Note: Descriptions are shown in the official language in which they were submitted.
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WO 2005/077361 1 PCT/EP2005/001232
86613pct
NOVEL, SUSTAINED-ACTION BETA-2-AGONISTS AND THEIR USE AS
MEDICAMENTS
The present invention relates to the use of compounds of formula 1
R'
OH N=
R3SOZNH ~ N %~N~N
Me ~(M~e~ ~'' ~Rz
wherein the groups R1, R2, R3, R4 and n may have the meanings given in the
claims and in
Io the specification, for preparing a pharmaceutical composition for the
treatment of
inflammatory and obstructive respiratory complaints, and new compounds of
formula 1 per
se.
is Background to the invention
Betamimetics (13-adrenergic substances) are known from the prior art.
For the 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
zo 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 wellbeing of the
patient to a
high degree.
zs 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.
3o The aim of the present invention is therefore to provide betamimetics which
are
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
CA 02552871 2006-07-06
WO 2005/077361 2 PCTBP2005/001232
used to prepare a drug for administration once a day. A further objective of
the invention
is to prepare new betamimetics which, by virtue of their long-lasting effect,
can be used to
prepare a drug for administration once a day for the treatment of inflammatory
or
obstructive respiratory complaints. In addition to the above objectives, the
present
invention also sets out to provide betamimetics which are not only
exceptionally potent but
are also characterised by a high degree of selectivity with respect to the (32-
adreno-receptor.
DESCRIPTION OF THE INVENTION
io
Surprisingly it has been found that the above-mentioned objectives are
achieved by
compounds of formula 1. Accordingly, the present invention relates to the use
of
compounds of formula 1
R'
OH H N=
R3SOZNH ~ N %~N~N
v Me ~(M~e~ ~'' R2
wherein
R1 denotes hydrogen, -C1_6-alkyl, -C1_6-haloalkyl, -OH, -O-C1_6-alkyl, halogen
or a group selected from among aryl or a heterocycle, while aryl or the
heterocycle are if possible each optionally substituted by 1, 2, 3, 4 or 5
Zo identical or different groups Rs;
RZ denotes hydrogen, -C~_6-alkyl, -C1_6-haloalkyl; preferably methyl;
R3 denotes -C~_6-alkyl; preferably methyl;
R4 denotes -OH, -NH2, halogen; preferably -OH;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl,
zs -COR6, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6,
-SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group
selected from -CZ_6-alkylene, -C2_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denotes hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, l, 2 or 3; preferably 1;
30 optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids, for preparing a pharmaceutical
composition
for the treatment of inflammatory and obstructive respiratory complaints.
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WO 200s/077361 3 PCT/EP2005/001232
It is preferable to use compounds of formula 1 as stated above wherein R1, R2,
R3 and n are
as hereinbefore defined and
R4 denotes -OH
optionally in the form of the individual optical isomers, mixtures of the
individual
s enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above
wherein RZ, R3,
R4 and n are as hereinbefore defined and
io Rl denotes hydrogen, -C1_6-alkyl, -C1_6-haloalkyl, -OH, -O-C1_6-alkyl,
halogen
or aryl, if possible optionally substituted by l, 2, 3, 4 or 5 identical or
different groups Rs;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl,
-CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6,
is -SORE, -S02R6 or -SO2NR6R7, or two Rs joined together denote a group
selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
Zo salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above
wherein
Rl denotes hydrogen, -C1_6-alkyl, -O-C1_6-alkyl, aryl, if possible optionally
substituted by 1, 2, 3, 4 or 5 identical or different groups Rs;
Zs RZ denotes hydrogen, -CI_6-alkyl; preferably methyl;
R3 denotes methyl;
R4 denotes -OH;
Rs denotes halogen, -CN, -N02, -C,_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl,
-CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6S02R7, -SR6,
30 -SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group
selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, 1, 2 or 3; preferably 1;
optionally in the form of the individual optical isomers, mixtures of the
individual
3s enantiomers or racemates, in the form of the free bases or the
corresponding acid addition
salts with pharmacologically acceptable acids.
It is particularly preferable to use compounds of formula 1 as stated above
wherein
Rl denotes hydrogen, aryl, if possible optionally substituted by 1, 2, 3, 4 or
5
ao identical or different groups Rs;
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WO 2005/077361 4 PCTBP2005/001232
R2 denotes hydrogen, -C1_6-alkyl; preferably methyl;
R3 denotes methyl;
R4 denotes -OH;
Rs denotes halogen, -CN, -N02, -Ct_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl,
s -CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7, -SR6,
-SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group
selected from -C2_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
R6 and R7 denotes hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 0, 1, 2 or 3; preferably 1;
to optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
is It is particularly preferable to use compounds of formula 1 as stated above
wherein
Rt denotes hydrogen, phenyl, optionally substituted by 1, 2, 3, 4 or 5
identical
or different groups Rs;
RZ denotes hydrogen, ethyl, methyl; preferably methyl or ethyl;
R3 denotes methyl;
ao R4 denotes OH;
Rs denotes halogen, -CN, -N02, -C1_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl,
-CORE, -COOR6, -CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR~, -SR6,
-SORE, -SOZR6 or -SOZNR6R7, or two Rs joined together denote a group
selected from -CZ_6-alkylene, -CZ_6-alkenylene and -O-C1_6-alkylene-O-;
is R6 and R' denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 1;
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
It is particularly preferable to use the compounds of general formula 1 as
detailed above
for preparing a pharmaceutical composition for the treatment of respiratory
complaints
selected from among obstructive pulmonary diseases of various origins,
pulmonary
emphysema of various origins, restrictive pulmonary diseases, interstitial
pulmonary
3s diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis,
ARDS (adult
respiratory distress syndrome) and all forms of pulmonary oedema.
The compounds are preferably used for preparing a pharmaceutical composition
for the
treatment of obstructive pulmonary diseases selected from among bronchial
asthma,
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WO 2005/077361 5 PCT/EP2005/001232
paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and
COPD
(chronic obstructive pulmonary disease), while it is particularly preferable
according to the
invention to use them for preparing a pharmaceutical composition for the
treatment of
bronchial asthma (optionally also referred to only as asthma within the scope
of the present
invention) and COPD.
It is also preferable to use the compounds as detailed above for preparing a
pharmaceutical
composition for the treatment of pulmonary emphysema which has its origins in
COPD or
al-proteinase inhibitor deficiency.
~o
It is also preferable to use the compounds as detailed above 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
1s for example lymphangiosis carcinomatosa, bronchoalveolar carcinoma and
lymphomas.
It is also preferable to use the compounds as detailed above for preparing a
pharmaceutical
composition for the treatment of interstitial pulmonary diseases selected from
among
pneumonia caused by infections, such as for example infection by viruses,
bacteria, fungi,
zo protozoa, helminths or other pathogens, pneumonitis caused by various
factors, such as for
example aspiration and left heart insufficiency, radiation-induced pneumonitis
or f brosis,
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)
2s
It is also preferable to use the compounds detailed above for preparing a
pharmaceutical
composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use the drug combinations according to the invention
for preparing a
3o 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 detailed above for preparing a
pharmaceutical
composition for the treatment of bronchiectasis.
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WO 2005/077361 6 PCT/EP2005/001232
It is also preferable to use the compounds detailed above for preparing a
pharmaceutical
composition for the treatment of ARDS (adult respiratory distress syndrome).
It is also preferable to use the compounds detailed above 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
io importance is the above-mentioned use of the drug combinations according to
the
invention 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.
is The invention also relates to new compounds of formula 1 per se. In
particular the present
invention relates to new compounds of formula 1 wherein R', R2 and n may have
the
meanings given above and wherein R3 methyl and R4 denote OH, optionally in the
form of
the individual optical isomers, mixtures of the individual enantiomers or
racemates, in the
form of the free bases or the corresponding acid addition salts with
pharmacologically
zo acceptable acids.
Preferred are compounds of formula 1 wherein R1 and n may have the meanings
given
above and wherein
RZ denotes methyl or ethyl;
zs R3 denotes methyl and
R4 denotes OH,
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
Also preferred are compounds of formula 1 wherein R1 may have the meanings
given
above and wherein
R2 denotes methyl or ethyl;
R3 denotes methyl;
3s R4 denotes OH and
n denotes 1,
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
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WO 2005/077361 7 PCT/EP2005/001232
Preferred according to the invention are compounds of formula 1 wherein
R1 denotes hydrogen, phenyl, optionally substituted by l, 2 or 3 identical or
different groups RS;
s RZ denotes methyl or ethyl, preferably methyl;
R3 denotes methyl;
R4 denotes OH;
RS denotes halogen, -CI_6-alkyl, -C3_6-cycloalkyl, -C1_6-haloalkyl, -COOR6,
-CONR6R7, -OR6, -NR6R7, -NR6COR7, -NR6SOZR7 or two RS joined
~o together denote a group selected from -C2_6-alkylene, -CZ_6-alkenylene and
-O-C 1 _6-alkylene-O-;
R6 and R' denote hydrogen, -C1_6-alkyl, -C3_6-cycloalkyl;
n denotes 1;
optionally in the form of the individual optical isomers, mixtures of the
individual
is enantiomers or racemates, in the form of the free bases or the
corresponding acid addition
salts with pharmacologically acceptable acids.
Also preferred are compounds of formula 1 wherein
Rl denotes hydrogen, phenyl, optionally substituted by 1, 2 or 3 identical or
Zo different groups R5;
RZ denotes ethyl or methyl; preferably methyl;
R3 denotes methyl;
R4 denotes OH;
RS denotes halogen, -CI_6-alkyl, -CI_6-haloalkyl, -COOR6, -CONR6R7, -OR6,
2s -NR6R7 or two RS joined together represent -O-C1_6-alkylene-O-;
R6 and R7 denote hydrogen, -C1_6-alkyl;
n denotes l;
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
3o salts with pharmacologically acceptable acids.
Particularly
preferred
are compounds
of formula
1 wherein
Rl denotes phenyl, optionally substituted by l, 2 or 3
identical or different
groups R5;
3s Rz denotes methyl, ethyl; preferably methyl;
R3 denotes methyl;
R4 denotes OH;
RS denotes chlorine, bromine, fluorine, methyl, ethyl,
-CF3, -COOH, -COOMe,
-OH, -OMe;
ao n denotes 1,
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WO 2005/077361 8 PCT/EP2005/001232
optionally in the form of the individual optical isomers, mixtures of the
individual
enantiomers or racemates, in the form of the free bases or the corresponding
acid addition
salts with pharmacologically acceptable acids.
s Particularly preferred compounds of formula 1 are selected from the group
consisting of:
~ N-[5-(2-{3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-
propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide,
~ N-[5-(2-{1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phenyl)-
[1,2,4]triazol-1-yl]-
propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide,
io ~ N-(5-{2-[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-
propylamino]-1-
hydroxy-ethyl } -2-hydroxy-phenyl)-methane sulphonamide,
~ N-[5-(2-{3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl-
propylamino)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulphonamide,
methyl3-(1-{3-[2-hydroxy-2-(4-hydroxy-3-methanesulphonylamino-phenyl)-
is ethylamino]-3-methyl-butyl}-S-methyl-1H-[1,2,4]triazol-3-yl)-benzoate,
~ N-[5-(2-{3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-l,l-
dimethyl-
propylamino } -1-hydroxy-ethyl)-2-hydroxy-phenyl] -methane sulphonamide,
~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(2-methoxy-phenyl)-5-methyl-[1,2,4]triazol-
1-yl]-
1,1-dimethyl-propylamino}-ethyl)-phenyl]-methanesulphonamide,
ao ~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-
[1,2,4]triazol-1-yl]-
1,1-dimethyl-propylamino}-ethyl)-phenyl]-methanesulphonamide,
~ N-(5-{2-[3-(3-benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-1,1-
dimethyl-propyl
amino]-1-hydroxy-ethyl } -2-hydroxy-phenyl)-methanesulphonamide,
~ N-[2-hydroxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-
1,1-dimet
Zs hyl-propylamino}-ethyl)-phenyl]-methanesulphonamide and
~ N-{5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-1-hydroxy-ethyl]-2-
hydroxy-
phenyl}-methanesulphonamide,
optionally in the form of the individual optical isomers, mixtures of the
individual
3o enantiomers or racemates, in the form of the free bases or the
corresponding acid addition
salts with pharmacologically acceptable acids.
The compounds of formula 1 may optionally be used in the form of the
individual optical
isomers, mixtures of the individual enantiomers or racemates. They are
particularly
3s preferably used in the form of the enantiomerically pure compounds, while
the compounds
of formula 1, wherein the asymmetric carbon centre "-CH(OH)-" benzylic to the
phenyl
ring is in the R-configuration. The particularly preferred R-enantiomers of
the compounds
of general formula 1 may be represented by general formula R-1,
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WO 2005/077361 9 PCT/EP2005/001232
R'
OH H N=
R3SOZNH ~ * N %~N~N
/ v Me ~M~e~ ~'' Rz
R-1
wherein the groups Rl, Rz, R3, R4 and n may have the meanings given above.
By acid addition salts with pharmacologically acceptable acids are meant, for
example, the
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 the hydrochloride,
io hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
Halogen within the scope of the present invention denotes fluorine, chlorine,
bromine or
iodine. Unless stated otherwise, fluorine and bromine are the preferred
halogens, while
is fluorine is generally preferred.
Unless otherwise stated, the alkyl groups (alkyl) are straight-chained or
branched alkyl
groups having 1 to 6, preferably 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
zo 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.
zs Examples of alkylene groups (alkylene), unless otherwise stated, are
branched and
unbranched alkylene groups with 1 to 6, preferably 1 to 4 carbon atoms. The
following are
mentioned by way of example: methylene, ethylene, propylene or butylene.
Unless stated
otherwise, the definitions propylene and butylene include all the possible
isomeric forms of
the groups in question.
Examples of alkenylene groups (alkenylene), unless otherwise stated, are
branched and
unbranched alkenylene groups with 1 to 6, preferably 1 to 4 carbon atoms. The
following
are mentioned by way of example: ethenylene, propenylene or butenylene.
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Examples of cycloalkyl groups (cycloalkyl), unless otherwise stated, are
cyclic alkyl
groups with 3 to 6. The following are mentioned by way of example:
cyclopropyl,
cyclobutanyl, cyclopentyl or cyclohexyl.
s Examples of alkyloxy groups (O-alkyl) , unless otherwise stated, are
branched and
unbranched alkyl groups with 1 to 6, preferably 1 to 4 carbon atoms, linked
via an oxygen
atom. The following are mentioned by way of example: methyloxy, ethyloxy,
propyloxy
or butyloxy. In some cases the abbreviations -OMe, -OEt, -Oprop or -OBu are
used to
denote the groups methyloxy, ethyloxy, propyloxy or butyloxy . Unless stated
otherwise,
io the definitions propyloxy and butyloxy include all the 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 may be used
instead of the
term alkyloxy. The groups methyloxy, ethyloxy, propyloxy or also butyloxy may
is optionally also be referred to as methoxy, ethoxy, propoxy or butoxy.
Examples of halogenoalkylene (haloalkyl) groups, unless otherwise stated, are
branched
and unbranched alkyl groups with 1 to 6 carbon atoms, wherein one or more
hydrogen
atoms are replaced by halogen atoms, preferably by fluorine . The following
are
2o mentioned, for example: CHF2, CF3, CH2CF3, CF2CF3.
Suitable aryl groups, unless otherwise stated, are aromatic ring systems with
6 to 10 carbon
atoms. Preferred aryl groups are phenyl and naphthyl, while phenyl is
particularly
preferred according to the invention.
Examples of heterocyclic groups (heterocycles) , unless otherwise stated, are
aromatic or
non-aromatic ring systems with 2 to 5 carbon atoms and 1, 2 or 3 atoms
selected from
among O, S or N, preferably N. Particularly preferred heterocycles are
piperidine,
piperazine, morpholine, pyrolidine, pyrrole, imidazole, triazole, pyridine,
pyrimidine,
3o thiophene, tetrahydrofuran or furan.
The compounds according to the invention may be prepared analogously to
methods
already known in the art. Suitable methods of preparation are known for
example from EP
43 940 or from WO 01/83462, to which reference is hereby made in its entirety.
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.
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WO 2005/077361 1 1 PCT/EP2005/001232
Intermediate product 1: 1.1-dimethvl-3-(5-methvl-3-n-tolvl-f 1.2.41triazol-1-
propylamine
Me,
~~--N
/ Me
Me Me
a) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide
1.65 g (72 mmol) sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol)
ethylacetimidate hydrochloride in 160 mL ethanol are added at ambient
temperature and
the precipitated sodium chloride is filtered off. The filtrate is combined
with 6.00 g (40
mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction
mixture is
evaporated down and cooled. The precipitated solid is filtered off and washed
with cold
io ethanol and diethyl ether (5.7 g white solid). A further 1.2 g of solid are
obtained from the
filtrate after distillation of the solvent and recrystallisation from ethanol.
Yield: 6.93 g (91 %); mass spectroscopy [M+H]+ = 192.
b) 5-methyl-3-p-tolyl-[ 1,2,4]triazole
is 7.58 g (40 mmol) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide are heated
to 180°C for
30 minutes with stirring. After cooling the solid is dissolved in chloroform.
The precipitate
formed on cooling is suction filtered and recrystallised from chloroform.
Yield: 4.82 g (70%); mass spectroscopy [M+H]+ = 174.
20 ~ tert-butyl [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4~triazol-1-yl)-
propyll-carbamate
1.35 g (34 mmol, 60%) sodium hydride are added at 0°C to a solution of
4.87 g (28 mmol)
5-methyl-3-p-tolyl-[1,2,4]triazole in 40 mL DMPU. The reaction mixture is
heated to
ambient temperature and then stirred for one hour. 9.35 g (42 mmol) tert-butyl
(3-chloro-
1,1-dimethyl-propyl)-carbaminate and 1.87 g (5 mmol) tetrabutylammonium iodide
are
2s added and the mixture is stirred overnight at ambient temperature and then
for another 2
hours at 80°C. It is combined with water and ethyl acetate, the aqueous
phase is separated
off and extracted with ethyl acetate. The combined organic phases are washed
with water
and sodium chloride solution, dried with sodium sulphate and evaporated down.
The
residue is purified by column chromatography (silica gel; petroleum
ether/ethyl acetate =
30 1:1). oil.
Yield: 2.97 g (30%); mass spectroscopy [M+H]+ = 359.
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WO 2005/077361 12 PCTBP2005/001232
_d) 1 1-dimethyl-3-(5-methyl-3-p-tolyl-[1 2 4]triazol-1-yll-nropylamine
A total of 11 mL trifluoroacetic acid are added dropwise to a solution of 2.97
g (8.3 mmol)
tert-butyl [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propyl]-
carbamate in 80
mL dichloromethane and the mixture is stirred overnight at ambient
temperature. The
solvent is distilled off and the residue is combined with diethyl ether and
stirred. The
precipitated solid is filtered off and washed.
Yield: 2.11 g (68%, trifluoroacetate); mass spectroscopy [M+H]+ = 259.
Intermediate product 2~ 3-[3-(4-fluoro-phenyl)-5-methyl-[1 2 4]triazol-1-yll-
1,1-dimethyl-
Io propylamine
Me,
~~--N
HZN N~ ~
N \ / F
Me Me
a) 4-fluoro-benzoic acid-(1-imino-ethyl)-hydrazide
Prepared from 7.2 g (58 mmol) ethylacetimidate hydrochloride and 5.00 g (32
mmol) 4-
is fluoro-benzoic acid hydrazide analogously to the method described for
intermediate
product 1, Step a).
Yield: 5.78 g (91 %); mass spectroscopy [M+H]+ = 196.
,b, 3-(4-fluoro~henyl)-5-methyl-[1,2,41triazole
Zo The product is prepared analogously to the method described for
intermediate product 1 b)
from 5.77 g (30 mmol) 4-fluoro-benzoic acid-(1-imino-ethyl)-hydrazide.
Yield: 4.11 g (78%); mass spectroscopy [M+H]+ = 178.
c) tert-butyl {3-f3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-~]-1,1-
dimethyl-propyl}-
zs carbamate
5.88 g (33 mmol) 3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazole are dissolved in
40 mL
DMPU and reacted with 11.04 g (50 mmol) tert-butyl (3-chloro-1,1-dimethyl-
propyl)-
carbamate, 1.59 g (40 mmol, 60%) sodium hydride and 2.21 g (6 mmol)
tetrabutylammonium iodide as described for intermediate product 1 c).
3o Yield: 4.22 g (35%); mass spectroscopy [M+H]+ = 363.
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WO 200s/077361 13 PCT/EP2005/001232
d) 3-[3-(4-fluoro=phenyl)-5-methyl-[1 2 4]triazol-1-yll-1 1-dimethyl-
propylamine
Obtained by reacting 4.22 g (11.6 mmol) tert-butyl {3-[3-(4-fluoro-phenyl)-5-
methyl-
[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl}-carbamate in 100 mL dichloromethane
and 15
mL trifluoroacetic acid. White solid.
Yield: 4.43 g (trifluoroacetate); mass spectroscopy [M+H]+ = 263.
Intermediate~roduct 3~ 3-[3-(3 5-difluoro-phen~)-5-methyl-f 1,2,41triazol-1-
yll-1,1-
dimethyl-propylamine
Me
~N F
hizN~~N~N \
Me 'M '~e
F
io a) 3 5-difluoro-benzoic acid-(1-imino-ethyl)-hydrazide
The compound is obtained analogously to the method described for intermediate
product
1 a) from 4.91 g (40 mmol) ethylacetimidate hydrochloride and 3.80 g (22 mmol)
3,5
difluoro-benzoic acid hydrazide.
Yield: 4.49 g (95%); mass spectroscopy [M+H]+ = 214.
is
b) 3-(3 5-difluoro-phen~)-5-methyl-f 1,2,41triazole
Prepared from 4.61 g (22 mmol) 3,5-difluoro-benzoic acid-(1-imino-ethyl)-
hydrazide.
Yield: 3.81 g (91 %); mass spectroscopy [M+H]+ = 196.
zo c) tert-butyl 13-f3-(3,5-difluoro-phenyl)-5-methyl-f 1,2,41triazol-1-yll-
1,1-dimethyl-
propYl 1-carbamate
3.74 g (19 mmol) 3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazole in 25 mL
DMPU are
reacted with 0.92 g (23 mmol, 60%) sodium hydride, 6.37 g (29 mmol) tent-butyl
(3-
chloro-1,1-dimethyl-propyl)-carbamate and 1.27 g (3.5 mmol) tetrabutylammonium
iodide
zs analogously to Example 1 c). Oil.
Yield: 2.62 g (36%); mass spectroscopy [M+H]+ = 381.
d) 3-f3-(3 5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yll-1,1-dimethyl-
uropylamine
2.62 g (6.9 mmol) tert-butyl {3-[3-(3,5-difluoro-phenyl)-5-methyl-
[1,2,4] triazol-1-yl]-l,l-
3o dimethyl-propyl}-carbamate in 65 mL dichloromethane are reacted with 9 mL
trifluoroacetic acid in the manner described for intermediate product 1d).
White solid.
Yield: 2.11 g (trifluoroacetate); mass spectroscopy [M+H]+ = 281.
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WO 2005/077361 14 PCT/EP2005/001232
Intermediate product 4: 3-f5-ethyl-3-(4-methoxv-phenyl)-f 1,2,41triazol-1-vll-
1,1-dimethvl-
propylamine
Me
-N
HzN /~~N~N ~ / OMe
Me 7~M ''e
a) 4-method-benzoic acid-(I-imino-propyl)-hydrazide
Prepared from 4.90 g (45 mmol) propioamidine hydrochloride and 5. 00 g (30
mmol) 4-
methoxy-benzoic acid hydrazide analogously to the method described for
intermediate
product 1 a). After the ethanol has been distilled off 10.0 g crude product
are obtained
io which is reacted without any further purification.
b) 5-ethyl-3-(4-methoxy-phen~)-[1,2,4]triazole
9.99 g (60%, approx. 28 mmol) 4-methoxy-benzoic acid-(1-imino-propyl)-
hydrazide are
heated to 1 SO°C for two hours. After cooling the melt is purified by
chromatography on a
is silica gel column (petroleum ether/ethyl acetate = 3/7). Light yellow
solid.
Yield: 4.56 g (75% over two steps); mass spectroscopy [M+H]+ = 204.
c tent-butyl ( 3-f 5-ethyl-3-(4-methox~phenyl)-[ 1,2,4]triazol-1-yl]-1,1-
dimethyl-propyl-
carbamate
20 4.30 g (21.2 mmol) S-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazole are
dissolved in 30 mL
DMPU and cooled to 0°C . Under a protective gas atmosphere 1.02 g (24
mmol, 60%)
sodium hydride are then added batchwise and the reaction mixture is slowly
heated to
ambient temperature and then stirred for one hour. 6.10 g (27.5 mmol) tent-
butyl (3-chloro-
1,1-dimethyl-propyl)-carbamate and 1.41 g (3.8 mmol) tetrabutylammonium iodide
are
zs added. The mixture is stirred overnight and the reaction is then stopped by
the addition of
water and ethyl acetate. The aqueous phase is separated off and extracted with
ethyl
acetate. The combined organic phases are washed with sodium chloride solution,
dried
with sodium sulphate and evaporated down. The oil remaining is purified by
chromatography on a silica gel column (petroleum ether/ethyl acetate = 3:7).
3o Yield: 6.82 g (83%); mass spectroscopy [M+H]+ = 389.
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WO 2005/077361 15 PCT/EP2005/001232
d) 3-[5-ethyl-3-(4-methoxy=phenyl)-f 1 2 4]triazol-1-yl]-1 1-dimethyl-
propylamine
A total of 20 mL trifluoroacetic acid are added dropwise to a solution of 6.81
g (17.5
mmol) tert-butyl {3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-
dimethyl-
propyl-carbamate in 150 mL dichloromethane. After three hour's stirring at
ambient
temperature the solution is evaporated down and the oil remaining is combined
with
diethyl ether. The precipitated white solid is filtered off, washed with
diethyl ether and
dried.
Yield: 7.86 g (trifluoroacetate); mass spectroscopy [M+H]+ = 289.
io Intermediate product 5' methyl 3-f 1-(3-amino-3-methyl-butyl)-5-methyl-1H-f
1,2,41triazol-
3-yll-benzoate
Me O
1=N _ OMe
Me Me
a) methyl 3-jN'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate
is 10.80 g (54.4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl
ether are added
dropwise to a solution of 9.04 g (54.4 mmol) benzyl hydrazinecarboxylate in
100 mL
diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while being cooled
with an
ice bath. The reaction mixture is stirred overnight at ambient temperature and
then
combined with water. The precipitated solid is filtered off and washed with
diethyl ether.
2o White solid.
Yield: 14.1 g (79%); mass spectroscopy [M-H]+ = 327.
b methyl3-hydrazinocarbonyl-benzoate
14.6 g (44.5 mmol) methyl 3-[N'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate
are
is dissolved in 75 mL methanol and hydrogenated in the presence of palladium
on charcoal
(10%) at ambient temperature and 3 bar hydrogen pressure. The catalyst is
filtered off and
the filtrate is freed from solvent. White solid.
Yield: 7.98 g (92%); mass spectroscopy [M+H]+ = 195.
3o c methyl3-[N'-(1-imino-ethyl)-hydrazinocarbonyl]-benzoate
Prepared analogously to the method described for intermediate product 1 a)
from methyl 3-
hydrazinocarbonyl-benzoate and ethylacetimidate hydrochloride. White solid.
Yield: 8.60 g (90%); mass spectroscopy [M+H]+ = 236.
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WO 2005/077361 16 PCT/EP2005/001232
d) methyl 3-(5-metal-1H-[1,24]triazol-3-yl)-benzoate
8.10 g (34.4 mmol) methyl 3-[N'-(1-imino-ethyl)-hydrazinocarbonyl]-benzoate
are heated
to 180°C for 30 minutes. 80 mL chloroform are added to the solid
obtained after cooling.
The suspension is filtered and the product is dried. White solid.
Yield: 4.03 g (SS%); mass spectroscopy [M+H]+ = 218.
e) methyl 3-[1-(3-tent-butox cad rbonylamino-3-methyl-butyl)-5-methyl-1H-
[1,2,4~triazol-3-
yl-benzoate
6.00 g (27.6 mmol) methyl 3-(S-methyl-1H-[1,24]triazol-3-yl)-benzoate and 9.19
g (41.4
io mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate are reacted and
worked up in
the manner described for intermediate product lc). Yellow oil.
Yield: 5.96 g (54%); mass spectroscopy [M+H]+ = 403.
fl methyl 3-[1-(3-amino-3-methyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-benzoate
is Obtained from methyl 3-[1-(3-tert-butoxycarbonylamino-3-methyl-butyl)-5-
methyl-1H-
[1,2,4]triazol-3-yl-benzoate analogously to the method described for
intermediate product
1 d).
Yield: 5.36 g (68%, di-trifluoroacetate); mass spectroscopy [M+H]+ = 303.
zo The following intermediate products may also be obtained analogously using
the methods
of synthesis described.
Intermediate product 6: 3-(5-methyl-3-(2-methoxv-nhenvll-f 1,2.41triazol-1-vll-
1.1
dimethyl-propylamine
Me, Me0
~I-N
Fi2N~~N~N
zs Me~M ~'e
Intermediate product 7: 3-(5-methyl-3-(4-methoxv-phenyl)-f 1,2,41triazol-1-vll-
1.1
dimethyl-propylamine
Me~
N
i
HZN~~N~N ~ / OMe
Me ~M ''e
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WO 2005/077361 17 PCT/EP2005/001232
Intermediate product 8: 3-fS-methyl-3-(3-benzo~1.31dioxol-S-vl)-f
1.2.41triazol-1-vll-1.1-
dimethyl-pr ropylamine
Me,
~~--N O
HN N N
\ /
Me Me
Intermediate product 9: 2-f3-(4-methoxv-phenyl)-f1.2,41triazol-1-vll-1.1-
dimeth
ethylamine
Me Me ~N
i
HZN~N~N ~ ~ OMe
Intermediate product 10: 1,1,-dimethyl-3-(jl 2,4]triazol-1-yl)-~ropylamine
io
N
HZN N
~ N
Me Me
General method 1 (AAV 1 ):
1 mmol of N-[2-benzyloxy-S-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-
methanesulphonamide
~s and 1 mmol of amine (or intermediate product) are stirred for 30 minutes in
S mL
tetrahydrofuran at ambient temperature. The mixture is cooled to 0°C
and l .S mL of a 2
molar solution of lithium borohydride in tetrahydrofuran are added dropwise
under an
argon atmosphere. The mixture is stirred for 1 S min at 0°C, combined
with 10 mL
dichloromethane and 3 mL water, stirred for a further hour at ambient
temperature and
Zo then filtered through kieselguhr, eluting with dichloromethane. The eluate
is freed from
solvent and the residue, if necessary, is purified by chromatography. The
benzyl ether thus
obtained is dissolved in methanol and hydrogenated with palladium on charcoal
(10%) as
catalyst at 2.S bar and ambient temperature. Then the catalyst is separated
off and the crude
product is purified by chromatography (reverse phase, acetonitrile/water
gradient with
is 0.1 % trifluoroacetic acid).
CA 02552871 2006-07-06
WO 2005/077361 18 PCT/EP2005/001232
Example 1: N~jS-(2- 3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-
dimethyl-
pro~ylamino~ 1-hydrox~-ethyl)-2-hydroxy-phenyl]-methanesulphonamide
Me
OH -N
MeSOzNH ~ N N~ i
N \ / OMe
Me Me
HO
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-
phenyl]-methanesulphonamide and 3-[S-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-
1-yl]-
1,1-dimethyl-propylamine.
Yield: 255 mg (40% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+
= 518.
to
Example 2: N-[5-(2-{1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-phen'rl~-
~1,2,4]triazol-1-yll-propylamino],-1-hydroxY ethyl)-2-hydroxy phe~lL
methanesu~honamide
Me
OH ~N
MeSO2NH ~ N N~ ~
N ~ /~
Me~ ~CF3
HO
is
Obtained according to AAV 1 by reacting N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-
acetyl)-
phenyl]-methanesulphonamide and 1,1-dimethyl-3-[5-methyl-3-(4-trifluoromethyl-
phenyl)-[1,2,4]triazol-1-yl]-propylamine. White solid.
2o Yield: 78 mg (12% over 2 steps, trifluoroacetate); mass spectroscopy:
[M+H]+ = 541.
Example 3: N-(~2-[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4~]triazol-1-yl)-
propylaminol-1-hydrox -Y ethyl}-2-hydroxy-phenyl)-methanesu~honamide
Me
OH ~N
MeSO2NH ~ N N~ ~
N
Me~ ~Me
2s H~
CA 02552871 2006-07-06
WO 2005/077361 19 PCT/EP2005/001232
Obtained according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-
phenyl]-methanesulphonamide and 1,1-dimethyl-3-(5-methyl-3-p-tolyl-
[1,2,4]triazol-1-yl)-
propylamine. White solid.
Yield: 7 mg (1% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
488.
Example 4: N-[5-(2-~3-f3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl)-1,1-
dimethyl=
propylamino)-1-h day-ethyl)-2-hydroxy-phenyll-methanesulphonamide
Me
OH ~N
MeSOzNH ~ N N~ i
N ~ / F
Me Me
HO
Prepared from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-
methanesulphonamide and 3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-
1,1-
dimethyl-propylamine according to AAV 1. White solid. Yield: 155 mg (26% over
2 steps,
trifluoroacetate); mass spectroscopy: [M+H]+ = 492.
is
Example 5: 3-(1-f 3-[2-hydroxy-2-(4-hydroxy-3-methanesulphonylamino-phenyl)-
ethylamino]-3-methyl-butyll-5-methyl-1H-[1,2,4]triazol-3-~)-benzoate meth
Me O
OH ~=N OMe
MeSO2NH ~ N~~N~ i
'' N
/ Me Me
HO
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-
phenyl]-methanesulphonamide and methyl 3-[1-(3-amino-3-methyl-butyl)-5-methyl-
1H-
[1,2,4]triazol-3-yl]-benzoate. White solid.
Yield: 36 mg (7% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
532.
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WO 2005/077361 20 PCT/EP2005/001232
Example 6: N-[5-(2-f 3-(3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4~triazol-1 yl]-
1,1-
dimethyl-propylamino> -~hydroxy-ethyl~2-hydroxy-phenyll-methanesulphonamide
Me
OH ~N F
MeSO2NH ~ N~~N~ ~
N
Me Me
HO F
Prepared according to AAV 1 from N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-
phenyl]-methanesulphonamide and 3-[3-(3,5-difluoro-phenyl)-5-methyl-
[1,2,4]triazol-1-
yl]-1,1-dimethyl-propylamine. White solid.
Yield: 20 mg (3% over 2 steps, trifluoroacetate); mass spectroscopy: [M+H]+ =
510.
io
Example 7: N [2-hydrox~(1-h droxy-~3-[3-(2-methoxyphen~)-S-methyl-
(1 2 4]triazol-1-yll-1 1-dimethyl-propylamino}-eth 1)-phenyl]'-
methanesulphonamide
Me Me0
OH H ~N
MeSO2NH ~ N~N,N~
''
Me Me
HO
~s
347 mg (1 mmol) 3-[3-(2-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-l,l-
dimethyl-
propylamine hydrochloride are combined with sodium hydroxide solution and
stirred for 2
hours at ambient temperature. The solution is added to kieselguhr and eluted
with
dichloromethane. The eluate is evaporated down and the residue is taken up in
5 mL THF.
2o 379 mg (1 mmol) N [2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-
methanesulphonamide are added and the mixture is stirred for 30 min at ambient
temperature. After cooling to 0°C 1.5 mL of a 2 molar solution of
lithium borohydride in
THF are added dropwise and the mixture is stirred for 30 minutes at ambient
temperature.
The reaction mixture is combined with 10 mL dichloromethane and 3 mL water,
stirred for
2s one hour and then filtered through kieselguhr with dichloromethane as
eluant. The solvent
is distilled off and the residue is taken up in 5 mL methanol. Then it is
hydrogenated with
100 mg palladium on charcoal at 2.5 bar. The catalyst is separated off and the
filtrate is
evaporated down. For further purification the residue is chromatographed (RP,
acetonitrile:water gradient with 0.1 % trifluoroacetate).
3o Yield: 323 mg (52%, trifluoroacetate); mass spectrometry: [M+H]+ = 504.
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WO 200s/077361 21 PCT/EP2005/001232
Example 8: N f 2-h~droxy-5-( 1-hydroxy-~ 3-[3-(4-methoxy-phenyl)-5-methyl-
[1 2 4]triazol-1-yll-1 1-dimethyl-propylamino}-ethyl)-phenyl]-
methanesulphonamide
Me
OH H ~=N
MeSO2NH ~ N N, ~
N ~ / OMe
Me Me
HO
379 mg (1 mmol) of N [2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-
methanesulphonamide and 274 mg (1 mmol) of 3-[3-(4-methoxy-phenyl)-S-methyl-
[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine are suspended in S mL ethanol
and heated to
70°C. The solution formed is stirred for one hour at 70°C and
then cooled to ambient
io temperature. After the addition of 113 mg (3 mmol) sodium borohydride the
mixture is
stirred for 3 hours at ambient temperature, combined with 0.7 mL saturated
potassium
carbonate solution and stirred for a further 30 minutes. It is filtered
through aluminium
oxide (basic), washed repeatedly with methylene chloride/methanol 15:1,
evaporated down
and chromatographed (silica gel; dichloromethane with 0-10% methanol:ammonia =
9:1).
is The benzyl compound thus obtained is dissolved in 10 mL methanol and
hydrogenated
with palladium on charcoal at 2.5 bar hydrogen pressure. Then it is filtered
and the filtrate
is evaporated down.
Yield: 339 mg (67%); mass spectrometry: [M+H]+ = 504.
2o Example 9: N (~2-[3-(3-benzo[1,3]dioxol-5-yl-5-meths[1,2,4]triazol-1-yl)-
1,1-
dimethyl-propylamino]-1-hydroxy-ethyl ~-2-hydroxy-phenyl)-methanesulphonamide
Me
OH H ~=N \ O
MeSO2NH ~ N~N,Ni~O
Me~Me '~ /
HO
as Analogously to the method described for Example 7, 379 mg (1 mmol) N [2-
benzyloxy-5-
[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 288 mg (1 mmol) 3-
(3-
benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-l,l-dimethyl-propylamine
are reacted
with one another. The subsequent debenzylation yields the target compound.
Yield: 371 mg (72%); mass spectrometry: [M+H]+ = 518.
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WO 2005/077361 22 PCT/EP2005/001232
Example 10: N [2-hydroxy-5-(1-hydroxy-2~3-[3-(4-methoxy-phenyl)-[1,2,41riazol-
1-yl]-
1, I-dimethyl-propylamino)-ethyl)-phenyl],-methanesulphonamide
OH H
MeSOZNH ~ N\ ~ ,N
N
Me Me ~N \ ~ OMe
HO
The target compound is obtained by reacting 379 mg (1 mmol) N-[2-benzyloxy-5-
[2-
ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 246 mg (1 mmol) 2-[3-
(4-
methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-ethylamine in the manner
described for
Example 7 followed by debenzylation.
to Yield: 305 mg (64%); mass spectrometry: [M+H)+ = 476.
Example 11: N- 5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-y~ropylamino)-1-hydroxy-
ethyll-
2-hydroxy-phenyl ) -m ethanesu~honami de
OH H ~=N
MeSOZNH ~ N~N,N
Me~M ''e
is HO
The target compound is prepared analogously to the methods described for
Example 7
from 379 mg (1 mmol) N [2-benzyloxy-S-[2-ethoxy-2-hydroxy-acetyl)-phenyl)-
methanesulphonamide and 154 mg (1 mmol) 1,1-dimethyl-3-[1,2,4)triazol-1-yl-
zo propylamine. Colourless solid.
Yield: 225 mg (59%); mass spectrometry: [M+H]+ = 384.
As has been found, the compounds of formula 1 are characterised by their range
of uses in
the therapeutic field. Particular mention should be made of those applications
for which the
zs compounds of formula 1 according to the invention may preferably be used on
the basis of
their pharmaceutical activity as betamimetics.
These include, for example, the treatment of inflammatory and obstructive
respiratory
complaints, selected from among obstructive pulmonary diseases of various
origins,
pulmonary emphysema of various origins, restrictive pulmonary diseases,
interstitial
3o pulmonary diseases, cystic fibrosis, bronchitis of various origins,
bronchiectasis, ARDS
(adult respiratory distress syndrome) and all forms of pulmonary oedema.
The compounds of formula 1 are preferably used for preparing a pharmaceutical
CA 02552871 2006-07-06
WO 2005/077361 23 PCT/EP2005/001232
composition for the treatment of obstructive pulmonary diseases selected from
among
bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks,
chronic
bronchitis and COPD (chronic obstructive pulmonary disease), while it is
particularly
preferable according to the invention to use them for preparing a
pharmaceutical
composition for the treatment of bronchial asthma and COPD.
It is also preferable to use the compounds of formula 1 for preparing a
pharmaceutical
composition for the treatment of pulmonary emphysema which has its origins in
COPD or
a,l-proteinase inhibitor deficiency.
io
It is also preferable to use the compounds of 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
~s for example lymphangiosis carcinomatosa, bronchoalveolar carcinoma and
lymphomas.
It is also preferable to use the compounds of 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,
bacteria, fungi,
zo 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).
2s
It is also preferable to use the compounds of formula 1 for preparing a
pharmaceutical
composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use the compounds of formula 1 for preparing a
pharmaceutical
3o 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 formula 1 for preparing a
pharmaceutical
composition for the treatment of bronchiectasis.
3s
CA 02552871 2006-07-06
WO 2005/077361 24 PCT/EP2005/001232
It is also preferable to use the compounds of 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 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 of formula 1 for preparing
a
pharmaceutical composition for the treatment of asthma or COPD. Also of
particular
io importance is the above-mentioned use for preparing a pharmaceutical
composition for
once-a-day treatment of inflammatory and obstructive respiratory complaints,
particularly
for the once-a-day treatment of asthma or COPD.
Suitable preparations for administering the compounds of formula 1 include for
example
is tablets, capsules, suppositories, solutions, powders, etc. The content of
the
pharmaceutically active compounds) 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 substances) with known excipients, for
example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
disintegrants such as
Zo 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.
zs Coated tablets may be prepared accordingly by coating cores produced
analogously to the
tablets with substances normally used for tablet coatings, for example
collidone or shellac,
gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or
prevent
incompatibilities the core may also consist of a number of layers. Similarly
the tablet
coating may consist of a number of layers to achieve delayed release, possibly
using the
3o 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
3s orange extract. They may also contain suspension adjuvants or thickeners
such as sodium
CA 02552871 2006-07-06
WO 2005/077361 25 PCT/EP2005/001232
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.
io
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
is 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
zo 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).
is
For oral use the tablets may obviously contain, in addition to the carriers
specified,
additives such as sodium citrate, calcium carbonate and dicalcium phosphate
together with
various additional substances such as starch, preferably potato starch,
gelatine and the like.
Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also
be used to
3o 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
3s according to the invention it is particularly preferred to use preparations
or pharmaceutical
CA 02552871 2006-07-06
WO 200s/077361 26 PCT/EP2005/001232
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
1 either
on its own or in admixture with suitable physiologically acceptable
excipients.
io 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,
~s 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
zo maximum average particle size of up to 250 Vim, preferably between 10 and
150 Vim, most
preferably between 15 and 80 Vim. In some cases it may seem appropriate to add
finer
excipient fractions with an average particle size of I to 9 ~m 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,
Zs micronised active substance 1, preferably with an average particle size of
0.5 to 10 ~,m,
more preferably from 1 to 5 Vim, 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
3o 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
CA 02552871 2006-07-06
WO 2005/077361 27 PCT/EP2005/001232
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.
s 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
io 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
is 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).
zo 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
zs particularly up to 60 percent by volume and most preferably up to 30
percent by volume.
The remainder of the volume is made up of water. The solutions or suspensions
containing
1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The
pH may be
adjusted using acids selected from inorganic or organic acids. Examples of
particularly
suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric
acid, sulphuric
3o acid and/or phosphoric acid. Examples of particularly suitable organic
acids include
ascorbic acid, citric acid, malic acid, tartaric acid, malefic 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,
3s ascorbic acid, fumaric acid and citric acid are preferred. If desired,
mixtures of the above
CA 02552871 2006-07-06
WO 2005/077361 28 PCT/EP2005/001232
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 I00 mg/100m1, preferably less
than
SOmg/100m1, more preferably less than 20mg/100m1. Generally, inhalable
solutions in
~o which the content of sodium edetate is from 0 to l0mg/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,
is 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
20 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
preservatives which guarantee or prolong the shelf life of the finished
pharmaceutical
is 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.
3o 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
CA 02552871 2006-07-06
WO 2005/077361 29 PCT/EP2005/001232
chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in
the concentration known from the prior art. The preservatives mentioned above
are
preferably present in concentrations of up to 50 mg/100 ml, more preferably
between 5 and
20 mg/100 ml.
s Preferred formulations contain, in addition to the solvent water and the
active substance 1,
only benzalkonium chloride and sodium edetate. In another preferred
embodiment, no
sodium edetate is present.
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
io by inhalation the compounds of formula 1 are characterised by a high
potency even at
doses in the ~g range. The compounds of formula 1 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
~5 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.
The following examples of formulations illustrate the present invention
without restricting
zo its scope:
A) Tablets per tablet
active substance of formula 1 100 mg
is lactose 140 mg
maize starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
30 500 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
~
~ ~ CA 02552871 2006-07-06
WO 2005/077361 30 PCT/EP2005/001232
magnesium stearate are screened and mixed together. The mixture is compressed
to
produce tablets of suitable shape and size.
s B) Tablets per tablet
active substance of formula 80 mg
1
lactose 55 mg
maize starch 190 mg
microcrystalline cellulose 35 mg
io polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 mg
is
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
zo 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
Zs 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
3o 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
3s sorbitolan trioleate 0.1
monofluorotrichloromethane and
TG134a : TG227 2:1 ad 100
CA 02552871 2006-07-06
WO 2005/077361 31 PCT/EP2005/001232
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).
F) Powder for inhalation
active substance of formula 1 12 ~g
lactose monohydrate ad 10 mg
The powder for inhalation is produced in the usual way by mixing the
individual
io ingredients together.
