radiation in a
closed
reaction vessel. The solvent is distilled off and the residue is
chromatographed (aluminium
oxide; ethyl acetate/methanol gradient). The product thus obtained is further
purified by
recrystallisation from a diethyl ether/diisopropylether mixture.
Yield: 5.33 g (63%); mass spectroscopy [M+H]+ = 477.
h) 6-h dy roxy-8- t(R)-1-hydroxy-2-[2-(4-methoxv-phenyl)-1,1-dimethyl-
ethylaminol-
ethyl}-4H-benzo[1 ,4,]oxazin-3 -one-hydrochloride
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A suspension of 5.33 g (11.2 mmol) 6-benyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-
phenyl)- 1,1-dimethyl-ethylamino] -ethyl }-4H-benzo[1,4,]oxazin-3-one in 120
mL methanol
is combined with 0.8 g palladium on charcoal (10%), heated to 50 C and
hydrogenated at 3
bar hydrogen pressure. Then the catalyst is suction filtered and the filtrate
is evaporated
down. The residue is dissolved in 20 mL isopropanol and 2.5 mL of 5 molar
hydrochloric
acid in isopropanol is added. The product is precipitated with 200 mL diethyl
ether, suction
filtered and dried. Yield: 4.50 g (95%, hydrochloride); mass spectroscopy
[M+H]+ = 387.
The following compounds of formula 1 are obtained analogously by reacting the
compound 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[ 1,4]oxazin-3 -one (Example 1,
Step f)
with the corresponding amine.
Example 2: 8-{(R)-242-(2 4-difluoro-phenyl)-1 1-dimethyl-ethylamino] -l-
hydroxy-
eth ll)-6-hvdroxv-4H-benzo [1 41oxazin-3-one-hydrochloride
O
~ OH F
HN N x HCI
I Me Me
F
OH
mass spectroscopy [M+H]+ = 393.
Example 3: 8-f (R)-2-[2-(3 5-difluoro-phenyl)-1 1-dimethvl-ethyl aminol-l-
hydroxy-
ethyl } -6-hydroxy-4H-benzo[ 1 4]oxazin-3-one-hydrochloride
O~O OH
H
HN N F x HCI
Me Me
OH F
mass spectroscopy [M+H]+ = 393.
Example 4: 8-{(R)-2-r2_(4-ethoxy-phenyl)-1 1-dimethvl-ethvlaminol-l-hvdroxv-
ethyl}-6-
hydroxy-4H-benzo[ 1,41 oxazin-3 -one-hydro chloride
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O~O OH
HN N
x HCI
Me Me I / n
O Me
OH
mass spectroscopy [M+H]+ = 401.
Example 5: 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylaminol-l-h dy roxy}-
6-
h dy roxy-4H-benzo[1,4]oxazin-3-one hydrochloride
OTO OH
HN N \ x HCI
I Me Me
F
OH
mass spectroscopy [M+H]+ = 375.
If in some cases the compounds of formula 1 according to the method of
synthesis
described by way of example hereinbefore do not lead to uniform crystal
modifications, it
may be useful to crystallise the salts of formula 1 obtained from suitable
solvents. In
addition, other salts may be obtained from the foregoing Examples by using
methods
known per se in the art.
In the next section some exemplary methods of preparing uniform salts of the
compounds
of formula 1 which are particularly suitable for the preparation of inhalable
formulations
will be described.
Example 6: 6-h dyroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-
ethylaminol-ethyl }-4H-benzo[1,4,]oxazin-3-one maleate
250 mg (0.65 mmol) 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-
dimethyl-
ethylamino] -ethyl }-4H-benzo[1,4,]oxazin-3-one are combined with enough
ethanol to
make the solid dissolve completely. Then 75 mg (0.65 mmol) maleic acid and a
crystallisation aid are added. The mixture is cooled with ice and the
precipitated solid is
filtered off and washed with ethanol and diethyl ether. In the salt the acid
and the
ethanolamine are present in the ratio 1:1.
Yield: 254 mg (78%); mass spectroscopy [M+H]+ = 387; melting point = 215 C.
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The highly crystalline product was further investigated by X-ray powder
diffraction . The
X-ray powder diagram was recorded as follows.
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuK(, -
radiation,
1.5418 A, 30 kV, 40 mA).
For the highly crystalline compound the following characteristic values dhkl
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 21.68 A; 8.62 A; 5.92 A; 5.01 A; 4.59 A; 4.36 A; 3.64 A and 3.52 A.
Example 7: 6-hydroxy-8- f (R)-1-hydroxy-2-j2-(4-methoxy-phenyl)-1,1-dimethyl-
ethylamino]-ethyl } -4H-benzo[ 1,4,]oxazin-3-one salicylate
250 mg (0.65 mmol) 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-
dimethyl-
ethylamino] -ethyl }-4H-benzo[1,4,]oxazin-3-one are dissolved in a little
ethanol and
combined with 90 mg (0.65 mmol) salicylic acid. After the addition of a
crystallisation aid
the mixture is left to stand overnight, during which time a solid is
precipitated. Diethyl
ether is added and the mixture is filtered after 30 minutes. The white solid
thus obtained is
washed with diethyl ether and dried.
Yield: 295 mg (87%); mass spectroscopy [M+H]+ = 387; melting point = 215 C.
The highly crystalline product was further investigated by X-ray powder
diffraction . The
X-ray powder diagram was recorded as follows.
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuK(, -
radiation, X _
1.5418 A, 30 kV, 40 mA).
For the highly crystalline compound the following characteristic values dhkl
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 9.06 A; 8.36 A; 8.02 A; 6.84 A; 6.73 A; 4.48 A; 4.35 A and 4.27 A.
Example 8: 6-h dy roxy-8-1(R)-l-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-
ethylamino]-ethyl} -4H-benzo[ 1,4,]oxazin-3-one succinate
500 mg (1.2 mmol) 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-
dimethyl-
ethylamino]-ethyl}-4H-benzo[1,4,]oxazin-3-one hydrochloride are combined with
ethyl
acetate and extracted with aqueous potassium carbonate solution, the organic
phase is dried
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WO 2005/111005 20 PCT/EP2005/005079
with sodium sulphate and freed from the solvent. The residue is dissolved in a
little ethanol
and combined with 140 mg (1.2 mmol) succinic acid. After 2 hours the
precipitated solid is
suction filtered and washed with cold ethanol and diethyl ether. In the salt
the
ethanolamine and acid are present in a ratio of I to 0.5.
Yield: 468 mg (85%); mass spectroscopy [M+H]+ = 387; melting point = 115 C.
The highly crystalline product was further investigated by X-ray powder
diffraction . The
X-ray powder diagram was recorded as follows.
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuK(, -
radiation, k _
1.5418 A, 30 kV, 40 mA).
For the highly crystalline compound the following characteristic values dhki
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 14.35 A; 8.49 A; 7.37 A; 7.25 A; 5.47 A; 4.78 A; 4.14 A and 3.59 A.
Example 9: 6-h dy roxy-8- {(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-
ethylaminol-ethyl}-4H-benzo[ 1,4,]oxazin-3-one-fumarate
300 mg (0.71 mmol) 6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-
dimethyl-
ethyl amino] -ethyl }-4H-benzo[1,4,]oxazin-3-one hydrochloride are combined
with ethyl
acetate and extracted with aqueous potassium carbonate solution. The organic
phase is
dried with sodium sulphate and freed from the solvent. The residue is
dissolved in ethanol
with the addition of a few drops of water. 82 mg (0.71 mmol) fumaric acid and
seed
crystals are added and the mixture is left to stand overnight. The white solid
is suction
filtered, washed with diethyl ether and ethanol and dried. In the salt the
ethanolamine and
the acid are present in a ratio of 1 to 0.5.
Yield: 208 mg (63%); mass spectroscopy [M+H]+ = 387; melting point = 130 C.
The highly crystalline product was further investigated by X-ray powder
diffraction. The
X-ray powder diagram was recorded as follows.
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuKa -
radiation, k _
1.5418 A, 30 kV, 40 mA).
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For the highly crystalline compound the following characteristic values dhki
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 14.23 A; 5.44 A; 4.76 A; 4.57 A; 4.26 A; 4.12 A; 3.57 A and 3.48 A.
Example 10: 6-h d~ roxy-8- { 1-hydroxy-2-[2-(4-methoxv-phenyl)-1,1-dimethl-
ethlam]-ethyl }-4H-benzo[1,4,]oxazin-3-one (free base)
Analogously to the preceding methods 500 mg (1.2 mmol) 6-hydroxy-8-{(R)-1-
hydroxy-2-
[2-(4-methoxy-phenyl)-1,1-dimethyl-ethyl amino] -ethyl }-4H-benzo[ 1,4,]oxazin-
3-one
hydrochloride are first of all combined with ethyl acetate. The organic phase
is extracted
with aqueous potassium carbonate solution, dried with sodium sulphate and
freed from the
solvent. The free base thus obtained is dissolved in acetonitrile with the
addition of a few
drops of water. The precipitated solid is suction filtered, washed and dried.
Yield: 168 mg (37%); mass spectroscopy [M+H]+ = 387; melting point = 128 C.
The highly crystalline product was further investigated by X-ray powder
diffraction. The
X-ray powder diagram was recorded as follows.
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuKa -
radiation, 2 _
1.5418 A, 30 kV, 40 mA).
For the highly crystalline compound the following characteristic values dhkl
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 14.96 A; 9.63 A; 7.05 A; 5.57 A; 5.28 A; 5.05 A; 4.63 A and 3.73 A.
Example 11: 6-hydroxy-8- {(R)-1-hydroxy-2-f 2-(4-methoxv-phenyl)-1,1-dimethyl-
ethylaminol-ethyl }-4H-benzo[ 1,4,1oxazin-3-one-hydrochloride
300 mg (0.71 mmol) 6-hydroxy-8- {(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-
dimethyl-
ethylamino]-ethyl }-4H-benzo[1,4,]oxazin-3-one hydrochloride are dissolved in
4 mL
isopropanol by heating. The solution is cooled to ambient temperature and then
placed in
an ice bath for 15 minutes. The precipitated solid is suction filtered and
dried.
Yield: 180 mg (60%); mass spectroscopy [M+H]+ = 387; melting point = 211 C.
The highly crystalline product was further investigated by X-ray powder
diffraction. The
X-ray powder diagram was recorded as follows.
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WO 2005/111005 22 PCT/EP2005/005079
The X-ray powder diagram was recorded within the scope of the present
invention using a
Bruker D8 Advanced with an LSD (= location sensitive detector) (CuK(, -
radiation,
1.5418 A, 30 kV, 40 mA).
For the highly crystalline compound the following characteristic values dhkl
[A], which
give the lattice plane distances measured in A, were determined, inter alia:
d= 5.92 A; 5.81 A; 5.51 A; 5.10 A; 4.65 A; 4.50 A; 4.15 A and 4.00 A.
Using the method described in Examples 6 to 11 the following compounds may be
obtained analogously:
Example 12: 8-{(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one maleate;
Example 13: 8-{(R)-2-[ 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl } -6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one salicylate;
Example 14: 8-{(R)-2-[ 2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[I,4]oxazin-3-one succinate;
Example 15: 8- {(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one fumarate;
Example 16: 8- {(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl }-6-hydroxy-4H-benzo[1,4] 1,4]oxazin-3 maleate;
Example 17: 8- {(R)-2-[ 2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one salicylate;
Example 18: 8- {(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one succinate;
Example 19: 8-{(R)-2-[ 2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[ 1,4] oxazin-3 -one fumarate;
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Example 20: 8-{ (R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo[ 1,4] oxazin-3 -one maleate;
Example 21: 8- {(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo[1,4]oxazin-3-one salicylate;
Example 22: 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one succinate;
Example 23: 8-{(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo[1,4]oxazin-3-one fumarate;
}-
Example 24: 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl
6-hydroxy-4H-benzo[1,4]oxazin-3-one maleate;
Example 25: 8- {(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-ethyl } -
6-hydroxy-4H-benzo[ 1,4]oxazin-3 -one salicylate;
Example 26: 8- {(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-ethyl}-
6-hydroxy-4H-benzo[1,4]oxazin-3-one succinate;
}-
Example 27: 8-{(R)-2- [2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino] -1-hydroxy-
ethyl
6-hydroxy-4H-benzo[ 1,4]oxazin-3-one fumarate;
Example 28: 8- {(R)-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one (free base);
Example 29: 8- {(R)-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethyl amino] -1-
hydroxy-
ethyl } -6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one (free base);
Example 30: 8- {(R)-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl } -
6-hydroxy-4H-benzo[1,4]oxazin-3-one (free base) or
Example 31: 8-{(R)-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-
ethyl}-
6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one (free base).
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The compounds of general formula 1 may be used on their own or in conjunction
with
other active substances of formula 1 according to the invention. If desired
the compounds
of general formula 1 may also be used in conjunction with other
pharmacologically active
substances.
Preferably the present invention also relates to drug combinations which
contain in
addition to one or more, preferably one compound of formula 1 , as an
additional active
substance one or more compounds selected from the categories of the
anticholinergics,
PDEIV inhibitors, steroids, LTD4-antagonists and EGFR inhibitors.
Anticholinergics are preferably used, while compounds selected from bromides
and
chlorides of the cations tiotropium, oxitropium, flutropium, ipratropium,
glycopyrronium
and trospium are of particular interest. Of particular importance is
tiotropium bromide,
preferably in the form of crystalline tiotropium bromide monohydrate, which is
known
from WO 02/30928. If tiotropium bromide is used in the drug combinations
according to
the invention in anhydrous form, it is preferable to use anhydrous crystalline
tiotropium
bromide, which is known from WO 03/000265.
In another preferred embodiment of the present invention the anticholinergic
used is the
compound
N
0-0 P O
O
Br HO
S
S
optionally in the form of the enantiomers thereof.
The following compounds are optionally also used as anticholinergics in
combination with
the compounds of formula 1:
tropenol 2,2-diphenylpropionate methobromide,
scopine 2,2- diphenylpropionate methobromide,
scopine 2-fluoro-2,2-diphenylacetate methobromide,
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- tropenol 2-fluoro-2,2-diphenylacetate methobromide,
- tropenol 3,3',4,4'-tetrafluorobenzilate methobromide,
- scopine 3,3',4,4'-tetrafluorobenzilate methobromide,
- tropenol 4,4'-difluorobenzilate methobromide,
- scopine 4,4'-difluorobenzilate methobromide,
- tropenol 3,3'-difluorobenzilate methobromide,
- scopine 3,3'-difluorobenzilate methobromide,
- tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;
- tropenol 9-fluoro-fluorene-9-carboxylate methobromide;
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide;
- scopine 9-fluoro-fluorene-9-carboxylate methobromide;
- tropenol 9-methyl-fluorene-9-carboxylate methobromide;
- scopine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine benzilate methobromide,
- cyclopropyltropine 2,2-diphenylpropionate methobromide;
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide ;
- cyclopropyltropine 9-methyl-xanthene-9-carboxyl ate methobromide;
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
- methyl cyclopropyltropine 4,4'-di fluorobenzilate methobromide,
tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropenol 9-methyl-xanthene-9-carboxylate methobromide;
- scopine 9-methyl-xanthene-9-carboxylate methobromide;
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide;
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide; or
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.
If PDE IV inhibitors are used in combination with one or more compounds of
general
formula 1, these are preferably selected from among Enprofyllin, Theophyllin,
Roflumilast, Ariflo (Cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-
12-
281 (GW-842470), N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-
cyclopropylmethoxybenzamide, NCS-613, Pumafentine, (-)p-[(4aR*, I ObS*)-9-
ethoxy-
1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][ 1,6]naphthyridin-6-yl]-
N,N-
3 5 diisopropylbenzamide, (R)-(+)- I -(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-
CA 02562859 2006-10-17
WO 2005/111005 26 PCT/EP2005/005079
methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-
cyano-
S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis [4-cyano-4-(3 -
cyclopentyloxy-4-
methoxyphenyl)cyclohexane-l-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3 -
cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one, cis[4-cyano-4-(3-
cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol], (R)-(+)-ethyl[4-
(3-
cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(-)-ethyl [4-
(3 -
cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene] acetate, CDP840, Bay-
198004, D-
4418, PD-168787, T-440, T-2585, Arofyllin, Atizoram, V-11294A, C1-1018, CDC-
801,
CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-
thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-
5,6-dihydro-7-
ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,
optionally in the
form of their racemates, enantiomers or diastereomers and optionally in the
form of their
pharmacologically acceptable acid addition salts, solvates and/or hydrates. By
acid
addition salts with pharmacologically acceptable acids are meant for example
salts selected
from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride,
hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.
If steroids are used in combination with one or more compounds of general
formula 1, they
are preferably selected from among prednisolone, prednisone,
butixocortpropionate, RPR-
106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,
mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, (S)-fluoromethyl
6a,9a-
difluoro-17a-[(2-furanylcarbonyl)oxy]-11(3-hydroxy-16a-methyl-3-oxo-androsta-
l,4-
diene-I7J3-carbothionate, and (S)-(2-oxo-tetrahydro-furan-3S-yl)6a,9a-difluoro-
11(3-
hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17(3-
carbothionate,
optionally in the form of their racemates, enantiomers or diastereomers and
optionally in
the form of their salts and derivatives, the solvates and/or hydrates thereof.
Any reference
to steroids includes a reference to any salts or derivatives, hydrates or
solvates thereof that
may exist. Examples of possible salts and derivatives of the steroids may be:
alkali metal
salts, such as for example sodium or potassium salts, sulphobenzoates,
phosphates,
isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates,
pivalates or
furoates.
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WO 2005/111005 27 PCT/EP2005/005079
If LTD4-antagonists are used in combination with one or more compounds of
general
formula 1, these are preferably selected from among montelukast, 1-(((R)-(3-(2-
(6.7-
difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-
propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((1(R)-3(3-(2-(2,3-
dichlorothieno[3,2-b]pyridine-5-yI)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-l-
methylethyl)phenyl)propyl)thio)methyl)cyclopropanacetic acid, pranlukast,
zafirlukast, [2-
[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid,
MCC-847
(ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321,
optionally in the form of their racemates, enantiomers or diastereomers,
optionally in the
form of their pharmacologically acceptable acid addition salts as well as
optionally in the
form of their salts and derivatives, the solvates and/or hydrates thereof. By
acid addition
salts with pharmacologically acceptable acids which the LTD4-antagonists may
be
capable of forming are meant, for example, salts selected from among
hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,
hydrofumarate,
hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-
toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate,
hydrophosphate, hydrofumarate and hydromethanesulphonate. By salts or
derivatives
which the LTD4-antagonists may be capable of forming are meant, for example:
alkali
metal salts, such as for example sodium or potassium salts, alkaline earth
metal salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen
phosphates,
palmitates, pivalates or furoates.
If EGFR inhibitors are used in combination with one or more compounds of
general
formula 1, they are preferably selected from among 4- [(3 -chloro-4-
fluorophenyl) amino]-6-
{ [4-(morpholin-4-yl)-1-oxo-2-buten- l -yl] amino } -7-cyclopropylmethoxy-
quinazoline, 4-
[(3-chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-
1-oxo-2-
buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-
4-fluoro-
phenyl)amino] -6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-
quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl -amino]-
1-oxo-
2-buten- l -yl } amino)-7-cyclopropylmethoxy-quinazoline, 4- [(3-ethynyl-
phenyl)amino] -
6.7-bis-(2-methoxy-ethoxy)-quinazoline, 4- [(3 -chloro-4-fluorophenyl) amino]-
6- { [4-
(morpholin-4-yl)-1-oxo-2-buten- l -yl] amino } -7- [(tetrahydrofuran-2-
yl)methoxy] -
quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-
yl)-1-
oxo-2-buten-l-yl]amino }-quinazoline, 4- [ (3 -chloro-4- fluoro-phenyl) amino]
-6-(trans-4-
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WO 2005/111005 28 PCT/EP2005/005079
methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-
4-
fluoro-phenyl) amino] -6-(tetrahydropyran-3 -yloxy)-7-methoxy-quinazoline, 4-
[(3-chloro-4-
fluoro-phenyl) amino] -6- 11 - [ (morpholin-4-yl)carbonyl] -piperidin-4-yloxyl
-7-methoxy-
quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6-{1-[2-(2-oxopyrrolidin-l-
yl)ethyl]-
piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-
acetyl-
piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-
methyl-
piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-
methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-
phenyl)amino]-6- { 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-
quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- { 1-[(2-
methoxyethyl)carbonyl]-
piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3 -chloro-4-fluoro -phenyl)
amino] -6- [cis-4-
(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-
[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-
cyclohexan-1-
yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-
methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-
yloxy] -7-
methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-
dimethylamino -
cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-
6-
(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-
7-
methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-
oxo-
morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-
[(3-chloro-
4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-
quinazoline
and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-
methoxy-
quinazoline, optionally in the form of their racemates, enantiomers or
diastereomers,
optionally in the form of their pharmacologically acceptable acid addition
salts, the
solvates and/or hydrates thereof.
By acid addition salts with pharmacologically acceptable acids which the above-
mentioned
EGFR inhibitors might be capable of forming are meant, for example, salts
selected from
among hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate,
hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,
hydrobenzoate
and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate,
hydrophosphate, hydrofumarate and hydromethanesulphonate.
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Suitable preparations for administering the compounds of formula 1 include
tablets,
capsules, suppositories, solutions, powders, etc. The proportion of
pharmaceutically active
compound or compounds should be in the range from 0.05 to 90 % by weight,
preferably
0.1 to 50 % by weight of the total composition. 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,
arabic gum, talc, titanium dioxide or sugar. To achieve delayed release or
prevent
incompatibilities the core may also consist of a number of layers. Similarly
the tablet
coating may consist of a number or layers to achieve delayed release, possibly
using the
excipients mentioned above for the tablets.
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
ethylenediamine tetraacetic acid, optionally using emulsifiers and/or
dispersants, whilst if
water is used as the diluent, for example, organic solvents may optionally be
used as
solvating agents or dissolving aids, and transferred into injection vials or
ampoules or
infusion bottles.
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Capsules containing the compounds of formula 1 according to the invention 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 administration the tablets may, of course, contain, apart from the
abovementioned
carriers, additives such as sodium citrate, calcium carbonate and dicalcium
phosphate
together with various additives such as starch, preferably potato starch,
gelatine and the
like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate
and talc
may be used at the same time for the tabletting process. In the case of
aqueous suspensions
the active substances may be combined with various flavour enhancers or
colourings in
addition to the excipients mentioned above.
When the compounds of formula 1 are used, as is particularly preferred
according to the
invention, for the treatment of respiratory complaints, it is particularly
preferable to use
preparations or pharmaceutical formulations that can be administered by
inhalation.
Suitable formulations for inhalation include inhalable powders, propellant-
driven 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 compounds of formula 1 which are particularly preferably used in
crystalline form
according to the invention are preferably used for preparing inhalable
powders. The
inhalable powders which may be used according to the invention may contain the
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crystalline compounds of formula 1 either on their own or in admixture with
suitable
physiologically acceptable excipients.
If the active substances 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 m, preferably between 10 and 150
m, most
preferably between 15 and 80 m. In some cases it may seem appropriate to add
finer
excipient fractions with an average particle size of 1 to 9 m to the
excipient mentioned
above. These finer excipients are also selected from the group of possible
excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders according to
the invention,
micronised active substance, preferably with an average particle size of 0.5
to 10 m, more
preferably from 1 to 5 m, is added to the excipient mixture. Processes for
producing the
inhalable powders according to the invention by grinding and micronising and
finally
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
dissolved in the propellant gas or in dispersed form. 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 in admixture. Particularly preferred propellant gases are halogenated
alkane
derivatives selected from TG134a and TG227 and mixtures thereof.
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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).
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 the formula are characterised by a high potency
even at
doses in the g range. The compounds of the formula may also be used
effectively above
the g range. The dosage may then be in the milligram range, for example.
In another aspect the present invention relates to the above-mentioned
pharmaceutical
formulations, characterised in that they contain a compound of formula 1, as
such,
particularly preferably the above-mentioned pharmaceutical formulations for
use by
inhalation.
The following formulation examples illustrate the present invention without
restricting its
scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
active substance 100 mg
lactose 140 mg
corn starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
500 mg
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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 80 mg
lactose 55 mg
corn starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 mg
The finely ground active substance, some of the corn starch, lactose, micro
crystalline
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 50 mg
sodium chloride 50 mg
water for inj. 5 ml
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
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WO 2005/111005 34 PCT/EP2005/005079
then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50
mg of
active substance.
D) Metering aerosol
Active substance 0.005
Sorbitan trioleate 0.1
TG134a : TG227 2:1 ad 100
The suspension is transferred into a conventional aerosol container with a
metering
valve. Preferably, 50 l of suspension are delivered per spray. The active
substance may
also be metered in higher doses if desired (e.g. 0.02 % by weight).
E) Solutions (in mg/ I 00ml)
Active substance 333.3 mg
Benzalkonium chloride 10.0 mg
EDTA 50.0 mg
HCl (In) ad pH 3.4
This solution may be prepared in the usual manner.
F) Powder for inhalation
Active substance 12 g
Lactose monohydrate ad 25 mg
The powder for inhalation is produced in the usual way by mixing the
individual
ingredients together.
