EP1942867A2 - Propellant for dosing aerosols comprising packagings - Google Patents

Propellant for dosing aerosols comprising packagings

Info

Publication number
EP1942867A2
EP1942867A2 EP06807454A EP06807454A EP1942867A2 EP 1942867 A2 EP1942867 A2 EP 1942867A2 EP 06807454 A EP06807454 A EP 06807454A EP 06807454 A EP06807454 A EP 06807454A EP 1942867 A2 EP1942867 A2 EP 1942867A2
Authority
EP
European Patent Office
Prior art keywords
substance
amino
phenyl
adsorbent
quinazoline
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Withdrawn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
EP06807454A
Other languages
German (de)
French (fr)
Inventor
Hans-Hermann Weil
Christel Schmelzer
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
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1942867A2 publication Critical patent/EP1942867A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
    • B65D83/75—Aerosol containers not provided for in groups B65D83/16 - B65D83/74

Definitions

  • a pharmaceutical product comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or substance mixture.
  • Propellant-containing metered dose aerosols have long been used for the treatment of patients. Especially in the treatment of respiratory diseases, these metered dose inhalers have proven to be effective with the corresponding active ingredients.
  • chlorofluorohydrocarbons CFCs
  • hydrofluorocarbons HFCs
  • HFC-134 (a) 1,1,1,2-tetrafluoroethane
  • the propellant-containing metered dose aerosols are sealed in a package that serves the drug safety.
  • the packaging consists - as known from the prior art - for example, aluminum composite foil or polyethylene films or other tightly closed containers, such as glass bottles or aluminum cans with screw caps.
  • this packaging is intended to guarantee that the pharmaceutical substance, substance formulation or substance mixture does not lose water or absorb water or moisture from the environment.
  • the water diffusion through the rubber components of the metered dose aerosols has a negative impact on the stability of the pharmaceutical product and may therefore affect the quality.
  • the propellant gas contained in the metered dose inhaler can escape from the metered dose aerosol over a relatively long period of time and escapes into the surrounding packaging. This then partially inflates. The amount of escaped propellant gas is so low that it does not affect the quality of the pharmaceutical product.
  • the inflated packaging may present a problem with the storage of the pharmaceutical product. In addition, this effect may lead to the uncertainty of patients who may find the product defective and no longer effective.
  • a pharmaceutical product comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or mixture of substances the adsorbent is in addition to the propellant-containing metered dose inhaler in the package.
  • the invention particularly relates to pharmaceutical products containing a pharmaceutically active substance, substance formulation or substance mixture, wherein the pharmaceutically active substance, substance formulation or substance mixture is used for the treatment of respiratory diseases.
  • the adsorbent absorbs the propellant gas and the package no longer inflates. At the same time it is surprisingly found that the adsorbent does not affect the water content of the pharmaceutically active substance, substance formulation or substance mixture of the propellant-containing metered dose inhaler.
  • Suitable adsorbents are the following substances available on the market: activated carbon, silica gels, molecular sieves, ion exchangers, alumina, zeolites and / or magnesium sulfate.
  • activated carbon silica gels, molecular sieves, ion exchangers, alumina, zeolites and / or magnesium sulfate.
  • a mixture of two or more adsorbents may be used.
  • charcoal tablets are used, as they are available in pharmacies for the treatment of diarrheal diseases. Most preferably, one charcoal tablet per metered dose inhaler is enclosed by the package.
  • HFCs CFCs 11, 12, 114, nitrous oxide (N 2 O nitrous oxide) or carbon dioxide (CO 2 ) or HFCs, preferably HFC 134a or HFC 227, are used as propellant gases in the dosing aerosol.
  • HFC propellants are HFC-32 (difluoromethane), HFC-143 (a) (1,1,1-trifluoroethane), HFC 134 (1,1,2,2-tetrafluoroethane) and HFC-152a (1,1 - difluoroethane)
  • 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, HI 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.
  • W represents a betamimetics combined with anticholinergics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
  • W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
  • W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
  • W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
  • W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and
  • 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 ,
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts the chloride salt, tolterodine.
  • the cations are the pharmacologically active ones
  • the abovementioned 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 as counterions are preferred.
  • 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-Toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates Significance are those drug combinations that contain the enantiomers of the formula AC-l-en
  • 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
  • any reference to steroids includes reference to their optionally existing salts or derivatives, hydrates or solvates
  • Examples of possible salts and derivatives of Steroids may be: alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or 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 - l - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2- hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid,
  • 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.
  • salts or derivatives whose formation the LTD4 antagonists are capable of are understood to be: 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 ICR-62 and
  • 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, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.
  • the substances, substance formulations or substance mixtures are preferably in the form of suspension or solution aerosols.
  • Suitable packaging materials are all tight-closing foils (for example polyethylene foils), preferably aluminum composite foils.
  • the packaging of the metered dose aerosols (with the substance, substance formulation or substance mixture) and the adsorbent is carried out by standard methods, as known from the literature.
  • Aluminum composite foil neutral, from Tscheulin-Rothal GmbH, Friedrich-Meyer-Str. 23, 79331 Teningen, Germany, according to DIN 1784.
  • the film thickness is 50 ⁇ m ⁇ 10%.
  • the metered dose inhalers used contained HFC 227.
  • the metered dose inhalers did not contain a pharmaceutical product but were so-called placebo metered dose inhalers.
  • the samples were stored at 5O 0 C and weighed after different periods of storage.
  • the aluminum bags were cut open and the aerosol containers weighed alone, as well as the flattened aluminum bags with charcoal tablets.
  • charcoal tablets prevents bloating aluminum bags.

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Abstract

The invention relates to a pharmaceutical product comprising a dosing aerosol containing a propellant, an effective quantity of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture, and a packaging enclosing the adsorbent and the dosing aerosol with the pharmaceutically active substance, substance formulation or substance mixture.

Description

TREIBGASABSORBTION BEI DOSIERAEROSOLEN MIT VERPACKUNGEN GAS ABSORPTION IN DOSIERAEROSOLS WITH PACKAGING
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
Erfindungsgemäß wird ein pharmazeutisches Produkt beansprucht, enthaltend ein Treibgas-enthaltendes Dosieraerosol, eine effektive Menge an Adsorbens, eine pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung und eine Verpackung, welche das Adsorbens und das Dosieraerosol mit der pharmazeutisch wirksamen Substanz, Substanzformulierung oder Substanzmischung umschließt.According to the invention, a pharmaceutical product is claimed, comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or substance mixture.
STAND DER TECHNIKSTATE OF THE ART
Treibgas-enthaltende Dosieraerosole werden seit langem für die Behandlung von Patienten eingesetzt. Vor allem bei der Behandlung von Atemwegserkrankungen haben sich diese Dosieraerosole mit den entsprechenden Wirkstoffen als wirksam erwiesen.Propellant-containing metered dose aerosols have long been used for the treatment of patients. Especially in the treatment of respiratory diseases, these metered dose inhalers have proven to be effective with the corresponding active ingredients.
Als Treibgas werden in den Dosieraerosolen entweder traditionell die Chlorofluorkohlenwasserstoffe (CFCs) oder die Hydrofluorkohlenwasserstoffe (HFCs) verwendet. Letztere werden aus Gründen des Umweltschutzes bevorzugt und ersetzten inzwischen die CFCs wei testgehend. Diese Systeme sind beispielsweise im U.S. Patent 4.174.295 beschrieben.As propellant gas, chlorofluorohydrocarbons (CFCs) or hydrofluorocarbons (HFCs) are traditionally used in metered aerosols. The latter are preferred for reasons of environmental protection and replaced the CFCs as far as possible. These systems are described, for example, in U.S. Pat. Patent 4,174,295.
Es ist bekannt, dass sich bestimmte HFCs insbesondere für die medizinische Anwendung eignen. Die europäische Anmeldung Nr. 0 372 777 beschreibt beispielsweise die Verwendung von 1,1,1,2-Tetrafluorethan (HFC- 134 (a)) im pharmazeutischen Bereich.It is known that certain HFCs are particularly suitable for medical use. For example, European Application No. 0 372 777 describes the use of 1,1,1,2-tetrafluoroethane (HFC-134 (a)) in the pharmaceutical field.
Die PCT-Anmeldung Nr. WO91/11496 beschreibt die Verwendung von 1,1,1,2,3,3,3- Heptafluorpropan (HFC-227) im Bereich der Dosieraerosole.PCT Application No. WO91 / 11496 describes the use of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) in the field of metered dose inhalers.
Die Treibgas-enthaltenden Dosieraerosole werden in eine Verpackung eingeschweißt, die der Arzneimittelsicherheit dient. Die Verpackung besteht - wie aus dem Stand der Technik bekannt - beispielsweise aus Aluminiumverbundfolie oder Polyethylenfolien oder anderen dichtschließenden Behältnissen, wie Glasflaschen oder Aludosen mit Schraubverschlüssen. Diese Verpackung soll unter anderem garantieren, dass die pharmazeutische Substanz, Substanzformulierung, oder Substanzmischung keinen Wasserverlust erleidet oder Wasser bzw. Feuchte aus der Umgebung aufnimmt. Die Wasserdiffusion durch die Gummibestandteile der Dosieraerosole hat einen negativen Einfluss auf die Stabilität des pharmazeutischen Produktes und beeinträchtigt damit möglicherweise die Qualität.The propellant-containing metered dose aerosols are sealed in a package that serves the drug safety. The packaging consists - as known from the prior art - for example, aluminum composite foil or polyethylene films or other tightly closed containers, such as glass bottles or aluminum cans with screw caps. Among other things, this packaging is intended to guarantee that the pharmaceutical substance, substance formulation or substance mixture does not lose water or absorb water or moisture from the environment. The water diffusion through the rubber components of the metered dose aerosols has a negative impact on the stability of the pharmaceutical product and may therefore affect the quality.
Aus dem Stand der Technik ist die gemeinsame Verpackung von Dosieraerosolen mit einem Adsorbens zur Aufnahme von Feuchtigkeit bekannt (JP 59174473). Als Adsorbens dienen Aktivkohle, Silikagele, Molekularsiebe und bestimmte Ionenaustauscher.From the prior art, the common packaging of metered aerosols with an adsorbent for absorbing moisture is known (JP 59174473). The adsorbent used are activated carbon, silica gels, molecular sieves and certain ion exchangers.
Es ist nun bekannt, dass das in dem Dosieraerosol enthaltene Treibgas über einen längeren Zeitraum aus dem Dosieraerosol entweichen kann und in die umgebende Verpackung entweicht. Diese bläht sich dann teilweise auf. Die Menge des entwichenen Treibgases ist so gering, dass diese die Qualität des pharmazeutischen Produktes nicht beeinträchtigt. Allerdings kann die aufgeblähte Verpackung ein Problem bei der Lagerung des pharmazeutischen Produktes darstellen. Außerdem kann dieser Effekt zur Verunsicherung der Patienten führen, die das Produkt unter Umständen für schadhaft und nicht mehr wirksam halten.It is now known that the propellant gas contained in the metered dose inhaler can escape from the metered dose aerosol over a relatively long period of time and escapes into the surrounding packaging. This then partially inflates. The amount of escaped propellant gas is so low that it does not affect the quality of the pharmaceutical product. However, the inflated packaging may present a problem with the storage of the pharmaceutical product. In addition, this effect may lead to the uncertainty of patients who may find the product defective and no longer effective.
KURZE ZUSAMMENFASSUNG DER ERFINDUNGBRIEF SUMMARY OF THE INVENTION
Erfindungsgemäß wird ein pharmazeutisches Produkt vorgeschlagen, enthaltend ein Treibgas-enthaltendes Dosieraerosol, eine effektive Menge an Adsorbens, eine pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung und eine Verpackung, welche das Adsorbens und das Dosieraerosol mit der pharmazeutisch wirksamen Substanz, Substanzformulierung oder Substanzmischung umschließt, wobei das Adsorbens sich zusätzlich zum Treibgas-enthaltenden Dosieraerosol in der Verpackung befindet. Die Erfindung betrifft insbesondere pharmazeutische Produkte enthaltend eine pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung, wobei die pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung zur Behandlung von Atemwegserkrankungen dient.According to the invention, a pharmaceutical product is proposed, comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or mixture of substances the adsorbent is in addition to the propellant-containing metered dose inhaler in the package. The invention particularly relates to pharmaceutical products containing a pharmaceutically active substance, substance formulation or substance mixture, wherein the pharmaceutically active substance, substance formulation or substance mixture is used for the treatment of respiratory diseases.
Es zeigte sich überraschenderweise, dass das Adsorbens das Treibgas aufnimmt und die Verpackung nicht mehr aufbläht. Gleichzeitig zeigt sich überraschenderweise, dass das Adsorbens den Wassergehalt der pharmazeutisch wirksamen Substanz, Substanzformulierung oder Substanzmischung des Treibgas-enthaltenden Dosieraerosols nicht beeinträchtigt.It was found, surprisingly, that the adsorbent absorbs the propellant gas and the package no longer inflates. At the same time it is surprisingly found that the adsorbent does not affect the water content of the pharmaceutically active substance, substance formulation or substance mixture of the propellant-containing metered dose inhaler.
Als Adsorbens eignen sich die folgenden, auf dem Markt verfügbaren Stoffe: Aktivkohle, Kieselgele, Molekularsiebe, Ionenaustauscher, Aluminiumoxid, Zeolithe und/oder Magnesiumsulfat. Es kann außerdem eine Mischung von zwei oder mehreren Adsorbens verwendet werden. Vorzugsweise werden Kohletabletten verwendet, wie sie in Apotheken zur Behandlung von Durchfallerkrankungen erhältlich sind. Ganz vorzugsweise wird eine Kohletablette pro ein Dosieraerosol von der Verpackung umschlossen.Suitable adsorbents are the following substances available on the market: activated carbon, silica gels, molecular sieves, ion exchangers, alumina, zeolites and / or magnesium sulfate. In addition, a mixture of two or more adsorbents may be used. Preferably, charcoal tablets are used, as they are available in pharmacies for the treatment of diarrheal diseases. Most preferably, one charcoal tablet per metered dose inhaler is enclosed by the package.
Als Treibgase im Dosierearosol werden CFCs, FCKW 11, 12, 114, Lachgas (N2O Distickstoffoxid) oder Kohlendioxid (CO2) oder HFCs, bevorzugt HFC 134a oder HFC 227, verwendet. Weitere Beispiele für HFC Treibgase sind HFC-32 (Difluormethan), HFC-143(a) (1,1,1-Trifluorethan), HFC 134 (1,1,2,2-Tetrafluorethan) und HFC-152a (1,1- Difluorethan)CFCs, CFCs 11, 12, 114, nitrous oxide (N 2 O nitrous oxide) or carbon dioxide (CO 2 ) or HFCs, preferably HFC 134a or HFC 227, are used as propellant gases in the dosing aerosol. Further examples of HFC propellants are HFC-32 (difluoromethane), HFC-143 (a) (1,1,1-trifluoroethane), HFC 134 (1,1,2,2-tetrafluoroethane) and HFC-152a (1,1 - difluoroethane)
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, HI-Antihistaminika, 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: - W stellt ein Betamimetika dar, kombiniert mit einem Anticholinergika, Corticosteroide, PDE4-Inhibitore, EGFR-Hemmern oder LTD4- Antagonisten, W stellt ein Anticholinergika dar, kombiniert mit einem Betamimetika, Corticosteroiden, PDE4-Inhibitoren, EGFR-Hemmern oder LTD4- Antagonisten, - W stellt ein Corticosteroiden dar, kombiniert mit einem PDE4-Inhibitoren, EGFR- Hemmern oder LTD4- AntagonistenThe 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, HI 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 represents a betamimetics combined with anticholinergics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists; W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists - W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
W 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 a PDE4 inhibitor 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 undPreferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and
- 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-benzyl-sulfonamid - 5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-on3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzyl-sulfonamide - 5- [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 l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)- 2-methyl-2-propylamino]ethanol4-Hydroxy-7- [2- {[2- {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone 1- (2-fluoro-4-) hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl ) -2-methyl-2-butylamino] ethanol 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl ) - 2-methyl-2-propylamino] ethanol
- l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2- propylamino]ethanol - l-[2H-5-hydroxy-3-oxo-4H-l,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}ethanol- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol - 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -l, 2,4-triazole-3 -yl] -2-methyl-2-butylamino} ethanol
- 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-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-methoxy-phenyl) -l, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [l, 4 ] oxazin-3-one
- 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-l,l-dimethyl- ethylamino]-ethyl}-4H-benzo[l,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
- 6-Hydroxy-8- { 1 -hydroxy-2- [2-(4-phenoxy-essigsäure)- 1 , 1 -dimethyl-ethylamino] - ethyl}-4H-benzo[l,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one
- 8-{2-[l,l-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-l-hydroxy-ethyl}-6- hydroxy-4H-benzo[l,4]oxazin-3-on- 8- {2- [l, l-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -l-hydroxy-ethyl} -6-hydroxy-4H-benzo [l, 4] oxazine-3 -one
- 6-Hydroxy-8- { 1 -hydroxy-2- [2-(4-hydroxy-phenyl)- 1 , 1 -dimethyl-ethylamino] -ethyl } - 4H-benzo[l,4]oxazin-3-on - 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-isopropyl-phenyl)-l,ldimethyl-ethylamino]-ethyl}- 4H-benzo [ 1 ,4] oxazin-3-on- 6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4-oxazin-3-one 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -l, -dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one
- 8- { 2- [2-(4-Ethyl-phenyl)- 1 , 1 -dimethyl-ethylamino] - 1 -hydroxy-ethyl } -6-hydroxy-4H- benzo [ 1 ,4] oxazin-3-on- 8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
8- { 2- [2-(4-Ethoxy-phenyl)- 1 , 1 -dimethyl-ethylamino] - 1 -hydroxy-ethyl } -6-hydroxy-4H- benzo[l,4]oxazin-3-on8- {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)-buttersäure- 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-Difluor-phenyl)- 1 , 1 -dimethyl-ethylamino]- 1 -hydroxy-ethyl } -6-hydroxy- 4H-benzo[l,4]oxazin-3-on - l-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol 2-Hydroxy-5-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-benzaldehyd8- {2- [2- (3,4-Difluoro-phenyl) -l, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4-oxazine-3-] on -? - (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol 2-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]-formamid - 8-Hydroxy-5-(l-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]- ethylamino } -ethyl)- lH-quinolin-2-on 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-onN- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide - 8 -Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] ethylamino} -ethyl) -1H-quinolin-2-one 8-Hydroxy-5- [1-hydroxy-2- (6-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- 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)-benzylsulfonamid - 3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}- propyl)-benzylsulfonamid3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide 3- (3- {7- [2-hydroxy -2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfonamide
- 4-(2-{6-[4-(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)-acetamid- 4- (2- {6- [4- (3-Cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -l-hydroxy-ethyl) -2-hydroxymethyl-phenol N-adamantan-2-yl-2- (3 - {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) 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 das 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 aktivenPreferred anticholinergic compounds here are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts the chloride salt, tolterodine. In the salts mentioned above, the cations are the pharmacologically active ones
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.Constituents. As anions, the abovementioned 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 as counterions are preferred. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
Ebenfalls bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-ILikewise 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-Toluolsulfonat, bevorzugt ein einfach negativ geladenes Anion, besonders bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Methansulfonat und p- Toluolsulfonat, insbesondere bevorzugt Bromid, bedeutet gegebenenfalls in Form ihrer Racemate, Enantiomere oder Hydrate. Von besonderer Bedeutung sind solche Arzneimittelkombinationen, die die Enantiomere der Formel AC-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-Toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates Significance are those drug combinations that contain the enantiomers of the formula AC-l-en
enthalten, worin X ~ die vorstehend genannten Bedeutungen aufweisen kann. Weiterhin bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-2 contain, 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-Methobromid2-fluoro-2,2-diphenylacetic acid copo-ester-methobromide 2-fluoro-2,2-diphenylacetic acid-tropol ester-methobromide - 3,3 ', 4,4'-tetrafluorobenzilic acid-tropol ester-methobromide 3,3', 4,4'-tetrafluorobenzilic acid copoprene-methobromide
- 4,4'-Difluorbenzilsäuretropenolester-Methobromid 4,4'-Difluorbenzilsäurescopinester-Methobromid 3,3 -Difluorbenzilsäuretropenolester-Methobromid - 3,3'-Difluorbenzilsäurescopinester-Methobromid4,4'-Difluorobenzilic acid-tropol ester-methobromide 4,4'-difluorobenzilic acid copoprene-methobromide 3,3-difluorobenzylic acid-tropol ester-methobromide 3,3'-difluorobenzilic acid copoprene methobromide
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-Methobromid9-Hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide 9-fluoro-fluoren-9-carboxylic acid-tropol ester-methobromide 9-Hydroxy-fluorene-9-carboxylic acid copo-ester-methobromide 9-fluoro-fluoren-9-carboxylic acid-co-ester methobromide 9-methyl-fluorene-9-carboxylic acid-tropol ester-methobromide
- 9-Methyl-fluoren-9-carbonsäurescopinester-Methobromid - Benzilsäurecyclopropyltropinester-Methobromid9-Methyl-fluorene-9-carboxylic acid-co-ester methobromide - Benzylic acid cyclopropyl-tropine ester methobromide
2,2-Diphenylpropionsäurecyclopropyltropinester-Methobromid2,2-Diphenylpropionsäurecyclopropyltropinester methobromide
- 9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid9-hydroxy-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide
- 9-Methyl-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid9-Methyl-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide
- 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid - 9-Hydroxy-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid9-Methyl-xanthene-9-carboxylic acid cyclopropyl-tropine ester methobromide 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide
- 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid- 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester methobromide
- 9-Hydroxy-xanthen-9-carbonsäuretropenolester-Methobromid9-hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide
- 9-Hydroxy-xanthen-9-carbonsäurescopinester-Methobromid9-hydroxy-xanthene-9-carboxylic acid copo-ester methobromide
- 9-Methyl-xanthen-9-carbonsäuretropenolester-Methobromid - 9-Methyl-xanthen-9-carbonsäurescopinester-Methobromid9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide - 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide
- 9-Ethyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Difluormethyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Hydroxymethyl-xanthen-9-carbonsäurescopinester-Methobromid9-Ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-Difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide
Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids, die Salze Metho-X zurThe abovementioned compounds can also be used in the context of the present invention as salts in which, instead of the methobromide, the salts Metho-X
Anwendung gelangen, wobei X die vorstehend für X" genannten Bedeutungen haben kann.Application, 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-carbothionsäure (S)-fluoromethylester - 6,9-Difluor-l l-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-l,4-dien-17- carbothionsäure (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, - 6α,9α-difluoro-llß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclo- propylcarbony^oxy-androsta-l^-diene-πß-carbonsäure cyanomethyl ester gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate. Jede Bezugnahme auf Steroide schließt eine Bezugnahme auf deren gegebenenfalls existierende Salze oder Derivate, Hydrate oder Solvate mit ein. Beispiele möglicher Salze und Derivate der Steroide können sein: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -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-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) ester . 6α, 9α-difluoro-LLβ-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopropylcarbonyloxy-androsta-1-diene-πβ-cyanomethyl ester, optionally in Form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates Any reference to steroids includes reference to their optionally existing salts or derivatives, hydrates or solvates Examples of possible salts and derivatives of Steroids may be: alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or 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- cyclopropylmethoxybenzamidN- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide
- (-)p-[(4αR*,10bS*)-9-Ethoxy-l,2,3,4,4a,10b-hexahydro-8-methoxy-2- methylbenzo[s][l,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid- (-) p - [(4αR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [l, 6] naphthyridine 6-yl] -N, N-diisopropylbenzamide
(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(R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N ' [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid] - 2-carbomethoxy-4- cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one
- 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]acetat - 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-l,2,4-triazolo[4,3- ajpyridin - 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]- 1,2,4- triazolo[4,3-a]pyridin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der PDE4-Inhibitoren ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.- cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene ] acetate (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate - 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2- thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-ajpyridine 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
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 und - l-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)phenyl)thio)methylcyclopropan-essigsäure,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 - 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 [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]essigsäure gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind diese Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, 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 Natriumoder Kaliumsalze, Erdalkalisalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate. Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Cetuximab, Trastuzumab, ABX-EGF, Mab ICR-62 und- 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] acetic acid optionally in 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. Examples of salts or derivatives whose formation the LTD4 antagonists are capable of are understood to be: 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 ICR-62 and
4- [(3 -Chlor-4-fluorphenyl)amino] -6- { [4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yl] amino } - 7-cyclopropylmethoxy-chinazolin4- [(3-Chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-butene-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline
- 4- [(3 -Chlor-4-fluorphenyl)amino] -6- { [4-(N,N-diethylamino)- 1 -oxo-2-buten- 1-yl]- amino } -7-cyclopropylmethoxy-chinazolin4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy quinazoline
- 4- [(3-Chlor-4-fluoφhenyl)amino] -6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - y]]amino}-7-cyclopropylmethoxy-chinazolin - 4-[(R)-(l-Phenyl-ethyl)amino]-6-{ [4-(morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7- cyclopentyloxy-chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 - y]] amino} -7-cyclopropylmethoxy quinazoline - 4 - [(R) - (1-phenylethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- cyclopentyloxy-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-cyclopropylmethoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -l-oxo-2-ol] butene-1-yl] amino} -7-cyclopropylmethoxyquinazoline
- 4- [(3 -Chlor-4-fluor-phenyl)amino] -6- { [4-((R)-6-methyl-2-oxo-morpholin-4-yl)- 1 -oxo- 2-buten-l-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- buten-l-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-2-methoxymethyl-6-oxo-moφholin-4- yl)- 1 -oxo-2-buten- 1 -yl]amino } -7-cyclopropylmethoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [(4 - ((R) -2-methoxymethyl-6-oxo-4-methyl-4-yl) -1-oxo-2-one butene-1-yl] amino} -7-cyclopropylmethoxyquinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-moφholin-4-yl)-ethoxy]- 7-methoxy-chinazolin - 4-[(3-Chlor-4-fluoφhenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l- oxo-2-buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazolin 4- [(3-Chlor-4-fluoφhenyl)amino]-6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yl]amino}-7-cyclopentyloxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-4-methyl-4-yl) -ethoxy] -7-methoxy- quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-butene-1 -yl} amino) -7-cyclopropylmethoxy-quinazoline 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino)-1-oxo-2-butene-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- 1 -yl]amino } -7-cyclopropylmethoxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo-2-butene] 1 -yl] amino} -7-cyclopropylmethoxy-quinazoline
- 4- [(R)-( 1 -Phenyl-ethyl)amino] -6-( { 4- [N-(2-methoxy-ethyl)-N-ethyl-amino] - 1 -oxo-2- buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazolin4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline
- 4- [(R)-( 1 -Phenyl-ethyl)amino] -6-( { 4- [N-(2-methoxy-ethyl)-N-methyl-amino] - 1 -oxo-2- buten-l-yl}amino)-7-cyclopropylmethoxy-chinazolin - 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-l- oxo-2-buten- 1 -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)-chinazolin4- [(R) - (1-phenylethyl) amino] -6- ({4- [N- (2-methoxy-ethyl) -N-methylamino] -1-oxo-2-butene l-yl} amino) -7-cyclopropylmethoxyquinazoline - 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl -amino] -l-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7 - ((R ) -tetrahydrofuran-3-yloxy) -quinazoline
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin - 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-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 - ((S. ) -tetrahydrofuran-3-yloxy) quinazoline - 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] - 1-oxo-2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline
4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(N-cyclopropyl-N-methyl-amino)-l-oxo-2- buten- 1 -yl] amino } -T-cyclopentyloxy-chinazolin4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N-cyclopropyl-N-methyl-amino) -l-oxo-2-but-1-yl] -amino} -T- cyclopentyloxy-quinazoline
- 4- [(3-Chlor-4-fluoφhenyl)amino] -6- { [4-(N,N-dimethylamino)- 1 -oxo-2-buten- 1 - yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin- 4- [(3-chloro-4-fluoro-phenyl) -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-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-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-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline
4- [(3-Chlor-4-fluoφhenyl)amino] -7- [3-(morpholin-4-yl)-propyloxy] -6- [(vinyl- carbonyl)amino]-chinazolin4- [(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-fluorphenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten- 1 -yljamino } -7-ethoxy-chinolin- 4 - [(R) - (1-Phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine 3-cyano-4 - [(3-chloro 4-fluorophenyl) 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-moφholin-4-yl)-l-oxo-2- buten- 1 -yl] amino } -7-methoxy-chinazolin- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- {[4 - ((R) -6-methyl-2-oxo-4-methyl-4-yl) -l-oxo-2-one] butene-1-yl] amino} -7-methoxy-quinazoline
4- [(3-Chlor-4-fluoφhenyl)amino] -6- { [4-(moφholin-4-yl)- 1 -oxo-2-buten- 1 -yl] amino } - 7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin - 4-[(3-Chlor-4-fluoφhenyl)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-moφholin-4-yl)-l-oxo-2- buten- 1 -yl]amino } -chinazolin4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (4-fluoro-4-yl)-1-oxo-2-butene-1-yl] -amino} -7 - [(tetrahydrofuran) 2-yl) methoxy] quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -l- oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline 4 - [(3-ethynylphenyl) amino] -6- {[4- (5.5 -dimethyl-2-oxo-4-fluoro-4-yl) -l-oxo-2-butene-1-yl] amino} quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-moφholin-4-yl)-ethoxy]- 7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- 7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-4-methyl-4-yl) -ethoxy] -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline
- 4- [(3 -Chlor-4-fluor-phenyl)amino] -7- [2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] - 6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin - 4- [(3-Chlor-4-fluor-phenyl)amino] -6- { 2- [4-(2-oxo-morpholin-4-yl)-piperidin- 1 -yl] - ethoxy } -7-methoxy-chinazolin- 4- [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - 6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline - 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) - piperidine-1-yl] ethoxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin4 - [(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-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-l- yloxy)-7-methoxy-chinazolin4 - [(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-chinazolin- 4 - [(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- chinazolin- 4 - [(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-chinazolin4 - [(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-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazolin-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-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxyquinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy- ethoxy)-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]- cyclohexan- 1 -yloxy } -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]- cyclohexan- 1 -yloxy } -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(moφholin-4-yl)sulfonylamino]- cyclohexan- 1 -yloxy } -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline-4 - [(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 - [(4-methyl-4-yl) -sulfonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino- ethoxy)-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- methansulfonylamino-ethoxy)-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline-4 - [(3-chloro-4-fluoro -phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) quinazoline
- 4-[(3-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- {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-chinazolin- 4 - [(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-[(moφholin-4-yl)carbonyl]-N-methyl- amino}-cyclohexan-l-yloxy)-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(moφholin-4-yl)sulfonyl]-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-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methyl-4-yl) -sulfonyl] -N-methyl - amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-l- yloxy)-7-methoxy-chinazolin4 - [(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-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy) -quinazoline-4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 4-[(3-Ethinyl-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-l-yl)carbonyl]-N-methyl- amino}-cyclohexan-l-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- 1 -yloxy)-7-methoxy-chinazolin- 4 - [(3-ethynylphenyl) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidine-1-one) yl) carbonyl] -N-methylamino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} - cyclohexane-1-oxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(moφholin-4-yl)carbonylamino]- cyclohexan- 1 -yloxy } -7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4- yloxy } -7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) -carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(moφholin-4-yl)carbonyl]-piperidin-4- yloxy } -7-(2-methoxy-ethoxy)-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- (4-methyl-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxyethoxy) - 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-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline-4 - [(3-ethynyl-phenyl) -amino] -6- ( l-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline
- 4-[(3-Ethinyl-phenyl)amino]-6-(l-methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin- 4 - [(3-ethynylphenyl) 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-Chlor-4-fluor-phenyl)amino]-6-(l-isopropyloxycarbonyl-piperidin-4-yloxy)-7- methoxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline-4 - [(3-chloro 4-fluoro-phenyl) amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin4 - [(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- 1 -yloxy } -7-methoxy-chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexane-1-yloxy} - 7-methoxy-quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin4 - [(3-ethynyl-phenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline
4-[(3-Ethinyl-phenyl)amino]-6-[l-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy- chinazolin4 - [(3-Ethynylphenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline
- 4-[(3-Ethinyl-phenyl)amino]-6-{ l-[(moφholin-4-yl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin- 4 - [(3-ethynyl-phenyl) -amino] -6- {1- (4-methyl-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(cis-2,6-dimethyl-moφholin-4-yl)carbonyl]- piperidin-4-yloxy} -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-4-aminol-4-yl) carbonyl] -piperidin-4-yloxy} -7- methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methyl-moφholin-4-yl)carbonyl]- piperidin-4-yloxy } -7-methoxy-chinazolin - 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-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methoxyethyl)carbonyl]-piperidin-4- yloxy } -7-methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-4-fluoro-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 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-chloro-4-fluoro -phenyl) amino] -6- {1- (2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline
4- [(3-Chlor-4-fluor-phenyl)amino] -6- { 1 - [(3-methoxypropyl-amino)-carbonyl] - piperidin-4-yloxy } -7-methoxy-chinazolin4- [(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-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l- yloxy]-7-methoxy-chinazolin4 - [(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-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-l-yloxy]-7-methoxy-chinazolin4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4-) fluorophenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline
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-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-l-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-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.4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (1-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.
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.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, optionally 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.
Ganz besonders bevorzugt sind die folgenden Substanzen, Substanzformulierungen oder Stubstanzmischungen: Ipratropium, Salbutamol, Salmeterol, Fenoterol, Oxitropium, Formoterol, Budesonid, Fluticason, Cyclesonid, Mometason, Flunisolid, Beclomethason, wobei die Substanzen, Substanzformulierungen oder Substanzmischungen auch als Salze oder Ester vorliegen können.Very particular preference is given to the following substances, substance formulations or mixtures of substance mixtures: ipratropium, salbutamol, salmeterol, fenoterol, oxitropium, formoterol, budesonide, fluticasone, cyclesonide, mometasone, flunisolide, beclomethasone, where the substances, substance formulations or substance mixtures can also be present as salts or esters ,
Die Substanzen, Substanzformulierungen oder Substanzmischungen liegen vorzugsweise als Suspensions- oder Lösungsaerosole vor.The substances, substance formulations or substance mixtures are preferably in the form of suspension or solution aerosols.
Als Verpackungsmaterial kommen alle dichtschließenden Folien (z.B. Polyethylenfolien), vorzugsweise Aluminiumverbundfolien in Betracht.Suitable packaging materials are all tight-closing foils (for example polyethylene foils), preferably aluminum composite foils.
Die Verpackung der Dosieraerosole (mit der Substanz, Substanzformulierung oder Substanzmischung) und des Adsorbens erfolgt durch Standardverfahren, wie sie aus der Literatur bekannt sind.The packaging of the metered dose aerosols (with the substance, substance formulation or substance mixture) and the adsorbent is carried out by standard methods, as known from the literature.
DETAILLIERTE BESCHREIBUNG DER ERFINDUNGDETAILED DESCRIPTION OF THE INVENTION
Es wurden Versuche durchgeführt, die belegen, dass bei Treibgas-enthaltenden Dosieraerosolen das Vorhandensein eines Adsorbens das Treibgas aufnimmt, somit die Verpackung nicht mehr oder kaum mehr aufbläht und der Wassergehalt des Arzneimittels, der -formulierung oder -mischung nicht beeinträchtigt wird und damit zur Produktsicherheit durch eine stabile Produktqualität beiträgt.Experiments have been carried out which show that with propellant-containing metered dose inhalers the presence of an adsorbent takes up the propellant gas, thus the package no longer or hardly inflates and the water content of the drug, Formulation or mixture is not impaired and thus contributes to product safety through a stable product quality.
Folgende Muster wurden hergestellt: 5 Dosieraerosole in Alubeuteln mit 3 Kohletabletten nicht evakuiert 5 Dosieraerosole in Alubeuteln mit 3 Kohletabletten evakuiert 5 Dosieraerosole in Alubeuteln ohne Kohletabletten nicht evakuiert 5 Dosieraerosole in Alubeuteln ohne Kohletabletten evakuiert.The following samples were prepared: 5 metered aerosols in aluminum bags with 3 charcoal tablets not evacuated 5 metered aerosols evacuated in aluminum bags with 3 charcoal tablets 5 metered aerosols in aluminum bags without charcoal tablets not evacuated 5 Metered aerosols evacuated in aluminum bags without charcoal tablets.
Bei der Evakuierung wurde nach dem Einlegen des Dosieraerosols in denIn the evacuation was after inserting the metered dose in the
Aluverbundbeutel mit einem dünnen Steigrohr die Luft herausgesaugt und sofort verschlossen.Aluverbundbeutel with a thin riser, the air sucked out and immediately closed.
Folgende Alubeutel (Standardverpackung mit Alubeschichtung, Alu mit Kunststoff ummantelt) wurden eingesetzt:The following aluminum bags (standard packaging with aluminum coating, aluminum coated with plastic) were used:
Aluminiumverbundfolie, neutral, der Fa. Tscheulin-Rothal GmbH, Friedrich- Meyer-Str. 23, 79331 Teningen, Deutschland, entsprechend DIN 1784. Die Folienstärke beträgt 50 μm ± 10%.Aluminum composite foil, neutral, from Tscheulin-Rothal GmbH, Friedrich-Meyer-Str. 23, 79331 Teningen, Germany, according to DIN 1784. The film thickness is 50 μm ± 10%.
Es wurden Kohletabletten der Firma Hevert Sobernheim / Nahe "medizinische Kohle a 250 mg" Charge No. 311297 eingesetzt.Charcoal tablets from Hevert Sobernheim / Nahe "Medicinal carbon a 250 mg" were used. 311297 used.
Die verwendeten Dosieraerosole enthielten HFC 227. Die Dosieraerosole enthielten kein pharmazeutisches Produkt, sondern waren sog. Placebo-Dosieraerosole.The metered dose inhalers used contained HFC 227. The metered dose inhalers did not contain a pharmaceutical product but were so-called placebo metered dose inhalers.
Die Muster wurden bei 5O0C eingelagert und nach verschiedenen Lagerzeiten gewogen.The samples were stored at 5O 0 C and weighed after different periods of storage.
Nach 14-monatiger Lagerung wurden die Alubeutel aufgeschnitten und die Aerosolbehälter alleine, sowie die flachgedrückten Alubeutel mit Kohletabletten gewogen.After 14 months of storage, the aluminum bags were cut open and the aerosol containers weighed alone, as well as the flattened aluminum bags with charcoal tablets.
Es wurden folgende Ergebnisse erhalten: The following results were obtained:
Folgende Erkenntnisse sind aus den Daten in der Tabelle abzuleiten:The following findings can be deduced from the data in the table:
Durch die Zugabe von Kohletabletten werden aufblähende Alubeutel verhindert.The addition of charcoal tablets prevents bloating aluminum bags.
Ein Unterschied zwischen evakuierten und nicht evakuierten Alubeuteln ist nicht festzustellen. ie Kohletabletten nehmen praktisch den gesamten Treibgasverlust der Aerosoldosen auf. ie Kontrolle der Beutel Nr. 3 und 6 zeigt, dass der erhöhte Gewichtsverlust der Beutel Nr. und 6 ist auf fehlerhaftes Verschweißen der Alubeutel zurückzuführen ist. There is no difference between evacuated and non-evacuated aluminum bags. The charcoal tablets absorb practically all the propellant gas loss of the aerosol cans. The control of the bags Nos. 3 and 6 shows that the increased weight loss of the bags Nos. 6 and 6 is due to defective welding of the aluminum bags.

Claims

PATENTANSPRÜCHE
1. Ein pharmazeutisches Produkt enthaltend: a) ein Treibgas-enthaltendes Dosieraerosol, b) eine effektive Menge an Adsorbens, c) eine pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung, d) eine Verpackung, welche das Adsorbens und das Dosieraerosol mit der pharmazeutisch wirksamen Substanz, Substanzformulierung oder Substanzmischung umschließt.1. A pharmaceutical product containing: a) a propellant-containing metered dose inhaler, b) an effective amount of adsorbent, c) a pharmaceutically active substance, substance formulation or substance mixture, d) a packaging containing the adsorbent and the metered dose inhaler with the pharmaceutically active substance , Substance formulation or mixture of substances.
2. Ein pharmazeutisches Produkt gemäß Anspruch 1, dadurch gekennzeichnet, dass das Adsorbens ein Material aus der folgenden Gruppe ist: Molekularsieb, Kieselgel, Aktivkohle, Zeolithe, Aluminiumoxid, Ionenaustauscher und/oder Magnesiumsulfat, gegebenenfalls in Mischung von zwei oder mehreren Adsorbens.2. A pharmaceutical product according to claim 1, characterized in that the adsorbent is a material from the following group: molecular sieve, silica gel, activated carbon, zeolites, alumina, ion exchanger and / or magnesium sulfate, optionally in a mixture of two or more adsorbent.
3. Ein pharmazeutisches Produkt gemäß Anspruch 2, dadurch gekennzeichnet, dass als Adsorbens eine Kohletablette verwendet wird.3. A pharmaceutical product according to claim 2, characterized in that a charcoal tablet is used as the adsorbent.
4. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1 oder4. A pharmaceutical product according to one or more of claims 1 or
2, dadurch gekennzeichnet, dass die pharmazeutisch wirksame Substanz, Substanzformulierung oder Substanzmischung zur Behandlung von Atemwegserkrankungen dient.2, characterized in that the pharmaceutically active substance, substance formulation or substance mixture is used for the treatment of respiratory diseases.
5. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1-4, dadurch gekennzeichnet, dass die pharmazeutisch wirksame Substanz eine Substanz aus der folgenden Gruppe der Anticholinergika, Betamimietika, Steroide, PDE IV-Inhibitoren, LTD4-Antagonisten, EGFR-Kinase-Hemmer, Antiallergika, Derivate der Mutterkornalkaloide, Triptane, CGRP-Antagonisten, PDE-V- Inhibitoren, sowie Mischungen von Substanzen dieser Substanzgruppen, deren5. A pharmaceutical product according to one or more of claims 1-4, characterized in that the pharmaceutically active substance is a substance from the following group of anticholinergics, Betamimietika, steroids, PDE IV inhibitors, LTD4 antagonists, EGFR kinase inhibitors , Antiallergic drugs, derivatives of ergot alkaloids, triptans, CGRP antagonists, PDE-V inhibitors, as well as mixtures of substances of these substance groups, their
Salze und Ester, sowie Mischungen der Salze und Ester. Salts and esters, and mixtures of salts and esters.
6. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche l-5„ dadurch gekennzeichnet, dass das Dosieraerosol eine oder mehrere der folgenden Substanzen, Substanzformulierungen oder Substanzmischungen enthalten kann: Ipratropium, Salbutamol, Salmeterol, Fenoterol, Oxitropium, Formoterol,6. A pharmaceutical product according to one or more of claims 1-5, characterized in that the metered dose inhaler may contain one or more of the following substances, substance formulations or substance mixtures: ipratropium, salbutamol, salmeterol, fenoterol, oxitropium, formoterol,
Budesonid, Fluticason, Cyclesonid, Mometason, Flunisolid, Beclomethason, wobei die Substanzen, Substanzformulierungen oder Substanzmischungen auch als Salze oder Ester vorliegen können.Budesonide, fluticasone, cyclesonide, mometasone, flunisolide, beclomethasone, wherein the substances, substance formulations or substance mixtures may also be present as salts or esters.
7. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1-6, dadurch gekennzeichnet, dass die pharmazeutische Substanz, Substanzformulierung oder Substanzmischung als Suspensions- oder Lösungsaerosol vorliegt.7. A pharmaceutical product according to one or more of claims 1-6, characterized in that the pharmaceutical substance, substance formulation or substance mixture is present as a suspension or solution aerosol.
8. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1-7, dadurch gekennzeichnet, dass das Verpackungsmaterial aus8. A pharmaceutical product according to one or more of claims 1-7, characterized in that the packaging material
Aluminiumverbundfolie besteht.Aluminum composite film exists.
9. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1-8, dadurch gekennzeichnet, dass das Treibgas HFC- 134a und/oder HFC-227 ist.9. A pharmaceutical product according to one or more of claims 1-8, characterized in that the propellant gas is HFC-134a and / or HFC-227.
10. Ein pharmazeutisches Produkt gemäß einem oder mehreren der Ansprüche 1-9, dadurch gekennzeichnet, dass das Dosieraerosol ein Mehrfachdosisgerät ist.10. A pharmaceutical product according to one or more of claims 1-9, characterized in that the metered dose inhaler is a multi-dose device.
11. Verwendung von einem Adsorbens in einem Treibgas-enthaltenden Dosieraerosol mit einem Arzneimittel, einer -formulierung oder -mischung, dadurch gekennzeichnet, dass das Adsorbens sich zusätzlich zum Treibgas-enthaltenden Dosieraerosol mit dem Arzneimittel, der -formulierung oder -mischung in der Verpackung befindet, welche das Adsorbens und das Dosieraerosol umschließt. 11. Use of an adsorbent in a propellant-containing metered dose inhaler with a drug, a formulation or mixture, characterized in that the adsorbent is in addition to the propellant-containing metered dose inhaler with the drug, the formulation or mixture in the package which encloses the adsorbent and metered dose inhaler.
12. Verwendung gemäß Anspruch 11, dadurch gekennzeichnet, dass das Adsorbens ein Material aus der folgenden Gruppe ist: Molekularsieb, Kieselgel, Aktivkohle, Zeolithe, Aluminiumoxid, Ionenaustauscher und/oder Magnesiumsulfat.12. Use according to claim 11, characterized in that the adsorbent is a material from the following group: molecular sieve, silica gel, activated carbon, zeolites, alumina, ion exchanger and / or magnesium sulfate.
13. Verwendung gemäß Anspruch 12, dadurch gekennzeichnet, dass das Adsorbens eine Kohletablette ist.13. Use according to claim 12, characterized in that the adsorbent is a charcoal tablet.
14. Verwendung gemäß Anspruch 12 oder 13, dadurch gekennzeichnet, dass das Treibgas HFC- 134a und/oder HFC-227 ist.14. Use according to claim 12 or 13, characterized in that the propellant gas is HFC-134a and / or HFC-227.
15. Verwendung gemäß einem oder mehreren der Ansprüche 12-14, dadurch gekennzeichnet, dass die pharmazeutisch wirksame Substanz eine Substanz aus der folgenden Gruppe der Anticholinergika, Betamimietika, Steroide, PDE IV- Inhibitoren, LTD4-Antagonisten, EGFR-Kinase-Hemmer, Antiallergika, Derivate der Mutterkornalkaloide, Triptane, CGRP-Antagonisten, PDE-V-Inhibitoren, sowie15. Use according to one or more of claims 12-14, characterized in that the pharmaceutically active substance is a substance from the following group of anticholinergics, Betamimietika, steroids, PDE IV inhibitors, LTD4 antagonists, EGFR kinase inhibitors, antiallergic agents , Derivatives of ergot alkaloids, triptans, CGRP antagonists, PDE-V inhibitors, as well as
Mischungen von Substanzen dieser Substanzgruppen, deren Salze und Ester, sowie Mischungen der Salze und Ester.Mixtures of substances of these substance groups, their salts and esters, and mixtures of salts and esters.
16. Verwendung gemäß einem oder mehreren der Ansprüche 12-15, Verpackungsmaterial aus Aluminiumverbundfolie besteht.16. Use according to one or more of claims 12-15, packaging material consists of aluminum composite film.
17. Verwendung gemäß einem oder mehreren der Ansprüche 12-16, dadurch gekennzeichnet, dass das Arzneimittel, die -formulierung oder -mischung des Dosieraerosol eine oder mehrere der folgenden Substanzen enthalten kann: Ipratropium, Salbutamol, Salmeterol, Fenoterol, Oxitropium, Formoterol,17. Use according to one or more of claims 12-16, characterized in that the medicament, the formulation or mixture of the metered dose inhaler may contain one or more of the following substances: ipratropium, salbutamol, salmeterol, fenoterol, oxitropium, formoterol,
Budesonid, Fluticason, Cyclesonid, Mometason, Flunisolid, Beclomethason, wobei die Substanzen, Substanzformulierungen oder Substanzmischungen auch als Salze oder Ester vorliegen können. Budesonide, fluticasone, cyclesonide, mometasone, flunisolide, beclomethasone, wherein the substances, substance formulations or substance mixtures may also be present as salts or esters.
8. Verwendung gemäß einem oder mehrerer der Ansprüche 12 - 17, dadurch gekennzeichnet, dass das Arzneimittel, die -formulierung oder -mischung als Suspensions- oder Lösungsaerosol vorliegt. 8. Use according to one or more of claims 12-17, characterized in that the medicament, the formulation or mixture is present as a suspension or solution aerosol.
EP06807454A 2005-10-28 2006-10-20 Propellant for dosing aerosols comprising packagings Withdrawn EP1942867A2 (en)

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DE102006009599A DE102006009599A1 (en) 2005-10-28 2006-03-02 Propellant gas absorption with MDIs with packaging
PCT/EP2006/067642 WO2007048764A2 (en) 2005-10-28 2006-10-20 Propellant for dosing aerosols comprising packagings

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US20120180785A1 (en) * 2009-09-29 2012-07-19 Helen Mary Trill Pressurized Metered Dose Inhalers
CN102416179B (en) 2010-09-28 2014-05-07 益得生物科技股份有限公司 Inhaled compound composition for asthma

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NL7708731A (en) * 1976-08-13 1978-02-15 Montedison Spa PROCESS FOR THE PREPARATION OF NEW DRIVER COMPOSITIONS FOR AEROSOLS.
JPS59174473A (en) * 1983-03-23 1984-10-02 エスエス製薬株式会社 Moistureproof packing method of aerosol agent
US5071587A (en) * 1990-05-31 1991-12-10 Aquatechnica, Inc. Composition and method for purifying water
US6315112B1 (en) * 1998-12-18 2001-11-13 Smithkline Beecham Corporation Method and package for storing a pressurized container containing a drug
US20030209453A1 (en) * 2001-06-22 2003-11-13 Herman Craig Steven Method and package for storing a pressurized container containing a drug
AU2002215902A1 (en) * 2000-10-13 2002-04-22 Glaxo Group Limited Medicament dispenser
GB2390645A (en) * 2002-05-22 2004-01-14 Cambridge Consultants Drug delivery assembly
GB0214667D0 (en) * 2002-06-26 2002-08-07 Aventis Pharma Ltd Method and packaging for pressurized containers

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