U.S. patent application number 12/812685 was filed with the patent office on 2011-02-24 for nozzle and inhaler and method for producing a nozzle.
This patent application is currently assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. Invention is credited to Stephen T. Dunne.
Application Number | 20110041844 12/812685 |
Document ID | / |
Family ID | 40548517 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110041844 |
Kind Code |
A1 |
Dunne; Stephen T. |
February 24, 2011 |
NOZZLE AND INHALER AND METHOD FOR PRODUCING A NOZZLE
Abstract
A nozzle (12), an inhaler (FIG. 1) with a nozzle (12) and a
method for producing a nozzle are proposed. The nozzle comprises
two holes (21) formed in a flat plate (22). Then, the plate (21) is
deformed such that the axes of the holes intersect so that jets of
fluids generated by the holes impinge with each other.
Inventors: |
Dunne; Stephen T.; (Suffolk,
GB) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim am Rhein
DE
|
Family ID: |
40548517 |
Appl. No.: |
12/812685 |
Filed: |
January 16, 2009 |
PCT Filed: |
January 16, 2009 |
PCT NO: |
PCT/EP09/00252 |
371 Date: |
August 17, 2010 |
Current U.S.
Class: |
128/203.12 ;
239/543 |
Current CPC
Class: |
A61M 11/007 20140204;
A61M 11/04 20130101; A61M 15/0045 20130101; B05B 11/3001 20130101;
A61M 11/00 20130101; A61M 11/001 20140204; A61M 15/009 20130101;
A61M 15/0021 20140204; A61M 2202/0468 20130101; A61M 11/02
20130101; B05B 1/26 20130101; B05B 11/3091 20130101; A61M 15/0065
20130101 |
Class at
Publication: |
128/203.12 ;
239/543 |
International
Class: |
A61M 15/00 20060101
A61M015/00; B05B 1/26 20060101 B05B001/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 16, 2008 |
GB |
0800709.8 |
Claims
1. In a nozzle (12) for generating at least two impinging jets
(20), the nozzle (12) comprising at least two holes (21) for
dispensing a fluid, in particular an inhalation formulation (2), in
order to generate the jets (20) of fluid, the improvement which is
characterized in that the nozzle (12) comprises a plate (22) with
the holes (21), the plate (22) being deformed or the holes (21)
being inclined in the flat plate (22) such that the axes (23) of
the holes (21) intersect each other at an outlet side (24) of the
nozzle (12).
2. The nozzle according to claim 1, characterized in that the plate
(22) is made of metal, in particular stainless steel, ceramic,
silicon or plastic.
3. The nozzle according to claim 1, characterized in that the plate
(22) is deformed by deep drawing or bending or folding.
4. The nozzle according to claim 1, characterized in that the plate
(22) is thin, in particular has a thickness (31) of less than 200
.mu.m, preferably of about 10 to 100 .mu.m.
5. The nozzle according to claim 1, characterized in that the plate
(22) is initially flat.
6. The nozzle according to claim 1, characterized in that the plate
(22) is deformed after forming the holes (21).
7. The nozzle according to claim 1, characterized in that the holes
(21) are formed by drilling, in particular laser drilling, or
punching the plate (22).
8. The nozzle according to claim 1, characterized in that the plate
(22) forms a depression (32), the holes (21) being located on
opposite sides of the depression (32).
9. The nozzle according to claim 1, characterized in that the
distance (30) between the holes (21) is about between 30 and 300
.mu.m, preferably about between 50 and 200 .mu.m.
10. The nozzle according to claim 1, characterized in that the
holes (21) have respectively a hydraulic diameter of 2 to 50 .mu.m,
in particular of 3 to 30 .mu.m, preferably between 5 and 15
.mu.m.
11. In an inhaler (1) for dispensing of an inhalation formulation
(2) as an aerosol (14), which comprises: a conveying means for
conveying and/or nebulising the inhalation formulation (2), in
particular for generating the aerosol (14), and a nozzle (12), the
improvement which is characterized in that the nozzle (12) is as
recited in claim 1.
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
Description
[0001] The present invention relates to a nozzle according to the
preamble of claim 1, to an inhaler according to the preamble of
claim 11 and to a method for producing a nozzle.
[0002] The present invention relates in particular to the
dispensing of an inhalation formulation by means of a nozzle or an
inhaler, preferably a gas free-metered dose inhaler.
[0003] US 2003/0075623 A1 describes a nozzle with one or more
nozzle outlets for the atomisation of fluids. The nozzle consists
of at least two plates which are connected together, possibly by a
intermediate layer. At least a base plate has a grooved structure
which connects an inlet to nozzle outlet(s). In one embodiment, two
or more nozzle outlets are provided which are orientated in such a
way that jets issuing from them impinge on one another. The nozzle
is typically made from a silicon plate and a glass plate welded
together to form the channels. A filter can be inbuilt.
[0004] The present invention relates in particular to active
inhalers such as an inhaler sold under the brand name "Respimat"
shown in its basic structure in WO 91/14468 A1 and in a specific
embodiment in WO 97/12687 A1 (FIGS. 6a, 6b). The inhaler has a
reservoir for a fluid, which is to be atomised, and a pressure
generator with a drive spring for delivering and atomising the
fluid. The known inhaler comprises a nozzle with at least two holes
for generating at least two impinging jets of the inhalation
formulation to be dispensed.
[0005] When an inhalation formulation is dispensed, usually only
small amounts are discharged. The inhalation formulation has to be
atomised in a very defined manner into very fine particles or
droplets. Therefore, the nozzle for generating fine jets of the
inhalation formulation has to meet very close tolerances and
comprises very fine openings or holes.
[0006] The known nozzles are difficult to produce and/or result in
high manufacturing costs.
[0007] Object of the present invention is to provide a nozzle for
generating at least two impinging jets, and an inhaler with such a
nozzle, and a method for producing a nozzle, wherein production is
facilitated and/or low production costs are possible.
[0008] The above object is achieved by a nozzle according to claim
1, by an inhaler according to claim 11 or by a method according to
claim 12. Preferred embodiments are subject of the subclaims.
[0009] Preferably, two or more holes are formed in a thin metal
plate and, then, the plate is deformed such that the axes of the
holes intersect each other at a distance from the plate surface
and/or at the outlet side of the nozzle.
[0010] The holes may be formed by drilling, laser drilling,
punching or in any other suitable way.
[0011] The plate is preferably deformed after the holes have been
formed or drilled. Thus, the holes can be formed or drilled into a
flat plate, in particular with axes parallel to each other or
perpendicular to the plate. This facilitates production. However,
it is also possible to form, drill or open the holes after the
plate has been deformed or without deformation of the plate.
[0012] In particular, the plate has a thickness of less than 200
.mu.m, preferably of about 10 to 100 .mu.m.
[0013] Preferably, the holes have respectively a hydraulic diameter
of 2 to 100 .mu.m, in particular of 3 to 30 .mu.m, more preferably
between 5 and 15 .mu.m.
[0014] The distance between the holes is in particular about
between 10 and 300 .mu.m, preferably about 50 and 200 .mu.m.
[0015] Preferably, the nozzle is formed only by the plate, and/or
made of only one single component or piece, e.g. the plate.
[0016] According to a further aspect of the present invention,
which can be realized independently, the nozzle is provided in
particular by laser drilling with at least one hole, preferably two
holes inclined to each other, in the preferably flat plate. The at
least one hole is provided preferably with a smooth inlet region or
entry area and preferably with a taper towards its outlet side
which helps to ensure that a jet of fluid formed by the hole is
essentially unbroken, e.g. until the jet impacts with another
jet.
[0017] Thus, a simple construction of the nozzle can be achieved
and/or low production costs are possible. Further, relatively easy
production is possible even if close tolerances have to be met.
[0018] Further aspects, features, properties and advantages of the
present invention are described in the claims and the subsequent
description of preferred embodiments with reference to the drawing.
There are shown in:
[0019] FIG. 1 a schematic section of an inhaler in the
non-tensioned state;
[0020] FIG. 2 a schematic section, rotated by 90.degree. compared
with FIG. 1, of the inhaler in the tensioned state;
[0021] FIG. 3 a schematic section of a nozzle of the inhaler;
[0022] FIG. 4 a schematic section of a flat plate of the nozzle
before deformation; and
[0023] FIG. 5 a schematic section of another nozzle.
[0024] In the Figures, the same reference numbers are used for
identical or similar parts, even if a repeated description is
omitted. In particular identical or corresponding advantages and
properties then also result or may be achieved.
[0025] FIGS. 1 and 2 show an inhaler 1 according to the present
invention for atomising an inhalation formulation 2 as an aerosol
14, particularly a highly effective pharmaceutical composition or
the like, diagrammatically shown in a non-tensioned state (FIG. 1)
and in a tensioned state (FIG. 2).
[0026] The term "aerosol" in this respect is not limited to an
inhalation formulation in liquid from, but also encompasses powder
formulations.
[0027] The inhaler 1 is constructed in particular as a portable
inhaler and preferably operates without propellant gas. Preferably,
the inhaler 1 is portable, works only mechanically and/or is
hand-held. However, the present invention may also be applied to
inhalers 1 using a propellant, such as so-called MDIs (metered dose
inhalers), a gas, such as compressed or liquefied gas or air, or
the like, i.e. in particular to all kind of inhalers 1.
[0028] The inhalation formulation 2 is preferably a liquid, in
particular a solution, suspension or suslution (mixture of solution
and suspension), but can have any form and can be e.g. a powder or
the like.
[0029] When the inhalation formulation 2, preferably a liquid, more
particularly a pharmaceutical composition, is nebulised, an aerosol
14 is formed, which can be breathed in or inhaled by a user (not
shown). Usually the inhaling is done at least once a day, more
particularly several times a day, preferably at set intervals,
depending on the complain from which the patient is suffering.
[0030] The inhaler 1 has in particular an insertable and preferably
exchangeable container 3 containing the inhalation formulation 2.
The container thus forms a reservoir for the inhalation formulation
2, which is to be nebulised. Preferably, the container 3 contains
an amount of inhalation formulation 2 or active substance which is
sufficient to provide up to 200 dosage units, for example, i.e. to
allow up to 200 sprays or applications. A typical container 3, as
disclosed in WO 96/06011 A1, holds a volume of about 2 to 10
ml.
[0031] The container 3 is substantially cylindrical or
cartridge-shaped and once the inhaler 1 has been opened the
container can be inserted therein from below and changed if
desired. It is preferably of rigid construction, the inhalation
formulation 2 in particular being held in a collapsible bag 4 in
the container 3.
[0032] The inhaler 1 has a conveying means, such as a propellant, a
pump, an air pump or any other pressure generator or compressed or
liquefied gas, in particular a pump or pressure generator 5 for
conveying gas, any other fluid and/or the inhalation formulation 2
and for nebulising the inhalation formulation 2, particularly in a
preset and optionally adjustable dosage amount.
[0033] The inhalation formulation 2 may be metered in the inhaler 1
as it is the case in the present embodiment or may be pre-metered
in an appropriate storage means, such as a blister with multiple
blister pockets or the like.
[0034] In the present embodiment, the pressure generator 5 has
preferably a holder 6 for the container 3, an associated drive
spring 7, only partly shown, with a locking element 8 which can be
manually operated to release it, a conveying member, preferably a
conveying tube 9, a non-return valve 10 and/or a pressure chamber
11. The inhaler 1 comprises further nozzle 12 preferably in the
region of a mouthpiece 13. The nozzle 12 will be described later in
more detail. The container 3 is fixed in the inhaler 1 via the
holder 6 such that the conveying tube 9 penetrates into the
container 3. The holder 6 may be constructed so that the container
3 is able to be exchanged.
[0035] As the drive spring 7 is axially tensioned the holder 6 with
the container 3 and the conveying tube 9 is moved downwards in the
drawings, and the inhalation formulation 2 is sucked out of the
container 3 into the pressure chamber 11 of the pressure generator
5 through the non-return valve 10. Preferably, the valve 10 is
attached to or formed by the conveying tube 9.
[0036] After actuation of the locking element 8 the inhalation
formulation 2 in the pressure chamber 11 is put under pressure as
the conveying tube 9 with its now closed non-return valve 10 is
moved back upwards by the relaxation of the drive spring 7 and now
acts as a pressing ram or piston. This pressure forces the
inhalation formulation 2 through the expulsion or dispensing nozzle
12, whereupon the formulation 2 is nebulised into an aerosol 14, as
shown in FIG. 1.
[0037] Preferably the inhaler 1 may have a spring pressure of 5 to
200 MPa, preferably 10 to 100 MPa on the fluid, and/or a volume of
fluid delivered per stroke of 5 to 100 .mu.l, preferably 10 to 30
.mu.l, most preferably about 15 .mu.l. The fluid is converted into
the aerosol 14 the droplets of which have an aerodynamic diameter
of up to 20 .mu.M, preferably 3 to 10 .mu.m. The nozzle 12 has
preferably a spray angle of 20.degree. to 160.degree., preferably
80.degree. to 100.degree..
[0038] A user (not shown) can inhale the aerosol 14, while an air
supply is sucked into the mouthpiece 13 through preferably at least
one air supply opening 15, preferably multiple air supply openings
15. Thus, a bypass is formed so that ambient air can be sucked into
the mouthpiece 13.
[0039] The inhaler 1 comprises preferably an upper housing part 16
and an inner part 17 which is rotatable relative thereto (FIG. 2)
having an upper part 17a and a lower part 17b (FIG. 1), while an in
particular manually operable housing part 18 is releasably fixed,
particularly fitted onto the inner part 17, preferably by means of
a retaining element 19. In order to insert and/or replace the
container 3 the housing part 18 can be detached from the inhaler
1.
[0040] FIG. 3 shows in a very schematic sectional view (not in
scale) the nozzle 12 in a preferred embodiment according to the
present invention. This nozzle 12 is preferably mounted in or at
the inhaler 1 previously described or any other inhaler 1. The
mounting means are not shown. The nozzle 12 can be mounted e.g. by
clamping or in any other suitable manner.
[0041] The nozzle 12 is for generating at least two impinging jets
20 of the fluid to be dispensed, here the inhalation formulation 2,
as schematically shown in FIG. 3. The jets 20 intersect each other
at the outlet side of the nozzle 12 or inhaler 1 and/or in a
predetermined point or collision area, spaced from the plate
22.
[0042] The nozzle 12 comprises at least two holes 21 for dispensing
the fluid, i.e. the inhalation formulation 2 in order to generate
the jets 20 of the fluid.
[0043] The nozzle 12 comprises a plate 22 which may be formed by
any plate portion of a component not shown or the like or which may
be a separate or the sole component of the nozzle 12.
[0044] The holes 21 are formed in the plate 22. Preferably, the
holes 21 are formed by drilling, in particular laser drilling, or
punching of the plate 22.
[0045] Preferably, the holes 21 are formed in the initially flat
plate 22 as schematically shown in FIG. 4 which shows also a
schematic sectional view of the nozzle 12 or plate 22.
[0046] It has to be pointed out that the production of the nozzle
12 is easy. The holes 21 can be formed easily by any suitable
manner in the flat plate 22 before deformation.
[0047] The holes 21 are preferably formed such that their axes 23
(shown by arrows) run at least essentially parallel to each other
and/or at least essentially perpendicular to the main plane of the
plate 22 and/or do not intersect when the holes 21 are formed in
the plate 22.
[0048] Afterwards, the plate 22 is deformed such that the axes 23
of the holes 21 cross or intersect each other with an angle 26
and/or at a distance 27 as schematically shown in FIG. 3. The
deformation is preferably achieved by deep drawing or in any other
suitable manner. For example, the plate 22 could also be bended or
folded, e.g. that it has a V-form, so that the axes 23
intersect.
[0049] The distance 27 is preferably about 50 to 500 .mu.m, in
particular about 100 to 300 .mu.m.
[0050] The angle 26 of intersection of the jets 20 or axes 23 is
preferably about 90 to 180 degrees, in particular about 100 to 150
degrees.
[0051] The holes 21 are preferably circular in cross section.
[0052] The holes 21 are preferably tapered, in particular such that
its outlet diameter is smaller at the outlet side 24 of the nozzle
12 or plate 22 than on the inlet side 25 of the nozzle 12 or plate
22. In particular, the holes 21 have a natural cone or taper angle
28 as schematically indicated in FIG. 4. Preferably, the angle is
about 5 to 20 degrees.
[0053] The mean and/or hydraulic diameter 29 of the holes 21 is
preferably about 2 to 50 .mu.m, in particular about 3 to 30 .mu.m,
more preferably between 5 and 15 .mu.m.
[0054] The term "hydraulic diameter" shall be understood as the
diameter of a circular cross section corresponding in areal size to
an actual, in particular non-circular cross section.
[0055] The holes 21 are spaced from each other by a distance 30.
This refers either to the distance of the axes 23 before
deformation of the plate 22 as schematically shown in FIG. 4 or to
the distance of the inner edges or centers of the holes 21 at the
outlet side 24 of the deformed plate 22 as schematically shown in
FIG. 3. The distance 30 is preferably about between 10 and 300
.mu.m, in particular about between 50 and 200 .mu.m.
[0056] The plate 22 is preferably made of metal, in particular of
stainless steel, or ceramic, silicon or plastic. However, any other
suitable material could be used as well.
[0057] The plate 22 is preferably thin. In particular it has a
thickness 31 of less than 200 .mu.m, preferably of about 10 to 100
.mu.m.
[0058] The deformed plate 22 forms preferably a bowl-like
depression 32, in particular wherein the holes 21 are located on
opposite sides of the depression 32, as schematically shown in FIG.
3.
[0059] The depression 32 is preferably about 50 to 250 .mu.m deep
and/or preferably has a diameter of about 150 to 500 .mu.m.
[0060] The fluid (inhalation formulation 2) flows from the inner
surface or inlet side 25 to the outer surface or outlet side 24
through the holes 21 in the direction of the taper. The helps to
ensure that the jets 20 are unbroken before they impact with each
other in the impaction region.
[0061] The impaction of the jets 20 supports atomisation of the
fluid into very fine droplets or particles and/or slows down the
main propagation speed of the aerosol 14. Alternatively or
additionally, the intersection of the jets 20 can support mixing of
different fluids if the jets 20 consist of different fluids.
[0062] FIG. 5 shows in a schematic sectional view similar to FIG. 3
another embodiment of the nozzle 12. Here, the plate 22 is flat,
i.e. not deformed. The holes 21 are directly inclined, i.e. formed
with an angle 33 relative to the main plane of plate 22 (e.g. half
of intersection angle 26), so that the axes 23 of the holes 21
intersect each other at the outlet side 24 of the nozzle 12 as
already described above.
[0063] The holes 21 are preferably laser drilled.
[0064] The holes 21 comprise preferably the same taper as
previously described. This helps to ensure that the jets 20 are
unbroken before impact.
[0065] The holes 21 preferably comprise a smooth entry or inlet
region 34 (e.g. a rounded or tapered or inclined edge) which helps
to ensure that the jets 20 are unbroken before impact at the
distance 27 from plate 22 where atomization takes place.
[0066] The thickness 31 of the plate 22 is preferably between 10
and 150 .mu.m.
[0067] The hydraulic diameter 29 of the holes 21 is preferably
between 5 and 30 .mu.m.
[0068] It has to be noted that the aspects and features of the
different embodiments and alternatives and the different
embodiments itself can be combined in any desired manner and/or
independently from each other.
[0069] Some preferred ingredients and/or compositions of the
preferably medicinal formulation 2 are listed below. As already
mentioned, they are in particular powders or liquids in the
broadest sense. Particularly preferably the formulation 2 contains
the following:
[0070] The compounds listed below may be used in the device
according to the invention on their own or in combination. In the
compounds mentioned below,
[0071] W is a pharmacologically active substance and is selected
(for example) from among the betamimetics, anticholinergics,
corticosteroids, PDE4-inhibitors, LTD4-antagonists,
EGFR-inhibitors, dopamine agonists, H1-antihistamines,
PAF-antagonists and PI3-kinase inhibitors. Moreover, double or
triple combinations of W may be combined and used in the device
according to the invention. Combinations of W might be, for
example: [0072] W denotes a betamimetic, combined with an
anticholinergic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or
LTD4-antagonist, [0073] W denotes an anticholinergic, combined with
a betamimetic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or
LTD4-antagonist, [0074] W denotes a corticosteroid, combined with a
PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist [0075] W denotes
a PDE4-inhibitor, combined with an EGFR-inhibitor or
LTD4-antagonist [0076] W denotes an EGFR-inhibitor, combined with
an LTD4-antagonist.
[0077] The compounds used as betamimetics are preferably compounds
selected from among albuterol, arformoterol, bambuterol,
bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol,
formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline,
levosalbutamol, mabuterol, meluadrine, metaproterenol,
orciprenaline, pirbuterol, procaterol, reproterol, rimiterol,
ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,
terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,
KUL-1248 and [0078]
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzyl-sulphonamide [0079]
5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one [0080]
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethy-
l]-2(3H)-benzothiazolone [0081]
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol [0082]
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-m-
ethyl-2-butylamino]ethanol [0083]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol [0084]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol [0085]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol [0086]
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol [0087]
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e [0088]
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)e-
thanol [0089]
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one [0090]
6-hydroxy-8-{1-hydroxy-2-[2-(ethyl
4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3--
one [0091] 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one
[0092]
8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one [0093]
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethylethyl-amino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one [0094]
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1dimethyl-ethylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one [0095]
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one [0096]
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one [0097]
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid [0098]
8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one [0099]
1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)etha-
nol [0100]
2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)p-
henyl]-ethylamino}-ethyl)-benzaldehyde [0101]
N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)phenyl]--
ethylamino}-ethyl)-phenyl]-formamide [0102]
8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)phenyl]-ethy-
lamino}-ethyl)-1H-quinolin-2-one [0103]
8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-
-2-one [0104]
5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-
-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one [0105]
[3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexy-
loxy}-butyl)-5-methyl-phenyl]-urea [0106]
4-(2-{6-[2-(2.6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-
-hydroxymethyl-phenol [0107]
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzylsulphonamide [0108]
3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hepty-
loxy}-propyl)-benzylsulphonamide [0109]
4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-
-ethyl)-2-hydroxymethyl-phenol [0110]
N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-e-
thylamino]-propyl}-phenyl)-acetamide optionally in the form of the
racemates, enantiomers, diastereomers thereof and optionally in the
form of the pharmacologically acceptable acid addition salts,
solvates or hydrates thereof. According to the invention the acid
addition salts of the betamimetics are preferably selected from
among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0111] The anticholinergics used are preferably compounds selected
from among the tiotropium salts, preferably the bromide salt,
oxitropium salts, preferably the bromide salt, flutropium salts,
preferably the bromide salt, ipratropium salts, preferably the
bromide salt, glycopyrronium salts, preferably the bromide salt,
trospium salts, preferably the chloride salt, tolterodine. In the
above-mentioned salts the cations are the pharmacologically active
constituents. As anions the above-mentioned salts may preferably
contain the chloride, bromide, iodide, sulphate, phosphate,
methanesulphonate, nitrate, maleate, acetate, citrate, fumarate,
tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,
while chloride, bromide, iodide, sulphate, methanesulphonate or
p-toluenesulphonate are preferred as counter-ions. Of all the salts
the chlorides, bromides, iodides and methanesulphonates are
particularly preferred.
[0112] Other preferred anticholinergics are selected from among the
salts of formula AC-1
##STR00001##
wherein X.sup.- denotes an anion with a single negative charge,
preferably an anion selected from among the fluoride, chloride,
bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate,
maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate,
benzoate and p-toluenesulphonate, preferably an anion with a single
negative charge, particularly preferably an anion selected from
among the fluoride, chloride, bromide, methanesulphonate and
p-toluenesulphonate, particularly preferably bromide, optionally in
the form of the racemates, enantiomers or hydrates thereof. Of
particular importance are those pharmaceutical combinations which
contain the enantiomers of formula AC-1-en
##STR00002##
wherein X.sup.- may have the above-mentioned meanings. Other
preferred anti-cholinergics are selected from the salts of formula
AC-2
##STR00003##
wherein R denotes either methyl or ethyl and wherein X.sup.- may
have the above-mentioned meanings. In an alternative embodiment the
compound of formula AC-2 may also be present in the form of the
free base AC-2-base.
##STR00004##
[0113] Other specified compounds are: [0114] tropenol
2,2-diphenylpropionate methobromide, [0115] scopine
2,2-diphenylpropionate methobromide, [0116] scopine
2-fluoro-2,2-diphenylacetate methobromide, [0117] tropenol
2-fluoro-2,2-diphenylacetate methobromide; [0118] tropenol
3,3',4,4'-tetrafluorobenzilate methobromide, [0119] scopine
3,3',4,4'-tetrafluorobenzilate methobromide, [0120] tropenol
4,4'-difluorobenzilate methobromide, [0121] scopine
4,4'-difluorobenzilate methobromide, [0122] tropenol
3,3'-difluorobenzilate methobromide, [0123] scopine
3,3'-difluorobenzilate methobromide; [0124] tropenol
9-hydroxy-fluorene-9-carboxylate methobromide; [0125] tropenol
9-fluoro-fluorene-9-carboxylate methobromide; [0126] scopine
9-hydroxy-fluorene-9-carboxylate methobromide; [0127] scopine
9-fluoro-fluorene-9-carboxylate methobromide; [0128] tropenol
9-methyl-fluorene-9-carboxylate methobromide; [0129] scopine
9-methyl-fluorene-9-carboxylate methobromide; [0130]
cyclopropyltropine benzilate methobromide; [0131]
cyclopropyltropine 2,2-diphenylpropionate methobromide; [0132]
cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
[0133] cyclopropyltropine 9-methyl-fluorene-9-carboxylate
methobromide; [0134] cyclopropyltropine
9-methyl-xanthene-9-carboxylate methobromide; [0135]
cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
[0136] cyclopropyltropine methyl 4,4'-difluorobenzilate
methobromide. [0137] tropenol 9-hydroxy-xanthene-9-carboxylate
methobromide; [0138] scopine 9-hydroxy-xanthene-9-carboxylate
methobromide; [0139] tropenol
9-methyl-xanthene-9-carboxylate-methobromide; [0140] scopine
9-methyl-xanthene-9-carboxylate-methobromide; [0141] tropenol
9-ethyl-xanthene-9-carboxylate methobromide; [0142] tropenol
9-difluoromethyl-xanthene-9-carboxylate methobromide; [0143]
scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,
[0144] The above-mentioned compounds may also be used as salts
within the scope of the present invention, wherein instead of the
methobromide the salts metho-X are used, wherein X may have the
meanings given hereinbefore for X.sup.-.
[0145] As corticosteroids it is preferable to use compounds
selected from among beclomethasone, betamethasone, budesonide,
butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol,
flunisolide, fluticasone, loteprednol, mometasone, prednisolone,
prednisone, rofleponide, triamcinolone, RPR-106541, NS-126, ST-26
and [0146] (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate [0147] (S)-(2-oxo-tetrahydro-furan-3
S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-
-diene-17-carbothionate, [0148] cyanomethyl
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17.beta-
.-carboxylate optionally in the form of the racemates, enantiomers
or diastereomers thereof and optionally in the form of the salts
and derivatives thereof, the solvates and/or hydrates thereof. Any
reference to steroids includes a reference to any salts or
derivatives, hydrates or solvates thereof which may exist. Examples
of possible salts and derivatives of the steroids may be: alkali
metal salts, such as for example sodium or potassium salts,
sulphobenzoates, phosphates, isonicotinates, acetates,
dichloroacetates, propionates, dihydrogen phosphates, palmitates,
pivalates or furoates.
[0149] PDE4-inhibitors which may be used are preferably compounds
selected from among enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin,
atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396
(Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,
PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052,
D-22888, YM-58997, Z-15370 and [0150]
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropy-
lmethoxybenzamide [0151]
(-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbe-
nzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide [0152]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone [0153]
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-5-methyl-isothioure-
ido]benzyl)-2-pyrrolidone [0154]
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid] [0155]
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cy-
clohexan-1-one [0156]
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol] [0157]
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2--
ylidene]acetate [0158]
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate [0159]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3.4-c]-1,2,4--
triazolo[4.3-a]pyridine [0160]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3.4-c]-1,2,4-
-triazolo[4.3-a]pyridine optionally in the form of the racemates,
enantiomers or diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts thereof, the
solvates and/or hydrates thereof. According to the invention the
acid addition salts of the betamimetics are preferably selected
from among the hydrochloride, hydrobromide, hydriodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0161] The LTD4-antagonists used are preferably compounds selected
from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),
MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
[0162]
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetic acid, [0163]
1-(((1(R)-3
(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)ethenyl)phenyl)-3-(2-(1--
hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic
acid [0164]
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]-
acetic acid optionally in the form of the racemates, enantiomers or
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates and/or
hydrates thereof. According to the invention the acid addition
salts of the betamimetics are preferably selected from among the
hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate. By salts or derivatives which the
LTD4-antagonists may optionally be capable of forming are meant,
for example: alkali metal salts, such as for example sodium or
potassium salts, alkaline earth metal salts, sulphobenzoates,
phosphates, isonicotinates, acetates, propionates, dihydrogen
phosphates, palmitates, pivalates or furoates.
[0165] EGFR-inhibitors which may be used are preferably compounds
selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
[0166]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-quinazoline [0167]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0168]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0169]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-quinazoline [0170]
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
[0171]
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]-quinazoli-
ne [0172]
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-quinazol-
ine [0173]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-mo-
rpholin-4-yl)-ethoxy]-7-methoxy-quinazoline [0174]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline
[0175]
4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(N,N-dimethylamino)-1-oxo-2-buten-
-1-yl]amino-7-cyclopentyloxy-quinazoline [0176]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)-1-ox-
o-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline [0177]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethylamino]-1--
oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline [0178]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methylamino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline [0179]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylami-
no] [0180]
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline [0181]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-
-2-buten-1-yl]amino}-7-(R)-tetrahydrofuran-3-yloxy)-quinazoline
[0182]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-(S)-tetrahydrofuran-3-yloxy)-quinazoline [0183]
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 [0184]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1--
oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline [0185]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0186]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0187]
4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline
[0188]
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(v-
inylcarbonyl)amino]-quinazoline [0189]
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine [0190]
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-ox-
o-2-buten-1-yl]amino}-7-ethoxy-quinoline [0191]
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-[(2-methanesulphon-
yl-ethyl)amino]methyl)-furan-2-yl)quinazoline [0192]
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 [0193]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline [0194]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)amino]--
1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline
[0195]
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4--
yl)-1-oxo-2-buten-1-yl]amino}-quinazoline [0196]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline [0197]
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
[0198]
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
[0199]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)piperid-
in-1-yl]-ethoxy}-7-methoxy-quinazoline [0200]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)piperidi-
n-4-yloxy]-7-methoxy-quinazoline [0201]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline [0202]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline [0203]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline [0204]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline [0205]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0206]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline [0207]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline [0208]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin--
4-yloxy]-7-methoxy-quinazoline [0209]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline [0210]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(S)-tetrahydrofuran-3-yloxy)-7-hydr-
oxy-quinazoline [0211]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline [0212]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0213]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0214]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0215]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline [0216]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline [0217]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0218]
4-[(3-chloro-4-fluoro-phenyl)amino]-6(1-aminocarbonylmethyl-piperidin-4-y-
loxy)-7-methoxy-quinazoline [0219]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0220]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0221]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0222]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclo-
hexan-1-yloxy)-7-methoxy-quinazoline [0223]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline [0224]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline [0225]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline [0226]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [0227]
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-ylo-
xy]-7-methoxy-quinazoline [0228]
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line [0229]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline [0230]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0231]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carb-
onylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0232]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline [0233]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline [0234]
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [0235]
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline [0236]
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline [0237]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline [0238]
4-[(3-chloro-4-fluoro-phenyl)amino-]-6-(1-isopropyloxycarbonyl-piperidin--
4-yloxy)-7-methoxy-quinazoline [0239]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline [0240]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline [0241]
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline
[0242]
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yl-
oxy]-7-methoxy-quinazoline [0243]
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline [0244]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0245]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0246]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-azabicyclo[2,2,1-
]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline
[0247]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethylamino-
)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline [0248]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline [0249]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline [0250]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)carbonyl-
]-piperidin-4-yloxy}-7-methoxy-quinazoline [0251]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [0252]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)cyc-
lohexan-1-yloxy]-7-methoxy-quinazoline [0253]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline [0254]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline [0255]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline [0256]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline
[0257]
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
[0258]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline [0259]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention the acid addition
salts of the betamimetics are preferably selected from among the
hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0260] The dopamine agonists used are preferably compounds selected
from among bromocriptin, cabergoline, alpha-dihydroergocryptine,
lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol,
tergurid and viozan, optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention the acid addition
salts of the betamimetics are preferably selected from among the
hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0261] H1-Antihistamines which may be used are preferably compounds
selected from among epinastine, cetirizine, azelastine,
fexofenadine, levocabastine, loratadine, mizolastine, ketotifen,
emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastine, desloratidine and
meclozine, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention the acid addition
salts of the betamimetics are preferably selected from among the
hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0262] It is also possible to use inhalable macromolecules, as
disclosed in EP 1 003 478 A1 or CA 2297174 A1.
[0263] In addition, the compounds may come from the groups of ergot
alkaloid derivatives, the triptans, the CGRP-inhibitors, the
phosphodiesterase-V inhibitors, optionally in the form of the
racemates, enantiomers or diastereomers thereof, optionally in the
form of the pharmacologically acceptable acid addition salts, the
solvates and/or hydrates thereof.
[0264] Examples of ergot alkaloid derivatives are dihydroergotamine
and ergotamine.
LIST OF REFERENCE NUMBERS
[0265] 1 inhaler [0266] 2 inhalation formulation [0267] 3 container
[0268] 4 bag [0269] 5 pressure generator [0270] 6 holder [0271] 7
drive spring [0272] 8 locking element [0273] 9 conveying tube
[0274] 10 nonreturn valve [0275] 11 pressure chamber [0276] 12
nozzle [0277] 13 mouthpiece [0278] 14 aerosol [0279] 15 air supply
opening [0280] 16 upper housing part [0281] 17 inner part [0282]
17a upper part of the inner part 34 inlet region [0283] 17b lower
part of the inner part [0284] 18 housing part (lower part) [0285]
19 retaining element [0286] 20 jet [0287] 21 hole [0288] 22 plate
[0289] 23 axis [0290] 24 outlet side [0291] 25 inlet side [0292] 26
intersection angle [0293] 27 distance of intersection form plate
[0294] 28 cone or taper angle [0295] 29 diameter of hole [0296] 30
distance of holes [0297] 31 thickness [0298] 32 depression [0299]
33 angle of inclination [0300] 34 inlet region
* * * * *