DE102007052871A1 - Capsule for receiving pharmaceutical drug formulations - Google Patents

Abstract

A capsule for receiving pharmaceutical drug formulations as a primary packaging component of a packaging unit is made entirely of a water-absorptive material and is conditioned at a low relative humidity.

Description

The The invention relates to a capsule for receiving pharmaceutical Drug formulations as primary packaging component a packaging unit and a use thereof.

capsules with pharmaceutical drug formulations are diverse used in the therapy and diagnosis of diseases. The capsules can be administered orally or come in certain medical devices such as powder inhalers. As a rule, the capsules consist of two parts, namely a capsule body and a capsule cap telescoping be pushed into each other. Also multi-part capsules are known.

about gelatin was used as capsule material for a longer period of time used for the primary packaging of pharmaceutical products. In addition to a number of advantages, the gelatin capsule, however also has significant disadvantages, among others, it is lower Ambient moisture becomes brittle. Furthermore led the discussion about BSE (bovine spongiform encephalopathy) u. a. for questioning gelatin as a product of animal origin in the production of capsules. If necessary, gelatine must be replaced by alternative Materials must be replaced. As one of the alternatives to gelatin the use of hydroxypropyl methylcellulose (HPMC) is discussed.

at the current search for alternatives is sought, if possible To use plastics, among other things, a very small Have water content to even as little water into the packaging. The very low water absorption capacity However, it is increasingly facing as a major disadvantage the highly water-absorptive gelatin capsule. It is Technically unavoidable over the rest Packaging materials, such. As films, bottles and the like, and by the product itself moisture in a primary packaging is registered. This moisture is after the packaging process enclosed in primary packaging and may be slow to diffuse out. Depending on the values of the relative humidity in or outside the packaging even diffuses even more moisture into the primary packaging. Lack of water-absorptive Packaging materials within the primary packaging are increasing as a result the relative humidity there is considerable and endangered thus the product. A decomposition, a clumping or a recrystallization of powders, etc. can be the result.

The WO 2006/122790 A1 discloses a capsule for packaging inhalation formulations in which at least one cavity is enclosed by a wall. At least part of the wall comprises a polymer composition containing at least one adsorbent. Here, not the polymer composition itself but the adsorbent, but the adsorbent, for example silica gel, drying or moisture or water adsorbing clays, aluminosilicates such as zeolites or bentonites, molecular sieves, activated carbon, alkaline earth oxides, calcium sulfate or mixtures thereof, is attached to the polymer composition. The adsorbent also has an influence on the mechanical properties of the polymer composition.

Currently trying to prevent this increase in humidity with relatively high effort by z. B. packaging components are conditioned, the packaging process itself is provided in conditioned climate and / or primary packaging with desiccant-equipped secondary packaging (pouches) are surrounded. Such a packaging unit is for example in the form of a carton with blister cards in the EP 0 479 282 A1 described.

The EP 1 100 474 A1 discloses z. B. plastic capsules consisting of a capsule body and a capsule cap, both made of the same non-water-soluble, hydrophobic plastic and which can be connected together so that a stable, closed cavity of defined volume is formed. In particular, the plastic is polyethylene.

Such capsules are intended, inter alia, for use in powder inhalers. As examples of such powder inhalers may be mentioned: HandiHaler ^® , as he z. B. in the EP 1 342 483 has been disclosed, Spinhaler ^®, Rotahaler ^®, Aerolizer ^®, FlowCaps ^®, Turbo Spin ^®, AIR DPI ^{®, ®} or orbital Directhaler ^® as inhalers, among others, in the documents DE 3345722 . EP 0591136 . DE 4318455 . WO91 / 02558 . A-2146202-FR . US-A 4069819 . EP 666085 . EP 869079 . US 3,991,761 . WO99 / 45987 . WO 200051672 , Bell, J. Pharm. Sci. 60, 1559 (1971); Cox, Brit. Med. J. 2, 634 (1969).

It The object of the invention is to avoid the abovementioned disadvantages an optimized in terms of moisture protection capsule the beginning to provide said type.

According to the invention solved the problem by the fact that the capsule completely consists of a water-absorptive material and at conditioned to a low relative humidity.

In contrast to the capsule described in the beginning according to the WO 2006/122790 A1 For example, the material from which the capsule is made is itself an adsorbent and is not composed of a base material and an adsorbent. The fact that the capsule is made of the water-absorptive material that is conditioned at a low relative humidity, that is, by the treatment has a relative residual moisture, capsule itself takes most of the moisture in the package ("moisture sink") and The conditioning of this capsule material before the packaging process at low humidity serves to maximize the water absorption capacity and thus the absorber function.Thus, the starting moisture in the packaging unit can be drastically reduced.Furthermore, the starting moisture can be determined and controlled by a suitable choice of conditioning Moreover, due to its high water absorption capacity, such a moisture absorber maintains the relative humidity in the packaging unit at low levels over the shelf life and thus protects the product r Technique is that the material of the capsule in its mechanical properties is not affected by an adsorbent, but the water absorbency of the material of the capsule determines the relative humidity.

When Water-receptive material is in particular polyamide (PA-6, PA-6.6) or cellulose acetate of particular advantage. These Plastics have one over other plastics extremely high water absorption capacity and are suitable therefore especially for targeted use as a water absorber.

alternative is preferred as a water-absorptive material gelatin suitable, which is previously heated. A sufficient heating is with regard to prevention of BSE (Bovine spongiform encephalopathy) beneficial.

In Further embodiment, the water-absorptive material a water absorption capacity of greater or equal to 1.5% at standard climate according to ISO 62. This is achieved in particular by polyamides. Underwater shooting in the range up to 3% can be achieved with these materials become.

Conveniently, is the water-absorptive material at a relative Humidity of less than or equal to 20% conditioned. Already can an effective moisture reduction can be achieved. To be a special Achieving effective moisture reduction is the most water-absorptive Material at a relative humidity of less than or equal to 10% conditioned.

to Achieving a simple conditioning with low process engineering Effort is the water-absorptive material as bulk goods conditioned. This allows the start value in the packaging targeted be determined.

Prefers is the water-absorptive material by a single Conditioning step conditioned. This can be a strong Simplification of the packaging process can be realized.

In In another embodiment, the capsule material is within the packaging unit the only water absorptive material. This is a stabilization of low moisture levels in the packaging over a long period without additional aids, such as pouch or desiccant.

A advantageous use of the capsule sees the use as primary packaging for the absorption of particularly moisture-sensitive drugs, eg. As of finely powdered pharmaceutical agents before. Especially In such inhalants, moisture absorption is important.

• – W stellt ein Betamimetika dar, kombiniert mit einem Anticholinergika, Corticosteroide, PDE4-Inhibitore, EGFR-Hemmern oder LTD4-Antagonisten,
• – W stellt ein Anticholinergika dar, kombiniert mit einem Betamimetika, Corticosteroiden, PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten,
• – W stellt ein Corticosteroiden dar, kombiniert mit einem PDE4-Inhibitoren, EGFR-Hemmern oder LTD4-Antagonisten
• – W stellt ein PDE4-Inhibitoren dar, kombiniert mit einem EGFR-Hemmern oder LTD4-Antagonisten
• – W stellt ein EGFR-Hemmern dar, kombiniert mit einem LTD4-Antagonisten.

The compounds mentioned below can be used alone or in combination for use in the device according to the invention. In the compounds listed below, W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF- Antagonists and PI3 kinase inhibitors. Furthermore, two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:

• W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
• W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
• W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
• W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
• W represents an EGFR inhibitor combined with a LTD4 antagonist.

• – 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulfonamid
• – 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-on
• – 4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolon
• – 1-(2-Fluor-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-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on
• – 1-(4-Amino-3-chlor-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyessigsäureethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäure)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on
• – 8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl)-6-hydroxy-4H-benzo[1,4]oxazin-3-on
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on
• – 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)- 1,1dimethyl-ethylamino]-ethyl)-4H-benzo[1,4]oxazin-3-on
• – 8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on
• – 8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on
• – 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-buttersaure
• – 8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on
• – 1-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol
• – 2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenylethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyd
• – N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamid
• – 8-Hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-on
• – 8-Hydroxy-5-[1-hydroxy-2-(6-phenethylaminohexylamino)-ethyl]-1H-quinolin-2-on
• – 5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-on
• – [3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-harnstoff
• – 4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol
• – 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulfonamid
• – 3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulfonamid
• – 4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]- hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol
• – N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamid

gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and

• - 3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzyl-sulfonamide
• - 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] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone
• - 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol
• - 1- [3- (4-methoxybenzylamino) -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-triazole-3 -yl] -2-methyl-2-butylamino} ethanol
• 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one
• - 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
• 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one
• - 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxy-ethyl) -6-hydroxy-4H-benzo [1,4] oxazine-3 -one
• - 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
• 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl) -4H-benzo [1,4] oxazin-3-one
• - 8- {2- [2- (4-ethylphenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• - 8- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• - 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2 methyl-propyl} -phenoxy) -buttersaure
• - 8- {2- [2- (3,4-Difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one
• - 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol
• 2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenylethylamino) -phenyl] -ethylamino} -ethyl) -benzaldehyde
• N- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide
• - 8-hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1H-quinolin-2-one
• 8-hydroxy-5- [1-hydroxy-2- (6-phenethylaminohexylamino) ethyl] -1H-quinolin-2-one
• - 5- [2- (2- {4- [4- (2-Amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinoline -2-one
• - [3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea
• - 4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
• - 3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide
• 3- (3- {7- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfone mid
• - 4- (2- {6- [4- (3-cyclopentanesulfonylphenyl) -butoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
• N-adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -propyl} -phenyl) -acetamide

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

When Anticholinergics are preferably compounds for Application, which are selected from the group consisting from 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 salts, the cations represent the pharmacologically active ingredients. As anions can the abovementioned salts preferably contain chloride, bromide, Iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, Citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, wherein chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as counterions. Of all the salts are the chlorides, Bromides, iodides and methanesulfonates are particularly preferred.

worin X – ein einfach negativ geladenes Anion, bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Malest, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluolsulfonat, bevorzugt ein einfach negativ geladenes Anion, besonders bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Methansulfonat und p-Toluolsulfonat, insbesondere bevorzugt Bromid, bedeutet gegebenenfalls in Form ihrer Racemate, Enantiomere oder Hydrate. Von besonderer Bedeutung sind solche Arzneimittelkombinationen, die die Enantiomere der Formel AC-1-en

enthalten, worin X – die vorstehend genannten Bedeutungen aufweisen kann. Weiterhin bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-2

worin R entweder Methyl oder Ethyl bedeuten und worin X – die vorstehend genannte Bedeutungen aufweisen kann. In einer alternativen Ausführungsform kann die Verbindung der Formel AC-2 auch in Form der freien Base AC-2-base vorliegen.Likewise preferred anticholinergics are selected from the salts of the formula AC-1

wherein X - is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, Malest, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates. Of particular importance are those drug combinations that contain the enantiomers of the formula AC-1-ene

in which X - may have the meanings given above. Further preferred anticholinergics are selected from the salts of the formula AC-2

wherein R is either methyl or ethyl and wherein X - may have the meanings given above. In an alternative embodiment, the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.

• – 2,2-Diphenylpropionsäuretropenolester-Methobromid
• – 2,2-Diphenylpropionsäurescopinester-Methobromid
• – 2-Fluor-2,2-Diphenylessigsäurescopinester-Methobromid
• – 2-Fluor-2,2-Diphenylessigsäuretropenolester-Methobromid
• – 3,3',4,4'-Tetrafluorbenzilsäuretropenolester-Methobromid
• – 3,3',4,4'-Tetrafluorbenzilsäurescopinester-Methobromid
• – 4,4'-Difluorbenzilsäuretropenolester-Methobromid
• – 4,4'-Difluorbenzilsäurescopinester-Methobromid
• – 3,3'-Difluorbenzilsäuretropenolester-Methobromid
• – 3,3'-Difluorbenzilsäurescopinester-Methobromid
• – 9-Hydroxy-fluoren-9-carbonsäuretropenolester-Methobromid
• – 9-Fluor-fluoren-9-carbonsäuretropenolester-Methobromid
• – 9-Hydroxy-fluoren-9-carbonsäurescopinester-Methobromid
• – 9-Fluor-fluoren-9-carbonsäurescopinester-Methobromid
• – 9-Methyl-fluoren-9-carbonsäuretropenolester-Methobromid
• – 9-Methyl-fluoren-9-carbonsäurescopinester-Methobromid
• – Benzilsäurecyclopropyltropinester-Methobromid
• – 2,2-Diphenylpropionsäurecyclopropyltropinester-Methobromid
• – 9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid
• – 9-Methyl-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid
• – 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid
• – 9-Hydroxy-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid
• – 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid
• – 9-Hydroxy-xanthen-9-carbonsäuretropenolester-Methobromid
• – 9-Hydroxy-xanthen-9-carbonsäurescopinester-Methobromid
• – 9-Methyl-xanthen-9-carbonsäuretropenolester-Methobromid
• – 9-Methyl-xanthen-9-carbonsäurescopinester-Methobromid
• – 9-Ethyl-xanthen-9-carbonsäuretropenolester-Methobromid
• – 9-Difluormethyl-xanthen-9-carbonsäuretropenolester-Methobromid
• – 9 -Hydroxymethyl-Xanthen-9-carbonsäurescopinester-Methobromid

Further named compounds are:

• 2,2-diphenylpropionic acid tropol ester methobromide
• 2,2-diphenylpropionic acid copoprene methobromide
• 2-fluoro-2,2-diphenylacetic acid copoprene methobromide
• 2-fluoro-2,2-diphenylacetic acid tropol ester methobromide
• 3,3 ', 4,4'-tetrafluorobenzylic acid tropol ester methobromide
• 3,3 ', 4,4'-tetrafluorobenzilate copoprene methobromide
• 4,4'-Difluorobenzylic acid tropol ester methobromide
• 4,4'-Difluorobenzic acid copoprene methobromide
• 3,3'-Difluorobenzylic acid tropol ester methobromide
• 3,3'-Difluorobenzilic acid copoprene methobromide
• 9-hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide
• 9-fluoro-fluoren-9-carboxylic acid-tropol ester-methobromide
• 9-Hydroxy-fluorene-9-carboxylic acid copo-ester methobromide
• 9-fluoro-fluorene-9-carboxylic acid copo-ester methobromide
• 9-Methyl-fluorene-9-carboxylic acid-tropol ester-methobromide
• 9-methyl-fluorene-9-carboxylic acid copo-ester methobromide
• Benzylic acid cyclopropyltropine ester methobromide
• 2,2-diphenylpropionic acid cyclopropyltropine ester methobromide
• 9-hydroxy-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide
• 9-Methyl-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide
• 9-methyl-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide
• 9-Hydroxy-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide
• - 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester methobromide
• 9-hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide
• 9-hydroxy-xanthene-9-carboxylic acid copo-ester methobromide
• 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide
• 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide
• 9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide
• 9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide
• 9-hydroxymethyl-xanthene-9-carboxylic acid copo-ester methobromide

The The aforementioned compounds are within the scope of the present invention Can also be used as salts in which, instead of the methobromide, the salts Metho-X are used, wherein X is the above for X- meanings may have.

• – 6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothionsäure(S)-fluoromethylester
• – 6,9-Difluor-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothionsäure(S)-(2-oxo-tetrahydro-furan-3S-yl)ester,
• – 6⎕,9-difluoro-11⎕-hydroxy-16⎕-methyl-3-oxo-17⎕- (2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17⎕-carbonsäurecyanomethylester

gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate. Jede Bezugnahme auf Steroide schließt eine Bezugnahme auf deren gegebenenfalls existierende Salze oder Derivate, Hydrate oder Solvate mit ein. Beispiele möglicher Salze und Derivate der Steroide können sein: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.Preferred corticosteroids here are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR -106541, NS-126, ST-26 and

• - 6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester
• 6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl ) ester,
• - 6⎕, 9-difluoro-11⎕-hydroxy-16⎕-methyl-3-oxo-17⎕- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-dienes-17⎕-cyanomethyl cyanide

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. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.

• – N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluormethoxy-3-cyclopropylmethoxybenzamid
• – (–)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid
• – (R)-(+)-1-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon
• – 3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano- S-methyl-isothioureido]benzyl)-2-pyrrolidon
• – cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carbonsäure]
• – 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-on
• – cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-1-ol]
• – (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat
• – (S)-(–)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat
• – 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin
• – 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin

gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der PDE4-Inhibitoren ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, 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, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

• - N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide
• - (-) p - [(4aR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1,6] naphthyridine 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-methylisothioureido] 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-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate
• 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine
• 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, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,

• – 1-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropan-essigsäure,
• – 1-(((1(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropanessigsäure
• – [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]essigsäure

gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydronitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat. Unter Salzen oder Derivaten zu deren Bildung die LTD4-Antagonisten gegebenenfalls in der Lage sind, werden beispielsweise verstanden: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Erdalkalisalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlu kast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF- 5078, VUF-K-8707, L-733321 and

• - 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -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
• - [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydronitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Examples of salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates ,

• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxychinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-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]-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-1[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-1[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxyethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-chinazolin
• – 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin
• – 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-1[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino)-7-ethoxychinolin
• – 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2-yl)chinazolin
• – 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-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxomorpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylaminoethyl)-piperidin-4-yloxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino)-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonylpiperidin-4-yloxy)-7-ethoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonylpiperidin-4-yloxy)-7-(2-methoxy-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxyacetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxychinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonylpiperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-chinazolin
• – 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methylmorpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-ethylpiperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxychinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonylpiperidin-4-yloxy)-7-methoxy-chinazolin
• – 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxy-chinazolin

gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakolo gisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.Preferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N -diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
• - 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy -China Zolin
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-ol buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-ol buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline
• 4-[(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-ol buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxy-quinazoline
• - 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline
• - 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1-yl] amino} -7-cyclopropylmethoxy-quinazoline
• - 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -1-oxo-2-buten-1 yl} amino) -7-cyclopropylmethoxy-quinazoline
• 4-[(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxy-quinazoline
• - 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxy-quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6-1- [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R ) -tetrahydrofuran-3-yloxy) -quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S. ) -tetrahydrofuran-3-yloxy) -quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -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-chloro-4-fluorophenyl) amino] -6-1 [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S. ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
• - 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) -amino] -quinazoline
• - 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine
• 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6-1 [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino) -7 -ethoxychinolin
• - 4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline
• - 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-one buten-1-yl] amino} -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran -2-yl) methoxy] -quinazoline
• - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene-1 yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline
• - 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
• - 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
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-aminocyclohexan-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-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -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 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-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- {trans-4 - [(morpholin-4-yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -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- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane-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-ethoxy-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-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-ethynylphenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxyquinazoline
• - 4 - [(3-ethynylphenyl) 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} -cyclohexane-1 yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} - cyclohexane-1-yloxy) -7-methoxy-quinazoline
• - 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-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) -quinazoline
• - 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-Ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline
• - 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} - 7-methoxy-quinazoline
• - 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
• - 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7 methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methylmorpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
• - 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
• - 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- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -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-1-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} -cyclohexane-1 yloxy) -7-methoxy-quinazoline
• - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
• - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-cyanopiperidin-4-yloxy) -7-methoxy-quinazoline

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

When Dopamine agonists in this case prefer connections to Application, which are selected from the group consisting from bromocriptine, cabergoline, alpha-dihydroergocryptine, lisurid, Pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and Viozan, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable Acid addition salts, solvates or hydrates. According to the invention preferred These acid addition salts are selected from the Group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, Hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, Hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate.

As H1-antihistamines here preferably compounds are used, the selected are from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexch loropheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

As pharmaceutically active substances, substance formulations or substance mixtures all inhalable compounds are used, such. B. also inhalable macromolecules, as in EP 1 003 478 disclosed. Preferably, substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.

Farther the compound from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable Acid addition salts, their solvates and / or hydrates.

When Derivatives of ergot alkaloids: dihydroergotamine, ergotamine.

Further Advantages of the capsule according to the invention result with a view to simpler manufacture and handling. For example, a simple conditioning to a specific relative humidity value possible, which is also reversible can be. In contrast, the moisture content of materials with integrated desiccant often no longer non-destructive removed or reduced. Incorrectly stored capsules with integrated Desiccants are thus unusable. Furthermore, through the Design of the capsule material a smaller wall thickness will be realized. Together with a lower specific weight of the capsule material over that with integrated Desiccant can significantly lower the weight of the capsule be achieved. This leaves in particular with regard to use in an inhaler (inhaler) a stronger Vibration and thus a faster and complete emptying the capsule too.

It It is understood that the above and below to be explained features not only in the specified Combination, but also usable in other combinations. Of the The scope of the invention is defined only by the claims.

The Invention will be described below with reference to a simulation calculation whose Result in the figure is shown in the form of a diagram, closer explained.

in the The scope of the simulation calculation was exemplified by the material polyamide-6 as capsule material in a common capsule-blister combination used.

• • Bodenfolie: Aluminium/Polypropylen (60 μm); Konditionierung bei 60% rel. Feuchte, Permeationsrate 0,4 μg/d (aus Spurenfeuchte),
• • Deckfolie: Aluminium/Heißsiegellack (7 g/m²); Konditionierung bei 60% rel. Feuchte,
• • Klima bei Verblisterung: 60% rel. Feuchte bzw. 10% rel. Feuchte,
• • Temperatur: 25°C,
• • Wasseraufnahmefähigkeit von Polyamid-6 (PA-6): ca. 1,9 bei Normklima gemäß ISO 62 (Literaturwert); einige Literaturwerte gehen für PA-Materialien sogar von wesentlich höheren Werten aus (PA-6 bis zu 3% und PA-6.6 bis 2,8%),
• • Konditionierung der PA-Kapsel inkl. angenommener Lactose-Füllung bei 10 rel. Feuchte,
• • Lagerung der Blister nach der Verpackung bei 25°C und 60% rel. Feuchte ohne Umverpackung (d. h. ohne Pouch).

The following assumptions were used:

• • Bottom film: aluminum / polypropylene (60 μm); Conditioning at 60% rel. Humidity, permeation rate 0.4 μg / d (from trace moisture),
• • Cover foil: aluminum / heat sealing lacquer (7 g / m ² ); Conditioning at 60% rel. humidity,
• • climate in case of blistering: 60% rel. Humidity or 10% rel. humidity,
• Temperature: 25 ° C,
• • Water absorption capacity of polyamide-6 (PA-6): approx. 1.9 at standard climate according to ISO 62 (literature value); some literature values even assume considerably higher values for PA materials (PA-6 up to 3% and PA-6.6 to 2.8%),
• • Conditioning of the PA capsule incl. Assumed lactose filling at 10 rel. humidity,
• • Storage of blisters after packaging at 25 ° C and 60% rel. Moisture without outer packaging (ie without pouch).

There are two traces in the diagram 13 . 14 the relative humidity 11 in% within the blister cavity at different conditions as a function of time 12 (Storage period) in months. The course curve 13 takes into account a climate of 10% rel. Moisture in the blistering and the course curve 14 however, a climate of 60% rel. Moisture in the blistering.

The From the diagram recognizable result shows that the high water absorbency of the absorber, so the polyamide-6, causes the Humidity entry of the other components hardly appreciable increased humidity starting value leads, since the humidity is absorbed by the packaging materials from the absorber. at an assumed conditioning of the absorber before packaging at 10% rel. Humidity are the calculated starting values in the packaging only at approx. 12% rel. Humidity. The lowest possible Starting moisture in a package is very often decisive for the stability of a product.

About that In addition, the results of the simulation show that with help a single - the dominant - component of a Packaging the starting moisture can be controlled and controlled specifically can. This option represents a significant reduction the effort involved in the packaging and its control process.

Furthermore the simulation calculation has already been realized on one of them Blister system performed. As only change the capsule used in this case was replaced by a PA capsule.

The results also show, due to the low increase in humidity, that the humidity which diffuses during the storage period can be absorbed to a high degree by the PA capsule. This means that even after 60 months of storage at 60% rel. Moisture the relative humidity 11 within the blister cavity still well below 30% rel. Humidity can be maintained.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 2006/122790 A1 [0005, 0011]
• EP 0479282 A1 [0006]
• EP 1100474 A1 [0007]
• EP 1342483 [0008]
• - DE 3345722 [0008]
• - EP 0591136 [0008]
• - DE 4318455 [0008]
• WO 91/02558 [0008]
• - FR 2146202 A [0008]
• - US 4069819 A [0008]
• - EP 666085 [0008]
• - EP 869079 [0008]
• US 3991761 [0008]
• WO 99/45987 [0008]
• WO 200051672 [0008]
• - EP 1003478 [0032]

Claims (11)

Capsule for receiving pharmaceutical active ingredient formulations as a primary packaging component of a packaging unit, characterized in that the capsule is completely made of a water-absorptive material and is conditioned at a low relative humidity. Capsule according to claim 1, characterized in that the water absorptive material of polyamide or cellulose acetate consists. Capsule according to claim 1, characterized in that the water absorptive material is gelatin, which is previously heated. Capsule according to one of claims 1 to 3, characterized in that the water-absorptive material a water absorption capacity of greater or equal to 1.5% at standard climate according to ISO 62. Capsule according to one of claims 1 to 4, characterized in that the water-absorptive material conditioned at a relative humidity of less than or equal to 20% is. Capsule according to one of claims 1 to 4, characterized in that the water-absorptive material at conditioned to a relative humidity of less than or equal to 10% is. Capsule according to one of claims 1 to 6, characterized in that the water-absorptive material is conditioned as a bulk product. Capsule according to one of claims 1 to 7, characterized in that the water-absorptive material conditioned by a single conditioning step. Capsule according to one of claims 1 to 8, characterized in that the capsule material within the packaging unit the only water absorptive material is. Use of the capsule according to one of the claims 1 to 9 for the intake of medicines. Use of the capsule according to one of the claims 1 to 9 for intake of inhalants.