Note: Descriptions are shown in the official language in which they were submitted.
CA 02533752 2006-O1-26
Boehringer Ingelheim Case 1/1537-Ro
D-55216 INGELHEIM foreign filing text
84562fft.210
Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
The present invention relates to the use of quinazolines selected from the
group
consisting of
~o (1) 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-
1-oxo-2-
buten-1-yl]amino}-7-methoxy-quinazoline,
(2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
yl]-
amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
(3) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-
1-
oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
(4) 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-
oxo-2-
2o buten-1-yl]amino}-quinazoline,
(5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-7-methoxy-quinazoline,
(6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
(7) 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
(8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-
piperidin-1-
yl]-ethoxy}-7-methoxy-quinazoline,
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(9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
(10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-
cyclohexan-1-yloxy]-7-methoxy-quinazoline,
(11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-
yloxy)-7-methoxy-quinazoline,
(12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-
methyl-
amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
(13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
yloxy)-7-methoxy-quinazoline,
(14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-
yl)carbonyl]-N-
methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
(15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxo-3-methyl-imidazolidin-
1-
2o yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
(16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxo-hexahydropyrimidin-1-
yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
(17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
(18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-
yloxy)-7-
methoxy-quinazoline and
(19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-
methoxy-
quinazoline,
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the tautomers, stereoisomers and salts thereof, particularly the
physiologically
acceptable salts thereof with inorganic or organic acids or bases, for
preparing a
pharmaceutical composition for the prevention and treatment of
diseases of the airways and lungs which are accompanied by increased or
altered
s production of mucus, e.g. in inflammatory diseases of the airways such as
acute
bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma,
bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic
fibrosis, a1-an
titrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis or
hyperreactive airways.
The compounds are also suitable for treating inflammatory diseases of the
gastrointestinal tract or bile duct and gall bladder which are associated with
disrupted
activity of the tyrosine kinases, such as may be found e.g. in acute or
chronic
inflammatory changes such as cholecystitis, Crohn's disease, ulcerative
colitis, and
1s ulcers or polyposis in the gastrointestinal tract or such as may occur in
diseases of
the gastrointestinal tract which are associated with increased secretions,
such as
Menetrier's disease, secreting adenomas and protein loss syndromes,
and also for treating inflammatory diseases of the joints, such as rheumatoid
arthritis,
2o inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps,
in colitis
cystica profunda or pneumatosis cystoides intestinalis.
Preferred fields of application are inflammatory diseases of the respiratory
organs or
of the intestine, such as chronic bronchitis (COPD), chronic sinusitis,
asthma,
2s Crohn's disease, ulcerative colitis or polyposis of the intestines.
Particularly preferred fields of application are inflammatory diseases of the
airways or
lungs such as chronic bronchitis (COPD) or asthma.
3o The present invention further relates to a process for treating
diseases of the airways and lungs which are accompanied by increased or
altered
production of mucus, e.g. in inflammatory diseases of the airways such as
acute
bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma,
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bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic
fibrosis,
a1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis
and
hyperreactive airways,
s for treating inflammatory diseases of the gastrointestinal tract and bile
duct and gall
bladder which are associated with disrupted activity of the tyrosine kinases,
such as
may be found e.g. in acute or chronic inflammatory changes such as
cholecystitis,
Crohn's disease, ulcerative colitis and ulcers or polyposis in the
gastrointestinal tract
or such as may occur in diseases of the gastrointestinal tract which are
associated
~o with increased secretions, such as Menetrier's disease, secreting adenomas
and
protein loss syndromes,
and also for treating inflammatory diseases of the joints, such as rheumatoid
arthritis,
inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps, in
colitis
~s cystica profunda and pneumatosis cystoides intestinalis,
comprising administering an effective amount of one or more of the above-
mentioned
compounds (1 ) to (19) or optionally one of the physiologically acceptable
salts
thereof to a patient requiring such treatment.
In the process according to the invention the above-mentioned compounds are
used
in doses from 0.001-10 mg/kg body weight, for example 0.5 - 7.0 mg/kg,
preferably
0.01-1.5 mg/kg, expediently administered 1 to 3 times a day.
The active substances may be administered by oral, buccal or parenteral route,
by
atomisation for inhalation, rectally or topically. They may be administered
parenterally
by subcutaneous, intravenous and intramuscular injections and infusion
techniques.
Conventional formulations may be used for administering them, such as the
3o formulations mentioned above with regard to the active substances. For
example, the
active substances may be formulated, optionally together with other active
substances, with one or more inert conventional carriers and/or diluents, e.g.
with
corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,
water/glycerol,
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water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetyl stearyl
alcohol,
carboxymethylcellulose or fatty substances such as hard fat or suitable
mixtures
thereof, to produce conventional galenic preparations such as plain or coated
tablets,
capsules, powders, suspensions or suppositories.
The active substances may be given orally in a variety of different dosage
forms, i.e.
they may be prepared with various pharmaceutically acceptable inert carriers
to form
tablets, capsules, pastilles, lozenges, sweets, powders, sprays, aqueous
suspensions, elixirs, syrups and the like. Such carriers include solid
diluents or fillers,
~o sterile aqueous media and various non-toxic organic solvents. In addition,
oral
pharmaceutical preparations of this kind may be suitably sweetened or
flavoured,
using various agents conventionally used for this purpose. In general the
active
substances are present in oral formulations of this kind in concentrations
ranging
from about 0.5 to about 90 wt.%, based on the total composition, in amounts
~5 sufficient to produce the desired dosage units. Other suitable dosage forms
for the
active substances include preparations and devices with controlled release,
with
which the skilled man will be familiar.
For parenteral administration solutions of the active substances in sesame or
2o groundnut oil or in aqueous propyleneglycol as well as sterile aqueous
solutions of
the corresponding pharmaceutically acceptable salts may be used. Aqueous
solutions of this kind should be suitably buffered as necessary and the liquid
diluent
may optionally be made isotonic with sufficient salt or glucose. These
specific
aqueous solutions are particularly suitable for intravenous, intramuscular and
25 subcutaneous injection. In this context, the sterile aqueous media used may
easily be
obtained by conventional methods well known to the skilled man. For example,
distilled water is normally used as a liquid diluent, and the finished
preparation is
passed through a suitable bacterial filter, e.g. a filter made of sintered
glass,
kieselguhr or unglazed porcelain. Preferred filters of this type include
Berkefeld,
3o Chamberland and asbestos disc metal Seitz filters, the liquid being
aspirated into a
sterile container using a suction pump. Throughout the entire process of
preparing
these injectable solutions the necessary steps should always be carried out in
such a
way as to obtain the end products in a sterile state. For transdermal
administration
the formulations of the particular compounds or compounds include for example
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solutions, lotions, ointments, creams, gels, suppositories, formulations for
long-
lasting speed-limited release preparations and devices therefor. These
formulations
comprise the particular compounds) and may contain ethanol, water, penetration
promoters and inert carriers, e.g. gel-forming materials, mineral oil,
emulsifiers,
s benzyl alcohol and the like.
The substances may be administered by inhalation in the form of powder
formulations with lactose and other excipients or in the form of aqueous
solutions as
an aerosol.
The inhalable powders which may be used according to the invention may contain
the active substance or combination of active substances either on its own or
in
admixture with suitable physiologically acceptable excipients. If the active
substance
or combination of active substances is present in admixture with
physiologically
1s 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 with one another. 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.
2s Inhalation aerosols containing propellant gas which may be used according
to the
invention may contain the active substance or combination of active substances
dissolved in the propellant gas or in dispersed form. The propellant gases
which may
be used to prepare the inhalation aerosols according to the invention are
known from
the prior art. Suitable propellant gases are selected from among hydrocarbons
such
3o as n-propane, n-butane or isobutane and halohydrocarbons such as preferably
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 fluorinated
alkane
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derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227
(1,1,1,2,3,3,3-
heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the
s invention may also contain other ingredients such as co-solvents,
stabilisers, surface
active agents (surfactants), antioxidants, lubricants and pH adjusters. All
these
ingredients are known in the art.
If the active substance or combination of active substances according to the
invention is administered by inhalation in the form of propellant-free
solutions or
~o suspension, aqueous or alcoholic, preferably ethanolic solutions may be
used as the
solvent. The solvent may be exclusively water or a mixture of water and
ethanol.
The relative proportion of ethanol to water is not restricted, but the maximum
limit 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
~5 water. The solutions or suspensions containing the active substance or
combination
of active substances are optionally 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
20 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 acid and
sulphuric
acid. Of the organic acids, ascorbic acid, fumaric acid and citric acid are
preferred. If
desired, mixtures of the above acids may also be used, particularly in the
case of
25 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.
so As already mentioned hereinbefore, the compounds of general formula (I) and
the
salts thereof have valuable properties, particularly an anti-inflammatory
activity.
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For example, the compounds
A = 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
oxo-
2-buten-1-yl]amino}-7-methoxy-quinazoline,
B = 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-
1-
oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
C = 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
~o ethoxy]-7-methoxy-quinazoline,
D = 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline and
E - 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-
yl)-
ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
were tested as follows to investigate their anti-inflammatory activity:
2o Test 1: Inhibition of the smoke-induced accumulation of granulocytes in
the lung tissue
Lung indications: Inhibition of the cigarette smoke-induced influx of
neutrophilic
granulocytes into the lung tissue by the EGF-receptor kinase inhibitor 4-[(R)-
(1-
phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-
yl]amino}-7-methoxy-quinazoline (compound A).
Method:
Male rats (strain: Sprague-Dawley) weighing from 250-300 g were exposed for 5
so days to the smoke from 8 cigarettes per day. The animals in the group
treated with
compound A, anaesthetised with isofluran, were given an intratracheal dose of
0.03
or 0.1 mg/kg of compound A in a volume of 0.05 ml each day 30 min before the
start
of the exposure to smoke. On the last day of the test the animals were killed
4 hours
after the last exposure to smoke and the lung tissue was removed. A sample of
70 -
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200 mg was taken from each lung and placed in a test tube prepared with 1 ml
of
0.5% hexadecyltrimethylammonium bromide. The samples were homogenised for 15
sec using an Ultraturrax. The homogenised samples were centrifuged at 15700 g
in
an Eppendort bench centrifuge for 5 min at ambient temperature. 50 ml of the
s supernatant was removed and mixed with 250 ml of phosphate buffer (50mmol/I)
containing 0.197 mg/ml of O-dianisidine dihydrochloride. After 10 minutes'
incubation
at ambient temperature the absorption was measured with a spectral photometer
at
a wavelength of 450 nm.
The dosage which led to a 50% inhibition of the MPO activity (= ID50) was
~o determined by linear regression.
Results:
Exposure to cigarette smoke in rats led to an influx of neutrophilic
granulocytes into
the lung tissue, measured by the content of myeloperoxidase in the tissues,
which is
~s specific for neutrophilic granulocytes. Intratracheal treatment of the
animals with the
EGFR kinase inhibitor A resulted in a significant (p<0.005) inhibition of the
smoke-
induced accumulation of granulocytes and thus produced an anti-inflammatory
activity.
2o Further results are shown in the following Table:
active substanceID50 [mg/kg]
A 0.3
B 0.2
C 1
D 1.1
E 0.4
