Note: Descriptions are shown in the official language in which they were submitted.
WO 2004/033412 CA 02501055 2005-04-O1 PCT/EP2003/010661
81900pct.211
NOVEL BETAMIMETICS WITH EXTENDED DURATION OF ACTION,
METHOD FOR PRODUCTION AND USE THEREOF AS MEDICAMENTS
The present invention relates to compounds of general formula 1
OR' OH
H
HO ~ ~ N\ ~Rs
/~,RZ
Ho
wherein the groups R', R2 and R3 may have the meanings given in the claims
and in the specification, processes for preparing them and their use as
pharmaceutical compositions, particularly for the treatment of inflammatory
and obstructive respiratory complaints.
BACKGROUND TO THE INVENTION
Betamimetics (f3-adrenergic substances) are known from the prior art. They
may be used to good effect in a variety of therapeutic fields.
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.
Another
major advantage of drugs with a longer duration of activity is apparent in the
case of diseases or illnesses the symptoms of which only appear in the
second half of the night. A single application of a drug with a longer
duration
of activity before going to sleep would make things much simpler for the
patient and represent an improvement in the quality of life. It is
particularly
desirable to prepare a pharmaceutical composition which can be used
therapeutically by administration once a day (single dose). The use of a drug
once a day has the advantage that the patient can become accustomed
relatively quickly to regularly taking the drug at certain times of the day.
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The aim of the present invention is therefore to provide 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 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 X32-adreno-
receptor.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly it has been found that the abovementioned problems are solved
by compounds of general formula 1.
Accordingly, the present invention relates to compounds of general formula 1
OR' OH
H
HO I ~ N~R3
,R2
HO
1
wherein
R' denotes C~-C4-alkyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono- or
polysubstituted, or
R2 and R3 together denote a double-bonded group selected from -CH2-CH2-
and -CH2-CH2-CH2-.
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Preferred are compounds of formula 1, wherein
R' denotes C,-C4-alkyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono-, di-, tri-
or tetrasubstituted by one or more groups selected from C~-C3-alkyl,
CF3, methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, -OCF3,
-CHF2, -NHCOCH3 and -NHS02CH3,
or
R2 and R3 together denote a double-bonded group selected from -CH2-CH2-
and
-C H2-C H2-C Hz-.
Also preferred are compounds of general formula 1, wherein
R' denotes C,-C4-alkyl, preferably methyl;
R2 denotes C~-C4-alkyl;
R3 denotes C~-C4-alkyl or phenyl, which may optionally be mono-, di-, tri-
or tetrasubstituted by one or more groups selected from methyl, ethyl,
CF3, methoxy, ethoxy and hydroxy, or
R2 and R3 together denote a double-bonded group selected from -CH2-CH2-
and -CHZ-CH2-CH2-.
Also preferred are compounds of general formula 1, wherein
R~ denotes C~-C4-alkyl, preferably methyl;
R2 denotes C~-C4-alkyl, preferably methyl;
R3 denotes C~-C4-alkyl, preferably methyl, or phenyl, which may optionally
be mono-, di-, tri- or tetrasubstituted by one or more groups selected
from methyl, CF3, methoxy and hydroxy, or
R2 and R3 together denote the double-bonded group -CH2-CH2-.
Preferred compounds of general formula 1 according to the invention are
those wherein
R' denotes methyl or ethyl, preferably methyl;
R2 denotes methyl;
R3 denotes methyl, ethyl or phenyl, which may optionally be mono-, di-, tri-
or tetrasubstituted by one or more groups selected from methyl, CF3,
methoxy and hydroxy,
or
R2 and R3 together denote the double-bonded group -CH2-CH2-.
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Particularly preferred are compounds of general formula 1 wherein
R' denotes methyl;
R2 denotes methyl;
R3 denotes methyl or phenyl, which may optionally be mono-, di- or
trisubstituted by one or more groups selected from methyl, ethyl and
hydroxy,
or
R2 and R3 together denote the double-bonded group -CH2-CH2-.
Also preferred according to the invention are compounds of general formula 1,
wherein
R' denotes methyl;
R2 denotes methyl;
R3 denotes methyl or phenyl,
or
R2 and R3 together denote the double-bonded group -CH2-CH2-.
Of exceptional importance according to the invention are for example the
following compounds of formula1:
~ 4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-
1,2-diol;
~ 4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-
1,2-diol;
~ 4-{2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-
ethyl}-3-methoxy-benzene-1,2-diol;
~ 4-{2-[1,1-dimethyl-2-phenyl)-ethylamino]-1-hydroxy-ethyl}-3-methoxy-
benzene-1,2-diol;
~ 4-{2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-ethylamino]-1-
hydroxy-ethyl}-3-methoxy-benzene-1,2-diol;
~ 4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-
benzene-1,2-diol.
The invention relates to the compounds of formula 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.
CA 02501055 2005-04-O1
The compounds of general formula 1 according to the invention may
optionally occur in the form of their individual optical isomers, mixtures of
the
individual enantiomers or racemates and may be separated into the pure
forms using methods known from the literature. If the compounds are used in
enantiomerically pure form, the R-enantiomers are preferred.
By acid addition salts are meant the salts formed with pharmacologically
acceptable acids selected from among hydrochloric acid, hydrobromic acid,
hydriodic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, nitric
acid, malefic acid, acetic acid, benzoic acid, citric acid, fumaric acid,
tartaric
acid; oxalic acid, succinic acid and p-toluenesulphonic acid, preferably
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric
acid and methanesulphonic acid.
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.
Of the abovementioned acid addition salts, the salts of hydrochloric acid,
methanesulphonic acid, benzoic acid and acetic acid are particularly preferred
according to the invention.
The compounds according to the invention may be prepared analogously to
the methods already known in the art. Suitable methods of preparation are
known for example from US 3657244, to the contents of which reference is
made hereby.
The examples of synthesis described below serve to illustrate the present
invention more fully. They are intended only as examples of procedure to
illustrate the invention without restricting it to the subject matter
described
hereinafter.
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EXAMPLE 1
4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-
1,2-diol
OMe OH
H
HO / I N\
HO
a) 2-(1,1-dimethyl-propylamino)-1-(4-methoxy-2,2-diphenyl-
benzo[1,3]dioxol-5-yl)-ethanone:
42.5 g of a bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone
(obtainable according to US 3657244) are refluxed with 30 g of 1,1-
dimethylpropylamine in 150 ml of ethanol for 3 hours with stirring. The
solvent is distilled off under reduced pressure and the residue is combined
with diethyl ether and extracted twice with water. After the solvent has
been distilled off under reduced pressure the residue remaining is
dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The
precipitated crystals are suction filtered and washed with ethyl acetate and
diethyl ether.
Yield: 26 g (56 %, hydrochloride); melting point = 174-176 °C.
b) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-propylamino)-
ethanone:
25 g of 2-(1,1-dimethyl-propylamino)-1-(4-methoxy-2,2-diphenyl-
benzo[1,3]dioxol-5-yl)-ethanone are refluxed with 50 ml of 15% methanolic
hydrochloric acid for 2 hours with stirring. The solvent is distilled off
under
reduced pressure and the residue is dissolved in acetonitrile and
combined with ethyl acetate. The precipitated crystals are suction filtered
and washed with acetonitrile and diethyl ether.
Yield: 15 g (92%) of the compound as the hydrochloride.
For further purification the free base may be released from the
hydrochloride under the usual conditions, then suspended in methanol,
combined with an equimolar amount of benzoic acid and heated. The
crystals thus obtained are suction filtered and washed with diethyl ether.
Melting point = 151-154 °C (benzoate).
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c) 4-[2-(1,1-dimethyl-propylamino)-1-hydroxy-ethyl]-3-methoxy-benzene-
1,2-diol:
6.5 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-propylamino)-
ethanone are hydrogenated with 0.1 g of platinum oxide as catalyst in 125
ml of methanol. The catalyst is suction filtered and the solvent is distilled
off under reduced pressure. The residue is dissolved in ethyl acetate, the
precipitated crystals are suction filtered and washed with ethyl acetate and
diethyl ether.
Yield: 5.5 g (85 %; benzoate); melting point = 172-174 °C.
EXAMPLE 2
4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-
1,2-diol
OMe OH
H
HO / I N\
H O ~/~~~//)\
a) 1-methyl-cyclopentylamine:
66.5 g of sodium cyanide are dissolved in 150 ml glacial acetic acid. A
solution of 300 ml of sulphuric acid and 150 ml of glacial acetic acid is
added dropwise at 5-10°C to the sodium cyanide solution. 126 g of
1-methyl-cyclopentanol are added to this mixture. The mixture obtained is
left to stand overnight. Then 210 ml of water and, while cooling with ice,
770 g of sodium hydroxide solution in 1.5 litres of water are added thereto.
The mixture is refluxed for 4 hours and the amine is isolated by steam
distillation. The distillate is acidified with conc. hydrochloric acid,
extracted
with diethyl ether and then made alkaline with 50% sodium hydroxide
solution. The residue is fractionally distilled (BP 760 mm= 114-115
°C).
Yield: 45 g (36 %).
b) 1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-2-(1-methyl-
cyclopentylamino)-ethanone:
35 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone are
refluxed for 1 hour with 45 g of 1-methyl-cyclopentylamine in 150 ml of
ethanol. The solvent is distilled off under reduced pressure, the residue is
dissolved in diethyl ether, extracted with water and the solvent is distilled
off under reduced pressure. The residue remaining is dissolved in
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g
acetonitrile, acidified with hydrochloric acid and the crystals obtained are
isolated.
Yield: 19 g (48%; hydrochloride); melting point = 173 °C
(decomposition).
c) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1-methyl-cyclopentyl-amino)-
ethanone:
19 g of 1-(4-methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-2-(1-methyl-
cyclopentylamino)-ethanone are refluxed in 190 ml of 15% methanolic
hydrochloric acid far 2 hours with stirring. The solvent is distilled off
under
reduced pressure and the residue remaining is dissolved in acetonitrile.
The precipitated crystals are washed with diethyl ether.
Yield: 11 g (88%; hydrochloride); melting point = 187-189 °C
(decomposition).
d) 4-[1-hydroxy-2-(1-methyl-cyclopentylamino)-ethyl]-3-methoxy-benzene-
1,2-diol:
g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1-methyl-cyclopentyl-amino)-
ethanone-hydrochloride are hydrogenated with 0.2 g of Pt02 in 200 ml
methanol. The catalyst is suction filtered and the solvent is distilled off
under reduced pressure. The residue remaining is dissolved in ethanol
and combined with 5 g of sodium benzoate. The title compound is isolated
in the form of its benzoate.
Yield: 4.5 g (70.5%; benzoate); melting point = 179-180 °C.
EXAMPLE 3
4-f2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-
ethyl}-3-methoxy-benzene-1,2-diol
OMe OH
H
HO / N
HO
a) 2-Chloromethyl-1,3,5-trimethyl-benzene:
400 g of mesitylene are combined with 130 g of paraformaldehyde and 2
litres of hydrochloric acid are piped in at 60-70°C within 7 hours.
Then the
mixture is extracted with benzene and the org. phase is then washed with
2N sodium hydroxide solution. The residue is fractionally distilled.
Yield: 204 g (36 %); by ~5 = 130-140 °C.
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b) (2,4,6-trimethyl-phenyl)-acetonitrile:
66 g of sodium cyanide are refluxed in 100 ml water and 140 ml of ethanol
with stirring, until a clear solution is formed. 136 g of 2-chloromethyl-1,3,5-
trimethyl-benzene are slowly added dropwise to this solution and the
mixture is refluxed for 3 hours with stirring. It is diluted with 1 litre of
water
and extracted three times with 200 ml of benzene. The combined organic
phases are washed with water and the solvent is distilled off under
reduced pressure. The residue is fractionally distilled.
Yield: 92 g (72%); by ,5 = 145-153 °C.
c) (2,4,6-trimethyl-phenyl)-acetic acid:
155 g (2,4,6-trimethyl-phenyl)-acetonitrile are added to a solution of 1.1
litre of water and 915 ml of conc. sulphuric acid heated to 50°C. The
mixture is refluxed for 6 hours with stirring. Then the reaction mixture is
poured onto 3 kg of ice. The solid is suction filtered and washed with
water.
Yield: 131 g (86%); melting point = 163-166 °C.
d) methyl (2,4,6-trimethyl-phenyl)-acetate:
173 g (2,4,6-trimethyl-phenyl)-acetic acid are refluxed in 131 ml of conc.
hydrochloric acid and 1.1 I of methanol for 3 hours with stirring. The
solvent is distilled off under reduced pressure and the aqueous phase
extracted twice with diethyl ether . The combined organic phases are
extracted twice with a saturated aqueous sodium hydrogen carbonate
solution and dried with sodium sulphate and the solvent is distilled off
under reduced pressure. The residue is fractionally distilled.
Yield: 116 g (57 %); by ~5 = 140 °C.
e) 2-methyl-1-(2,4,6-trimethyl-phenyl)-propan-2-ol:
97 g (79 %) of the title compound are prepared from 38 g of magnesium
and 222 g of methyl iodide in 1.2 I of diethyl ether and 116 g of methyl
(2,4,6-trimethyl-phenyl)-acetate under standard conditions in a Grignard
reaction. by ~5 = 140 °C.
f) N-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethyl]-formamide:
90 ml of glacial acetic acid and 33 g of potassium cyanide are combined
while cooling with ice. 90 ml of sulphuric acid and 90 ml of glacial acetic
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IU
acid are then added dropwise at 20°C. 65 g of 2-methyl-1-(2,4,6-
trimethyl-
phenyl)-propan-2-of are slowly added to the solution at constant
temperature. After the addition has ended the mixture is stirred for a
further hour. The mixture is poured onto ice water, neutralised with
sodium carbonate solution and extracted with diethyl ether. The solvent is
distilled off under reduced pressure and the residue is fractionally
distilled.
Yield: 55 g (74 %); by o.~ = 155 °C.
g) 1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamine:
61 g of N-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethyl]-formamide are
refluxed with 35 g of potassium hydroxide in 155 ml ethyleneglycol for 9
hours with stirring and after the reaction has ended the mixture is poured
onto 1 kg of ice. The aqueous phase is extracted three times with diethyl
ether and the solvent is distilled off under reduced pressure. The residue
is fractionally distilled.
Yield: 48 g (89 %); by ~5 = 135-140 °C.
h) 2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-(4-methoxy-
2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
42.5 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone
are refluxed with 22 g of 1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamine
and 17 g of potassium carbonate in 150 ml of ethanol and 50 ml of
acetonitrile for 3 hours with stirring. The solids are filtered off and the
solvent is distilled off under reduced pressure. The residue is dissolved in
a little acetonitrile and combined with ethereal hydrochloric acid. The
crystals precipitated are suction filtered and washed with acetonitrile and
ethyl acetate.
Yield: 25 g (44 %; hydrochloride); melting point = 240-250°C.
i) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-(2,4,6-trimethyl-
phenyl)-ethylamino]-ethanone:
17 g of 2-(1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-(4-
methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are
refluxed with 170 ml of 15% methanolic hydrochloric acid for 90 min with
stirring. The solvent is largely distilled off under reduced pressure. The
residue remaining crystallises out. The crystals are filtered off and washed
with diethyl ether.
Yield: 10 g (80%; hydrochloride) melting point = 199-201 °C.
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j) 4-{2-[1,1-dimethyl-2-(2,4,6-trimethyl-phenyl)-ethylamino]-1-hydroxy-
ethyl}-3-methoxy-benzene-1,2-diol:
9 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-(2,4,6-
trimethyl-phenyl)-ethylamino]-ethanone-hydrochloride are hydrogenated
with 0.4 g of platinum(IV)oxide in 125 ml of methanol. The catalyst is
filtered off and the solvent is distilled off under reduced pressure. The
residue is dissolved in 50 ml of ethyl acetate and the precipitated crystals
are suction filtered and washed with diethyl ether and ethyl acetate.
Yield: 6 g (67 %, hydrochloride); melting point = 98-105 °C.
EXAMPLE 4
4-[2-(1,1-dimethyl-2-phenyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-
benzene-1,2-diol
OMe OH
H
HO / N
HO
a) 2-(1,1-dimethyl-phenylethylamino)-1-(4-methoxy-2,2-diphenyl-
benzo[1,3]dioxol-5-yl)-ethanone:
45 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone are
refluxed with 39 g of 1,1-dimethyl-2-phenylethylamine in 200 ml of ethanol
for 3 hours. The reaction mixture is acidified with conc. hydrochloric acid
and combined with water. The precipitated crystals are suction filtered and
washed successively with water, toluene and ethyl acetate.
Yield: 34 g (61 %, hydrochloride); melting point = 167-170°C.
b) 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-
phenylethylamino)-ethanone:
34 g of the HCI salt of 2-(1,1-dimethyl-2-phenylethylamino)-1-(4-methoxy-
2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone are refluxed in 340 ml of
15% methanolic hydrochloric acid for 2 hours. Then the solvent is distilled
off under reduced pressure and the residue is dissolved in ethyl acetate.
The solid precipitated is suction filtered and washed with ethyl acetate and
diethyl ether.
Yield: 18 g (77%, hydrochloride); melting point 192-196°C.
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c) 4-{2-[1,1-dimethyl-2-phenyl-ethylaminoJ-1-hydroxy-ethyl-3-methoxy-
benzene-1,2-diol:
g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-
phenylethylamino)-ethanone hydrochloride are hydrogenated with 0.5 g of
Pt02 in 200 ml methanol. The catalyst is suction filtered and the solvent is
distilled off under reduced pressure. The residue remaining is dissolved in
200 ml acetonitrile, combined with 5 g of sodium benzoate and refluxed for
min. After the excess sodium benzoate has been filtered off the product
which crystallises out of the filtrate is filtered off and washed with
acetonitrile and diethyl ether.
Yield: 64.5% (benzoate); melting point 149-150°C.
EXAMPLE 5
4-~2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-ethylamino]-1-hydroxy-
ethyl}-3-methoxy-benzene-1,2-diol
OMe OH
H
HO / N
HO
a) 2-[1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine]-1-(4-
methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
28.5 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone,
11 g of 1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine and 8 g of
sodium carbonate are refluxed for 3 hours in a solution of 100 ml of
ethanol and 10 ml of acetonitrile. Then the inorganic salts are filtered off
and the solvent is distilled off. The residue is dissolved in ethyl acetate,
acidified with ethereal hydrochloric acid and combined with diethyl ether.
The solid precipitated is filtered off, washed with diethyl ether and then
boiled in water. The product is obtained after filtering and drying.
Yield 11 g (hydrochloride); melting point 194-198°C.
b) Preparation of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-
(2, 3, 5,6-tetramethyl-phenyl)-ethylamine]-ethanone:
11 g of 2-[1,1-dimethyl-2-(2,3,5,6-tetramethyl-phenyl)-ethylamine]-1-(4-
methoxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are
refluxed for 1.5 hours in 110 ml of 15% methanolic hydrochloric acid. The
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crude product is suction filtered, washed with acetonitrile and then
precipitated from methanol/diethyl ether.
Yield: 7 g (hydrochloride); melting point 213-215°
(decomposition).
c) Preparation of 4-{2-[1,1-dimethyl-2-(2,3,5,6-tetra-methyl-phenyl)-
ethylamino]-1-hydroxy-ethyl-3-methoxy-benzene-1,2-diol:
7 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-[1,1-dimethyl-2-(2,3,5,6-
tetramethyl-phenyl)-ethylamine]-ethanone-hydrochloride are hydrogenated
with 0.2 g of platinum(IV)oxide in 100 ml of methanol. Then the catalyst is
filtered off and the solvent is distilled off. The residue is dissolved in 20
ml
water and combined with 1 N hydrochloric acid. The crystals precipitated
on cooling are filtered off, washed with ice water and after drying
recrystallised from ethyl acetate.
Yield: 5 g; melting point 165-168°C.
EXAMPLE 6
4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-3-methoxy-
benzene-1,2-diol
OMe OH
H
HO / N
HO
a) Preparation of 2-(1,1-dimethyl-2-o-tolyl-ethylamine)-1-(4-methoxy-2,2-
diphenyl-benzo[1,3]dioxol-5-yl)-ethanone:
26 g of a-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone, 10
g of 1,1-dimethyl-2-o-tolyl-ethylamine and 9.5 g of sodium carbonate are
refluxed for 3 hours in acetonitrile. The inorganic salts are filtered off and
the solvent is distilled off. The residue is dissolved in ethyl acetate and
acidified with ethereal hydrochloric acid, whereupon the starting amine is
precipitated and suction filtered. After the addition of diethyl ether to the
filtrate the product crystallises out.
Yield 10 g (30%; hydrochloride); melting point 180-184°C.
b) Preparation of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-o-
tolyl-ethylamine)-ethanone:
g of 2-(1,1-dimethyl-2-o-tolyl-ethylamine)-1-(4-methoxy-2,2-diphenyl-
benzo[1,3]dioxol-5-yl)-ethanone-hydrochloride are refluxed in 100 ml of
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15% methanolic hydrochloric acid for 1.5 hours. The reaction mixture is
evaporated down and the residue is recrystallised from ethyl acetate. The
solid obtained after filtration is washed with diethyl ether.
Yield 6 g (85%; hydrochloride); melting point 198-201 °
(decomposition).
c) Preparation of 4-[2-(1,1-dimethyl-2-o-tolyl-ethylamino)-1-hydroxy-ethyl]-
3-methoxy-benzene-1,2-diol:
4 g of 1-(3,4-dihydroxy-2-methoxy-phenyl)-2-(1,1-dimethyl-2-o-tolyl-
ethylamine)- ethanone-hydrochloride are hydrogenated with 0.2 g of
platinum(IV)oxide in 50 ml of methanol under normal conditions. Then the
catalyst is filtered off and the solvent is distilled off. The residue is
combined with 100 ml of acetonitrile and 3 g of sodium benzoate. It is
refluxed for 20 minutes and the inorganic matter is filtered off. The product
which crystallises out of the filtrate is suction filtered and recrystallised
from acetonitrile.
Yield 2.4 g (benzoate); melting point 114°C.
It has been found that the compounds of general formula 1 are characterised
by their versatility of use in the therapeutic field. Particular mention
should be
made of those applications for which the compounds of formula 1 according to
the invention are preferably used by virtue of their pharmaceutical
effectiveness as betamimetics.
These include for example the treatment of asthma, COPD (chronic
obstructive pulmonary disease), the inhibition of premature labour in
midwifery
(tocolysis), the restoration of sinus rhythm in the heart in atrio-ventricular
block, as well as the elimination of bradycardic heart rhythm disorders
(antiarrhythmic), the treatment of cardiovascular shock (vasodilatation and
increasing the cardiac output) as well as the treatment of itching and
irritations
of the skin.
The compounds of general formula 1 may be used on their own or in
conjunction with other active substances of formula 1. The compounds of
general formula 1 may also be used in combination with other
pharmacologically active substances. These may be, in particular,
anticholinergics, antiallergics, PAF antagonists, PDE-IV inhibitors,
leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and
corticosteroids as well as combinations of active substances thereof.
CA 02501055 2005-04-O1
IS
Examples of preferred anticholinergics which may be used in conjunction with
the compounds of formula 1 are compounds selected from among the
tiotropium salts, ipratropium salts, oxitropium salts,
salts of the compounds known from WO 02/32899
tropenol N-methyl-2,2-diphenylpropionate,
scopine N-methyl-2,2-diphenylpropionate,
scopine N-methyl-2-fluoro-2,2-diphenylacetate and
tropenol N-methyl-2-fluoro-2,2-diphenylacetate
as well as salts of the compounds known from WO 02/32899
tropenol N-methyl-3,3',4,4'-tetrafluorobenzilate,
scopine N-methyl-3,3',4,4'-tetrafluorobenzilate;
scopine N-methyl-4,4'-dichlorobenzilate,
scopine N-methyl- 4,4'-difluorobenzilate,
tropenol N-methyl-3,3'-difluorobenzilate,
scopine N-methyl- 3,3'-difluorobenzilate and
tropenol N-ethyl-4,4'-difluorobenzilate, optionally in the form of their
hydrates
and solvates. By salts are meant those compounds which contain, in addition
to the abovementioned cations, as counter-ion, an anion with a single
negative charge selected from among the chloride, bromide and
methanesulphonate.
Particularly preferably the active substances within the scope of the present
invention are the bromides or methanesulphonates of the abovementioned
structures.
Of exceptional interest within the scope of the present invention are, for
example, the anticholinergics tiotropium bromide, ipratropium bromide,
oxitropium bromide, tropenol 2,2-diphenylpropionate-methobromide, scopine
2,2-diphenylpropionate-methobromide, scopine 2-fluoro-2,2-diphenylacetate-
methobromide, tropenol 2-fluoro-2,2-diphenylacetate-methobromide, tropenol
3,3',4,4'-tetrafluorobenzilate-methobromide, scopine 3,3',4,4'-tetra-
fluorobenzilate-methobromide; scopine 4,4'-dichlorobenzilate-methobromide,
scopine 4,4'-difluorobenzilate-methobromide, tropenol 3,3'-difluorobenzilate-
methobromide, scopine 3,3'-difluorobenzilate-methobromide and tropenol
4,4'-difluorobenzilate-ethylbromide, while tiotropium bromide, ipratropium
bromide, tropenol 2,2-diphenylpropionate -methobromide, scopine 2,2-
diphenylpropionate-methobromide, scopine 2-fluoro-2,2-diphenylacetate-
CA 02501055 2005-04-O1
16
methobromide and tropenol 2-fluoro-2,2-diphenylacetate-methobromide are
particularly important.
Drug combinations which contain tiotropium bromide as another active
substance in addition to the compounds of formula 1 according to the
invention are particularly preferred according to the invention. This
combination is particularly important for the treatment of asthma or COPD,
particularly COPD. Of outstanding importance are particularly those
combinations which contain tiotropium bromide in the form of its crystalline
monohydrate known from WO 02/30928 or in the form of its crystalline
anhydrate known from WO 03/000265.
Within the scope of the present invention, the corticosteroids which may
optionally be used in conjunction with the compounds of formula 1 may be
compounds selected from among flunisolide, beclomethasone, triamcinolone,
budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864,
KSR 592, ST-126 and dexamethasone. Preferably, within the scope of the
present invention, the corticosteroids are selected from among flunisolide,
beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,
ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone
and ciclesonide are important and budesonide and fluticasone are particularly
important. In some cases, within the scope of the present patent application,
the term steroids is used on its own instead of the word corticosteroids. Any
reference to steroids within the scope of the present invention includes a
reference to salts or derivatives which may be formed from the steroids.
Examples of possible salts or derivatives include: sodium salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the
corticosteroids may also occur in the form of their hydrates.
Examples of PDE-IV inhibitors which may be used according to the invention
as a combination with the compound of formula 1 include compounds
selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP-
325,366, BY343, D-4396 (Sch-351591 ), V-11294A, Z-15370 and AWD-12-
281. Preferred PDE-IV inhibitors are selected from among enprofylline,
roflumilast, ariflo, 215370 and AWD-12-281, while AWD-12-281 is particularly
preferred as the combination partner with the compound of formula 1
according to the invention. Any reference to the abovementioned PDE-IV
inhibitors also includes, within the scope of the present invention, a
reference
CA 02501055 2005-04-O1
17
to any pharmacologically acceptable acid addition salts thereof which may
exist. By the physiologically acceptable acid addition salts which may be
formed by the abovementioned PDE-IV inhibitors are meant, according to the
invention, pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid or malefic acid. According to the invention, the
salts
selected from among the acetate, hydrochloride, hydrobromide, sulphate,
phosphate and methanesulphonate are preferred in this context.
Within the scope of the present invention, the term dopamine agonists, which
may optionally be used in conjunction with the compounds of formula 1,
denotes compounds selected from among bromocriptine, cabergolin, alpha-
dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol,
talipexol, tergurid and viozan. It is preferable within the scope of the
present
invention to use, as combination partners with the compounds of formula 1,
dopamine agonists selected from among pramipexol, talipexol and viozan,
pramipexol being of particular importance. Any reference to the
abovementioned dopamine agonists also includes, within the scope of the
present invention, a reference to any pharmacologically acceptable acid
addition salts and hydrates thereof which may exist. By the physiologically
acceptable acid addition salts thereof which may be formed by the
abovementioned dopamine agonists are meant, for example,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid and malefic acid.
Examples of antiallergic agents which may be used according to the invention
as a combination with the compounds of formula 1 include epinastin, cetirizin,
azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen,
emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastin, desloratidine and meclizine.
Preferred antiallergic agents which may be used within the scope of the
present invention in combination with the compounds of formula 1 according
to the invention are selected from among epinastin, cetirizin, azelastin,
fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin,
CA 02501055 2005-04-O1
Ig
epinastin and desloratidine being particularly prE~ferred. Any reference to
the
abovementioned antiallergic agents also includes, within the scope of the
present invention, a reference to any pharmacologically acceptable acid
addition salts thereof which may exist.
Examples of PAF antagonists which may be used according to the invention
as a combination with the compounds of formula 1 include
4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-
thieno-[3,2-f] [1,2,4]triazolo[4.3-a][1,4]diazepine and 6-(2-chlorophenyl)-8,9-
dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-
[4.5]thieno-[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepine.
Examples of EGFR kinase inhibitors which may be used as a combination
with the compounds of formula 1 according to the invention include, in
particular, 4-[(3-chloro-4-fluoro-phenyl)amino)-7-[4-((R)-6-methyl-2-oxo-
morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-
fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-
[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-
{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-
6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-
((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-
quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-E~-[(4-{N-[2-(ethoxycarbonyl)-
ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-fi-{[4-
(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-
methoxy-quinazoline. Any reference to the above~mentioned EGFR kinase
inhibitors also includes, within the scope of the present invention, a
reference
to any pharmacologically acceptable acid addition salts thereof which may
exist. By the physiologically or pharmacologically acceptable acid addition
salts thereof which may be formed by the EGFR kinase inhibitors are meant,
according to the invention, pharmaceutically acceptable salts selected from
among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid or malefic acid. The salts of
the EGFR
kinase inhibitors selected from among the salts of acetic acid, hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid and methanesulphonic
acid are preferred according to the invention.
CA 02501055 2005-04-O1
19
Particularly preferred examples of p38 kinase inhibitors which may be used as
a combination with the compounds of formula 1 according to the invention
include 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-
ethoxy)naphthalen-1-yl]-urea; 1-[5-tent-butyl-2-p-tolyl-2H-pyrazol-3-ylj-3-[4-
(2-
(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-ylj-urea; 1-[5-tert-butyl-2-(2-
methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-
yl]-urea; 1-[5-terf-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-
morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea or 1-[5-tert-butyl-2-methyl-2H-
pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea. Any
reference to the abovementioned p38 kinase inhibitors also includes, within
the scope of the present invention, a reference to any pharmacologically
acceptable acid addition salts thereof which may exist. By the physiologically
or pharmacologically acceptable acid addition salts thereof which may be
formed by the p38 kinase inhibitors are meant, according to the invention,
pharmaceutically acceptable salts selected from among the salts of
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid and malefic acid.
If the compounds of formula 1 are used in conjunction with other active
substances, the combination with steroids, PDE IV inhibitors or
anticholinergics is particularly preferred, of the categories of compounds
mentioned above. The combination with anticholinergics is of particular
importance.
Suitable preparations for administering the compounds of formula 1 include
for example tablets, capsules, suppositories and solutions, etc.
Administration
of the compounds according to the invention by inhalation is of particular
importance according to the invention (particularly for treating asthma or
COPD). 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 corn starch or alginic acid, binders such as starch or
gelatine, lubricants such as magnesium stearate or talc and/or agents for
CA 02501055 2005-04-O1
delaying release, such as carboxymethyl cellulose, cellulose acetate
phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced
analogously to the tablets with substances normally used for tablet coatings,
for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
To achieve delayed release or prevent 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 thereof
according to the invention may additionally contain a sweetener such as
saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a
flavouring such as vanillin or orange extract. They may also contain
suspension adjuvants or thickeners such as sodium carboxymethyl cellulose,
wetting agents such as, for example, condensation products of fatty alcohols
with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of isotonic
agents, preservatives such as p-hydroxybenzoates or stabilisers such as
alkali metal salts of ethylenediaminetetraacetic acid, optionally using
emulsifiers and/or dispersants, while if water is used as diluent, for
example,
organic solvents may optionally be used as solubilisers or dissolving aids,
and
the solutions may be transferred into injection vials or ampoules or infusion
bottles.
Capsules containing one or more active substances or combinations of active
substances may for example be prepared by mixing the active substances
with inert carriers such as lactose or sorbitol and packing them into gelatine
capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for this purpose, such as neutral fats or polyethyleneglycol or the
derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically
acceptable organic solvents such as paraffins (e.g. petroleum fractions),
CA 02501055 2005-04-O1
21
vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional
alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral
powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose
and glucose), emulsifiers (e.g. lignin, spent sulphite liquors,
methylcellulose,
starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,
talc,
stearic acid and sodium lauryl sulphate).
For oral use the tablets may obviously contain, in addition to the carriers
specified, additives such as sodium citrate, calcium carbonate and dicalcium
phosphate together with various additional substances such as starch,
preferably potato starch, gelatine and the like. Lubricants such as magnesium
stearate, sodium laurylsulphate and talc may also be used to produce the
tablets. In the case of aqueous suspensions the active substances may be
combined with various flavour enhancers or colourings in addition to the
abovementioned excipients.
In the preferred use of the compounds of formula 1 for the treatment of
asthma or COPD it is particularly preferred according to the invention to use
preparations or pharmaceutical formulations which are suitable for inhalation.
Inhalable preparations include inhalable powders, propellant-containing
metering 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 their own or in admixture with suitable physiologically
acceptable excipients.
If the active substances 1 are present in admixture with physiologically
acceptable excipients, the following physiologically acceptable excipients may
be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose,
saccharose, maltose), oligo- and polysaccharides (e.g. dextrans),
polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients. Preferably, mono- or
CA 02501055 2005-04-O1
22
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 Nm, preferably
between 10 and 150 pm, most preferably between 15 and 80 pm. In some
cases it may seem appropriate to add finer excipient fractions with an average
particle size of 1 to 9 pm to the excipient mentioned above. These finer
excipients are also selected from the group of possible excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders according to
the invention, micronised active substance 1, preferably with an average
particle size of 0.5 to 10 Vim, 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 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 the compounds 1 dissolved in the propellant gas or in dispersed
form. The compounds 1 may be contained in separate formulations or in a
common formulation, in which the compounds 1 are either both dissolved,
both dispersed or in each case only one component is dissolved and the other
is dispersed. The propellant gases which may be used to prepare the
inhalation aerosols are known from the prior art. Suitable propellant gases
are selected from among hydrocarbons such as n-propane, n-butane or
isobutane and halohydrocarbons such as halogenated alkane derivatives
selected from TG134a and TG227 and mixtures thereof.
The propellant-driven inhalation aerosols may also contain other ingredients
such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH
adjusters. All these ingredients are known in the art.
CA 02501055 2005-04-O1
23
The propellant-driven inhalation aerosols according to the invention
mentioned above may be administered using inhalers known in the art (MDIs
= metered dose inhalers).
Moreover, the active substances 1 according to the invention may be
administered in the form of propellant-free inhalable solutions and
suspensions. The solvent used may be an aqueous or alcoholic, preferably
an ethanolic solution. The solvent may be water on its own or a mixture of
water and ethanol. The relative proportion of ethanol compared with water is
not limited but the maximum is preferably up to 70 percent by volume, more
particularly up to 60 percent by volume and most preferably up to 30 percent
by volume. The remainder of the volume is made up of water. The solutions
or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5,
using suitable acids. The pH may be adjusted using acids selected from
inorganic or organic acids. Examples of particularly suitable inorganic acids
include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid
and/or
phosphoric acid. Examples of particularly suitable organic acids include
ascorbic acid, citric acid, malic acid, tartaric acid, 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, ascorbic acid, fumaric acid and
citric
acid are preferred. If desired, mixtures of the above acids may be used,
particularly in the case of acids which have other properties in addition to
their
acidifying qualities, e.g. as flavourings, antioxidants or complexing agents,
such as citric acid or ascorbic acid, for example. According to the invention,
it
is particularly preferred to use hydrochloric acid to adjust the pH.
If desired, the addition of editic acid (EDTA) or one of the known salts
thereof,
sodium edetate, as stabiliser or complexing agent is unnecessary in these
formulations. Other embodiments may contain this compound or these
compounds. In a preferred embodiment the content based on sodium edetate
is less than 100 mg/100m1, preferably less than 50mg/100m1, more preferably
less than 20mg/100m1. Generally, inhalable solutions in which the content of
sodium edetate is from 0 to 10mg/100m1 are preferred.
Co-solvents and/or other excipients may be added to the propellant-free
inhalable solutions. Preferred co-solvents are those which contain hydroxyl
CA 02501055 2005-04-O1
24
groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol,
glycols - particularly propyleneglycol, polyethyleneglycol,
polypropyleneglycol,
glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid
esters. The terms excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active substance but
which can be formulated with the active substance or substances in the
physiologically suitable solvent in order to improve the qualitative
properties of
the active substance formulation. Preferably, these substances have no
pharmacological effect or, in connection with the desired therapy, no
appreciable or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya lecithin, oleic
acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other
stabilisers, complexing agents, antioxidants and/or preservatives which
guarantee or prolong the shelf life of the finished pharmaceutical
formulation,
flavourings, vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium chloride as
isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for
example, provided that it has not already been used to adjust the pH, vitamin
A, vitamin E, tocopherols and similar vitamins and provitamins occurring in
the
human body.
Preservatives may be used to protect the formulation from contamination with
pathogens. Suitable preservatives are those which are known in the art,
particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid
or
benzoates such as sodium benzoate in the concentration known from the
prior art. The preservatives mentioned above are preferably present in
concentrations of up to 50 mg/100 ml, more preferably between 5 and 20
mg/100 ml.
Preferred formulations contain, in addition to the solvent water and the
active
substance 1, only benzalkonium chloride and sodium edetate. In another
preferred embodiment, no sodium edetate is present.
The dosage of the compounds according to the invention is naturally highly
dependent on the method of administration and the complaint which is being
treated. When administered by inhalation the compounds of formula 1 are
CA 02501055 2005-04-O1
characterised by a high potency even at doses in the Ng range. The
compounds of for mula 1 may also be used effectively above the pg range.
The dosage may then be in the gram range, for example.
Particularly when administered by routes other than by inhalation the
compounds according to the invention may be administered in higher doses
(for example, but not restrictively, in the range from 1 to 1000 mg).
The following examples of formulations illustrate the present invention
without
restricting its scope:
EXAMPLES OF PHARMACEUTICAL FORMULATIONS
A) TABLETS
per tablet
active substance 100 ma
lactose 140 mg
maize starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
500 ma
The finely ground active substance, lactose and some of the maize starch are
mixed together. The mixture is screened, then moistened with a solution of
polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The
granules, the remaining maize starch and the magnesium stearate are
screened and mixed together. The mixture is pressed into tablets of suitable
shape and size.
B) TABLETS
per tablet
active substance 80 ma
lactose 55 mg
maize starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
CA 02501055 2005-04-O1
26
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 ma
The finely ground active substance, some of the maize starch, lactose,
microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the
mixture is screened and worked with the remaining maize starch and water to
form granules which are dried and screened. To these are added the sodium
carboxymethyl starch and the magnesium stearate, they are mixed together
and the mixture is pressed into tablets of suitable size.
C) AMPOULE SOLUTION
active substance 50 ma
sodium chloride 50 mg
water for ini. 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 the solution isotonic. The
resulting solution is filtered to remove pyrogens and the filtrate is
transferred
under aseptic conditions into ampoules which are then sterilised and heat-
sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.
D) METERED-DOSE AEROSOL
active substance 0.005
sorbitan trioleate 0.1
monofluorotrichloromethane and ad 100
TG 134a : TG227 2:1
The suspension is transferred into a conventional aerosol container with
metering valve. Preferably 50 pl suspension are released on each actuation.
The active substance may also be released in higher doses if desired
(e.g. 0.02 wt.-%).
E) SOLUTIONS
(in mg/100m1)
CA 02501055 2005-04-O1
27
active substance 333.3 mg
tiotropium bromide 333.3 mg
benzalkonium chloride10.0 mg
EDTA 50.0 mg
HCI (1 n) ad pH 3.4
This solution may be prepared in the conventional manner.
F) INHALABLE POWDER
active substance 6 Ng
tiotropium bromide 6 pg
lactose monohydrate ad 25 ma
The inhalable powder is prepared in the conventional manner by mixing the
individual ingredients.
