Patent Application
20070282276
The sole FIGURE is a diagrammatic cross-sectional view of a device according to the proposal.
The device 1 according to the illustrated embodiment of the invention for administering or dispensing, in particular, for dispensing or dosing, a pharmaceutical agent, preferably a liquid 2, is designed, in particular, for very small pump volumes or dosages. In the illustrative example, the pump volumes are 1 μl to 1 ml, preferably 1 μl to 500 μl, in particular 5 μl to 100 μl, quite especially preferably 5 μl to 30 μl, and in particular, essentially 15 μl, per piston stroke.
To be able to ensure delivery of a specific desired volume, in particular, even in the case of a first actuation after extended non-use, no air should enter into device 1, since otherwise the dosage is no longer in the desired accuracy.
Device 1 has a guide pipe 3 (second component), a long-travel piston 4 (additional component) and a shaped seal 5 (first component) in a recess 6 as well as optionally a support ring 7 (additional component) for securing seal 5.
Guide pipe 3, optionally together with support ring 7, forms recess 5, which surrounds the piston 4 in an annular manner and in particular is designed as a groove, here as a ring groove. In the illustrative example, support ring 4 forms an axial side or limiting of recess 5, so that guide pipe 3 essentially forms a ring shoulder and a radial outside constraint for recess 5.
If necessary, recess 5 can also be designed separately from guide pipe 3.
In the illustrative example, piston 4 has a circular cross section with a diameter of 0.25 mm to 4 mm, preferably 0.5 mm to 3 mm, in particular 0.75 mm to 2.25 mm.
Piston 4 preferably is made of metal, in particular high-grade steel. It is designed, in particular, as a hollow pipe or capillary. Piston 4 is preferably drawn and consequently has a relatively low tolerance with respect to its diameter.
Shaped seal 5 is preferably designed in a through-going annular manner corresponding to recess 6. In particular, shaped seal 5 is an O-ring with an at least essentially circular cross-section in the uninstalled state.
In the illustrative example, the cross-section or the cord thickness of uninstalled shaped seal 5 is 0.3 mm to 3 mm, preferably 0.5 mm to 2 mm, in particular 1 mm to 1.5 mm. The inside diameter corresponds approximately to the piston diameter.
Shaped seal 5 preferably made of silicone or another rubber-elastic material that is suitable, in particular, for pharmaceutical agents or food.
In the installed state i.e., in the assembled device 1—seal 5 is taken up at least essentially in recess 6. Support ring 7 axially adjoins and axially fixes the shaped seal 5 in recess 6. In addition, shaped seal 5 radially adjoins piston 4 which penetrates the shaped seal 5 in a sealing manner. Shaped seal 5 is pressed or deformed in recess 6. Shaped seal 5 has an essentially rectangular shape in cross-section, deviating from its uninstalled configuration, in cross-section or at least at a flat side contiguous with piston 4.
The “fill level” corresponds to the quotient from the volume of the incorporated shaped seal 5 through the volume of recess 6. To be able to achieve a good seal and consequently accurate dosing of device 1, the desired fill level, thus the “set fill level” in the agent is preferably 90%, in particular less than 95%, with a tolerance of at most 5%, in particular 4% or less.
In the illustrative example, support ring 7 is preferably attached by a cap-shaped holding element 8 or the like to guide pipe 3. By corresponding axial or frontal attachments, a defined length of support ring 7 and thus a defined width B (axial length) of recess 6 for shaped seal 5 is achieved.
In addition, the volume of recess 6 is decisively determined by depth T of recess 6 in guide pipe 3, i.e., the radial extension of recess 6.
Piston 4 borders a pump chamber 9 in guide pipe 3. Piston 4 is preferably provided with a nonreturn valve 10, which is located, in particular, on the end of piston 4 that faces pump chamber 9.
In the illustrative example, the preferably hollow piston 4 forms a supply channel 11 for liquid 2. With the corresponding axial movement, liquid 2 can be delivered, in particular, by aspiration, through supply channel 11 via the intake valve or the nonreturn valve 10 into pump chamber 9.
On the pressure or output side, device 1 optionally has an exhaust valve (not shown), and, for example, a nozzle 12 for exhaust and optionally spraying of liquid 2.
Shaped seals 5 are produced in batches—thus in groups. In particular, a batch that consists of a specific amount of starting materials that are as homogeneous as possible is produced.
Shaped seals 5 are preferably produced by injection-molding, in particular, by means of an injection-molding tool (not shown) with a plurality of cavities. Accordingly, in each injection-molding process, a plurality of shaped seals 5 is produced.
Shaped seals 5 can vary from batch to batch, in particular, with respect to significant sizes, such as ring diameter, cross-section, volume, compressibility or the like. In addition to dimensions (ring diameter, thickness, and/or volume) that are imposed by the tools, values that are material-related or values that are produced by process technology, such as compressibility, can also vary.
Shaped seals 5 represent first components in terms of the process according to the proposal. The significant values (in particular, only volume and compressibility) of shaped seals 5 are preferably determined only for a portion of all shaped seals 5 of a batch, and decisively significant values, in particular, mean value and standard deviation, taking into consideration the varied influences of dimensions and tolerances imposed by the tools as well as optionally other dimensions, and keeping in mind the distribution function, are determined therefrom.
According to the proposal, guide pipe 3 is classified preferably based only on an essential value in the illustrative example based on depth T of recess 6. Guide pipes 3 represent second components in terms of the process according to the proposal, and thus, are divided into different groups based on depth T. In particular, guide pipes 3 are produced with different depths T to be able to prepare the necessary groups of guide pipes 3. The groups in depth T, in each case, are preferably distinguished from one another by more than the production tolerance.
According to the proposal, a first component, i.e., a shaped seal 5, of a specific batch is combined or assembled only with a second component, i.e., a guide pipe 3, of a group that is suitable to the specific batch. The group that is suitable to the respective batch is selected based on at least one decisively significant value of this batch, in particular, based on the mean and standard deviation of the volume and compressibility of shaped seals 5 of this charge, in such a way that the essential value, i.e., in particular depth T of recess 6, of the respective groups results in a desired setpoint, here, the set fill level, or a specific seal in device 1. The selection is made in particular with consideration of error propagation and available groups.
In the illustrative example, device 1 has additional components, namely piston 4 and support ring 7, whose sizes or dimensions for reaching the setpoint, i.e., the set fill level; of respective device 1 are decisive. Consequently, preferably also the significant values of the additional components, in particular, the diameter of piston 4 and width B of recess 6, stated more specifically, the values of support ring 7 and guide pipe 3 that are decisive in this respect, are determined preferably on a random-sample basis, and additional significant values, in particular, mean value and standard deviation, are determined therefrom. These additional significant values are preferably taken into consideration in addition in the above-mentioned selection of the group of guide pipes 3 to reach the desired setpoint, i.e., set fill level, and thus, the desired sealing and dosing accuracy.
The indicated values, such as volume, compressibility, depth, width or the like, should represent values that are possibly significant only by way of example. Depending on the design and structure of device 1, production of the component, and in particular, tolerances of the components, additional and/or other values can be used as significant and/or essential values. As an alternative or in addition, other values can also be used as setpoints instead of the fill level. Instead of guide pipe 3, other components can serve as “variable” components—i.e., components divided into groups with different essential values—can also be combined with batches of other components for achieving a setpoint or an improved dosing accuracy in finished device 1.
To dose liquid 2 or the pharmaceutical agent, the first and second components, thus in particular guide pipe 3 and shaped seal 5, are moved relative to one another, wherein the combination of the components according to the proposal leads to an optimal sealing between the components and thus an improved dosing accuracy in the production or in the administration.
In the illustrative example, device 1 according to the proposal is designed in particular, as a sprayer or an inhaler. Liquid 2 is drawn off by piston 4 with a corresponding axial back-and-forth motion alternately through supply channel 11 into pump chamber 9 or is pressurized there and dispensed via nozzle 12, and in this case, dispensed or administered, preferably sprayed; thus, a spray mist or aerosol A is formed from liquid 2, as indicated in the FIGURE.
Device 1 is especially preferably designed as a sprayer or inhaler, as in the basic principle in International Patent Application Publication No. WO 91/14468 A1 and corresponding U.S. Pat. No. 5,497,944 and in a concrete embodiment in International Patent Application Publication No. WO 97/12687 A1 (FIGS. 6a, 6b) and corresponding Canadian Patent Application 2 473 681, as well as in FIGS. 1 and 2 of International Patent Application Publication No. WO 2005/080001A1 and corresponding U.S. Patent Application Publication 2005/0247305, Quite preferably, this is the sprayer or inhaler that is offered under the trademark RESPIMAT® by Boehringer Ingelheim GmbH.
However, device 1 can also be used, for example, as a metering pump, in particular, for accurate supply of pharmaceutical agents or the like, in particular as explained in the above-mentioned European Patent Application EP 1 426 662 A1 and corresponding U.S. Patent Application Publication 2004/0134495.
In particular, device 1 is a medical device. Liquid 2 is preferably a pharmaceutical agent, as already explained initially, or a medication, therapeutic agent, diagnostic agent or the like.
Device 1 can also be used, in particular, to make provide one or several active ingredients or pharmaceutical agents; if several active ingredients or pharmaceutical agents are to be dispensed, they are preferably provided at the same time. In this case, liquid 2 is, in particular, a solution. The principle of the suslution is based on the fact that several active ingredients in a formulation can be formulated together as a solution and as a suspension. In this connection, reference is made to European Patent Application EP 1 087 750 A1.
Device 1, however, can also be used in principle for cosmetic purposes or for other purposes.
Below, preferred components and/or formulations of the pharmaceutical agent or liquid 2 are cited:
As pharmaceutically active substances, substance formulations or substance mixtures, all compounds that can be inhaled are used, such as, e.g., macromolecules that can also be inhaled, as disclosed in European Patent Application EP 1 003 478 A1. Substances, substance formulations or substance mixtures for treating diseases of the respiratory system that are used in the inhalational area preferably are used.
Especially preferred in this connection are pharmaceutical agents that are selected from the group that consists of anti-cholinergic agents, beta-mimetic agents, steroids, phiosphodiesterase IV inhibitors, LTD4 antagonists, and EGFR-kinase inhibitors, anti-allergic agents, derivatives of ergot alkaloids, 2,2,3-trimethylbutanes, CGRP antagonists, phosphodiesterase-V inhibitors, as well as combinations of such active ingredients, e.g. beta-mimetic agents plus anti-cholinergic agents or beta-mimetic agents plus anti-allergic agents. In the case of combinations, at least one of the active ingredients preferably has chemically bonded water. Anti-cholinergic agent-containing active ingredients are preferably used as monopreparations or in the form of combination preparations.
The following can be mentioned in detail as examples of the active components or their salts:
Anti-cholinergic agents that are used are preferably selected from the group that consists of tiotropium bromide, oxitropium bromide, flutropium bromide, ipratropium bromide, glycopyrronium salts, trospiumn chloride, tolterodine, 2,2-diphenylpropionic acid tropenol ester-methobromide, 2,2-diphenylpropionic acid scopine ester-methobromide, 2-fluoro-2,2-diphenylacetic acid scopine ester-methobromide, 2-fluoro-2,2-diphenylacetic acid tropenol ester-methobromide, 3,3′,4,4′-tetrafluorobenzilic acid tropenol ester-methobromide, 3,3′,4,4′-tetrafluorobenzilic acid scopine ester-methobromide, 4,4′-difluorobenzilic acid tropenol ester-methobromide, 4,4′-difluorobenzilic acid scopine ester-methobromide, 3,3′-difluorobenzilic acid tropenol ester-methobromide, 3,3′-difluorobenzilic acid scopine ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid tropenol ester methobromide, 9-fluoro-fluorene-9-carboxylic acid tropenol ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid scopine ester-methobromide, 9-fluoro-flurone-9-carboxylic acid scopine ester methobromide, 9-methyl-fluorene-9-carboxylic acid tropenol ester methobromide, 9-methyl-fluorene-9-carboxylic acid scopine ester methobromide, benzilic acid cyclopropyl tropine ester-methobromide, 2,2-diphenyl-propionic acid cyclopropyl tropine ester-methobromide, 9-hydroxy-xanthene-9-carboxylic acid cyclopropyl tropine ester-methobromide, 9-methyl-fluorene-9-carobyxlic acid cyclopropyl tropine ester-methobromide, 9-methyl-xanthene-9-carboxylic acid cyclopropyl tropine ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid cylopropyl tropine ester-methobromide, 4,4′-difluorobenzilic acid methyl ester cyclopropyl tropine ester-methobromide, 9-hydroxy-xanthene-9-carboxylic acid tropenol ester-methobromide, 9-hydroxy-xanthene-9-carboxylic acid scopine ester methobromide, 9-methyl-xanthene-9-carboxylic acid tropenol ester-methobromide, 9-methyl-xanthene-9-carboxylic acid scopine ester-methobromide, 9-ethyl-xanthene-9-carboxylic acid tropenol ester methobromide, 9-difluoromethyl-xanthene-9-carboxylic acid tropenol ester-methobromide, and 9-hydroxymethyl-xanthene-9-carboxylic acid scopine ester-methobromide, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their solvates and/or hydrates.
Beta-mimetic agents that are used are preferably selected from the group that consists of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, indacaterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulfonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 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, 5-hydroxy-8-(1-hydroxy-2-isopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, optionally in the form of their racemates, enantiomers or diastereomers, and optionally, in the form of their pharmacologically compatible acid addition salts, solvates and/or hydrates.
Steroids that are used are preferably selected from the group that consists of prednisolone, prednisone, butixocort propionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-11b-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17b-carbothionic acid (S-fluoromethylester, 6a,9a-difluoro-11b-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17b-carbothionic acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester and etiprednol-dichloroacetate (BNP-166), optionally in the form of their racemates, enantiomers or diastereomers, and optionally, in the form of their salts and derivatives, their solvates and/or hydrates.
PDE IV inhibitors that are used are preferably selected from the group that consists of enprofylline, theophylline, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzaniide, NCS-613, pumafentine, (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-[(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoro-methoxyphenyl)cyclohexan-1-one, cis[4-cyano-4(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(−)-ethyl[4-(3-cyclopentyl-oxy-4-methoxyphenyl)-pyrrolidin-2-ylidene]acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofylline, atizoram, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, and 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 their racemates, enantiomers or diastereomers, and optionally, in the form of their pharmacologically compatible acid addition salts, solvates and/or hydrates.
LTD4 antagonists that are used are preferably selected from the group that consists of montelukast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl-cyclopropane-acetic acid, 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)cyclopropane acetic acid, pranlukast, zafirlukast, [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically compatible acid addition salts as well as optionally in the form of their salts and derivatives, their solvates and/or hydrates.
EGFR-Kinase inhibitors that are used are preferably selected from the group that consists of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62, 4-[(3-chloro-4-fluorophenyl)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-fluorophenyl)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-[2-((S)-6-methyl-2-oxo-morphlin-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-[(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-fluoro-phenyl)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,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 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, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(cis-4-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclo-hexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinaozline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 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, 4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically compatible acid addition salts, their solvates and/or hydrates.
Acid addition salts with pharmacologically compatible acids that can optionally be formed by the compounds, are defined as, for example, salts that are selected from the group that consists of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofimarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluene sulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofimarate and hydromethanesulfonate.
As anti-allergic agents: disodium cromoglicate, nedocromil.
As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.
For inhalation, pharmaceutical agents with the above-mentioned active ingredients are considered, as well as their salts, esters, as well as the combination of these active ingredients, salts and esters.
