EP2001536A1 - Packaging means for multi-dose powder inhalers with optimized discharging properties - Google Patents

Packaging means for multi-dose powder inhalers with optimized discharging properties

Info

Publication number
EP2001536A1
EP2001536A1 EP07727327A EP07727327A EP2001536A1 EP 2001536 A1 EP2001536 A1 EP 2001536A1 EP 07727327 A EP07727327 A EP 07727327A EP 07727327 A EP07727327 A EP 07727327A EP 2001536 A1 EP2001536 A1 EP 2001536A1
Authority
EP
European Patent Office
Prior art keywords
amino
phenyl
quinazoline
chloro
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07727327A
Other languages
German (de)
French (fr)
Inventor
Herbert Wachtel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2001536A1 publication Critical patent/EP2001536A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0048—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged in a plane, e.g. on diskettes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the invention relates to a package for pharmaceutical compositions, blends or formulations for use in a powder inhaler.
  • the multi-dose powder inhalers contain the drug, mixture or formulation either in the form of a powder supply from which a single unit dose is withdrawn from a cavity by a built-in dosing unit or pre-dosed, packaged unit doses that are either stored together in the device ( eg in the form of packaging in blisters) or when used individually in the device (eg in the form of capsules).
  • Powder formulation packaged in the device for the product quality and thus the suitability for inhalation application, crucial.
  • one of the main purposes of the package is to keep the chemical composition of the atmosphere inside the package constant to prevent or stabilize physical or chemical changes in the drug, mixture or formulation.
  • fine particle dose is understood to mean the dose that reaches the lungs of the patient.
  • the fine particle dose is influenced by the interactions of the micronized drug particles with each other as well as the interactions with the excipients.
  • a packaging has a shape and an opening pattern (ie, the locations of the packaging, which allow the opening of the blister by piercing or cutting), the optimized air flow and thus an optimized application of the drug, the mixture or allow formulation.
  • EP 0 703 800 B1 or EP 0 911 047 A1 disclose a powder inhaler consisting of a cup-shaped lower part and a likewise cup-shaped lid.
  • the patient can press an actuator which is displaceable from a rest position into a movement and cooperates with at least one injectable into the capsule holder needle. With the help of the needle or the needles, the capsule is pierced and the drug released.
  • DE 3348370 and DE 3336486 disclose inhalers containing a disc-shaped blister pack having a plurality of circularly arranged cavities.
  • the individual cavities each contain a dose of a medicament powder intended for inhalation.
  • the cavities are closed on both sides, eg by a sealing foil.
  • the cavitate is opened to expose the medicament powder.
  • An air channel connects the opened cavity with the mouthpiece of the inhaler.
  • the inhaler of DE 3336486 is described more closely by way of example.
  • This housing has a housing in which a chamber (storage chamber) is located which has an air inlet and in which is a disc-shaped, round blister with packaged drug pockets
  • the blister is loosely connected to a round, rotatable disc on the disc holes are formed circumferentially, which have in the axial direction contact with the medicine bags, ie the pockets and holes are above or below each other
  • the chamber has an air outlet.
  • the inhaler also has a piston arranged so that it can open in each case a medicament pocket pierceable so that the medicament is released into the chamber and can be inhaled via a mouthpiece.
  • the package packaging is characterized in that it is in direct contact with the inhalation formulation.
  • the package packaging may be surrounded by a second external protection, the secondary packaging means
  • Capsule a solid or flexible blister with cavities or a disc with cavities
  • the secondary packaging may be a blister, a bag, a bag or other container.
  • the secondary packaging generally encloses the packaging material completely. Secondary packaging is used in particular when the packaging material does not provide adequate protection against moisture
  • the P ⁇ marpackstoff and optionally the secondary packaging have the task to protect the drug and the entire inhalation formulation from chemical or physical change, so that it remains stable in the long term.
  • physical changes include changes that may alter the application of the predetermined fine particle dose.
  • the choice of a suitable material for the packaging material is determined by two factors: Firstly, the material must be able to fulfill the mentioned protective function. On the other hand, the material must be such that the package can be given the necessary form for use in the powder inhaler and that can fulfill its intended function.
  • the present invention therefore relates to packaging for inhalable powders, which are optimized in their shape, in their piercing pattern, as well as in the level of a drug, a mixture or formulation.
  • the invention relates to optimized packaging means, as described above, which due to the shape of their opening pattern in their piercing pattern, as well as the level of a drug, a mixture or formulation allow improved air flow and thus improved application of the drug, the mixture or formulation ,
  • the packaging means are preferably a capsule, a blister, a blister disc, a blister screw or a blister band.
  • blisters these various forms are collectively referred to as blisters (with the exception of the capsule).
  • the capsule usually consists of two parts, a capsule body (body) and a capsule cap (cap), which are telescoped into one another. But also multi-part capsules are known.
  • capsules of size 2-4, most preferably size 3 are used.
  • the capsule material is made of non-digestible plastic or gelatin, in particular hard gelatin.
  • the blister disk can be, for example, a cylinder-like disk of up to 5 mm in height and a diameter of up to 15 cm. Holes or holes are formed in the disk perpendicular to the disk plane (cavities).
  • a disk can be used for example in an inhaler according to DE 3348370 or DE 3336486.
  • Such an inhaler has a housing in which the disc-shaped, round blister with packaged medicine bags is located.
  • the inhaler has u.a. a pen which is arranged so that it can each open a medicine bag, so that the drug is released into the chamber and can be inhaled via a mouthpiece.
  • the shape of the packaging material according to the invention is fundamentally predetermined by the powder inhaler to be used.
  • the packaging has a teardrop-shaped or oval shape or the shape of an eight.
  • the inflow surfaces and the outflow surface or surfaces are at a maximum distance from each other.
  • the packaging material which is a blister, initially has a base element which consists of a thermoplastic and at least two cavities separated from one another by a web.
  • the cavities are open at least to one side, possibly also after two, opposite sides. These openings are closed in the ready-to-use packaging, for example, a firmly bonded to the base element sealing film.
  • the packaging may consist of the commercially available materials. Preferably, it consists of a plastic. Very particular preference is given to plastics from the group of thermoplastic polymers, for example polystyrenes, polyolefins, polyamides, polyvinyl chlorides, polyethylene, polycarbonate, polyesters, polypropylene,
  • Polyethylene terephthalate or polyurethanes used. These have the necessary stiffness or mobility to fulfill the mechanical tasks of the primary packaging. Also suitable, for example, natural products such as gelatin or composite materials of plastic and metals, such as aluminum.
  • all walls of the cavity consist of the same material.
  • at least the wall closing the opening may be of a different material than the remaining walls.
  • the level of the drug, formulation or mixture in the packaging can be optimized and depends on the fluidity of the drug, formulation or mixture.
  • Flowability refers to the ability of the drug, formulation or
  • ⁇ i is the solidification stress and ⁇ c is the bulk solids strength.
  • the flowability is determined by means of ring shear device.
  • the flowability is 4> ff c > 1.
  • you use packaging that is partially filled are, in the way that a free air passage between at least one inlet opening and an outlet opening exists.
  • the flowability is 4 ⁇ ff c .
  • packaging means which are partially filled, such that a free air passage between at least one inlet opening and an outlet opening or which are filled, so that an advantageous filling method (simple and inexpensive) can be applied.
  • the filling volume is determined by the shape of the packaging and a special dosing can be omitted.
  • inhalable compounds are used, e.g. also inhalable macromolecules, as disclosed in EP 1 003 478.
  • 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, HIV antihistamines, P AF antagonists and PI3 kinase inhibitors.
  • a pharmacologically active agent selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, P AF antagonists and PI3 kinase inhibitors.
  • 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
  • W represents a PDE4 Inhibitors combined with an EGFR inhibitor or LTD4 antagonist
  • W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • 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, Sulphoneterol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- ⁇ 6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexy
  • 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 ,
  • anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the
  • the cations are the pharmacologically active ingredients.
  • the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • anticholinergics are selected from the salts of the formula AC-I
  • X is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluene sulfonate, 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.
  • anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, cit
  • R is either methyl or ethyl and in which X ⁇ may have the abovementioned meanings.
  • the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.
  • Preferred corticosteroids 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
  • Reference to steroids includes a reference to their possibly existing ones Salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • Preferred PDE4 inhibitors here 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, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
  • 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 ,
  • Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
  • 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 ,
  • Preferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab 1CR-62 and - 4 - [(3-Ch] or-4-fluoro-phenyl) -amino] -6- ⁇ [4- (morpholin-4-yl) -l-oxo-2-buten-1-yl] -amino ⁇ -7-cyclopropylmethoxy -quinazoline
  • 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.
  • Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, 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.
  • 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.
  • HI-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, 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.
  • 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.
  • inhalable macromolecules can be used as disclosed in EP 1 003 478.
  • the compound may be derived from the group of derivatives of ergot alkaloids, the triptans, the CGRP inhibitors, the phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, if appropriate in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.
  • FIGS. 1-10 show, by way of example, the various forms of a capsule or a single cavity of a blister (called packaging in its entirety) and the corresponding piercing positions.
  • Fig. 1 Ball or hemisphere, 5 hole-shaped inlet openings, 1 outlet Fig. 2: Ball or hemisphere, 4 hole-shaped inlet openings, 1 outlet Fig. 3: Oval shape, 6 hole-shaped inlet openings, 1 outlet Fig.
  • Figure 10 Shape of the number "eight”, 2x2 hole-shaped inlet openings, asymmetric, 1
  • FIG. 11 Drop shape, 3 hole-shaped inlet openings, 1 outlet
  • FIG. 12 Drop shape, 4 hole-shaped inlet openings, 1 outlet
  • FIG. 13 Drop shape, sickle cut inlet, 1 outlet Example:
  • the emptying properties were determined with a model powder (glass beads) in such a way that the time until emptying was measured at a given, constant volume flow (corresponding to 10 L / min air).
  • Table 1 gives the results of the various forms for capsules or blisters.
  • the inlet openings are illustrated as small circles, the outlet openings are shown as large circles.
  • Table 1 shows that the emptying characteristics of a package depend substantially on its shape and opening or openings.
  • the flow rate of the air through the packaging in commercial size 10 liters / minute
  • the active ingredient in micronized form has a particle size of 1-5 microns.
  • the powder mixture also contains lactose 200 m.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a package for pharmaceutical mixtures or formulations for use in a powder inhaler.

Description

PACKMITTEL FUR MEHRDOSISPUL VERINHALATOREN MIT OPTIMIERTEN ENTLEERUNGSEIGENSCHAFTEN PACKAGING FOR MULTI-DOSISPULATED COMPOUNDS WITH OPTIMIZED EMPTYING PROPERTIES
Die Erfindung betrifft eine Verpackung für Arzneimittel, -mischungen oder -formulierungen zur Verwendung in einem Pulverinhalator.The invention relates to a package for pharmaceutical compositions, blends or formulations for use in a powder inhaler.
Stand der TechnikState of the art
Die medizinische, auf die pulmonale Inhalation ausgerichtete Aerosoltherapie mittels Verneblern, Dosieraerosolen oder Pulverinhalatoren spielt eine wichtige Rolle in der Behandlung von zahlreichen Lungenkrankheiten.Medical pulmonary inhalation aerosol therapy using nebulisers, metered aerosols or powder inhalers plays an important role in the treatment of numerous lung diseases.
Auf dem Gebiet der Pulverinhalatoren sind Einzeldosen- und Mehrdosen-Geräte bekannt. Die Mehrdosis-Pulverinhalatoren enthalten das Arzneimittel, die -mischung oder die -formulierung entweder in Form eines Pulvervorrats, aus dem durch eine eingebaute Dosiereinheit die jeweilige Einzeldosis aus einer Kavität entnommen wird oder vordosierte, verpackte Einzeldosen, die entweder gemeinsam in dem Gerät bevorratet sind (z.B. in Form von Abpackungen in Blistern) oder bei Gebrauch einzeln in das Gerät eingesetzt werden (z.B. in Form von Kapseln).In the field of powder inhalers, single-dose and multi-dose devices are known. The multi-dose powder inhalers contain the drug, mixture or formulation either in the form of a powder supply from which a single unit dose is withdrawn from a cavity by a built-in dosing unit or pre-dosed, packaged unit doses that are either stored together in the device ( eg in the form of packaging in blisters) or when used individually in the device (eg in the form of capsules).
Insbesondere bei den Mehrdosis-Pulverinhalatoren ist die Art und Weise, wie dieIn particular, in the case of the multi-dose powder inhalers, the way in which the
Pulverformulierung in dem Gerät verpackt vorliegen, für die Produktqualität und damit die Eignung für die inhalative Anwendung, entscheidend.Powder formulation packaged in the device, for the product quality and thus the suitability for inhalation application, crucial.
Daher ist es eine Hauptaufgabe der Verpackung, die chemische Zusammensetzung der Atmosphäre im Inneren der Verpackung konstant zu halten, um physikalischen oder chemischen Veränderungen des Arzneimittels, der -mischung oder der -formulierung vorzubeugen, bzw. diese stabil zu halten.Therefore, one of the main purposes of the package is to keep the chemical composition of the atmosphere inside the package constant to prevent or stabilize physical or chemical changes in the drug, mixture or formulation.
In diesem Zusammenhang unterscheidet man zwischen einer auf eine kurze Zeit ausgerichteten Stabilität, die das Arzneimittels, die -mischung oder -formulierung per se besitzen muss, auch wenn sich nicht durch das Packmittel ausreichend geschützt wird („in- use-Stabilität") und der Langzeitstabilität, d.h. der Stabilität, die gewährleistet sein muss, solange sich das Arzneimittels, die -mischung oder -formulierung in dem ungeöffneten Packmittel befindet.In this context, a distinction is made between a short-term stability which the drug, mixture or formulation must possess per se, even if the packaging does not adequately protect it (" use stability ") and the long-term stability, ie stability, which must be ensured as long as the drug, mixture or formulation is in the unopened packaging.
Es ist weiterhin wichtig, dass der Patient die richtige Dosis der Inhalationsformulierung beim Einatmen erhält.It is also important that the patient receives the right dose of the inhalation formulation when inhaling.
Unter dem Begriff Feinpartikeldosis versteht man dabei die Dosis, die die Lunge des Patienten erreicht. Die Feinpartikeldosis wird von den Wechselwirkungen der mikronisierten Wirkstoffpartikel untereinander als auch der Wechselwirkungen mit den Hilfsstoffen beeinflusst.The term fine particle dose is understood to mean the dose that reaches the lungs of the patient. The fine particle dose is influenced by the interactions of the micronized drug particles with each other as well as the interactions with the excipients.
Es ist weiterhin bekannt, dass besonders durch Änderung des Feuchtigkeitsgrades im Inneren der Verpackung diese Wechselwirkungen derart zunehmen können, dass die Feinpartikeldosis deutlich vermindert ist. Derartige Veränderungen schließen dabei das Eindringen von Wasser in die Verpackung genauso ein, wie das Entfernen von Wasser aus dem Inneren der Verpackung.It is also known that, especially by changing the degree of moisture inside the package, these interactions can increase in such a way that the fine particle dose is significantly reduced. Such changes include the ingress of water into the package as well as the removal of water from inside the package.
Außerdem ist es erforderlich, dass ein Packmittel eine Form sowie ein Öffnungsmuster besitzt (d.h. die Stellen des Packmittels, die mittels Anstechen oder Schneiden die Öffnung des Blisters ermöglichen), die eine optimierte Luftführung und damit eine optimierte Ausbringung des Arzneimittels, der -mischung oder der -formulierung ermöglichen.In addition, it is necessary that a packaging has a shape and an opening pattern (ie, the locations of the packaging, which allow the opening of the blister by piercing or cutting), the optimized air flow and thus an optimized application of the drug, the mixture or allow formulation.
Beispiele für Mehrdosispulverinhalatoren sind im Stand der Technik bekannt. Beispielsweise aus EP 0 703 800 Bl oder der EP 0 911 047 Al, welche einen Pulverinhalator, bestehend aus einem schalenförmigen Unterteil und einem ebenfalls schalenförmigen Deckel, offenbaren. Der Patient kann nach dem Einlegen der Kapsel in die Kapseihalterung ein Betätigungsorgan drücken, welches aus einer Ruhestellung in eine Bewegung versetzbar ist und dabei mit mindestens einer in die Kapselhalterung einstoßbaren Nadel zusammenwirkt. Mit Hilfe der Nadel bzw. der Nadeln wird die Kapsel angestochen und das Arzneimittel freigesetzt.So offenbaren weiterhin z.B. die DE 3348370 und die DE 3336486 Inhalatoren, die eine scheibenförmige Blisterpackung, die mehrere kreisförmig angeordnete Kavitäten aufweist, beinhalten. Die einzelnen Kavitäten enthalten jeweils eine Dosis eines zur Inhalation bestimmten Medikamenten-Pulvers. Die Kavitäten sind beidseitig z.B. durch eine Siegelfolie geschlossen. Zum Ausbπngen des Medikamentenpulvers wird die Kavitat geöffnet Ein Luftkanal verbindet die geöffnete Kavitat mit dem Mundstuck des Inhalators Beispielhaft wird der Inhalator der DE 3336486 naher beschπeben Dieser weist ein Gehäuse auf, in dem sich eine Kammer (Vorratskammer) findet, die einen Lufteinlass aufweist und in welcher sich ein scheibenförmiger, runder Blister mit abgepackten Medikamententaschen befindet Der Blister ist lose mit einer runden, rotierbaren Scheibe verbunden Auf der Scheibe sind umlaufend Locher ausgebildet, die in axialer Richtung Kontakt mit den Medikamententaschen haben, d h die Taschen und Locher liegen über- bzw untereinander Die Kammer weist einen Luftauslass auf. Der Inhalator weist auch einen Kolben auf, der so angeordnet ist, dass er jeweils eine Medikamententasche durchstossend offnen kann, so dass das Medikament in die Kammer freigesetzt wird und über ein Mundstuck eingeatmet werden kann Es wird auf die Zeichnungen der Patentanmeldung bzw der US-Patentschπft verwiesen.Examples of multidose powder inhalers are known in the art. For example, EP 0 703 800 B1 or EP 0 911 047 A1, which disclose a powder inhaler consisting of a cup-shaped lower part and a likewise cup-shaped lid. After inserting the capsule in the Kapseihalterung the patient can press an actuator which is displaceable from a rest position into a movement and cooperates with at least one injectable into the capsule holder needle. With the help of the needle or the needles, the capsule is pierced and the drug released. Thus, for example, DE 3348370 and DE 3336486 disclose inhalers containing a disc-shaped blister pack having a plurality of circularly arranged cavities. The individual cavities each contain a dose of a medicament powder intended for inhalation. The cavities are closed on both sides, eg by a sealing foil. The cavitate is opened to expose the medicament powder. An air channel connects the opened cavity with the mouthpiece of the inhaler. The inhaler of DE 3336486 is described more closely by way of example. This housing has a housing in which a chamber (storage chamber) is located which has an air inlet and in which is a disc-shaped, round blister with packaged drug pockets The blister is loosely connected to a round, rotatable disc on the disc holes are formed circumferentially, which have in the axial direction contact with the medicine bags, ie the pockets and holes are above or below each other The chamber has an air outlet. The inhaler also has a piston arranged so that it can open in each case a medicament pocket pierceable so that the medicament is released into the chamber and can be inhaled via a mouthpiece. Reference is made to the drawings of the patent application or the US patent directed.
Bezuglich der Verpackung der Medikamentenpulver unterscheidet man zwischen der Pπmarverpackung und der Sekundarverpackung Die Pπmarverpackung ist dadurch gekennzeichnet, dass sie sich unmittelbar mit der Inhalationsformulierung in Kontakt befindet Gegebenenfalls kann die Pπmarverpackung von einem zweiten äußeren Schutz umgeben sein, dem Sekundarpackmittel Das Pπmarpackmittel kann dabei z.B eineThe package packaging is characterized in that it is in direct contact with the inhalation formulation. Optionally, the package packaging may be surrounded by a second external protection, the secondary packaging means
Kapsel, ein fester oder flexibler Blister mit Kavitaten oder eine Scheibe mit Kavitaten seinCapsule, a solid or flexible blister with cavities or a disc with cavities
Das Sekundarpackmittel kann ein Blister sein, eine Tasche, ein Beutel oder ein anderes Behältnis Das Sekundarpackmittel umschließt dabei in der Regel das Pnmarpackmittel vollständig Sekundarpackmittel werden insbesondere dann verwendet, wenn das Pπmarpackmittel keinen ausreichenden Schutz vor Feuchtigkeit bietetThe secondary packaging may be a blister, a bag, a bag or other container. The secondary packaging generally encloses the packaging material completely. Secondary packaging is used in particular when the packaging material does not provide adequate protection against moisture
Das Pπmarpackmittel und gegebenenfalls das Sekundarpackmittel haben die Aufgabe, den Wirkstoff als auch die gesamte Inhalationsformulierung vor chemischer oder physikalischer Veränderung zu schützen, sodass dieser langfristig stabil bleibt. Zu den physikalischen Veränderungen zählen dabei insbesondere Veränderungen, die das Ausbringen der vorbestimmten Feinpartikeldosis verändern können.The Pπmarpackmittel and optionally the secondary packaging have the task to protect the drug and the entire inhalation formulation from chemical or physical change, so that it remains stable in the long term. To the In particular, physical changes include changes that may alter the application of the predetermined fine particle dose.
Die Auswahl eines geeigneten Materials für das Packmittel wird durch zwei Faktoren bestimmt: Zum einen muss das Material die angesprochene Schutzfunktion erfüllen können. Zum anderen muss das Material derart sein, dass der Verpackung die zur Verwendung in dem Pulverinhalator notwendige Form gegeben werden kann und das die ihr zugedachte Funktion erfüllen kann.The choice of a suitable material for the packaging material is determined by two factors: Firstly, the material must be able to fulfill the mentioned protective function. On the other hand, the material must be such that the package can be given the necessary form for use in the powder inhaler and that can fulfill its intended function.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, die Form des Packmittels, das Anstechmuster des Packmittels, sowie den Füllstand eines Arzneimittels, einer -mischung oder -formulierung zu optimieren, um die Ausbringung eines Arzneimittels, einer - mischung oder -formulierung zu verbessern.It is an object of the present invention to optimize the shape of the package, the puncture pattern of the package, and the level of a drug, blend, or formulation to improve the delivery of a drug, mixture, or formulation.
Die obige Aufgabe wird durch ein Packmittel gemäß Anspruch 1 gelöst. Vorteilhafte Weiterbildungen sind Gegenstand der Unteransprüche.The above object is achieved by a packaging according to claim 1. Advantageous developments are the subject of the dependent claims.
Beschreibung der ErfindungDescription of the invention
Die vorliegende Erfindung betrifft daher Packmittel für Inhalationspulver, welche in ihrer Form, in ihrem Anstechmuster, sowie im Füllstand eines Arzneimittels, einer -mischung oder -formulierung optimiert sind.The present invention therefore relates to packaging for inhalable powders, which are optimized in their shape, in their piercing pattern, as well as in the level of a drug, a mixture or formulation.
Beschreibung der Erfindung im DetailDescription of the invention in detail
Die Erfindung betrifft optimierte Packmittel, wie oben beschrieben, die aufgrund der Form ihres Öffnungsmusters in ihrem Anstechmuster, sowie des Füllstands eines Arzneimittels, einer -mischung oder -formulierung eine verbesserte Luftführung und damit eine verbesserte Ausbringung des Arzneimittels, der -mischung oder -formulierung ermöglichen. Vorzugsweise handelt es sich bei den Packmitteln um eine Kapsel, einen Blister, eine Blisterscheibe, eine Blisterschnecke oder ein Blisterband. Nachfolgend werden diese verschiedenen Formen in ihrer Gesamtheit als Blister bezeichnet (mit Ausnahme der Kapsel). Die Kapsel besteht in der Regel aus zwei Teilen, einem Kapselkörper (Körper) und einer Kapselkappe (Kappe), die teleskopartig ineinander geschoben werden. Aber auch mehrteilige Kapseln sind bekannt. Vorzugsweise werden Kapseln der Größe 2-4, ganz vorzugsweise der Größe 3 verwendet.The invention relates to optimized packaging means, as described above, which due to the shape of their opening pattern in their piercing pattern, as well as the level of a drug, a mixture or formulation allow improved air flow and thus improved application of the drug, the mixture or formulation , The packaging means are preferably a capsule, a blister, a blister disc, a blister screw or a blister band. Hereafter, these various forms are collectively referred to as blisters (with the exception of the capsule). The capsule usually consists of two parts, a capsule body (body) and a capsule cap (cap), which are telescoped into one another. But also multi-part capsules are known. Preferably, capsules of size 2-4, most preferably size 3 are used.
Das Kapselmaterial ist aus nicht-verdaulichem Kunststoff oder aus Gelatine, insbesondere Hartgelatine.The capsule material is made of non-digestible plastic or gelatin, in particular hard gelatin.
Die Blisterscheibe kann beispielsweise eine zylinderartige Scheibe von bis zu 5 mm Höhe und einem Durchmesser von bis zu 15 cm sein. In der Scheibe sind senkrecht zur Scheibenebene Mulden oder Löcher ausgebildet (Kavitäten). Eine derartige Scheibe kann beispielsweise in einem Inhalator gemäß der DE 3348370 oder der DE 3336486 eingesetzt werden. Ein solcher Inhalator weist ein Gehäuse auf, in dem sich der scheibenförmige, runde Blister mit abgepackten Medikamententaschen befindet. Der Inhalator weist u.a. einen Stift auf, der so angeordnet ist, dass er jeweils eine Medikamententasche öffnen kann, so dass das Medikament in die Kammer freigesetzt wird und über ein Mundstück eingeatmet werden kann.The blister disk can be, for example, a cylinder-like disk of up to 5 mm in height and a diameter of up to 15 cm. Holes or holes are formed in the disk perpendicular to the disk plane (cavities). Such a disk can be used for example in an inhaler according to DE 3348370 or DE 3336486. Such an inhaler has a housing in which the disc-shaped, round blister with packaged medicine bags is located. The inhaler has u.a. a pen which is arranged so that it can each open a medicine bag, so that the drug is released into the chamber and can be inhaled via a mouthpiece.
Die Gestalt des erfindungsgemäßen Packmittels einschließlich der Form der Kavität wird grundsätzlich durch den zu verwendenden Pulverinhalator vorgegeben. Vorzugsweise hat das Packmittel eine tropfenförmige oder ovale Form oder die Form einer Acht. Die Einströmflächen und die Ausströmfläche bzw. -flächen liegen maximal voneinander entfernt.The shape of the packaging material according to the invention, including the shape of the cavity, is fundamentally predetermined by the powder inhaler to be used. Preferably, the packaging has a teardrop-shaped or oval shape or the shape of an eight. The inflow surfaces and the outflow surface or surfaces are at a maximum distance from each other.
Das Packmittel, welches ein Blister ist, weist zunächst ein Basiselement auf, welches aus einem thermoplastischen Kunststoff besteht und wenigstens zwei durch einen Steg voneinander getrennte Kavitäten. Die Kavitäten sind wenigstens nach einer Seite hin offen, gegebenenfalls auch nach zwei, sich gegenüberliegenden Seiten. Diese Öffnungen sind im einsatzfertigen Packmittel geschlossen, z.B. auch eine mit dem Basiselement fest verbunden Siegelfolie. Das Packmittel kann aus den handelsüblichen Materialien bestehen. Bevorzugt besteht es aus einem Kunststoff. Ganz besonders bevorzugt werden als Materialien Kunststoffe aus der Gruppe der thermoplastische Polymere wie z.B. Polystyrole, Polyolefine, Polyamide, Polyvinylchloride, Polyethylen, Polycarbonat, Polyester, Polypropylen,The packaging material, which is a blister, initially has a base element which consists of a thermoplastic and at least two cavities separated from one another by a web. The cavities are open at least to one side, possibly also after two, opposite sides. These openings are closed in the ready-to-use packaging, for example, a firmly bonded to the base element sealing film. The packaging may consist of the commercially available materials. Preferably, it consists of a plastic. Very particular preference is given to plastics from the group of thermoplastic polymers, for example polystyrenes, polyolefins, polyamides, polyvinyl chlorides, polyethylene, polycarbonate, polyesters, polypropylene,
Polyethylenterephthalat oder Polyurethane verwendet. Diese besitzen die notwendige Steifheit bzw. Beweglichkeit, um die mechanischen Aufgaben des Primärpackmittels zu erfüllen. Auch eignen sich zum Beispiel Naturstoffe wie Gelatine oder Verbundmaterialien aus Kunststoff und Metallen, beispielsweise Aluminium.Polyethylene terephthalate or polyurethanes used. These have the necessary stiffness or mobility to fulfill the mechanical tasks of the primary packaging. Also suitable, for example, natural products such as gelatin or composite materials of plastic and metals, such as aluminum.
Erfindungsgemäß ist es nicht notwendig, aber bevorzugt, dass alle Wände der Kavität aus dem gleichen Material bestehen. Bei einer Kavität kann zumindest die die Öffnung verschließende Wandung von anderem Material als die restlichen Wandungen sein.According to the invention it is not necessary, but preferred, that all walls of the cavity consist of the same material. In a cavity, at least the wall closing the opening may be of a different material than the remaining walls.
Weitere Angaben zur Zusammensetzung oder die Verarbeitung betreffend können dem Stand der Technik entnommen werden, insbesondere der EP599690, EP432438 oder der EP400460.Further details concerning the composition or the processing can be found in the prior art, in particular EP599690, EP432438 or EP400460.
Der Füllstand des Arzneimittels, -formulierung oder -mischung im Packmittel kann optimiert werden und richtet sich nach der Fließfähigkeit des Arzneimittels, -formulierung oder -mischung.The level of the drug, formulation or mixture in the packaging can be optimized and depends on the fluidity of the drug, formulation or mixture.
Als Fließfähigkeit bezeichnet man die Fähigkeit des Arzneimittels, -formulierung oderFlowability refers to the ability of the drug, formulation or
-mischung als Schüttgut leicht fließen zu können. In der Technik wird die Fließfähigkeit ffc definiert wie folgt: Mixture as bulk material to flow easily. In the art, the flowability ff c is defined as follows:
Hierbei ist σi die Verfestigungsspannung und σc die Schüttgutfestigkeit. Üblicherweise wird die Fließfähigkeit mittels Ringschergerät bestimmt.Here, σi is the solidification stress and σ c is the bulk solids strength. Usually, the flowability is determined by means of ring shear device.
Für schwer bis nicht fließende Arzneimittel, -formulierungen oder -mischungen gilt für die Fließfähigkeit 4 > ffc > 1. In diesem Fall verwendet man Packmittel, die teilgefüllt sind, in der Art, dass ein freier Luftdurchgang zwischen mindestens einer Einlassöffnung und einer Auslassöffnung besteht.For heavy to non-fluent drugs, formulations or mixtures, the flowability is 4> ff c > 1. In this case, you use packaging that is partially filled are, in the way that a free air passage between at least one inlet opening and an outlet opening exists.
Für leicht fließende Arzneimittel, -formulierungen oder -mischungen gilt für die Fließfähigkeit 4 < f f c . In diesem Fall verwendet man Packmittel, die teilgefüllt sind, in der Art, dass ein freier Luftdurchgang zwischen mindestens einer Einlassöffnung und einer Auslassöffnung besteht oder die vollgefüllt sind, so dass sich ein vorteilhaftes Befüllungsverfahren (einfach und kostengünstig) anwenden lässt. In letzterem Fall wird das Füllvolumen durch die Form des Packmittels vorgegeben und ein spezielles Dosierverfahren kann entfallen.For flowable drugs, formulations or blends, the flowability is 4 <ff c . In this case, one uses packaging means which are partially filled, such that a free air passage between at least one inlet opening and an outlet opening or which are filled, so that an advantageous filling method (simple and inexpensive) can be applied. In the latter case, the filling volume is determined by the shape of the packaging and a special dosing can be omitted.
Als Arzneimittel, -formulierungen oder -mischungen werden alle inhalierbaren Verbindungen eingesetzt, wie z.B. auch inhalierbare Makromoleküle, wie in EP 1 003 478 offenbart.As medicaments, formulations or mixtures, all inhalable compounds are used, e.g. also inhalable macromolecules, as disclosed in EP 1 003 478.
Die unten genannten Verbindungen können allein oder in Kombination zur Anwendung in der erfindungsgemäßen Vorrichtung gelangen. In den unten genannten Verbindungen ist W einen pharmakologisch, aktiver Wirkstoff und (beispielsweise) ausgewählt aus der Gruppe bestehend aus Betamimetika, Anticholinergika, Corticosteroiden, PDE4- Inhibitoren, LTD4- Antagonisten, EGFR-Hemmern, Dopamin-Agonisten, Hl -Anti - histaminika, P AF- Antagonisten und PI3-Kinase Inhibitoren. Weiterhin können zwei- oder dreifach Kombinationen von W kombiniert werden und zur Anwendung in der erfindungsgemäßen Vorrichtung gelangen. Beispielhaft genannte Kombinationen von W wären: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, HIV antihistamines, P AF 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 stellt ein Betamimetika dar, kombiniert mit einem Anticholinergika, Corticosteroide, PDE4-Inhibitore, EGFR-Hemmern oder LTD4-Antagonisten,W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
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.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 inhibitors or LTD4 antagonists - W represents a PDE4 Inhibitors combined with an EGFR inhibitor or LTD4 antagonist W represents an EGFR inhibitor combined with a LTD4 antagonist.
Als Betamimetika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Albuterol, Arformoterol, Bambuterol, Bitolterol, Broxaterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenaline, Ibuterol, Isoetharine, Isoprenaline, Levosalbutamol, Mabuterol, Meluadrine, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphonterol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 und - 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-benzyl-sulfonamidPreferred 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, Sulphoneterol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide
5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-on5- [2- (5,6-diethyl-indan-2-ylamino) -l-hydroxy-ethyl] -8-hydroxy-lH-quinolin-2-one
- 4-Hydroxy-7-[2-{ [2-{ [3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]- 2(3H)-benzothiazolon - l-(2-Fluor-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamino]ethanol l-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(l-benzimidazolyl)-2-methyl- 2-butylamino]ethanol- 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- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- benzimidazolyl) -2-methyl-2-butylamino] ethanol
- l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)- 2-methyl-2-propylamino]ethanol - l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2- propylaminojethanol l-[2H-5-hydroxy-3-oxo-4H-l,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- [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 l- [2H 5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol
- l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-l,2,4- triazol-3-yl]-2-methyl-2-butylamino Jethanoi- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -l, 2,4-triazole-3 -yl] -2-methyl-2-butylamino Jethanoi
5-Hydroxy-8-(l-hydroxy-2-isopropylaminobutyl)-2H-l,4-benzoxazin-3-(4H)-on l-(4-Amino-3-chlor-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-methoxy-phenyl)-l,l-dimethyl-ethylamino]-ethyl}- 4H-benzo[l,4]oxazin-3-on - 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-l,l-dimethyl- ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-on - 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-essigsäure)-l,l-dimethyl-ethylamino]- ethyl }-4H-benzo[l,4]oxazin-3-on5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -on- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert .-butylamino) ethanol 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazine 3-one - 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, l-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazine -3-one 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -l, 1-dimethyl-ethylamino] 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[l ,4]oxazin-3-on - 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-hydroxy-phenyl)-l,l-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] oxazine-3 -one - 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -l, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazine-3 -one
- 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-isopropyl-phenyl)-l,ldimethyl-ethylamino]-ethyl }- 4H-benzo[ 1 ,4]oxazin-3-on 8-{ 2-[2-(4-Ethyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl}-6-hydroxy-4H- benzo[l,4]oxazin-3-on6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -l, ldimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one 8- {2- [2- (4-Ethyl-phenyl) -l, 1-dimethyl-ethylamino] -l-hydroxy-ethyl} -6-hydroxy-4H-benzo [l, 4] oxazin-3-one
8- { 2-[2-(4-Ethoxy-phenyl)- 1,1 -dimethyl-ethylamino]-l -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[l,4]oxazin-8-yl)- ethylamino]-2-methyl-propyl}-phenoxy)-buttersäure - 8- { 2-[2-(3 ,4-Difluor-phenyl)- 1 , 1 -dimethyl-ethylamino]- 1 -hydroxy-ethyl } -6-hydroxy-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 [l, 4] oxazin-8-yl) ethylamino] -2- methyl-propyl} -phenoxy) -butyric acid - 8- {2- [2- (3,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy
4H-benzo[ 1 ,4]oxazin-3-on l-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol4H-benzo [1,4] oxazin-3-one 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol
- 2-Hydroxy-5-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-benzaldehyd - N-[2-Hydroxy-5-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-phenyl]-formamid2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -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-(l-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]- ethylamino}-ethyl)-lH-quinolin-2-on8-Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxybiphenyl-3-ylamino) -phenyl] ethylamino} -ethyl) -1H-quinolin-2-one
8-Hydroxy-5-[l-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-lH-quinolin-2-on - 5- [2-(2- { 4- [4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl } -ethylamino)- 1 - hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-on8-Hydroxy-5- [1-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -1H-quinolin-2-one - 5- [2- (2- {4- [4- (2-amino 2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one
[3-(4-{ 6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-5-methyl-phenyl]-harnstoff[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}-l-hydroxy-ethyl)-2- hydroxymethyl-phenol 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-benzylsulfonamid4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -l-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-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}- propyl)-benzylsulfonamid - 4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-l-hydroxy-ethyl)-2- hydroxymethyl-phenol3- (3- {7- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfonamide 4- (2- {6- [4- (2- 3-cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -l-hydroxy-ethyl) -2-hydroxymethyl-phenol
- N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)- ethylamino]-propyl}-phenyl)-acetamidN-adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -propyl} -phenyl) -acetamide
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, Hydro- citrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro- p-toluolsulfonat.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 ,
Als Anticholinergika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Tiotropiumsalzen, bevorzugt dasAs anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the
Bromidsalz, Oxitropiumsalzen, bevorzugt das Bromidsalz, Flutropiumsalzen, bevorzugt das Bromidsalz, Ipratropiumsalzen, bevorzugt das Bromidsalz, Glycopyrroniumsalzen, bevorzugt das Bromidsalz, Trospiumsalzen, bevorzugt das Chloridsalz, Tolterodin. In den vorstehend genannten Salzen stellen die Kationen die pharmakologisch aktiven Bestandteile dar. Als Anionen können die vorstehend genannten Salze bevorzugt enthalten Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat oder p-Toluolsulfonat, wobei Chlorid, Bromid, Iodid, Sulfat, Methansulfonat oder p-Toluolsulfonat als Gegenionen bevorzugt sind. Von allen Salzen sind die Chloride, Bromide, Iodide und Methansulfonate besonders bevorzugt.Bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts, the cations are the pharmacologically active ingredients. As anions, the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
Ebenfalls bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-I Likewise preferred anticholinergics are selected from the salts of the formula AC-I
worin X " ein einfach negativ geladenes Anion, bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluol- sulfonat, 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-l-enwherein X "is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluene sulfonate, 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 which contain the enantiomers of the formula AC-I-ene
enthalten, worin X ~ die vorstehend genannten Bedeutungen aufweisen kann. Weiterhin bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-2contain, wherein X ~ can have the meanings given above. Further preferred anticholinergics are selected from the salts of the formula 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. wherein R is either methyl or ethyl and in which X ~ may have the abovementioned meanings. 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.
Weiterhin genannte Verbindungen sind:Further named compounds are:
2,2-Diphenylpropionsäuretropenolester-Methobromid - 2,2-Diphenylpropionsäurescopinester-Methobromid2,2-Diphenylpropionic acid tropol ester methobromide - 2,2-diphenylpropionic acid copoprene methobromide
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-Methobromid2-Fluoro-2,2-Diphenylacetic Acid Copoester Methobromide 2-Fluoro-2,2-Diphenylacetic Acid Sterol Esters-Methobromide 3,3 ', 4,4'-Tetrafluorobenzilic Acid Sterol Ester Methobromide - 3,3', 4,4'-Tetrafluorobenzilic Acid Copoester Methobromide - 4,4'-Difluorobenzilic acid-tropol ester-methobromide 4,4'-difluorobenzilic acid-co-ester methobromide 3,3'-difluorobenzilic acid-tropol ester-methobromide 3,3'-difluorobenzilic acid-co-ester methobromide 9-hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide - 9-fluoro-fluorene 9-Carboxylic Acid Sterol Esters-Methobromide 9-Hydroxyfluorene-9-Carboxylic Acidcopine Ester Methobromide 9-Fluoro-Fluoren-9-Carboxylic Acidcopine Ester Methobromide 9-Methylfluorene-9-Carboxylic Acid Sterol Ester Methobromide 9-Methylfluorene-9-Carboxylic Acidcopine Ester Methobromide - Benzilsäurecyclopropyltropinester methobromide
2,2-Diphenylpropionsäurecyclopropyltropinester-Methobromid 9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid 9-Methyl-fluoren-9-carbonsaurecyclopropyltropinester-Methobrornid 9-Methyl-xanthen-9-carbonsaurecyclopropyltropinester-Methobromid 9-Hydroxy-fluoren-9-carbonsaurecyclopropyltropinester-Methobromid 4,4'-Difluorbenzilsauremethylestercyclopropyltropinester-Methobromid - 9-Hydroxy-xanthen-9-carbonsauretropenolester-Methobromid 9-Hydroxy-xanthen-9-carbonsaurescopinester-Methobromid 9-Methyl-xanthen-9-carbonsauretropenolester-Methobromid 9-Methyl-xanthen-9-carbonsaurescopinester-Methobromid 9-Ethyl-xanthen-9-carbonsauretropenolester-Methobromid - 9-Difluormethyl-xanthen-9-carbonsauretropenolester-Methobromid - 9-Hydroxymethyl-xanthen-9-carbonsaurescopmester-Methobromid Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids, die Salze Metho-X zur Anwendung gelangen, wobei X die vorstehend für X genannten Bedeutungen haben kann2,2-Diphenylpropionic acid cyclopropyltropic 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'-difluorobenzilic acid methyl ester cyclopropyltropine ester methobromide - 9-hydroxy-xanthene-9- Carboxyauretropenol ester methobromide 9-Hydroxy-Xanthene-9-carboxylic acid copopriester methobromide 9-Methyl-Xanthene-9-carboxylic acid tropol ester-methobromide 9-Methyl-Xanthene-9-carboxylic acid copopriester methobromide 9-Ethyl-Xanthene-9-Carboxylate-Methestyrene-Methobromide - 9- Difluoromethyl-xanthene-9-carbonsauretropenol ester-methobromide - 9-hydroxymethyl-xanthene-9-carboxylic acid copmester-methobromide The abovementioned compounds can also be used in the context of the present invention as salts in which the salts Metho-X are used instead of the methobromide where X may have the meanings given above for X.
Als Corticosteroide gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Beclomethason, Betamethason, Budesonid, Butixocort, Ciclesonid, Deflazacort, Dexamethason, Etiprednol, Flunisolid, Fluticason, Loteprednol, Mometason, Prednisolon, Prednison, Rofleponid, Triamcinolon, RPR- 106541 , NS-126, ST-26 undPreferred 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-Difluor-17-[(2-furanylcarbonyl)oxy]-l l-hydroxy-16-methyl-3-oxo-androsta-l,4- dien-17-carbothionsaure (S)-fluoromethylester - 6,9-Difluor-l l-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-l,4-dien-17- carbothionsaure (S)-(2-oxo-tetrahydro-furan-3S-yl)ester,6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -1,1-hydroxy-16-methyl-3-oxo-androsta-1, 4-diene-17-carbothionic acid (S) -fluoromethyl ester - 6,9 -Difluoro-1-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) ester,
6α,9α-difluoro-l lß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclo- piopylcarbonyl)oxy-androsta-l,4-diene-17ß-carbonsaure cyanomethyl ester gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Deπvate, ihrer Solvate und/oder Hydrate Jede6α, 9α-difluoro-1β-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopiopylcarbonyl) oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester, 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, each
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.Reference to steroids includes a reference to their possibly existing ones Salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
Als PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, Ariflo (Cilomilast), Tofimilast, Pumafentrin, Lirimilast, Arofyllin, Atizoram, D-4418, Bay- 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS- 613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 undPreferred PDE4 inhibitors here 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, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
N-(3,5-Dichloro-l-oxo-pyridin-4-yl)-4-difluormethoxy-3- cyclopropylmethoxybenzamid - (-)p-[(4αR*,106S*)-9-Ethoxy- 1,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[s][l,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid (R)-(+)-l-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon 3-(Cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N-2-cyano-S-methyl- isothioureido]benzyl)-2-pyrrolidon - cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carbonsäure] 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy- phenyl)cyclohexan-l-on cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-l-ol] (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat - (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetatN- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-) p - [(4αR *, 106S *) - 9-ethoxy-1,2, 3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [l, 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide (R) - (+) - l- (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-difluoromethoxy) phenyl) 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]-l,2,4-triazolo[4,3- a]pyridin9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine
- 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(feA-t-butyl)-9H-pyrazolo[3,4-c]-l,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.9-cyclopentyl-5,6-dihydro-7-ethyl-3- (feA-t-butyl) -9H-pyrazolo [3,4-c] -l, 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 ,
Als LTD4-Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L- 733321 undPreferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and
- l-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)phenyl)thio)methylcyclopropan-essigsäure,- l - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,
- l-(((l(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(l- hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropanessigsäure- l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid
[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,[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,
Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, 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.Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, 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 ,
Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Cetuximab, Trastuzumab, ABX-EGF, Mab 1CR-62 und - 4-[(3-Ch]or-4-fluoφhenyl)amino]-6-{ [4-(morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}- 7-cyclopropylmethoxy-chinazolinPreferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab 1CR-62 and - 4 - [(3-Ch] or-4-fluoro-phenyl) -amino] -6- {[4- (morpholin-4-yl) -l-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy -quinazoline
- 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(N,N-diethylamino)-l-oxo-2-buten-l-yl]- amino } -7-cyclopropylmethoxy-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino}-7-cyclopropylmethoxy-chinazolin- 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -l-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline
- 4-[(R)-(I -Phenyl-ethyl)amino]-6-{ [4-(morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7- cyclopentyloxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-moφholin-4-yl)-l-oxo- 2-buten- 1 -yl] amino } -7-cyclopropylmethoxy-chinazolin- 4 - [(R) - (1-Phenylethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxo-4-methyl-4-yl) -l-oxo-2 -butene-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo- 2-buten- 1-yl] amino} -7- [(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-butene - 1-yl] amino} -7- [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-2-methoxymethyl-6-oxo-morpholin-4- yl )- 1 -oxo-2-buten- 1 -yljamino } -7-cyclopropylmethoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-moφholin-4-yl)-ethoxy]- 7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl]-1-oxo-2-ol butene-1-ylamino] -7-cyclopropylmethoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholine] 4-yl) -ethoxy] - 7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l- oxo-2-buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazolin- 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1 - yl} amino) -7-cyclopropylmethoxy-quinazoline
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl] amino } -7-cyclopentyloxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazoline
- 4-[(R)-( 1 -Phenyl-ethyl)amino]-6- { [4-(N,N-bis-(2-methoxy-ethyl)-amino)- 1 -oxo-2- buten-l-yl]amino}-7-cyclopropylmethoxy-chinazolin- 4 - [(R) - (1-phenyl-ethyl) -amino] -6- {[4- (N, N-bis (2-methoxy-ethyl) -amino]-1-oxo-2-butene l-yl] amino} -7-cyclopropylmethoxy-quinazoline
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-l-oxo-2- buten-l-yl }amino)-7-cyclopropylmethoxy-chinazolin - 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2- buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazolin- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -l-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxyquinazoline - 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl -amino] -l-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-l- oxo-2-buten-l-yl }amino)-7-cyclopropylmethoxy-chinazolin 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- 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 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -l-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-butene-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-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l- oxo-2-buten- 1 -yl } amino)-7-cyclopentyloxy-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(N-cyclopropyl-N-methyl-amino)-l-oxo-2- buten-l-ylJaminoJ-V-cyclopentyloxy-chinazolin- 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1 - yl} amino) -7-cyclopentyloxy-quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N-cyclopropyl-N-methylamino) -l-oxo-2-yl} -amino) -7-cyclopentyloxy-quinazoline buten-l-ylJaminoJ-V-cyclopentyloxy-quinazoline
- 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-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-Chlor-4-fluorphenyl)amino] -6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin- 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S. ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
- 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin- 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxy-ethoxy) -quinazoline
- 4-[(3-Chlor-4-fluoφhenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) -amino] -quinazoline
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin - 3-Cyano-4-[(3-chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten- 1 -yl]amino } -7-ethoxy-chinolin- 4 - [(R) - (1-Phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine-3-cyano-4 - [(3 chloro-4-fluoro-phenyl) -amino] -6- {4- (N, N-dimethylamino) -l-oxo-2-butene-1-yl} amino} -7-ethoxy-quinoline
- 4-{ [3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{ [(2-methansulfonyl- ethyl)amino]methyl }-furan-2-yl)chinazolin- 4- {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5- {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2- buten- 1 -yl] amino } -7-methoxy-chinazolin- 4 - [(R) - (1-phenylethyl) amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-2-one butene-1-yl] amino} -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}- 7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin- 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-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-l-oxo-2- buten-l-yl }amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin - 4-[(3-Ethinyl-phenyl)amino]-6-{ [4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-l-oxo-2- buten- 1 -yljamino } -chinazolin- 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-but-1-ene yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline - 4 - [(3-ethynylphenyl) amino] -6- {[4- (5,5-dimethyl-2-oxo) morpholin-4-yl) -1-oxo-2-butene-1-ylamino} quinazoline
- 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-moφholin-4-yl)-ethoxy]- 7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-moφholin-4-yl)-ethoxy]- 6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin- 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-4-methyl-4-yl) -ethoxy] - 7 - [(R) - ( tetrahydrofuran-2-yl) methoxy] -quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-4-methyl-4-yl) -ethoxy] - 6 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-moφholin-4-yl)-piperidin-l-yl]- ethoxy}-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-4-methyl-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-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-l-yloxy)-7-methoxy- chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-l- yloxy)-7-methoxy-chinazolin- 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-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy- chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(moφholin-4-yl)carbonyl]-piperidin-4-yl- oxy}-7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(4-methyl-4-yl) carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(methoxymethyl)carbonyl]-piperidin-4-yl- oxy } -7-methoxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline 4 - [(3 chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7- methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline
- 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-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-methoxyethoxy) quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]- cyclohexan-l-yloxyj^-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy-1-methoxy-quinazoline
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-l-yloxy}-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino- ethoxy)-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-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-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- methansulfonylamino-ethoxy)-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(piperidin-l-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline-4 - [(3-chloro-4- fluorophenyl) amino] -6- {1- (piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-aminocarbonylmethyl-piperidin-4-yloxy)-7- methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N- methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1-one yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl- amino }-cyclohexan-l-yloxy)-7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1-one yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl- amino}-cyclohexan-l-yloxy)-7-methoxy- chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-l- yloxy)-7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane-1-one yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-ethoxy- chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2- methoxy-ethoxy)-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy) -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin - 4-[(3-Ethinyl-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline - 4 - [(3-ethynyl-phenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazolin4 - [(3-ethynyl-phenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-l-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-l-yl)carbonyl]-N- methyl-amino} -cyclohexan- l-yloxy)-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-l-yloxyJ-7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxyquinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] - N-methyl-amino} -cyclohexan-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-Chlor-4-fluor-phenyl)amino]-6-{ l-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4- yloxy}-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy}-7-(2-methoxy-ethoxy)-chinazolin- 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-Ethinyl-phenyl)amino]-6-(l-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin 4-[(3-Ethinyl-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin 4-[(3-Ethinyl-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin- 4 - [(3-Ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (1 -methyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7(2-methoxy- ethoxy)-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-isopropyloxycarbonyl-piperidin-4-yloxy)-7- methox y-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-7- methox y-chinazolin4 - [(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-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexan-l-yloxyj^-methoxy-chinazolin 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin - 4-[(3-Ethinyl-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy- chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxyj ^ - methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazolin-4 - [(3-ethynyl-phenyl) -amino] -6- [1-10] (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
- 4-[(3-Ethinyl-phenyl)amino]-6-{ l-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7- methox y-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(cis-2,6-dimethyl-moφholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methox y-chinazolin- 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-4-chloro-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methox y-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy- quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(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-{ l-[(N-methyl-N-2-methoxyethyl- amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-ethyl-piperidin-4-yloxy)-7-methoxy- chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [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-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methoxyethyl)carbonyl]-piperidin-4- yloxy } -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(3-methoxypropyl-amino)-carbonyl]- piperidin-4-yloxy } -7-methoxy-chinazolin- 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-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-l-yloxy]-7-methoxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l- yloxy]-7-methoxy-chinazolin- 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-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-l-yloxyj^-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy-1-yl-methoxy-quinazoline-4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 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-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane 1 - yloxy) -7-methoxy-quinazoline
- 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-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7- methoxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-cyano-piperidin-4-yloxy)-7-methoxy- chinazolin 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, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat. Als Dopamin-Agonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Bromocriptin, Cabergolin, Alpha- Dihydroergocryptin, Lisurid, Pergolid, Pramipexol, Roxindol, Ropinirol, Talipexol, Tergurid und Viozan, 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, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-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. Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, 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, 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.
Als HI-Antihistaminika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Epinastin, Cetirizin, Azelastin, Fexofenadin, Levocabastin, Loratadin, Mizolastin, Ketotifen, Emedastin, Dimetinden, Clemastin, Bamipin, Cexchlorpheniramin, Pheniramin, Doxylamin, Chlorphenoxamin, Dimenhydrinat, Diphenhydramin, Promethazin, Ebastin, Desloratidin und Meclozin, 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, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.As HI-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, 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.
Außerdem können inhalierbare Makromoleküle verwendet werden, wie in EP 1 003 478 offenbart.In addition, inhalable macromolecules can be used as disclosed in EP 1 003 478.
Weiterhin kann die Verbindung aus der Gruppe der Derivate von Mutterkornalkaloiden, der Triptane, der CGRP-Hemmern, der Phosphodiesterase-V-Hemmer stammen, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.Furthermore, the compound may be derived from the group of derivatives of ergot alkaloids, the triptans, the CGRP inhibitors, the phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, if appropriate in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.
Als Derivate der Mutterkornalkaloide: Dihydroergotamin, Ergotamin.As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.
Für die Inhalation kommen Arzneimittel, Arzneimittelformulierungen und -mischungen mit den o.g. Wirkstoffen in Betracht, sowie deren Salze, Ester sowie die Kombination dieser Wirkstoffe, Salze und Ester.For inhalation, medicines, drug formulations and mixtures containing the Active ingredients, as well as their salts, esters and the combination of these agents, salts and esters.
Beschreibung der Abbildungen:Description of the pictures:
Die Abbildungen zeigen exemplarisch die verschiedenen Formen einer Kapsel oder einer Einzelkavität eines Blisters (in ihrer Gesamtheit Packmittel genannt) sowie die entsprechenden Anstechpositionen.The figures show, by way of example, the various forms of a capsule or a single cavity of a blister (called packaging in its entirety) and the corresponding piercing positions.
Die Abbildungen dienen der Illustration ohne den Umfang der Erfindung einzuschränken.The figures are for illustration without limiting the scope of the invention.
Fig 1 : Kugel oder Halbkugel, 5 lochförmige Einlass-Öffnungen, 1 Auslass Fig 2: Kugel oder Halbkugel, 4 lochförmige Einlass-Öffnungen, 1 Auslass Fig 3: Ovalform, 6 lochförmige Einlass-Öffnungen, 1 Auslass Fig 4: Ovalform, 5 lochförmige Einlass-Öffnungen, asymmetrisch, 1 Auslass Fig 5: Ovalform, 3 lochförmige Einlass-Öffnungen, asymmetrisch, 1 Auslass Fig 6: Ovalform, 2 lochförmige Einlass-Öffnungen Fig 7: Knochenform, 2x3 lochförmige Einlass-Öffnungen, 1 Auslass Fig 8: Knochenform, 2x2 lochförmige Einlass-Öffnungen, asymmetrisch, 1 Auslass Fig 9: Form der Zahl "Acht", 2x3 lochförmige Einlass-Öffnungen, 1 AuslassFig. 1: Ball or hemisphere, 5 hole-shaped inlet openings, 1 outlet Fig. 2: Ball or hemisphere, 4 hole-shaped inlet openings, 1 outlet Fig. 3: Oval shape, 6 hole-shaped inlet openings, 1 outlet Fig. 4: Oval shape, 5 hole-shaped Inlet ports, asymmetric, 1 outlet Fig 5: Oval shape, 3 hole-shaped inlet ports, asymmetric, 1 outlet Fig 6: Oval shape, 2 hole-shaped inlet ports Fig 7: Bone shape, 2 × 3 hole-shaped inlet ports, 1 outlet Fig 8 Bone shape , 2x2 hole-shaped inlet openings, asymmetric, 1 outlet Fig 9: Shape of the number "eight", 2x3 hole-shaped inlet openings, 1 outlet
Fig 10: Form der Zahl "Acht", 2x2 lochförmige Einlass-Öffnungen, asymmetrisch, 1Figure 10: Shape of the number "eight", 2x2 hole-shaped inlet openings, asymmetric, 1
Auslassoutlet
Fig 11 : Tropfenform, 3 lochförmige Einlass-Öffnungen, 1 AuslassFIG. 11: Drop shape, 3 hole-shaped inlet openings, 1 outlet
Fig 12: Tropfenform, 4 lochförmige Einlass-Öffnungen, 1 Auslass Fig 13: Tropfenform, Sichelschnitt-Einlass, 1 Auslass Beispiel:FIG. 12: Drop shape, 4 hole-shaped inlet openings, 1 outlet FIG. 13: Drop shape, sickle cut inlet, 1 outlet Example:
Die Entleerungseigenschaften wurden mit einem Modellpulver (Glaskugeln) in der Weise bestimmt, dass bei vorgegebenem, konstantem Volumenstrom (entsprechend 10 L/min Luft) die Zeit bis zur Entleerung gemessen wurde. Tabelle 1 gibt die Ergebnisse der verschiedenen Formen für Kapseln oder Blister wieder. Die Einlassöffnungen sind zeichnerisch als kleine Kreise, die Auslassöffnungen als große Kreise dargestellt.The emptying properties were determined with a model powder (glass beads) in such a way that the time until emptying was measured at a given, constant volume flow (corresponding to 10 L / min air). Table 1 gives the results of the various forms for capsules or blisters. The inlet openings are illustrated as small circles, the outlet openings are shown as large circles.
Tabelle 1Table 1
Die Ergebnisse der Tabelle 1 zeigen, dass die Entleerungseigenschaften eines Packmittels wesentlich von ihrer Form und ihrer Öffnung bzw. ihrer Öffnungen abhängen. Tabelle 2The results of Table 1 show that the emptying characteristics of a package depend substantially on its shape and opening or openings. Table 2
Die Flussrate der Luft durch das Packmittel in handelsüblicher Größe: 10 Liter/MinuteThe flow rate of the air through the packaging in commercial size: 10 liters / minute
Der Wirkstoff in mikronisierter Form besitzt eine Teilchengröße von 1 - 5 μm. Die Pulvermischung enthält außer dem Wirkstoff weiterhin Laktose 200 m.The active ingredient in micronized form has a particle size of 1-5 microns. In addition to the active substance, the powder mixture also contains lactose 200 m.
Die Ergebnisse der Tabelle 2 zeigen für die Wirkstoffe Fenoterol und Tiotropium a) den in der Kavität verbleibenden Rückstand, sowie b) die Entleerungszeit der Kavität. Eine Kavität eines Packmittels, welche einen optimierten Luftstrom aufgrund ihrer Form und ihres Öffnungsmusters hat, zeigt deutlich verbesserte Entleerungseigenschaften. Für das Verhältnis V (Summe der Einströmflächen dividiert durch Summe der Ausströmflächen) gilt: 0,5 < V < 2. Bevorzugt sollte die Summe der Einströmflächen gleich der Summe der Ausströmflächen sein. The results of Table 2 show for the active ingredients fenoterol and tiotropium a) the residue remaining in the cavity, and b) the emptying time of the cavity. A cavity of a packaging material which has an optimized air flow due to its shape and opening pattern exhibits significantly improved evacuation properties. For the ratio V (sum of the inflow areas divided by the sum of the outflow areas): 0.5 <V <2. The sum of the inflow areas should preferably be equal to the sum of the outflow areas.

Claims

PATENTANSPRÜCHE
1. Packmittel zur Verwendung im Pulverinhalator, dadurch charakterisiert, dass das Packmittel in seiner Form, sowie den Füllstand eines Arzneimittels, einer -mischung oder -formulierung optimiert ist und das Packmittel derart geöffnet werden kann, dass die Ausbringung des Arzneimittels, -mischung oder -formulierung optimiert ist.1. Packaging for use in the powder inhaler, characterized in that the packaging is optimized in its shape and the level of a drug, a mixture or formulation and the packaging can be opened so that the application of the drug, mixture or formulation is optimized.
2. Packmittel nach Anspruch 1, dadurch gekennzeichnet, dass es sich um eine Kapsel handelt.2. Packaging according to claim 1, characterized in that it is a capsule.
3. Packmittel nach Anspruch 2, dadurch gekennzeichnet, dass es sich um eine Kapsel der Größe 2-4, vorzugsweise der Größe 3, handelt.3. Packaging according to claim 2, characterized in that it is a capsule of size 2-4, preferably of size 3, is.
4. Packmittel nach Anspruch 1, dadurch gekennzeichnet, dass es sich um einen Blister, eine Blisterscheibe, eine Blisterschnecke oder ein Blisterband mit einer oder mehreren Kavitäten handelt.4. Packaging according to claim 1, characterized in that it is a blister, a blister disc, a blister screw or a blister band with one or more cavities.
5. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass pro Kavität oder Kapsel die Summe der Einströmflächen gleich der Summe der Ausströmfläche bzw. -flächen ist.5. Packaging according to one or more of the preceding claims, characterized in that per cavity or capsule, the sum of the inflow is equal to the sum of the outflow area or surfaces.
6. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel maximal mit Luft durchströmt wird.6. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule is perfused with air.
7. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel tropfenförmig ist und die Einströmflächen sowie die Ausströmfläche bzw. -flächen maximal voneinander entfernt liegen.7. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule is drop-shaped and the inflow surfaces and the outflow surface or surfaces are at a maximum distance from each other.
8. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel eine ovale Form besitzt und die Einströmflächen sowie die Ausströmfläche bzw. -flächen maximal voneinander entfernt liegen.8. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule has an oval shape and the Influential surfaces and the outflow surface or surfaces are maximally removed from each other.
9. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel die Form einer Acht besitzt und die9. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule has the shape of an eight and the
Einströmflächen sowie die Ausströmfläche bzw. -flächen maximal voneinander entfernt liegen.Influential surfaces and the outflow surface or surfaces are maximally removed from each other.
10. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel eine Form gemäß Figur 1-13 hat.10. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule has a shape according to Figure 1-13.
11. Packmittel nach einem oder mehreren der vorangegangenen Ansprüche, dadurch gekennzeichnet, dass die Kavität oder Kapsel ein Öffnungsmuster gemäß Figur 1-13 hat.11. Packaging according to one or more of the preceding claims, characterized in that the cavity or capsule has an opening pattern according to Figure 1-13.
12. Pulverinhalator enthaltend ein Packmittel nach einem oder mehreren der vorangegangenen Ansprüche. 12. powder inhaler containing a packaging according to one or more of the preceding claims.
EP07727327A 2006-03-27 2007-03-26 Packaging means for multi-dose powder inhalers with optimized discharging properties Withdrawn EP2001536A1 (en)

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DE102006014434A DE102006014434A1 (en) 2006-03-27 2006-03-27 Packaging for multidose powder inhalers with optimized emptying properties
PCT/EP2007/052854 WO2007110402A1 (en) 2006-03-27 2007-03-26 Packaging means for multi-dose powder inhalers with optimized discharging properties

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EP2001536A1 true EP2001536A1 (en) 2008-12-17

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EP07727327A Withdrawn EP2001536A1 (en) 2006-03-27 2007-03-26 Packaging means for multi-dose powder inhalers with optimized discharging properties

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US (1) US20070221535A1 (en)
EP (1) EP2001536A1 (en)
JP (1) JP2009531238A (en)
KR (1) KR20080110866A (en)
CN (1) CN101410147A (en)
AR (1) AR060073A1 (en)
AU (1) AU2007229530A1 (en)
BR (1) BRPI0710106A2 (en)
CA (1) CA2646337A1 (en)
DE (1) DE102006014434A1 (en)
EA (1) EA200801917A1 (en)
EC (1) ECSP088768A (en)
MX (1) MX2008011694A (en)
NO (1) NO20083890L (en)
PE (1) PE20071301A1 (en)
TW (1) TW200803933A (en)
UY (1) UY30234A1 (en)
WO (1) WO2007110402A1 (en)
ZA (1) ZA200807579B (en)

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Also Published As

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NO20083890L (en) 2008-11-17
WO2007110402A1 (en) 2007-10-04
AU2007229530A8 (en) 2008-11-13
BRPI0710106A2 (en) 2011-08-02
AU2007229530A1 (en) 2007-10-04
JP2009531238A (en) 2009-09-03
CN101410147A (en) 2009-04-15
ZA200807579B (en) 2009-10-28
MX2008011694A (en) 2008-09-24
PE20071301A1 (en) 2008-02-04
UY30234A1 (en) 2007-10-31
ECSP088768A (en) 2008-10-31
AR060073A1 (en) 2008-05-21
EA200801917A1 (en) 2009-04-28
TW200803933A (en) 2008-01-16
KR20080110866A (en) 2008-12-19
DE102006014434A1 (en) 2007-10-04
CA2646337A1 (en) 2007-10-04
US20070221535A1 (en) 2007-09-27

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