Note: Descriptions are shown in the official language in which they were submitted.
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25771-924
1
New pharmaceutical compositions based on anticholinergics
and EGFR kinase inhibitors
The present invention relates to novel pharmaceutical compositions based on
anticholinergics and EGFR kinase inhibitors, processes for preparing them
and their use in the treatment of respiratory complaints.
BRIEF DESCRIPTION OF THE FIGURES
FIG.1 shows an inhaler for using the pharmaceutical composition according to
the invention.
FIG. 2 a/b shows a nebuliser that can be used for inhaling the aqueous aerosol
preparation
according to the invention.
Description of the invention
The present invention relates to novel pharmaceutical compositions based on
anticholinergics and EGFR-kinase inhibitors, processes for preparing them
and their use in the treatment of respiratory complaints.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a
synergistic effect can be observed in the treatment of inflammatory and/or
obstructive diseases of the respiratory tract if one or more, preferably one,
anticholinergic is used with one or more, preferably one, EGFR-kinase
inhibitor. In view of this synergistic effect the pharmaceutical combinations
according to the invention can be used in smaller doses than would be the
case with the individual compounds used in monotherapy in the usual way.
The combinations of active substances according to the invention are
surprisingly characterised both by a rapid onset of activity and also by a
long-
lasting duration of activity. This is very important to the patient's feeling
of
well-being, as on the one hand they experience a rapid improvement in their
condition once the combination has been administered and on the other hand
the drug need only be taken once a day, thanks to its long-lasting effects.
These effects are observed both when the active substances are
administered simultaneously within a single active substance formulation and
also when the two active substances are administered successively in
separate formulations. It is preferable according to the invention to
administer
the two active ingredients simultaneously in a single formulation.
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1a
Within the scope of the present invention the term anticholinergics 1 denotes
salts which are preferably selected from among the tiotropium salts,
oxitropium salts and ipratropium salts, of which the tiotropium salts are
particularly preferred. In the above-mentioned salts the cations tiotropium,
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oxitropium and ipratropium are the pharmacologically active ingredients.
Within the scope of the present patent application, a reference to the above
cations is indicated by the use of the number 1'. Any reference to compounds
1 naturally also includes a reference to the ingredients 1' (tiotropium,
oxitropium or ipratropium).
By the salts 1 which may be used within the scope of the present invention
are meant the compounds which contain, in addition to tiotropium, oxitropium
or ipratropium as counter-ion (anion), chloride, bromide, iodide, sulphate,
methanesulphonate, para-toluenesulphonate or methylsulphate. Within the
scope of the present invention, the methanesulphonate, chloride, bromide and
iodide are preferred of all the salts 1, the methanesulphonate and bromide
being of particular importance. Of outstanding importance according to the
invention are salts 1 selected from among tiotropium bromide, oxitropium
bromide and ipratropium bromide. Tiotropium bromide is particularly
preferred. Tiotropium bromide in the form of its crystalline monohydrate is of
particular importance.
Within the scope of the present invention the term EGFR kinase inhibitors
(hereinafter 2) preferably denotes those compounds which are selected from
among 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-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-fluorophenyl)amino]-6-{[4-
(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-
yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(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]-6-
{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-
buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-
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phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-
yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-
yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-
buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-
quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-
methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-
1-yl]am ino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)am ino]-6-
{[4-
(N, N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-
methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-
methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-
(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-
cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-
(N, N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-
yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-
dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-
quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-
methyl-am ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-
chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-
buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-
fluorophenyl)am ino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]am ino}-7-
[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-
fIuorophenyl)am ino]-6-{[4-(N, N-dimethylam ino)-1-oxo-2-buten-1-yl]am ino}-7-
[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-
fluorophenyl)am ino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-
chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-
carbonyl)am ino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-
fIuorophenyl)am ino]-6-{[4-(N, N -dim ethyl am ino)-1 -oxo-2 -buten-1 -yl]am
ino}-7-
ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-
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methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline Cetuximab,
Trastuzumab, ABX-EGF and Mab ICR-62.
Preferred EGFR kinase inhibitors 2 are selected from among 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-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-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)-butyloxy]-6-
[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-
(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)am ino]-6-{[4-(N, N-diethylam ino)-1-oxo-2-buten-1-
yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-
fIuorophenyl)am ino]-6-{[4-(N, N-d im ethy lam ino)-1 -oxo-2 -buten- 1 -yl]am
ino}-7-
cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-
[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)methyl] am ino}-1-oxo-2-buten-1-
yl)amino]-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-
{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-
buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-
yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1-oxo-2-buten-1-yl}amino)-
7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-
((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-
(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)am ino]-6-
{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-
cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-
6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-
buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]am ino}-7-
cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((S)-2-
methoxymethyl-6-oxo-m orpholin-4-yl)-1-oxo-2-buten-1-yl]am ino}-7-
cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-
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(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-
quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-
amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-
(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-
buten-1-yl}am ino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-
ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-
1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-{[4-(N,N-dim ethyl amino)-1-oxo-2-buten-1-yI]amino}-7-
((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-
6-{[4-(N, N-dimethylam ino)-1-oxo-2-buten-1-yl]am ino}-7-((S)-tetrahydrofuran-
3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-.(2-methoxy-
ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-
quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-
am ino)-1-oxo-2-buten-1-yl]am ino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-
4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-
7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-
fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]am ino}-7-
[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-
phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]-pyrimido[5,4-
d]pyrimidine or 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-
propyloxy]-7-methoxy-quinazoline.
Particularly preferred EGFR kinase inhibitors 2 are selected from among
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]-6-[(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]-6-{[4-
(morpholin-4-yl)-1-oxo-2-buten-1-yl]am ino}-7-cyclopropylmethoxy-quinazoline
and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-
methoxy-quinazoline.
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Any reference to the abovementioned EGFR kinase inhibitors 2 also includes
within the scope of the present invention a reference to any pharmacologically
acceptable acid addition salts thereof which may exist.
By physiologically or pharmacologically acceptable acid addition salts which
may be formed from 2 are meant according to the invention pharmaceutically
acceptable salts which are selected from 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
maleic acid. According to the invention, the salts of the compounds 2
selected from among the salts of acetic acid, hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid and methanesulphonic acid are
preferred.
The pharmaceutical combinations of 1 and 2 according to the invention are
preferably administered by inhalation. Suitable inhalable powders packed into
suitable capsules (inhalettes) may be administered using suitable powder
inhalers. Alternatively, the drug may be inhaled by the application of
suitable
inhalation aerosols. These also include powdered inhalation aerosols which
contain HFA1 34a, HFA227 or a mixture thereof as propellant gas, for
example. The drug may also be inhaled using suitable solutions of the
pharmaceutical combination consisting of 1 and 2.
In one aspect, therefore, the invention relates to a pharmaceutical
composition which contains a combination of 1 and 2.
In another aspect the present invention relates to a pharmaceutical
composition which contains one or more salts 1 and one or more compounds
2, optionally in the form of their solvates or hydrates. The active substances
may be combined in a single preparation or contained in two separate
formulations. Pharmaceutical compositions which contain the active
substances 1 and 2 in a single preparation are preferred according to the
invention.
In another aspect the present invention relates to a pharmaceutical
composition which contains, in addition to therapeutically effective
quantities
of 1 and 2, a pharmaceutically acceptable carrier or excipient. In another
particularly preferred aspect the present invention relates to a
pharmaceutical
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composition which does not contain any pharmaceutically acceptable
excipient in addition to therapeutically effective quantities of 1 and 2.
The present invention also relates to the use of 1 and 2 for preparing a
pharmaceutical composition containing therapeutically effective quantities of
1
and 2 for treating inflammatory and/or obstructive diseases of the respiratory
tract, particularly asthma or chronic obstructive pulmonary disease (COPD),
as well as complications thereof such as pulmonary hypertension, as well as
allergic and non-allergic rhinitis, provided that treatment with EGFR kinase
inhibitors is not contraindicated from a therapeutic point of view, by
simultaneous or successive administration.
The present invention also relates to the simultaneous or successive use of
therapeutically effective doses of the combination of the above
pharmaceutical compositions 1 and 2 for treating inflammatory and/or
obstructive diseases of the respiratory tract, particularly asthma or chronic
obstructive pulmonary disease (COPD), as well as complications thereof such
as pulmonary hypertension, as well as allergic and non-allergic rhinitis,
provided that treatment with EGFR kinase inhibitors is not contraindicated
from a therapeutic point of view, by simultaneous or successive
administration.
In the active substance combinations of 1 and 2 according to the invention,
ingredients 1 and 2 may be present in the form of their enantiomers, mixtures
of enantiomers or in the form of racemates.
The proportions in which the active substances 1 and 2 may be used in the
active substance combinations according to the invention are variable. Active
substances 1 and 2 may possibly be present in the form of their solvates or
hydrates. Depending on the choice of the compounds 1 and 2, the weight
ratios which may be used within the scope of the present invention vary on
the basis of the different molecular weights of the various compounds and
their different potencies. As a rule, the pharmaceutical combinations
according to the invention may contain compounds 1 and 2 in ratios by weight
ranging from 1:800 to 20:1, preferably from 1:600 to 10:1.
In the particularly preferred pharmaceutical combinations which contain
tiotropium salt as compound 1 and a compound selected from among
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4-[(3-chloro-4-fluoro-phenyl)am ino]-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]-6-[(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]-6-{[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 as EGFR kinase inhibitors 2, the weight ratios of 1 to 2
are preferably in a range wherein tiotropium 1' and 2 is present in
proportions
ranging from 1:500 to 5:1, more preferably from 1:450 to 1:1, most preferably
from 1:400 to 1:100.
For example and without restricting the scope of the invention thereto,
preferred combinations of 1 and 2 according to the invention may contain
tiotropium 1' and EGFR kinase inhibitors 2 in the following weight ratios:
1:200, 1:205, 1:210, 1:215, 1:220, 1:225, 1:230, 1:235, 1:240, 1:245, 1:250,
1:255, 1:260, 1:265, 1:270, 1:275, 1:280, 1:285, 1:290, 1:295, 1:300, 1:305,
1:310, 1:315, 1:320, 1:325, 1:330, 1:335, 1:340, 1:345, 1:350.
The pharmaceutical compositions according to the invention containing the
combinations of I and 2 are normally used so that I and 2 may be present
together in doses from 1000 to 100000 pg, preferably from 1500 to 50000 pg,
more preferably from 2000 to 10000pg, even more preferably from 2500 to
7500pg per single dose. For example combinations of 1 and 2 according to
the invention contain an amount of tiotropium 1' and EGFR kinase inhibitors 2
such that the total dosage per single dose is 2500pg, 2550pg, 2600pg,
2650pg, 2700pg, 2750pg, 2800pg, 2850pg, 2900pg, 2950 g, 3000pg,
3050pg, 3100pg, 3150pg, 3200pg, 3250pg, 3300pg, 3350pg, 3400pg,
3450pg, 3500pg, 3550pg, 3600pg, 3650pg, 3700pg, 3750pg, 3800pg,
3850pg, 3900pg, 3950pg, 4000pg, 4050pg, 4100pg, 4150pg, 4200pg,
4250pg, 4300pg, 4350pg, 4400pg, 4450pg, 4500pg, 4550pg, 4600pg,
4650pg, 4700pg, 4750pg, 4800pg, 4850pg, 4900pg, 4950pg, 5000pg,
5050pg, 5100pg, 5150pg, 5200pg, 5250pg, 5300pg, 5350pg, 5400pg,
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5450pg, 5500pg, 5550pg, 5600pg, 5650pg, 5700pg, 5750pg, 5800pg,
5850pg, 5900pg, 5950pg, 6000pg, 6050pg, 6100pg, 6150pg, 6200pg,
6250pg, 6300pg, 6350pg, 6400pg, 6450pg, 6500pg, 6550pg, 6600pg,
6650pg, 6700pg, 6750pg, 6800pg, 6850pg, 6900pg, 6950pg, 7000pg,
7050pg, 7100pg, 7150pg, 7200pg, 7250pg, 7300pg, 7350pg, 7400pg,
7450pg, 7500pg or the like. These proposed dosages per single dose are not
to be regarded as being restricted to the numerical values explicitly
mentioned
but are merely disclosed by way of example. Obviously, dosages which
fluctuate around these values within a range of about +/- 25pg are also
covered by the values mentioned by way of example. In these dosage ranges
the active substances 1' and 2 may be present in the weight ratios described
above.
For example and without restricting the scope of the invention thereto, the
combinations of 1 and 2 according to the invention may contain an amount of
tiotropium 1' and EGFR kinase inhibitor 2 such that 5pg of 1' and 2500pg of 2,
5pg of 1' and 3000pg of 2, 5pg of 1' and 3500pg of 2, 5pg of 1' and 4000pg of
2, 5pg of 1' and 4500pg of 2, 5pg of 1' and 5000pg of 2, 5pg of 1' and 5500pg
of 2, 5pg of 1' and 6000pg of 2, 5pg of 1' and 6500pg of 2, 5pg of 1' and
7000pg of 2, 1 Opg of 1' and 2500pg of 2, 1 Opg of 1' and 3000pg of 2, 1 Opg
of
1' and 3500pg of 2, 1Opg of 1' and 4000pg of 2, 1 Opg of 1' and 4500pg of 2,
1 Opg of 1' and 5000pg of 2, 1 Opg of 1' and 5500pg of 2, 1 Opg of 1' and
6000pg of 2, 1 Opg of 1' and 6500pg of 2, 1 Opg of 1' and 7000pg of 2, 18pg of
1' and 2500pg of 2, 18pg of 1' and 3000pg of 2, 18pg of It and 3500pg of 2,
18pg of 1' and 4000pg of 2, 18pg of 1' and 4500pg of 2, 18pg of 1' and
5000pg of 2, 18pg of 1' and 5500pg of 2, 18pg of 1' and 6000pg of 2, 18pg of
1' and 6500pg of 2, 18pg of 1' and 7000pg of 2, 20pg of 1' and 2500pg of 2,
20pg of 1' and 3000pg of 2, 20pg of 1' and 3500pg of 2, 20pg of 1' and
4000pg of 2, 20pg of 1' and 4500pg of 2, 20pg of 1' and 5000pg of 2, 20pg of
1' and 5500pg of 2, 20pg of 1' and 6000pg of 2, 20pg of 1' and 6500pg of 2,
20pg of 1' and 7000pg of 2, 36pg of 1' and 2500pg of 2, 36pg of 1' and
3000pg of 2, 36pg of 1' and 3500pg of 2, 36pg of 1' and 4000pg of 2, 36pg of
1' and 4500pg of 2, 36pg of 1' and 5000pg of 2, 36pg of 1' and 5500pg of 2,
36pg of 1' and 6000pg of 2, 36pg of 1' and 6500pg of 2, 36pg of 1' and
7000pg of 2, 40pg of 1' and 2500pg of 2, 40pg of 1' and 3000pg of 2, 40pg of
1' and 3500pg of 2, 40pg of 1' and 4000pg of 2, 40pg of 1' and 4500pg of 2,
40pg of 1' and 5000pg of 2, 40pg of 1' and 5500pg of 2 or 40pg of 1' and
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WO 03/068264 10 PCT/EP03/01357
6000pg of 2, 40pg of 1' and 6500pg of 2, 40pg of 1' and 7000pg of 2 are
administered per single dose.
If the active substance combination wherein 1 denotes tiotropium bromide is
used as the preferred combination of 1 and 2 according to the invention, the
quantities of active substances 1' and 2 administered per single dose as
specified by way of example correspond to the following quantities of 1 and 2
administered: 6pg of 1 and 2500pg of 2, 6pg of 1 and 3000pg of 2, 6pg of 1
and 3500pg of 2, 6pg of 1 and 4000pg of 2, 6pg of 1 and 4500pg of 2, 6pg of
1 and 5000pg of 2, 6pg of 1 and 5500pg of 2, 6pg of 1 and 6000pg of 2, 6pg
of 1 and 6500pg of 2, 6pg of 1 and 7000pg of 2, 12pg of 1 and 2500pg of 2,
12pg of 1 and 3000pg of 2, 12pg of 1 and 3500pg of 2, 12pg of 1 and 4000pg
of 2, 12pg of 1 and 4500pg of 2, 12pg of 1 and 5000pg of 2, 12pg of 1 and
5500pg of 2, 12pg of 1 and 6000pg of 2, 12pg of 1 and 6500pg of 2, 12pg of 1
and 7000pg of 2, 21.7pg of 1 and 2500pg of 2, 21.7pg of 1 and 3000pg of 2,
21.7pg of 1 and 3500pg of 2, 21.7pg of 1 and 4000pg of 2, 21.7pg of 1 and
4500pg of 2, 21.7pg of 1 and 5000pg of 2, 21.7pg of 1 and 5500pg of 2,
21.7pg of 1 and 6000pg of 2, 21.7pg of 1 and 6500pg of 2, 21.7pg of 1 and
7000pg of 2, 24.1 pg of 1 and 2500pg of 2, 24.1 pg of 1 and 3000pg of 2,
24.1 pg of 1 and 3500pg of 2, 24.1 pg of 1 and 4000pg of 2, 24.1 pg of 1 and
4500pg of 2, 24.1 pg of 1 and 5000pg of 2, 24.1 pg of 1 and 5500pg of 2,
24.1 pg of 1 and 6000pg of 2, 24.1 pg of 1 and 6500pg of 2, 24.1 pg of it and
7000pg of 2, 43.3pg of 1 and 2500pg of 2, 43.3pg of 1 and 3000pg of 2,
43.3pg of 1 and 3500pg of 2, 43.3pg of 1 and 4000pg of 2, 43.3pg of 1 and
4500pg of 2, 43.3pg of 1 and 5000pg of 2, 43.3pg of 1 and 5500pg of 2,
43.3pg of 1 and 6000pg of 2, 43.3pg of 1 and 6500pg of 2, 43.3pg of 1 and
7000pg of 2, 48.1 pg of 1 and 2500pg of 2, 48.1 pg of 1 and 3000pg of 2,
48.1 pg of 1 and 3500pg of 2, 48.1 pg of 1 and 4000pg of 2, 48.1 pg of 1 and
4500pg of 2, 48.1 pg of 1 and 5000pg of 2, 48.1 pg of 1 and 5500pg of 2,
48.1 pg of 1 and 6000pg of 2, 48.1 pg of 1 and 6500pg of 2 or 48.1 pg of 1 and
7000pg of 2.
If the active substance combination wherein 1 denotes tiotropium bromide
monohydrate is used as the preferred combination of 1 and 2 according to the
invention, the quantities of active substances 1' and 2 administered per
single
dose as mentioned above by way of example correspond to the following
quantities of 1 and 2 administered per single dose: 6.2pg of 1 and 2500pg of
2, 6.2pg of 1 and 3000pg of 2, 6.2pg of 1 and 3500pg of 2, 6.2pg of 1 and
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WO 03/068264 11 PCT/EP03/01357
4000pg of 2, 6.2pg of 1 and 4500pg of 2, 6.2pg of I and 5000pg of 2, 6.2pg of
1 and 5500pg of 2, 6.2pg of I and 6000pg of 2, 6.2pg of I and 6500pg of 2,
6.2pg of I and 7000pg of 2, 12.5pg of 1 and 2500pg of 2, 12.5pg of I and
3000pg of 2, 12.5pg of 1 and 3500pg of 2, 12.5pg of I and 4000pg of 2,
12.5pg of I and 4500pg of 2, 12.5pg of I and 5000pg of 2, 12.5pg of I and
5500pg of 2, 12.5pg of 1 and 6000pg of 2, 12.5pg of 1 and 6500pg of 2,
12.5pg of 1 and 7000pg of 2, 22.5pg of 1 and 2500pg of 2, 22.5pg of 1 and
3000pg of 2, 22.5pg of 1 and 3500pg of 2, 22.5pg of 1 and 4000pg of 2,
22.5pg of 1 and 4500pg of 2, 22.5pg of 1 and 5000pg of 2, 22.5pg of 1 and
5500pg of 2, 22.5pg of 1 and 6000pg of 2, 22.5pg of 1 and 6500pg of 2,
22.5pg of 1 and 7000pg of 2, 25pg of 1 and 2500pg of 2, 25pg of 1 and
3000pg of 2, 25pg of 1 and 3500pg of 2, 25pg of 1 and 4000pg of 2, 25pg of 1
and 4500pg of 2, 25pg of 1 and 5000pg of 2, 25pg of 1 and 5500pg of 2, 25pg
of 1 and 6000pg of 2, 25pg of 1 and 6500pg of 2, 25pg of 1 and 7000pg of 2,
45pg of I and 2500pg of 2, 45pg of 1 and 3000pg of 2, 45pg of 1 and 3500pg
of 2, 45pg of 1 and 4000pg of 2, 45pg of 1 and 4500pg of 2, 45pg of 1 and
5000pg of 2, 45pg of 1 and 5500pg of 2, 45pg of 1 and 6000pg of 2, 45pg of 1
and 6500pg of 2, 45pg of 1 and 7000pg of 2, 50pg of 1 and 2500pg of 2, 50pg
of 1 and 3000pg of 2, 50pg of 1 and 3500pg of 2, 50pg of 1 and 4000pg of 2,
50pg of 1 and 4500pg of 2, 50pg of 1 and 5000pg of 2, 50pg of 1 and 5500pg
of 2, 50pg of 1 and 6000pg of 2, 50pg of 1 and 6500pg of 2 or 50pg of 1 and
7000pg of 2.
The active substance combinations of 1 and 2 according to the invention are
preferably administered by inhalation. For this purpose, ingredients 1 and 2
have to be made available in forms suitable for inhalation. Inhalable
preparations include inhalable powders, propellant-containing metering
aerosols or propellant-free inhalable solutions. Inhalable powders according
to the invention containing the combination of active substances 1 and 2 may
consist of the active substances on their own or of a mixture of the active
substances with physiologically acceptable excipients. Within the scope of the
present invention the term carrier may optionally be used instead of the term
excipient. Within the scope of the present invention, the term propellant-free
inhalable solutions also includes concentrates or sterile inhalable solutions
ready for use. The preparations according to the invention may contain the
combination of active substances 1 and 2 either together in one formulation or
in two or three separate formulations. These formulations which may be used
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within the scope of the present invention are described in more detail in the
next part of the specification.
A) Inhalable powder containing the combinations of active substances 1
and 2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either
on their own or in admixture with suitable physiologically acceptable
excipients.
If the active substances 1 and 2 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. dextran), polyalcohols
(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium
carbonate)
or mixtures of these excipients. Preferably, mono- or disaccharides are used,
while the use of lactose or glucose is preferred, particularly, but not
exclusively, in the form of their hydrates. For the purposes of the invention,
lactose is the particularly preferred excipient, while lactose monohydrate is
most particularly preferred.
Within the scope of the inhalable powders according to the invention the
excipients have a maximum average particle size of up to 250pm, preferably
between 10 and 150pm, most preferably between 15 and 80pm. It may
sometimes seem appropriate to add finer excipient fractions with an average
particle size of 1 to 9pm 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 and 2, preferably with an
average particle size of 0.5 to 10 m, more preferably from 1 to 6 m, is added
to the excipient mixture. Processes for producing the inhalable powders
according to the invention by grinding and micronising and by finally mixing
the ingredients together are known from the prior art. The inhalable powders
according to the invention may be prepared and administered either in the
form of a single powder mixture which contains both 1 and 2 or in the form of
separate inhalable powders which contain only I or 2.
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WO 03/068264 13 PCT/EP03/01357
The inhalable powders according to the invention may be administered using
inhalers known from the prior art. Inhalable powders according to the
invention which contain a physiologically acceptable excipient in addition to
I
and 2 may be administered, for example, by means of inhalers which deliver a
single dose from a supply using a measuring chamber as described in
US 4570630A, or by other means as described in DE 36 25 685 A. Preferably,
the inhalable powders according to the invention which contain physiologically
acceptable excipients in addition to 1 and 2 are packed into capsules (to
produce so-called inhalettes) which are used in inhalers as described, for
example, in WO 94/28958.
A particularly preferred inhaler for using the pharmaceutical combination
according to the invention in inhalettes is shown in Figure 1.
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions
from capsules is characterised by a housing 1 containing two windows 2, a
deck 3 in which there are air inlet ports and which is provided with a screen
5
secured via a screen housing 4, an inhalation chamber 6 connected to the
deck 3 on which there is a push button 9 provided with two sharpened pins 7
and movable counter to a spring 8, and a mouthpiece 12 which is connected
to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to
be
flipped open or shut and air holes 13 for adjusting the flow resistance.
If the inhalable powders according to the invention are packed into capsules
(inhalers) for the preferred use described above, the quantities packed into
each capsule should be 1 to 50mg, preferably 3 to 45mg, more particularly 5
to 40mg of inhalable powder per capsule. These capsules contain, according
to the invention, either together or separately, the doses of 1' and 2
mentioned hereinbefore for each single dose.
B) Propellant gas-driven inhalation aerosols containing the
combinations of active substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may
contain substances 1 and 2 dissolved in the propellant gas or in dispersed
form. 1 and 2 may be present in separate formulations or in a single
preparation, in which 1 and 2 are either each dissolved, dispersed or only one
or two of the components is or are dissolved and the other or others is or are
dispersed. The propellant gases which may be used to prepare the inhalation
aerosols according to the invention are known from the prior art. Suitable
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WO 03/068264 14 PCT/EP03/01357
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
propellant gases mentioned above may be used on their own or in mixtures
thereof. Particularly preferred propellant gases are halogenated alkane
derivatives selected from TG 11, TG 12, TG134a and TG227. Of the
abovementioned halogenated hydrocarbons, TG134a (1,1,1,2-
tetrafluoroethano) and TG227 (1,1,1,2, 3,3,3-heptafluoropropane) and
mixtures thereof are preferred according to the invention.
The propellant-driven inhalation aerosols according to the invention may also
contain other ingredients such as co-solvents, stabilisers, surfactants,
antioxidants, lubricants and pH adjusters. All these ingredients are known in
the art.
The inhalation aerosols containing propellant gas according to the invention
may contain up to 5 wt.-% of active substance 1 and 2. Aerosols according
to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%,
0.015
to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active
substance
1 and/or 2.
If the active substances 1 and/or 2 are present in dispersed form, the
particles of active substance preferably have an average particle size of up
to
m, preferably from 0.1 to 5 m, more preferably from 1 to 5 m.
The propellant-driven inhalation aerosols according to the invention
mentioned above may be administered using inhalers known in the art (MDIs
= metered dose inhalers). Accordingly, in another aspect, the present
invention relates to pharmaceutical compositions in the form of propellant-
driven aerosols as hereinbefore described combined with one or more
inhalers suitable for administering these aerosols. In addition, the present
invention relates to inhalers which are characterised in that they contain the
propellant gas-containing aerosols described above according to the
invention. The present invention also relates to cartridges which are fitted
with a suitable valve and can be used in a suitable inhaler and which contain
one of the above-mentioned propellant gas-containing inhalation aerosols
according to the invention. Suitable cartridges and methods of filling these
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cartridges with the inhalable aerosols containing propellant gas according to
the invention are known from the prior art.
C) Propellant-free inhalable solutions or suspensions containing the
combinations of active substances 1 and 2 according to the invention:
It is particularly preferred to use the active substance combination according
to the invention 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 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 I _and 2, separately or together, 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 suitable
inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid,
sulphuric acid and/or phosphoric acid. Examples of particularly suitable
organic acids include ascorbic acid, citric acid, malic acid, tartaric acid,
maleic
acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic
acid
etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is
also
possible to use the acids which have already formed an acid addition salt with
one of the active substances. Of the organic acids, ascorbic acid, fumaric
acid and citric acid are preferred. If desired, mixtures of the above acids
may
be used, particularly in the case of acids which have other properties in
addition to their acidifying qualities, e.g. as flavourings, antioxidants or
complexing agents, such as citric acid or ascorbic acid, for example.
According to the invention, it is particularly preferred to use hydrochloric
acid
to adjust the pH.
According to the invention, the addition of editic acid (EDTA) or one of the
known salts thereof, sodium edetate, as stabiliser or complexing agent is
unnecessary in the present formulation. Other embodiments may contain this
compound or these compounds. In a preferred embodiment the content
based on sodium edetate is less than 100 mg/100ml, preferably less than
50mg/100ml, more preferably less than 20mg/100ml. Generally, inhalable
solutions in which the content of sodium edetate is from 0 to 10mg/100mI are
preferred.
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Co-solvents and/or other excipients may be added to the propellant-free
inhalable solutions according to the invention. Preferred co-solvents are
those which contain hydroxyl groups or other polar groups, e.g. alcohols -
particularly isopropyl alcohol, glycols - particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any pharmacologically
acceptable substance which is not an active substance but which can be
formulated with the active substance or substances in the physiologically
suitable solvent in order to improve the qualitative properties of the active
substance formulation. Preferably, these substances have no
pharmacological effect or, in connection with the desired therapy, no
appreciable or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya lecithin, oleic
acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other
stabilisers, complexing agents, antioxidants and/or 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 physiologically 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 50mg/100m1, more preferably between 5 and
20mg/100ml.
Preferred formulations contain, in addition to the solvent water and the
combination of active substances 1 and 2, only benzalkonium chloride and
sodium edetate. In another preferred embodiment, no sodium edetate is
present.
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The propellant-free inhalable solutions according to the invention are
administered in particular using inhalers of the kind which are capable of
nebulising a small amount of a liquid formulation in the required therapeutic
dose within a few seconds to produce an aerosol suitable for therapeutic
inhalation. Within the scope of the present invention, preferred nebulisers
are
those in which a quantity of less than 100 L, preferably less than 50 L, more
preferably between 20 and 30pL of active substance solution can be
nebulised in preferably one spray action to form an aerosol with an average
particle size of less than 20 m, preferably less than 10 m, in such a way that
the inhalable part of the aerosol corresponds to the therapeutically effective
quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity
of a
liquid pharmaceutical composition for inhalation is described for example in
International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in
particular Figures 6a and 6b). The nebulisers (devices) described therein are
known by the name Respimat .
This nebuliser (Respimat ) can advantageously be used to produce the
inhalable aerosols according to the invention containing the combination of
active substances 1 and 2. Because of its cylindrical shape and handy size of
less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at
all
times by the patient. The nebuliser sprays a defined volume of
pharmaceutical formulation using high pressures through small nozzles so as
to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
housing, a nozzle, a locking mechanism, a spring housing, a spring and a
storage container, characterised by
- a pump housing which is secured in the upper housing part and which
comprises at one end a nozzle body with the nozzle or nozzle
arrangement,
- a hollow plunger with valve body,
- a power takeoff flange in which the hollow plunger is secured and
which is located in the upper housing part,
- a locking mechanism situated in the upper housing part,
- a spring housing with the spring contained therein, which is rotatably
mounted on the upper housing part by means of a rotary bearing,
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- a lower housing part which is fitted onto the spring housing in the axial
direction.
The hollow plunger with valve body corresponds to a device disclosed in
WO 97/12687. It projects partially into the cylinder of the pump housing and
is axially movable within the cylinder. Reference is made in particular to
Figures 1 to 4, especially Figure 3, and the relevant parts of the
description.
The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about
50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid,
the measured amount of active substance solution, at its high pressure end at
the moment when the spring is actuated. Volumes of 10 to 50 microlitres are
preferred, while volumes of 10 to 20 microlitres are particularly preferred
and
a volume of 15 microlitres per spray is most particularly preferred.
The valve body is preferably mounted at the end of the hollow plunger facing
the valve body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by
microtechnology. Microstructured valve bodies are disclosed for example in
WO-94/07607; reference is hereby made to the contents of this specification,
particularly Figure 1 therein and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon
firmly joined together, at least one of which has one or more microstructured
channels which connect the nozzle inlet end to the nozzle outlet end. At the
nozzle outlet end there is at least one round or non-round opening 2 to 10
microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5
microns while the length is preferably 7 to 9 microns.
In the case of a plurality of nozzle openings, preferably two, the directions
of
spraying of the nozzles in the nozzle body may extend parallel to one another
or may be inclined relative to one another in the direction of the nozzle
opening. In a nozzle body with at least two nozzle openings at the outlet end
the directions of spraying may be at an angle of 20 to 160 to one another,
preferably 60 to 150 , most preferably 80 to 100 . The nozzle openings are
preferably arranged at a spacing of 10 to 200 microns, more preferably at a
spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of
50 microns are most preferred. The directions of spraying will therefore meet
in the vicinity of the nozzle openings.
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The liquid pharmaceutical preparation strikes the nozzle body with an entry
pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an
inhalable aerosol through the nozzle openings. The preferred particle or
droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical
compression spring, as a store for the mechanical energy. The spring acts on
the power takeoff flange as an actuating member the movement of which is
determined by the position of a locking member. The travel of the power
takeoff flange is precisely limited by an upper and lower stop. The spring is
preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an
external torque which is produced when the upper housing part is rotated
counter to the spring housing in the lower housing part. In this case, the
upper housing part and the power takeoff flange have a single or multiple
V-shaped gear.
The locking member with engaging locking surfaces is arranged in a ring
around the power takeoff flange. It consists, for example, of a ring of
plastic
or metal which is inherently radially elastically deformable. The ring is
arranged in a plane at right angles to the atomiser axis. After the biasing of
the spring, the locking surfaces of the locking member move into the path of
the power takeoff flange and prevent the spring from relaxing. The locking
member is actuated by means of a button. The actuating button is connected
or coupled to the locking member. In order to actuate the locking mechanism,
the actuating button is moved parallel to the annular plane, preferably into
the
atomiser; this causes the deformable ring to deform in the annular plane.
Details of the construction of the locking mechanism are given in
WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers
the mounting, the drive of the spindle and the storage container for the
fluid.
When the atomiser is actuated the upper housing part is rotated relative to
the
lower housing part, the lower housing part taking the spring housing with it.
The spring is thereby compressed and biased by means of the helical thrust
gear and the locking mechanism engages automatically. The angle of
rotation is preferably a whole-number fraction of 360 degrees, e.g. 180
degrees. At the same time as the spring is biased, the power takeoff part in
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25771-924
the upper housing part is moved along by a given distance, the hollow plunger
is withdrawn inside the cylinder in the pump housing, as a result of which
some of the fluid is sucked out of the storage container and into the high
pressure chamber in front of the nozzle.
If desired, a number of exchangeable storage containers which contain the
fluid to be atomised may be pushed into the atomiser one after another and
used in succession. The storage container contains the aqueous aerosol
preparation according to the invention.
The atomising process is initiated by pressing gently on the actuating button.
As a result, the locking mechanism opens up the path for the power takeoff
member. The biased spring pushes the plunger into the cylinder of the pump
housing. The fluid leaves the nozzle of the atomiser in atomised form.
Further details of construction are disclosed in PCT Applications
WO 97/12683 and WO 97/20590.
The components of the atomiser (nebuliser) are made of a material which is
suitable for its purpose. The housing of the atomiser and, if its operation
permits, other parts as well, are preferably made of plastics, e.g. by
injection
moulding. For medicinal purposes, physiologically safe materials are used.
Figures 2a/b attached to this patent application, which are identical to
Figures
6a/b of WO 97/12687, show the nebuliser (Respimat ) which can
advantageously be used for inhaling the aqueous aerosol preparations
according to the invention.
Figure 2a shows a longitudinal section through the atomiser with the spring
biased while Figure 2b shows a longitudinal section through the atomiser with
the spring relaxed.
The upper housing part (51) contains the pump housing (52) on the end of
which is mounted the holder (53) for the atomiser nozzle. In the holder is the
nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power
takeoff flange (56) of the locking mechanism projects partially into the
cylinder
of the pump housing. At its end the hollow plunger carries the valve body
(58). The hollow plunger is sealed off by means of the seal (59). Inside the
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WO 03/068264 21 PCT/EP03/01357
upper housing part is the stop (60) on which the power takeoff flange abuts
when the spring is relaxed. On the power takeoff flange is the stop (61) on
which the power takeoff flange abuts when the spring is biased. After the
biasing of the spring the locking member (62) moves between the stop (61)
and a support (63) in the upper housing part. The actuating button (64) is
connected to the locking member. The upper housing part ends in the
mouthpiece (65) and is sealed off by means of the protective cover (66) which
can be placed thereon.
The spring housing (67) with compression spring (68) is rotatably mounted on
the upper housing part by means of the snap-in lugs (69) and rotary bearing.
The lower housing part (70) is pushed over the spring housing. Inside the
spring housing is the exchangeable storage container (71) for the fluid (72)
which is to be atomised. The storage container is sealed off by the stopper
(73) through which the hollow plunger projects into the storage container and
is immersed at its end in the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted in the covering of the
spring housing. At the end of the spindle facing the upper housing part is the
drive pinion (75). The slider (76) sits on the spindle.
The nebuliser described above is suitable for nebulising the aerosol
preparations according to the invention to produce an aerosol suitable for
inhalation.
If the formulation according to the invention is nebulised using the method
described above (Respimat ) the quantity delivered should correspond to a
defined quantity with a tolerance of not more than 25%, preferably 20% of this
amount in at least 97%, preferably at least 98% of all operations of the
inhaler
(spray actuations). Preferably, between 5 and 30 mg of formulation, most
preferably between 5 and 20 mg of formulation are delivered as a defined
mass on each actuation.
However, the formulation according to the invention may also be nebulised by
means of inhalers other than those described above, e.g. jet stream inhalers.
Accordingly, in a further aspect, the invention relates to pharmaceutical
formulations in the form of propellant-free inhalable solutions or suspensions
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as described above combined with a device suitable for administering these
formulations, preferably in conjunction with the Respimat . Preferably, the
invention relates to propellant-free inhalable solutions or suspensions
characterised by the combination of active substances 1 and 2 according to
the invention in conjunction with the device known by the name Respimat .
In addition, the present invention relates to the above-mentioned devices for
inhalation, preferably the Respimat , characterised in that they contain the
propellant-free inhalable solutions or suspensions according to the invention
as described hereinbefore.
The propellant-free inhalable solutions or suspensions according to the
invention may take the form of concentrates or sterile inhalable solutions or
suspensions ready for use, as well as the above-mentioned solutions and
suspensions designed for use in a Respimat . Formulations ready for use
may be produced from the concentrates, for example, by the addition of
isotonic saline solutions. Sterile formulations ready for use may be
administered using energy-operated fixed or portable nebulisers which
produce inhalable aerosols by means of ultrasound or compressed air by the
Venturi principle or other principles.
Accordingly, in another aspect, the present invention relates to
pharmaceutical compositions in the form of propellant-free inhalable solutions
or suspensions as described hereinbefore which take the form of
concentrates or sterile formulations ready for use, combined with a device
suitable for administering these solutions, characterised in that the device
is
an energy-operated free-standing or portable nebuliser which produces
inhalable aerosols by means of ultrasound or compressed air by the Venturi
principle or other methods.
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The Examples which follow serve to illustrate the present invention in more
detail without restricting the scope of the invention to the following
embodiments by way of example.
Starting materials
Tiotropium bromide:
The tiotropium bromide used in the following formulation examples may be
obtained as described in European Patent Application 418 716 Al.
In order to prepare the inhalable powders according to the invention,
crystalline tiotropium bromide monohydrate may also be used. This
crystalline tiotropium bromide monohydrate may be obtained by the method
described below.
15.0 kg of tiotropium bromide are placed in 25.7 kg of water in a suitable
reaction vessel. The mixture is heated to 80-90 C and stirred at constant
temperature until a clear solution is formed. Activated charcoal (0.8 kg)
moistened with water is suspended in 4.4 kg of water, this mixture is added to
the solution containing the tiotropium bromide and the resulting mixture is
rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least
15
minutes at 80-90 C and then filtered through a heated filter into an apparatus
preheated to an external temperature of 70 C. The filter is rinsed with 8.6 kg
of water. The contents of the apparatus are cooled at 3-5 C for every 20
minutes to a temperature of 20-25 C. The apparatus is cooled further to
10-15 C using cold water and crystallisation is completed by stirring for at
least another hour. The crystals are isolated using a suction filter dryer,
the
crystal slurry isolated is washed with 9 litres of cold water (10-15 C) and
cold
acetone (10-15 C). The crystals obtained are dried at 25 C in a nitrogen
current over a period of 2 hours.
Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).
The crystalline tiotropium bromide monohydrate thus obtained is micronised
by known methods in order to prepare the active substance in the form of the
average particle size corresponding to the specifications according to the
invention.
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In order to prepare compounds 2 mentioned within the scope of the present
invention and not yet known in the art:
I.) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-{3-[4-(2-oxo-tetrahydrofuran-4-yl)-
piperazin-1-yl]-propyloxy}-6-[(vinylcarbonyl)am ino]-quinazoline
A mixture of 166 mg acrylic acid and 0.77 ml triethylamine in 10 ml of
tetrahydrofuran is cooled to -50 C in a dry ice/acetone cooling bath and
combined with a solution of 175 pI acrylic acid chloride in 4 ml of
tetrahydrofuran. The reaction mixture is stirred at this temperature for 45
minutes. Then a solution of 427 mg of 6-amino-4-[(3-chloro-4-fluoro-
phenyl)amino]-7-{3-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]-propyloxy}-
quinazoline in 10 ml of tetrahydrofuran is added dropwise within 20 minutes.
The reaction mixture is then slowly allowed to warm up to 0 C and stirred at
this temperature until the reaction is complete. It is then combined with ice
water whereupon a viscous precipitate is formed. This is extracted thoroughly
several times with ethyl acetate/methanol. The combined organic phases are
washed with saturated sodium chloride solution, dried over magnesium
sulphate and evaporated down. The yellowish, resinous crude product is
purified by chromatography over a silica gel column with methylene
chloride/methanol (95:5) as eluant.
Yield: 148 mg (31 % of theory),
Rf value: 0.45 (silica gel, methylene chloride/methanol/concentrated aqueous
ammonia solution = 90:10:0.1)
Mass spectrum (ESI+): m/z = 567, 569 [M-H]+
The following compound is obtained analogously to I.):
4-[(3-chloro-4-fluoro-phenyl)am ino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-
yl)carbonyl]piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)am ino]-quinazoline
Rf value: 0.46 (silica gel, methylene chloride/methanol/concentrated aqueous
ammonia solution = 90:10:0.1)
Mass spectrum (ESI+): m/z = 581, 583 [M-H]+
II.) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline
0.47 ml triethylamine are added to 101 mg of acrylic acid in 5 ml of
tetrahydrofuran under a nitrogen atmosphere. This mixture is cooled to about
-50 C in a dry ice/acetone cooling bath and combined with 119 mg acrylic
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acid chloride in 3 ml of tetrahydrofuran, whereupon a colourless precipitate
is
formed. The suspension is stirred for about another hour at this temperature.
Then 240 mg of 6-amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(2,2-
dimethyl-6-oxo-morpholin-4-yl)-propyloxy]-quinazoline in 7 ml of
tetrahydrofuran are added dropwise at -55 C. The reaction mixture is allowed
to heat up slowly to -30 C. After about an hour the dry ice/acetone cooling
bath is exchanged for an ice /sodium chloride cooling bath. The reaction
mixture is then allowed to come up to 0 C therein. As soon as the reaction is
complete, the reaction mixture is combined with water and methylene chloride
and made alkaline with sodium hydroxide solution. The aqueous phase
separated off is extracted again with methylene chloride and a little
methanol.
The combined organic extracts are washed with water, dried and evaporated
down. A yellow resin remains which is chromatographed through a silica gel
column with methylene chloride/methanol (98:2) as eluant. The desired
product is stirred with a little tert. butylm ethyl ether, the fine
crystalline
precipitate is suction filtered, washed again with tert.butylmethyl ether and
dried in vacuo at 50 C.
Yield: 160 mg (60 % of theory),
Rf value: 0.42 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 526, 528 [M-H]+
The following compounds are obtained analogously to II.):
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-
yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline
Rf value: 0.32 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 498, 500 [M-H]+
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-
yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline
Rf value: 0.30 (silica gel, methylene chloride/methanol = 95:5)
Mass spectrum (ESI+): m/z = 550, 552 [M+Na] +
(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-
yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline
Mass spectrum (ESI+): m/z = 526, 528 [M-H]+
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III.) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-
buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
0.67 ml oxalyl chloride and one drop of dimethylformamide are added at
ambient temperature to a solution of 640 mg of 4-bromo-2-butenoic acid in 10
ml methylene chloride. The reaction mixture is stirred for about another half
hour at ambient temperature until the development of gas has ended. The
acid chloride produced is largely freed from solvent using the rotary
evaporator in vacuo. Then the crude product is dissolved in 10 ml of
methylene chloride and added dropwise while cooling with an ice bath to a
mixture of 1.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-
7-cyclopropylmethoxy-quinazoline and 1.60 ml of HUnig base in 50 ml of
tetrahydrofuran. The reaction mixture is stirred for 1.5 hours in the ice bath
and for a further 2 hours at ambient temperature. Then 2.90 ml of
diethylamine are added and the mixture is stirred for 2.5 days at ambient
temperature. For working up, the reaction mixture is filtered and the filtrate
is
evaporated down. The flask residue is purified by chromatography over a
silica gel column with ethyl acetate/methanol (19:1).
Yield: 550 mg (40 % of theory)
melting point: 114 C
Mass spectrum (ESI+): m/z = 498, 500 [M+H] +
The following compounds are obtained analogously to III.):
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
yl]amino}-7-cyclopropylmethoxy-quinazoline
Rf value: 0.53 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+): m/z = 510, 512 [M-H]+
(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
buten-1-yl]am ino}-7-cyclopropylmethoxy-quinazoline
melting point: 137 C
Mass spectrum (ESI+): m/z = 470, 472 [M+H] +
(3) 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
yl]am ino}-7-cyclopropylmethoxy-quinazoline
Rf value: 0.37 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+): m/z = 488 [M+H] +
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(4) 4-[(R)-(1-phenyl-ethyl)am ino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
yl]am ino}-7-cyclopentyloxy-quinazoline
Rf value: 0.35 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+): m/z = 502 [M+H] +
IV.) 4-[(3-methylphenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-
N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline
0.86 ml of oxalyl chloride and one drop of dimethylformamide are added to a
solution of 842 mg of 4-bromo-2-butenoic acid in 15 ml methylene chloride at
ambient temperature. The reaction mixture is stirred for about another hour at
ambient temperature until the development of gas has ended. The acid
chloride formed is largely freed from solvent in vacuo using the rotary
evaporator. Then the crude product is taken up in 10 ml methylene chloride
and added dropwise within five minutes to a mixture of 1.0 g of 6-amino-4-[(3-
methylphenyl)amino]-7-methoxy-quinazoline and 2.0 ml of Hunig base in
50 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture
is
stirred for two hours while cooling with an ice bath and then for another two
hours at ambient temperature. Then 6.7 ml Hunig base, 5.48 g sarcosine
ethylester hydrochloride and 3 ml of dimethylformamide are added and the
whole is stirred overnight at ambient temperature. For working up the reaction
mixture is evaporated down in vacuo using the rotary evaporator and the flask
residue is distributed between 75 ml ethyl acetate and 75 ml of water. The
organic phase is washed with water and saturated sodium chloride solution,
dried over magnesium sulphate and evaporated down. The crude product is
purified by chromatography over a silica gel column with methylene
chloride/methanol (20: 1).
Yield: 326 mg (20 % of theory)
melting point: 122-124 C
Mass spectrum (ESI+): m/z = 464 [M+H] +
The following compound is obtained analogously to IV.):
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-
[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-
cyclopropylmethoxy-quinazoline
Rf value: 0.62 (aluminium oxide, cyclohexane/ethyl acetate = 1:1)
Mass spectrum (El): m/z = 627, 629 [M] +
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V.) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-
morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
950 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-
[(ethoxycarbonyl)methyl]-N-((R)-2-hydroxy-3-methoxy-propyl)-amino}-1-oxo-2-
buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline and 195 pl of
methanesulphonic acid in 10 ml acetonitrile are refluxed for about four hours.
For working up the reaction mixture is cooled in a bath of ice water, combined
with 75 ml ethyl acetate and 25 ml saturated sodium hydrogen carbonate
solution and stirred vigorously for 10 minutes. The organic phase is separated
off, washed with saturated sodium hydrogen carbonate solution and saturated
sodium chloride solution and dried over magnesium sulphate. The solvent is
distilled off in vacuo, leaving a brownish foam.
Yield: 610 mg (69 % of theory),
Rf value: 0.55 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+): m/z = 570, 572 [M+H] +
VI.) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((S)-6-methyl-2-oxo-morpholin-
4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
A mixture of 700 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(4-{N-
[(tert. butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1-yl)-amino}-1-oxo-2-
buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline and 228 mg of
p-toluenesulphonic acid hydrate in 20 ml of acetonitrile is refluxed for five
hours. Then a further 200 mg of p-toluenesulphonic acid hydrate are added
and the mixture is again refluxed for five hours. For working up the reaction
mixture is evaporated to dryness. The flask residue is distributed between
ethyl acetate and saturated sodium carbonate solution. The organic phase is
separated off, washed with saturated sodium carbonate solution, water and
saturated sodium chloride solution, dried over magnesium sulphate and
evaporated down. The oily residue is brought to crystallisation by stirring
with
15 ml diethyl ether.
Melting point: 173-175 C
Mass spectrum (ESI+): m/z = 540, 542 [M+H] +
The following compounds are obtained analogously to VI.):
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+): m/z = 540, 542 [M+H] +
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(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline
(The reaction is carried out with methanesulphonic acid in acetonitrile)
Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)
Mass spectrum (ESI+): m/z = 556, 558 [M+H] +
VII.) 4-[(3-bromo-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-
ethoxy]-7-methoxy-quinazoline
90 pI methanesulphonic acid are added to 380 mg of 4-[(3-bromo-
phenyl)am ino]-6-(2-{N-[(tert. butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-
propyl)-amino}-ethoxy)-7-methoxy-quinazoline in 8 ml acetonitrile. The
reaction mixture is refluxed for about three hours, then another equivalent of
methanesulphonic acid is added and refluxing is continued until the reaction
is
complete. For working up the reaction mixture is diluted with ethyl acetate
and
washed with saturated sodium hydrogen carbonate solution and saturated
sodium chloride solution. The organic phase is dried over magnesium
sulphate and evaporated down in vacuo. The flask residue is stirred with
diethyl ether and suction filtered. The title compound is obtained as a white
solid.
Yield: 280 mg (85 % of theory),
Melting point: 190 C
Mass spectrum (ESI+): m/z = 485, 487 [M-H]+
The following compound is obtained analogously to VII.):
4-[(3-chloro-4-fluoro-phenyl)am ino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-
ethoxyj-7-m ethoxy-quinazoline
(The reaction is carried out with trifluoroacetic acid in acetonitrile)
melting point: 212-213 C
Mass spectrum (ESI+): m/z = 461, 463 [M+H] +
VIII.) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-
amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
4.70 ml of oxalyl chloride are added dropwise to a solution of 4.50 g of
bromocrotonic acid in 60 ml of methylene chloride. Then one drop of N,N-
dimethylformamide is added. After about 30 minutes the development of gas
has ended and the reaction mixture is evaporated down in the rotary
evaporator. The crude bromocrotonic acid chloride is taken up in 30 ml
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methylene chloride and added dropwise to a solution of 7.00 g 4-[(3-chloro-4-
fluorophenyl)am ino]-6-amino-7-cyclopropylmethoxy-quinazoline and 10.20 ml
Honig base in 150 ml of tetrahydrofuran while cooling with an ice bath. The
reaction mixture is stirred for about 1.5 hours while cooling with an ice bath
and for a further two hours at ambient temperature. Then 5.20 g of N-(2-
methoxy-ethyl)-N-methyl-amine are added and the reaction mixture is stirred
overnight at ambient temperature. For working up it is diluted with methylene
chloride and washed thoroughly with water. The organic phase is dried over
magnesium sulphate and evaporated down. The crude product is purified by
chromatography over a silica gel column with ethyl acetate followed by ethyl
acetate/methanol (19:1) as eluant.
Yield: 5.07 g (51 % of theory)
Mass spectrum (ESI+): m/z = 512, 514 [M-H]+
Rf value: 0.25 (silica gel, ethyl acetate/methanol = 9:1)
The following compounds are obtained analogously to VIII):
(1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
buten-1-yl]am ino}-7-cyclopentyloxy-quinazoline
Mass spectrum (ESI+): m/z = 482, 484 [M-H1+
Rf value: 0.11 (silica gel, ethyl acetate/methanol = 9:1)
(2) 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-
oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline
Mass spectrum (ESI+): m/z = 532 [M-H]+
Rf value: 0.40 (silica gel, ethyl acetate/methanol = 9:1)
(3) 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
Mass spectrum (ESI+): m/z = 502 [M-H]+
Rf value: 0.20 (silica gel, ethyl acetate/methanol = 9:1)
(4) 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
Mass spectrum (ESI+): m/z = 488 [M-H1+
Rf value: 0.25 (silica gel, ethyl acetate/methanol = 9:1)
(5) 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-
amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
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Mass spectrum (ESI+): m/z = 514 [M-H]+
Rf value: 0.15 (silica gel, ethyl acetate/methanol = 9:1)
(6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
buten-1-yl]am ino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline
Mass spectrum (ESI+): m/z = 486, 488 [M+H] +
(7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dim ethylamino)-1-oxo-2-
buten-1-yl]am ino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline
Mass spectrum (ESI+): m/z = 486, 488 [M+H] +
Rf value: 0.45 (silica gel, methylene chloride/methanol = 5:1)
(8) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-
amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline
Mass spectrum (ESI+): m/z = 528, 530 [M-H]+
Rf value: 0.25 (silica gel, ethyl acetate/methanol = 9:1)
(9) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-
1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline
Mass spectrum (ESI+): m/z = 508, 510 [M-H]+
melting point: 140 C
(10) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethyl amino)-1-oxo-2-
buten-1-yl]am ino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
Mass spectrum (ESI+): m/z = 500, 502 [M+H] +
melting point: 110-112 C
(11) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-
buten-1-yl]am ino}-7-[(S)-(tetrahydrofuran-2-yl)m ethoxy]-quinazoline
Mass spectrum (ESI+): m/z = 500, 502 [M+H] +
Rf value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia =
90:10:0.1)
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Some particularly preferred formulations according to the invention containing
the two components 1 and 2 are described hereinafter without restricting the
core of the invention thereto.
Formulation Examples
Inhalable powders:
1)
Ingredients lag per capsule
tiotropium bromide 10.8
EGFR kinase inhibitor 2 3500
Lactose 3489.2
Total 7000
2)
Ingredients lag per capsule
tiotropium bromide 21.7
EGFR kinase inhibitor -2 3000
Lactose 3978.3
Total 7000
3)
Ingredients lag per capsule
tiotropium bromide x H2O 22.5
EGFR kinase inhibitor 2 5000
Lactose 4022.5
Total 10000
4)
Ingredients lag per capsule
tiotropium bromide x H2O 22.5
EGFR kinase inhibitor 2 5000
Lactose 1977.5
Total 7000
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5)
Ingredients pg per capsule
tiotropium bromide x H2O 22.5
EGFR kinase inhibitor 2 5000
Total 5022.5
