WO2007141203A1 - Atomizer - Google Patents

Atomizer Download PDF

Info

Publication number
WO2007141203A1
WO2007141203A1 PCT/EP2007/055383 EP2007055383W WO2007141203A1 WO 2007141203 A1 WO2007141203 A1 WO 2007141203A1 EP 2007055383 W EP2007055383 W EP 2007055383W WO 2007141203 A1 WO2007141203 A1 WO 2007141203A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
phenyl
chloro
fluoro
methoxy
Prior art date
Application number
PCT/EP2007/055383
Other languages
German (de)
French (fr)
Inventor
Dieter Hochrainer
Bernd Zierenberg
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Inghelheim Pharma Gmbh & 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 Inghelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to JP2009512611A priority Critical patent/JP2009538656A/en
Priority to CA002653422A priority patent/CA2653422A1/en
Priority to EP07729784A priority patent/EP2029205A1/en
Publication of WO2007141203A1 publication Critical patent/WO2007141203A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0065Inhalators with dosage or measuring devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/006Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
    • A61M11/007Syringe-type or piston-type sprayers or atomisers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0001Details of inhalators; Constructional features thereof
    • A61M15/0021Mouthpieces therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0065Inhalators with dosage or measuring devices
    • A61M15/0066Inhalators with dosage or measuring devices with means for varying the dose size
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/08Inhaling devices inserted into the nose
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B11/00Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
    • B05B11/01Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
    • B05B11/10Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
    • B05B11/109Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle the dispensing stroke being affected by the stored energy of a spring

Definitions

  • the invention relates to a nebulizer for delivering a certain amount of, in particular having a drug, fluid as an aerosol through a nozzle from a pressure accumulator, wherein a mechanical pressure generator applied to the measured fluid in the pressure accumulator, which is to release abruptly for sputtering.
  • EP 0 521 061 B1 discloses a dosing device for dispensing a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs by dispensing the metered amount of liquid through a nebulizer comprising a chamber for receiving the metered Amount of liquid, an energy storage and means for delivering a predetermined amount of energy to the energy storage comprises.
  • means are provided for releasing the predetermined amount of energy from the energy store to the chamber so as to expose the liquid therein to a predetermined pressure rise from a low pressure to a higher pressure and to initiate a discharge of the liquid from the chamber.
  • a nebulizer is used to nebulize the metered amount of the pressurized fluid.
  • 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, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprene cream, ibuterol, isoethanol, isoprenalm, levosalbutamol, mabuterol, meluadnone , Metaproterenol, orciprene cream, pirbuterol, procaterol, reproterol, rimiterol, ritodnone, salmefamol, salmetrol, soterenol, sulphoneterol, terbutaline, tiaramide, toluubuterol, 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, preferably the chloride salt, tolterodine.
  • the cations are the pharmacologically active constituents.
  • the abovementioned salts may preferably contain chloride, bromide, iodine, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate,
  • Oxalate, succinate, benzoate or p-toluenesulfonate with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • X is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates.
  • anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, cit
  • AC-2 wherein 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 - 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -1-hydroxy-16-methyl-3-oxo-androsta-1, 4- dien-17-carbothionic acid (S) -fluoromethyl ester
  • Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • alkali metal salts such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, A- ⁇ flo (cilomilast), tofimilast, pumafent ⁇ n, Li ⁇ milast, Arofyllm, 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, hydroxalate, 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-quinohnyl) ethenyl) phenyl) -3- (2
  • Alkali salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates
  • the EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- ⁇ [4- (morphony-4-yl) -1-oxo-2-buten-1-yl] amino ⁇ -
  • these acid addition salts are preferred selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
  • Hydromethanesulfonate hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotaitrat, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
  • Preferred dopamine agonists are compounds which are selected from the group consisting of bromocidin, cabergolm, alpha-dihydroergocryptine, lisium, pergohd, pramipexole, roxindole, ropinirole, tahpexol, tergucone and viozane, 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, hydrotaitrat , Hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
  • Hl -Antihistaminika here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, Emedastm, Dimetinden, Clemastin, Bamipm, Cexchlorpheniramin, pheniram, Doxylamin , Chlorphenoxamm, Dimenhydn- nat, diphenhydramine, promethazine, ebastine, Desloratidm and meclocine, optionally in
  • these acid addition salts are preferably 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
  • substance formulations or mixtures of substances all inhalable compounds are used, such as, for example, inhalable macromolecules, as disclosed in EP 1 003 478.
  • substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.
  • the object is achieved in that the nozzle is associated with a nose piece
  • the nose piece can be used in at least one of the nostrils and by means of the atomizer the fluid is evenly and reproducibly nebulized for absorption through the mucous membranes.
  • the finely distributed fluid passes in fine particles on the nasal mucous membranes, from where the active ingredient Diffusion either directly reaches its site of action or enters the bloodstream and thus reaches its effective range. Due to the distribution over a large area of the nasal mucosa, a high bioavailability is given.
  • the nose piece is advantageously removably attached.
  • the nozzle is arranged in a mouthpiece of the atomizer, which carries the nose piece sealed.
  • the nebulizer with the mouthpiece in a known manner as an inhaler for administering a particular respirable fluid for respiratory treatment and with the nosepiece attached to the mouthpiece, which can also be referred to as nose tube, for the nasal application of solutions, suspensions and so-called Solutions, namely a mixture of solution and suspension to use.
  • a known atomizer is offered under the trade name "Respimat" by Boehringer Ingelheim KG in the form of an inhaler and is shown in WO 91/14468 A1 as well as WO 97/12687 A1.
  • the nosepiece in the attachment area assigned to the mouthpiece preferably has a geometry which is congruent to the mouthpiece. Due to this measure, it is not necessary to provide a seal between the Aufsteck Scheme the nose piece and the mouthpiece. Rather, a contour-dependent positive sealing is given after placement of the nose piece.
  • the attachment area of the nosepiece is expediently elliptical in cross-section.
  • the nose insertion area of the nosepiece is preferably elliptically shaped.
  • the opening in the Naseneincertify College is smaller than the opening dimensioned in Aufsteck Bachelor.
  • the cross section of the nose piece narrows continuously from the attachment area to the nasal insertion area.
  • the pressure generator comprising a piston comprises a holder for the reservoir, an associated drive spring with a release button and a conveyor tube, wherein axial tensioning of the drive spring displaces the support with the reservoir and the delivery tube in a direction opposite the nosepiece and sucks fluid from a reservoir into the pressure chamber.
  • the specific amount is adjustable.
  • an actuation of the release button causes a relaxation of the tensioned drive spring, which moves the delivery tube in the direction of the nosepiece and thereby pressurizes the fluid for discharge through the nozzle.
  • a non-return valve is associated with the delivery pipe.
  • a reservoir for the fluid is interchangeably disposed within a housing.
  • the nozzle comprises a nozzle channels for generating two spray jets meeting one another for producing a spray system associated with a spray cloud.
  • the nozzle channels are designed such that two approximately at a right angle to each other impinging spray jets are formed.
  • the filter system associated with the nozzle channels causes retention of solid particles and prevents clogging of the nozzle channels.
  • the nozzle comprises a filter system and at least two nozzle channels for generating at least two spray jets meeting one another to produce a spray cloud.
  • Fig. 1 is a sectional view of an atomizer according to the invention.
  • FIG. 2 shows a schematic plan view of a nose piece of the atomizer according to FIG. 1.
  • the nebulizer 1 is used for nebulizing a fluid 2, in particular a highly effective drug, and is designed as a portable inhaler, which operates without propellant gas.
  • a fluid 2 in particular a highly effective drug
  • a portable inhaler which operates without propellant gas.
  • an aerosol is formed, which can be inhaled by a user, not shown.
  • the atomizer 1 has an exchangeable storage container 3 with the fluid 2, which has a substantially cylindrical structure and can be inserted from below into the opened atomizer 1.
  • the atomizer 1 comprises a pressure generator 5 comprising a piston 24 with a holder 6 for the container 3, a drive spring 7 with a release button 8 which can be manually actuated for relaxation, a delivery tube 9 with an inserted non-return valve 10, a pressure chamber 11 and a nozzle 12 to which a mouthpiece 13 is assigned.
  • the support 6 is moved downwards with the storage container 3 and the delivery pipe 9 and fluid from the container 3 sucked via the check valve 10 in the piston 24 of the pressure generator 5 associated pressure chamber 11.
  • the fluid 2 is pressurized in the pressure chamber 11 of the conveyor tube 9 upwardly displacing the drive spring 7 and discharged through the nozzle 12, wherein a sputtering takes place.
  • the atomization takes place, for example, in particles in the ⁇ m range, preferably in particles with a size of about 20 ⁇ m, which form a cloud or a jet of an aerosol.
  • a user can inhale the aerosol, wherein supply air can be sucked into the mouthpiece 13 via supply air openings 15.
  • a nose piece 19 is detachably attached to the mouthpiece 13.
  • the nosepiece 19 has a geometry which is congruent to the mouthpiece 13 and is substantially elliptical in cross-section both in the attachment region 20 and in the nose insertion region 21.
  • the opening 22 in the nasal introduction area 21 of the nose piece 19 is smaller than the opening 23 in the attachment area 20 and widens continuously up to the attachment area 20 which is sealed against the mouthpiece 13.
  • the dimensions of the nosepiece 19 are, of course, the dimensions of a human nostril adapted, wherein the dimensions of the largest and the smallest outer diameter, for example, 16 mm and 10 mm

Abstract

In an atomizer (1) for dispensing a defined amount of a fluid (2), in particular one containing a pharmaceutical, as aerosol through a nozzle (12) from a pressure chamber (11), wherein a mechanical pressure generator (5) acts on the measured fluid (2) in the pressure chamber and is abruptly released for the atomization, a nosepiece (19) is assigned to the nozzle (12).

Description

Zerstäuber atomizer
Beschreibungdescription
Die Erfindung bezieht sich auf einen Zerstäuber zur Abgabe einer bestimmten Menge eines, insbesondere ein Arzneimittel aufweisenden, Fluids als Aerosol durch eine Düse aus einem Druckspeicher, wobei ein mechanischer Druckerzeuger das abgemessene Fluid in dem Druckspeicher beaufschlagt, der schlagartig zum Zerstäuben freizugeben ist.The invention relates to a nebulizer for delivering a certain amount of, in particular having a drug, fluid as an aerosol through a nozzle from a pressure accumulator, wherein a mechanical pressure generator applied to the measured fluid in the pressure accumulator, which is to release abruptly for sputtering.
Es ist bekannt, ein Arzneimittel in Form eines Sprays durch die Nase oder den Mund zu verabreichen, um es durch die Schleimhäute in der Nasenhöhle oder durch die Lunge zu absorbieren.It is known to administer a drug in the form of a spray through the nose or mouth to absorb it through the mucous membranes in the nasal cavity or through the lungs.
Im Weiteren offenbart die EP 0 521 061 Bl ein Dosiergerät zur Abgabe einer abgemesse- nen Menge einer Flüssigkeit als Spray mit Tröpfchen von einer für die Inhalation in die Lunge geeigneten Größe durch Abgabe der abgemessenen Flüssigkeitsmenge durch ein Zerstäubungsmittel, das eine Kammer zur Aufnahme der abgemessenen Menge der Flüssigkeit, einen Energiespeicher und Mittel zur Abgabe einer vorbestimmten Energiemenge an den Energiespeicher umfasst. Darüber hinaus sind Mittel zur Freigabe der vorbestimm- ten Energiemenge aus dem Energiespeicher auf die Kammer vorgesehen, um so die darin befindliche Flüssigkeit einem vorbestimmten Druckanstieg von einem niedrigen Druck auf einen höheren Druck auszusetzen und eine Abgabe der Flüssigkeit aus der Kammer einzuleiten. Ein Zerstäubungsmittel dient zum Zerstäuben der abgemessenen Menge der unter Druck gesetzten Flüssigkeit.Furthermore, EP 0 521 061 B1 discloses a dosing device for dispensing a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs by dispensing the metered amount of liquid through a nebulizer comprising a chamber for receiving the metered Amount of liquid, an energy storage and means for delivering a predetermined amount of energy to the energy storage comprises. In addition, means are provided for releasing the predetermined amount of energy from the energy store to the chamber so as to expose the liquid therein to a predetermined pressure rise from a low pressure to a higher pressure and to initiate a discharge of the liquid from the chamber. A nebulizer is used to nebulize the metered amount of the pressurized fluid.
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, Corticosteroi- de, PDE4-Inhibitore, EGFR-Hemmern oder LTD4- Antagonisten, W stellt ein Anticholinergika dar, kombiniert mit einem Betamimetika, Corticosteroi- den, 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, Bitolte- rol, Broxaterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenahne, Ibuterol, Isoethaπne, Isoprenalme, Levosalbutamol, Mabuterol, Meluadπne, Metaproterenol, Or- ciprenahne, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodπne, Salmefamol, Salmete- rol, 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, bitolertrol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprene cream, ibuterol, isoethanol, isoprenalm, levosalbutamol, mabuterol, meluadnone , Metaproterenol, orciprene cream, pirbuterol, procaterol, reproterol, rimiterol, ritodnone, salmefamol, salmetrol, soterenol, sulphoneterol, terbutaline, tiaramide, toluubuterol, 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-quinohn-2-on3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzyl-sulfonamide - 5- [2- (5,6- diethyl-indan-2-ylamino) -l-hydroxy-ethyl] -8-hydroxy-lH-quinohn-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-benzoxazm-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-benzoxazm-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- propylammo]ethanol - l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylammo] ethanol - 1 - [2H-5-hydroxy-3-oxo-4H-l, 4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-
2-propylamino]ethanol2-propylamino] ethanol
- l-[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-l,2,4- tπazol-3-yl]-2-methyl-2-butylammo}ethanol [3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-5-methyl-phenyl]-harnstoff- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1,4,4-tazazole-3 -yl] -2-methyl-2-butylammo} ethanol [3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea
4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-l-hydroxy-ethyl)-2- hydroxymethyl-phenol - 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-benzylsulfonamid4- (2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -l-hydroxy-ethyl) -2-hydroxymethyl-phenol-3- (4- {6- [2 Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide
3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}- propyl)-benzylsulfonamid3- (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-phenol4- (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)-acetamidN-adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -propyl} -phenyl) -acetamide
gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hyd- rophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, 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 Bromid- salz, Oxitropiumsalzen, bevorzugt das Bromidsalz, Flutropiumsalzen, bevorzugt das Bro- midsalz, Ipratropiumsalzen, bevorzugt das Bromidsalz, Glycopyrroniumsalzen, bevorzugt das Bromidsalz, Trospiumsalzen, bevorzugt das Chloridsalz, Tolterodin. In den vorstehend genannten Salzen stellen die Kationen die pharmakologisch aktiven Bestandteile dar. Als Anionen können die vorstehend genannten Salze bevorzugt enthalten Chlorid, Bromid, Io- did, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat,Preferred 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, preferably the chloride salt, tolterodine. In the abovementioned salts, the cations are the pharmacologically active constituents. As anions, the abovementioned salts may preferably contain chloride, bromide, iodine, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate,
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. 5-Hydroxy-8-(l-hydroxy-2-isopropylaminobutyl)-2H-l,4-benzoxazin-3-(4H)-on l-(4-Amino-3-chlor-5-tπfluormethylphenyl)-2-tert.-butylammo)ethanol 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-methoxy-phenyl)-l,l-dimethyl-ethylammo]-ethyl }- 4H-benzo[ 1 ,4]oxazin-3-on - 6-Hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-essigsaureethylester)-l,l-dimethyl- ethylamino]-ethyl}-4H-benzo[l,4]oxazm-3-onOxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred. 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -on- (4-amino-3-chloro-5-t-fluoromethylphenyl) -2-tert .-butylammo) ethanol 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylammo] -ethyl} -4H-benzo [1,4] oxazine 3-one - 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, l-dimethyl-ethylamino] -ethyl} -4H-benzo [l, 4] oxazm -3-one
6-Hydroxy-8-{ l-hydroxy-2-[2-(4-phenoxy-essigsaure)-l,l-dimethyl-ethylamino]- ethyl }-4H-benzo[l,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -l, l-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one
- 8-{2-[ l,l-Dimethyl-2-(2,4,6-tπmethylphenyl)-ethylamino]-l-hydroxy-ethyl}-6- hydroxy-4H-benzo[l,4]oxazin-3-on- 8- {2- [l, l-dimethyl-2- (2,4,6-t-methylphenyl) -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[ 1 ,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one
6-Hydroxy-8-{ l-hydroxy-2-[2-(4-isopropyl-phenyl)-l,ldimethyl-ethylamino]-ethyl }- 4H-benzo[ 1 ,4]oxazin-3-on - 8-{2-[2-(4-Ethyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxy-ethyl}-6-hydroxy-4H- benzo[ 1 ,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropyl-phenyl) -l, ldimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one - 8- {2- [2- (4-Ethyl-phenyl) -l, 1-dimethyl-ethylamino] -l-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one
8- { 2- [2-(4-Ethoxy-phenyl)- 1 , 1 -dimethyl-ethylamino]- 1 -hydroxy-ethyl } -6-hydroxy-4H- benzo[ 1 ,4]oxazm-3-on8- {2- [2- (4-Ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazm-3-one
- 4-(4-{ 2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)- ethyldmino]-2-methyl-propyl }-phenoxy)-buttersaure- 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [l, 4] oxazin-8-yl) -ethyldmino] -2 -methyl-propyl} -phenoxy) -butyric acid
8- { 2- [2-(3 ,4-Difluor-phenyl)- 1 , 1 -dimethyl-ethylamino] - 1 -hydroxy-ethyl } -6-hydroxy- 4H-benzo[ 1 ,4]oxazm-3-on l-(4-Ethoxy-carbonylammo-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-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazm-3- on 1- (4-ethoxycarbonylammo-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-(l-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino } -ethyl)-phenyl]-formamidN- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide
8-Hydroxy-5-(l -hydroxy-2- {2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]- ethylamino}-ethyl)-lH-quinohn-2-on - 8-Hydroxy-5-[l-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-lH-quinohn-2-on8-Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -LH-quin-2-one - 8- hydroxy-5- [l-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -lH-quinohn-2-one
5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-l- hydroxy-ethyl]-8-hydroxy-lH-quinolm-2-on Ebenfalls bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-I5- [2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -l-hydroxy-ethyl] -8-hydroxy-1H-quinolm 2-one Likewise preferred anticholinergics are selected from the salts of the formula AC-I
Figure imgf000007_0001
Figure imgf000007_0001
worin X " ein einfach negativ geladenes Anion, bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Iodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat und p-Toluol- sulfonat, bevorzugt ein einfach negativ geladenes Anion, besonders bevorzugt ein Anion ausgewählt aus der Gruppe bestehend aus Fluorid, Chlorid, Bromid, Methansulfonat und p- Toluolsulfonat, insbesondere bevorzugt Bromid, bedeutet gegebenenfalls in Form ihrer Racemate, Enantiomere oder Hydrate. Von besonderer Bedeutung sind solche Arzneimittelkombinationen, die die Enantiomere der Formel AC-l-enwherein X "is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluene sulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates. Of particular importance are those drug combinations which contain the enantiomers of the formula AC-I-ene
Figure imgf000007_0002
Figure imgf000007_0002
enthalten, worin X ~ die vorstehend genannten Bedeutungen aufweisen kann. Weiterhin bevorzugte Anticholinergika sind ausgewählt aus den Salzen der Formel AC-2contain, wherein X ~ can have the meanings given above. Further preferred anticholinergics are selected from the salts of the formula AC-2
Figure imgf000007_0003
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.
Figure imgf000007_0003
AC-2 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.
Figure imgf000008_0001
Figure imgf000008_0001
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-Methobromid2-fluoro-2,2-Diphenylessigsäurescopinester methobromide
- 2-Fluor-2,2-Diphenylessigsäuretropenolester-Methobromid 3,3',4,4'-Tetrafluorbenzilsäuretropenolester-Methobromid 3,3',4,4'-Tetrafluorbenzilsäurescopinester-Methobromid - 4,4'-Difluorbenzilsäuretropenolester-Methobromid 4,4'-Difluorbenzilsäurescopinester-Methobromid 3,3'-Difluorbenzilsäuretropenolester-Methobromid 3,3'-Difluorbenzilsäurescopinester-Methobromid2-fluoro-2,2-diphenylacetic acid tropol ester methobromide 3,3 ', 4,4'-tetrafluorobenzilic acid tropol ester methobromide 3,3', 4,4'-tetrafluorobenzilate copoprene methobromide - 4,4'-difluorobenzilic acid, tropol ester methobromide 4,4 '-Difluorobenzilatecopine ester 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-Methobromid9-Hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide - 9-fluoro-fluoren-9-carboxylic acid-tropol ester-methobromide
- 9-Hydroxy-fluoren-9-carbonsäurescopinester-Methobromid 9-Fluor-fluoren-9-carbonsäurescopinester-Methobromid9-Hydroxy-fluorene-9-carboxylic acid copo-ester methobromide 9-fluoro-fluoren-9-carboxylic acid copo-ester methobromide
- 9-Methyl-fluoren-9-carbonsäuretropenolester-Methobromid9-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-Methobromid 9-Hydroxy-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid 9-Methyl-fluoren-9-carbonsäurecyclopropyltropinester-Methobromid 9-Methyl-xanthen-9-carbonsäurecyclopropyltropinester-Methobromid θ-Hydroxy-fluoren-θ-carbonsäurecyclopropyltropinester-Methobromid 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid 9-Hydroxy-xanthen-9-carbonsäuretropenolester-Methobromid 9-Hydroxy-xanthen-9-carbonsäurescopinester-Methobromid - 9-Methyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Methyl-xanthen-9-carbonsäurescopinester-Methobromid 9-Ethyl-xanthen-9-carbonsäuretropenolester-Methobromid 9-Difluormethyl-xanthen-9-carbonsäuretropenolester-Methobromid - 9-Hydroxymethyl-xanthen-9-carbonsäurescopinester-Methobromid Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids, die Salze Metho-X zur Anwendung gelangen, wobei X die vorstehend für X" genannten Bedeutungen haben kann.2,2-Diphenylpropionic acid cyclopropyltropine ester methobromide 9-Hydroxy-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide 9-Methyl-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide 9-Methyl-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide θ-Hydroxy-fluorene-θ-carboxylic acid cyclopropyltropine ester methobromide 4,4'-difluorobenzilate methylcyclopropyltropine ester methobromide 9-hydroxy-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxy-xanthene-9-carboxylic acid-co-ester methobromide - 9-methyl-xanthene-9- carboxylic acid-tropol ester-methobromide 9-methyl-xanthene-9-carboxylic acid-co-ester methobromide 9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide - 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide The above In the context of the present invention, these compounds can also be used as salts in which, instead of the methobromide, the salts Metho-X are used, 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, Lo- teprednol, Mometason, Prednisolon, Prednison, Rofleponid, Triamcinolon, RPR-106541, NS-126, ST-26 und - 6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-l l-hydroxy-16-methyl-3-oxo-androsta-l,4- dien-17-carbothionsäure (S)-fluoromethylesterPreferred corticosteroids here are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone , RPR-106541, NS-126, ST-26 and - 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -1-hydroxy-16-methyl-3-oxo-androsta-1, 4- dien-17-carbothionic acid (S) -fluoromethyl ester
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,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-l lß-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclo- propylcarbonyl)oxy-androsta-l,4-diene-17ß-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 Steroi- de können sein: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoa- te, Phosphate, Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate. Als PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, A- πflo (Cilomilast), Tofimilast, Pumafentπn, Liπmilast, Arofyllm, 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 und6α, 9α-difluoro-1-l-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester, if appropriate in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, A-πflo (cilomilast), tofimilast, pumafentπn, Liπmilast, Arofyllm, 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-pyπdin-4-yl)-4-difluormethoxy-3- cyclopropylmethoxybenzamid - (-)p-[(4αR*,10^S*)-9-Ethoxy-l,2,3,4,4a,10b-hexahydro-8-methoxy-2- methylbenzo[s][l,6]naphthyπdin-6-yl]-N,N-dnsopropylbenzamidN- (3,5-dichloro-1-oxo-pyidin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-) p - [(4αR *, 10 ^ S *) - 9-ethoxy-1, 2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [l, 6] naphthyldin-6-yl] -N, N-dnsopropylbenzamide
(R)-(+)-l-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon(R) - (+) - l- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone
3-(Cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N-2-cyano-S-methyl- isothioureido]benzyl)-2-pyrrohdon - cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-carbonsaure]3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone - cis [4-cyano-4- (3-cyclopentyloxy -4-methoxyphenyl) cyclohexane-l-carboxylic acid]
2-carbomethoxy-4-cyano-4-(3-cyclopropylrnethoxy-4-difluoromethoxy- phenyl)cyclohexan-l-on2-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)pyrrohdin-2-yhden]acetat - (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yhden]acetat- cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-yhdene ] acetate - (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-yhden] acetate
- 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-l,2,4-tπazolo[4,3- a]pyπdin9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-tazazolo [4,3-a] pyidin
- 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-l,2,4- tπazolo[4,3-a]pyπdin gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch vertraglichen Saureadditionssalze, Solvate oder Hydrate Erfindungsgemaß bevorzugt sind die Saureadditionssalze der PDE4-Inhibitoren ausgewählt aus der Gruppe bestehend aus Hydrochloπd, Hydrobromid, Hydroiodid, Hydrosul- fat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydro- citrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro- p-toluolsulfonat 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-quinohnyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)pheny])thio)methylcyclopropan-essigsaure,9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3,4-c] -1,4,4-tazazolo [4,3-a] pyidin, 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, hydroxalate, 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-quinohnyl) 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]pyπdin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(l- hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropanessigsaure [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]essigsaure gegebenenfalls in Form ihrer Racemate, Enanüomere, Diastereomere und gegebenenfalls m Form ihrer pharmakologisch vertraglichen Saureadditionssalze, Solvate oder Hydrate Erfindungsgemaß bevorzugt sind diese Saureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochloπd, 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. Alkahsalze, wie beispielsweise Natrium- o- der Kahumsalze, Erdalkahsalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propio- nate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate- l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pynidine-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 The acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, are preferably used according to the invention in the form of their racemates, enanüomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. Hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate By salts or derivatives whose formation the LTD4-antagonists are optionally capable of, are for example understood. Alkali salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates
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 - 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(moφhohn-4-yl)-l-oxo-2-buten-l-yl]amino}-The EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morphony-4-yl) -1-oxo-2-buten-1-yl] amino} -
7-cyclopropylmethoxy-chmazohn7-cyclopropylmethoxy-chmazohn
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-diethylammo)-l-oxo-2-buten-l-yl]- amino } -7-cyclopropylmethoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-diethylammo) -l-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy chinazohn
- 4-[(3-Chlor-4-fluorphenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino}-7-cyclopropylmethoxy-chinazolin- 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
- 4-[(R)-( 1 -Phenyl-ethyl)amino]-6-{ [4-(morphohn-4-yl)- l-oxo-2-buten- 1 -yl]amino } -7- cyclopentyloxy-chinazohn 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholm-4-yl)-l-oxo- 2-buten- l-yl]amino }-7-cyclopropylmethoxy-chinazohn- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- {[4- (morphino-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -chinazohn 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxomorpholm-4-yl) -l-oxo-2-butene - l-yl] amino} -7-cyclopropylmethoxy-quinazone
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morphohn-4-y])-l-oxo- 2-buten- l -yl]amino }-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chmazolm - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ [4-((R)-2-methoxymethyl-6-oxo-moφhohn-4- yl )- 1 -oxo-2-buten- 1 -yl]amino } -7-cyclopropylmethoxy-chinazolin- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4 - ((R) -6-methyl-2-oxo-morphomo-4-yl]) - 1-oxo-2 -butene-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -mazazole-4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [ 4 - ((R) -2-methoxymethyl-6-oxo-moφhohn-4-yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morphohn-4-yl)-ethoxy]- 7-methoxy-chinazohn 4-[(3-Chlor-4-fluoφhenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- l- oxo-2-buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morphomo-4-yl) -ethoxy] -7-methoxy quinazone 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1 - yl} amino) -7-cyclopropylmethoxy-quinazone
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)- l-oxo-2-buten-l- yl]amino }-7-cyclopentyloxy-chinazohn- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazone
- 4-[(R)-( 1 -Phenyl-ethyl)amino]-6- { [4-(N,N-bis-(2-methoxy-ethyl)-amino)- 1 -oxo-2- buten-l-yl]amino }-7-cyclopropylmethoxy-chinazohn - 4- [(R)-( 1 -Phenyl-ethyl)amino] -6-( { 4-[N-(2-methoxy-ethyl)-N-ethyl-amino] - 1 -oxo-2- buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazohn- 4 - [(R) - (1-phenyl-ethyl) -amino] -6- {[4- (N, N-bis (2-methoxy-ethyl) -amino]-1-oxo-2-butene l-yl] amino} -7-cyclopropylmethoxy-quinazone - 4- [(R) - (1-phenyl-ethyl) -amino] -6- ({4- [N- (2-methoxy-ethyl) -N-ethyl -amino] - 1 -oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazone
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2- buten- l -yl }amino)-7-cyclopropylmethoxy-chinazohn- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene l -yl} amino) -7-cyclopropylmethoxy-quinazone
- 4-[(R)-(l-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- l- oxo-2-buten- 1 -yl } amino)-7-cyclopropylmethoxy-chinazohn- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -l-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy-quinazone
4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino }-7-((R)-tetrahydrofuran-3-yloxy)-chinazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7 - ((R) -tetrahydrofuran-3-yloxy) -chinazohn
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino } -7-((S)-tetrahydrofuran-3-yloxy)-chinazohn - 4-[(3-Chlor-4-fluoφhenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- l- oxo-2-buten- l-yl } amino)-7-cyclopentyloxy-chinazohn- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7 - ((S. ) -tetrahydrofuran-3-yloxy) -quinazone - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] - 1-oxo-2-butenyl-amino) -7-cyclopentyloxy-quinazone
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N-cyclopropyl-N-methyl-amino)-l-oxo-2- buten- l-yπamino
Figure imgf000012_0001
- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N-cyclopropyl-N-methyl-amino) -l-oxo-2-butene-1-ylamino
Figure imgf000012_0001
- 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten-l- yl]amino }-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazohn- 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7 - [(R ) - (tetrahydrofuran-2-yl) methoxy] -chinazohn
4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(N,N-dimethylamino)-l -oxo-2-buten- 1 - yl]amino }-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chmazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] -amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -chmazohn
- 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazohn - 4-[(3-Chlor-4-fluoφhenyl)amino]-7-[3-(morphohn-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazohn- 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazone - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (morphohn-4-yl) -propyloxy] -6 - [(vinylcarbonyl) -amino] -quinazone
- 4-[(R)-(I -Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyπmidin 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{ [4-(N,N-dimethylamino)-l-oxo-2-buten- l-yl]amino}-7-ethoxy-chinohn- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] -pymidine 3-cyano-4 - [(3-chloro 4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-butenyl] -amino} -7-ethoxy-quinone
4-{ [3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{ [(2-methansulfonyl- ethyl)amino]methyl }-furan-2-yl)chmazolin4- {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5- {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -chmazoline
- 4-[(R)-( 1 -Phenyl-ethyl)amino]-6- { [4-((R)-6-methyl-2-oxo-morphohn-4-yl)- 1 -oxo-2- buten-l-yl]amino}-7-methoxy-chinazohn - 4-[(3-Chlor-4-fluoφhenyl)amino]-6-{ [4-(moφhohn-4-yl)-l-oxo-2-buten-l-yl]amino}- 7-[(tetrahydrofuran-2-yl)methoxy]-chmazohn- 4 - [(R) - (1-phenyl-ethyl) -amino] -6- {[4 - ((R) -6-methyl-2-oxo-morphomo-4-yl]-1-oxo-2-ol buten-1-yl] amino} -7-methoxy-quinazone - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {[4- (momo-hohn-4-yl) -l-oxo-2-one] buten-1-yl] amino} - 7 - [(tetrahydrofuran-2-yl) methoxy] -mahzoin
- 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-l-oxo-2- buten-l-yl }amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazohn 4-[(3-Ethinyl-phenyl)amino]-6-{ [4-(5,5-dimethyl-2-oxo-morphohn-4-yl)-l-oxo-2- buten-l-yl]amino}-chinazohn- 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-but-1-ene yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazone 4 - [(3-ethynylphenyl) amino] -6- {[4- (5,5-dimethyl-2-oxomorphohne 4-yl) -1-oxo-2-buten-1-yl] amino} quinazole
- 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- 7-methoxy-chinazohn- 4 - [(3-chloro-4-fluorophenyl) ammo] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)ammo]-6-[2-(2,2-dimethyl-6-oxo-morphohn-4-yl)-ethoxy]- 7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morphohn-4-yl)-ethoxy]- 6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazohn4 - [(3-chloro-4-fluoro-phenyl) ammo] -6- [2- (2,2-dimethyl-6-oxo-morphohn-4-yl) -ethoxy] - 7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazone - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorphohn-4-yl ) -ethoxy] - 6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-moφhohn-4-yl)-pipeπdin-l-yl]- ethox y } -7-methoxy-chmazohn 4-[(3-Chlor-4-fluor-phenyl)dmino]-6-[l-(tert -butyloxycarbonyl)-pipeπdin-4-yloxy]-7- methoxy-chmazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-momo-hohn-4-yl) -pipeπdin-1-yl] -ethoxy} -7- methoxy-chmazoone 4 - [(3-chloro-4-fluoro-phenyl) -dmino] -6- [1- (tert -butyloxycarbonyl) -piphenyl-4-yloxy] -7-methoxy-chymazolone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ammo-cyclohexan-l-yloxy)-7-methoxy- chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ammo-cyclohexan-1-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-(trans-4-methansulfonylamino-cyclohexan-l- yloxy) 7 methoxy-chmazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolm4-[(3-chloro-4-fluorophenyl) ammo] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) 7-methoxy-chymazoan-4 - [(3-chloro-4-fluoro) phenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-chinazolm
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methyl-pipeπdin-4-yloxy)-7-methoxy- chinazolin - 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-methyl-piperidine-4-yloxy) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(4-methyl-4-yl) carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-pheny])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-quinazoline-4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7- methoxy-chinazolin4 - [(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-chinazolin4 - [(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- chinazolin4 - [(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-[(moφholin-4-yl)carbonylamino]- 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 - [(monoolholin-4-yl) carbonylamino] -cyclohexane-1-ylxy} -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(moφholin-4-yl)sulfonylamino]- cyclohexan- 1 -yloxy } -7-methoxy-chinazolin- 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-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- methansulfonylamino-ethoxy)-chinazolin4 - [(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}-4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(piperidin-1-yl) -carbonyl] -piperidin-4-yloxy} -
7-methoxy-chinazolin - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-aminocarbonylmethyl-piperidin-4-yloxy)-7- methoxy-chinazolin7-Methoxy-quinazoline - 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- 1 -yloxy)-7-methoxy-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1-yloxy ) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl- amino} -cyclohexan- l-yloxy)-7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-one yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl- amino} -cyclohexan- l-yloxy)-7-methoxy- chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylammo-cyclohexan-l- yloxy)-7-methoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexan-1-one yloxy) -7-methoxyquinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylammo-cyclohexan-1-yloxy) -7-methoxy-quinazone
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-pipeπdin-4-yloxy)-7-ethoxy- chinazohn - 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-(l-methansulfonyl-pipeπdin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidine-4-yloxy) -7-ethoxy-quinazone - 4 - [(3-chloro-4-fluoro) phenyl) ammo] -6- (1-methanesulfonyl-piperidine-4-yloxy) -7- (2-methoxyethoxy) -quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[l-(2-methoxy-acetyl)-pipeπdin-4-yloxy]-7-(2- methoxy-ethoxy)-chinazohn4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piphenyl-4-yloxy] -7- (2-methoxy-ethoxy) -quinazone
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin- 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)-pipeπdin-4-yloxy]-7- methoxy-chinazohn4 - [(3-ethynylphenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piphenyl-4-yloxy] -7-methoxy-quinazone
4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazohn 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(pipeπdin-l-yl)carbonyl]-N-methyl- dmino}-cyclohexan-l-yloxy)-7-methoxy-chmazohn4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazone 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis) 4- {N - [(Pipeπdin-1-yl) carbonyl] -N-methyl-dmino} -cyclohexan-1-yloxy) -7-methoxy-chymazolone
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-l-yl)carbonyl]-N- methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} - cyclohexan-l-yloxy) -7-methoxy-chinazohn
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morphohn-4-yl)carbonylamino]- cyclohexan-l-yloxyJ-7-methoxy-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[2-(2-oxopyrrohdin-l-yl)ethyl]-pipeπdm-4- yloxy } -7-methoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morphohn-4-yl) carbonylamino] -cyclohexan-1-yloxy-7-methoxy-quinazone-4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrohdin-1-yl) -ethyl] -pipe-dm-4-yloxy} -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(morphohn-4-yl)carbonyl]-pipeπdm-4- yloxy}-7-(2-methoxy-ethoxy)-chinazohn 4-[(3-Ethinyl-phenyl)amino]-6-(l-acetyl-pipeπdin-4-yloxy)-7-methoxy-chinazohn - 4-[(3-Ethinyl-phenyl)amino]-6-(l-methyl-pipeπdm-4-yloxy)-7-methoxy-chmazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morphohn-4-yl) -carbonyl] -pipeπdm-4-yloxy} -7- (2-methoxy-ethoxy) - quinazone 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-pipptin-4-yloxy) -7-methoxy-quinazone-4 - [(3-ethynyl-phenyl) -amino] -6- ( l-methyl-pipeπdm-4-yloxy) -7-methoxy-chmazolin
4-[(3-Ethinyl-phenyl)amino]-6-(l-methansulfonyl-pipeπdin-4-yloxy)-7-methoxy- chinazohn4 - [(3-ethynylphenyl) amino] -6- (1-methanesulfonyl-piperidine-4-yloxy) -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methyl-pipeπdin-4-yloxy)-7(2-methoxy- ethoxy)-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-isopropyloxycarbonyl-pipeπdin-4-yloxy)-7- methoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidine-4-yloxy) -7 (2-methoxy-ethoxy) -quinazone-4 - [(3-chloro-4-yloxy) 4-fluoro-phenyl) amino] -6- (1-isopropyloxycarbonyl-piperidine-4-yloxy) -7-methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-7- methoxy-chinazolin 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexan-l-yloxyJ-7-methoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxyJ-7 methoxy-chinazohn
4-[(3-Ethinyl-phenyl)amino]-6-(pipeπdin-4-yloxy)-7-methoxy-chinazohn4 - [(3-ethynyl-phenyl) amino] -6- (pipeπdin-4-yloxy) -7-methoxy-chinazohn
- 4-[(3-Ethinyl-phenyl)amino]-6-[l-(2-methoxy-acetyl)-pipeπdin-4-yloxy]-7-methoxy- chmazohn- 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-chymazolone
4-[(3-Ethinyl-phenyl)amino]-6-{ l-[(morpholm-4-yl)carbonyl]-pipeπdin-4-yloxy}-7- methoxy-chinazolm4 - [(3-ethynylphenyl) amino] -6- {1- (morpholm-4-yl) carbonyl] -piphenyl-4-yloxy} -7-methoxy-quinazole m
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(cis-2,6-dimethyl-moφholm-4-yl)carbonyl]- pipeπdin-4-yloxy}-7-methoxy-chmazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methyl-morphohn-4-yl)carbonyl]- pipeπdin-4-yloxy } -7-methoxy-chinazolin- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-4-methyl-4-yl) -carbonyl] -pipeπdin-4-yloxy} -7 -methoxy-chymazohn - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morphohn-4-yl) -carbonyl] -pipeπdin-4-yloxy} -7 methoxy-quinazoline
- 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-{ l-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)carbonyl]-pipeπdin-4-yloxy}-7-methoxy-chinazohn- 4 - [(3-Chloro-4-fluorophenyl) ammo] -6- {1- [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl ) carbonyl] -pipeπdin-4-yloxy} -7-methoxy-chinazohn
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(N-methyl-N-2-methoxyethyl- amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolm- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy -chinazolm
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-ethyl-pipeπdin-4-yloxy)-7-methoxy- chinazohn4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidine-4-yloxy) -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(2-methoxyethyl)carbonyl]-pipeπdin-4- yloxy}-7-methoxy-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{ l-[(3-methoxypropyl-amino)-carbonyl]- pipeπdin-4-yloxy } -7-methoxy-chinazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- (2-methoxy-ethyl) -carbonyl-piperidine-4-yloxy} -7-methoxy-quinazone-4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piphenyl-4-yloxy} -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-l-yloxyl^-methoxy-chinazohn 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-l- yloxy]~7-methoxy-chmazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxyl-methoxy-quinazone 4 - [( 3-chloro-4-fluoro-phenyl) ammo] -6- [cis-4- (N-acetyl-N-methylamino) -cyclohexan-1-yloxy] ~ 7-methoxy-chymazoyl
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7- methoxy-chmazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-chymazolone
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-l-yloxyj^-methoxy-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)ammo]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7- methoxy-chinazohn- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy-1-methoxy-quinazone-4- [(3-chloro-4-fluoro-phenyl) ammo] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazone
4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morphohn-4-yl)carbonyl]-N- methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-moφhohn-4-yl)-ethoxy]- 7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazohn4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morphohn-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-chinazohn - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-moφhohn-4-yl) -ethoxy] - 7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -chinazohn
- 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-methansulfonyl-pipeπdin-4-yloxy)-7- methoxy-chinazohn - 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(l-cyano-pipendin-4-yloxy)-7-methoxy- chinazohn gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch vertraglichen Saureadditionssalze, Solvate oder Hydrate Erfindungsgemaß bevorzugt sind diese Saureadditionssalze ausgewählt aus der Gruppe be- stehend aus Hydrochloπd, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat,- 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidine-4-yloxy) -7-methoxy-quinazone - 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- (1-cyano-pipendin-4-yloxy) -7-methoxy-quinazone 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 preferred selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotaitrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonatHydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotaitrat, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
Als Dopamin-Agonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Bromocπptin, Cabergolm, Alpha- Dihydroergocryptin, Lisuπd, Pergohd, Pramipexol, Roxindol, Ropinirol, Tahpexol, Tergu- πd und Viozan, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch vertraglichen Saureadditionssalze, Solvate oder Hydrate Erfindungsgemaß bevorzugt sind diese Saureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochloπd, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotaitrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p- toluolsulfonatPreferred dopamine agonists are compounds which are selected from the group consisting of bromocidin, cabergolm, alpha-dihydroergocryptine, lisium, pergohd, pramipexole, roxindole, ropinirole, tahpexol, tergucone and viozane, 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, hydrotaitrat , Hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
Als Hl -Antihistaminika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Epinastin, Cetirizin, Azelastin, Fexofena- din, Levocabastin, Loratadin, Mizolastin, Ketotifen, Emedastm, Dimetinden, Clemastin, Bamipm, Cexchlorpheniramin, Pheniramm, Doxylamin, Chlorphenoxamm, Dimenhydn- nat, Diphenhydramin, Promethazin, Ebastin, Desloratidm und Meclozin, gegebenenfalls inAs Hl -Antihistaminika here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, Emedastm, Dimetinden, Clemastin, Bamipm, Cexchlorpheniramin, pheniram, Doxylamin , Chlorphenoxamm, Dimenhydn- nat, diphenhydramine, promethazine, ebastine, Desloratidm and meclocine, optionally in
Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch vertraglichen Saureadditionssalze, Solvate oder Hydrate. Erfindungsgemaß bevorzugt sind diese Saureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochloπd, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansul- fonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccmat, Hydrobenzoat und Hydro-p-toluolsulfonatForm 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 preferably 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
5 Als pharmazeutisch wirksame Substanzen, Substanzformulierungen oder Substanzmischungen werden alle inhalierbaren Verbindungen eingesetzt, wie z.B auch inhalierbare Makromoleküle, wie in EP 1 003 478 offenbart. Vorzugsweise werden Substanzen, Substanzformulierungen oder Substanzmischungen zur Behandlung von Atemwegserkrankungen eingesetzt, die im inhalativen Bereich Verwendung finden.As pharmaceutically active substances, substance formulations or mixtures of substances, all inhalable compounds are used, such as, for example, inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.
Weiterhin kann die Verbindung aus der Gruppe der Deπvate von Mutterkornalkaloiden, der Tπptane, der CGRP-Hemmern, der Phosphodiesterase-V-Hemmer stammen, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch vertraglichen Saureadditionssalze, ihrer Solvate und/oder Hydrate 5Furthermore, the compound from the group of the derivatives of ergot alkaloids, the Tπptane, 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 5
Als Derivate der Mutterkornalkaloide' Dihydroergotamin, Ergotamin.As derivatives of ergot alkaloids' dihydroergotamine, ergotamine.
Es ist Aufgabe der Erfindung, einen Zerstäuber der eingangs genannten Art zu schaffen, der treibmittelfrei ein Fluid zum Absorbieren durch die Schleimhäute in der Nasenhohle o gleichmäßig und reproduzierbar vernebeltIt is an object of the invention to provide an atomizer of the type mentioned, the blowing agent free a fluid for absorbing through the mucous membranes in the nasal cavity o uniformly and reproducibly nebulized
Erfindungsgemaß wird die Aufgabe dadurch gelost, dass der Düse ein Nasenstuck zugeordnet istAccording to the invention, the object is achieved in that the nozzle is associated with a nose piece
5 Das Nasenstuck ist in mindestens eines der Nasenlocher einsetzbar und mittels des Zerstäubers wird das Fluid gleichmäßig und reproduzierbar zum Absorbieren durch die Schleimhäute vernebelt Durch das in das Nasenloch eingesetzte Nasenstuck gelangt das fein verteilte Fluid in feinen Partikeln auf die Nasenschleimhaute, von wo der Wirkstoff durch Diffusion entweder unmittelbar seinen Wirkort erreicht oder in den Blutkreislauf ge- o langt und auf diese Weise seinen Wirkbereich erreicht Durch die Verteilung auf eine große Flache der Nasenschleimhaute ist eine hohe Bioverfugbarkeit gegeben Selbstverständlich ist es möglich, das Nasenstuck derart auszulegen, dass es zum gleichzeitigen Einsetzen in beide Nasenlocher oder zum Einfuhren in ein Nasenloch ausgebildet ist. Um das Nasenstück bei Bedarf austauschen und/oder reinigen zu können, ist vorteilhafterweise das Nasenstück abnehmbar befestigt.5 The nose piece can be used in at least one of the nostrils and by means of the atomizer the fluid is evenly and reproducibly nebulized for absorption through the mucous membranes. Through the nostril inserted into the nostril the finely distributed fluid passes in fine particles on the nasal mucous membranes, from where the active ingredient Diffusion either directly reaches its site of action or enters the bloodstream and thus reaches its effective range. Due to the distribution over a large area of the nasal mucosa, a high bioavailability is given. It is of course possible to design the nose piece in such a way that it can be inserted simultaneously is formed in both nostrils or for imports into a nostril. In order to replace the nosepiece when needed and / or to be able to clean, the nosepiece is advantageously removably attached.
In Ausgestaltung ist die Düse in einem Mundstück des Zerstäubers angeordnet, das das Nasenstück abgedichtet trägt. Demnach ist der Zerstäuber mit dem Mundstück in bekannter Weise als Inhalator zur Verabreichung eines insbesondere lungengängigen Fluids zur Atemwegsbehandlung und mit dem auf das Mundstück aufgesetzten Nasenstück, das auch als Nasenrohr zu bezeichnen ist, für die nasale Applikation von Lösungen, Suspensionen und so genannter Solutions, nämlich einer Mischung aus Lösung und Suspension, zu verwenden. Ein bekannter Zerstäuber wird unter dem Handelsnamen "Respimat" von der Boehringer Ingelheim KG in Form eines Inhalators angeboten und ist in der WO 91/14468 Al sowie der WO 97/12687 Al dargestellt.In an embodiment, the nozzle is arranged in a mouthpiece of the atomizer, which carries the nose piece sealed. Accordingly, the nebulizer with the mouthpiece in a known manner as an inhaler for administering a particular respirable fluid for respiratory treatment and with the nosepiece attached to the mouthpiece, which can also be referred to as nose tube, for the nasal application of solutions, suspensions and so-called Solutions, namely a mixture of solution and suspension to use. A known atomizer is offered under the trade name "Respimat" by Boehringer Ingelheim KG in the form of an inhaler and is shown in WO 91/14468 A1 as well as WO 97/12687 A1.
Um unerwünschte Verwirbelungen oder Verluste des Fluids beim nasalen Applizieren zu vermeiden, weist bevorzugt das Nasenstück in dem dem Mundstück zugeordneten Aufsteckbereich eine zum Mundstück kongruente Geometrie auf. Aufgrund dieser Maßnahme ist es nicht erforderlich, eine Dichtung zwischen dem Aufsteckbereich des Nasenstücks und dem Mundstück vorzusehen. Vielmehr ist eine konturbedingte formschlüssige Abdich- tung nach dem Aufsetzen des Nasenstückes gegeben.In order to avoid undesired turbulences or losses of the fluid during nasal application, the nosepiece in the attachment area assigned to the mouthpiece preferably has a geometry which is congruent to the mouthpiece. Due to this measure, it is not necessary to provide a seal between the Aufsteckbereich the nose piece and the mouthpiece. Rather, a contour-dependent positive sealing is given after placement of the nose piece.
Da zum Inhalieren ein an die Mundform angepasstes Mundstück von einem Benutzer als angenehm empfunden wird, ist aufgrund deckungsgleicher Geometrien zweckmäßigerweise der Aufsteckbereich des Nasenstückes im Querschnitt elliptisch ausgebildet.Since for inhalation a mouthpiece adapted to the mouth shape is perceived as pleasant by a user, due to congruent geometries, the attachment area of the nosepiece is expediently elliptical in cross-section.
Zur Anpassung des Nasenstückes an die Form eines menschlichen Nasenlochs ist vorzugsweise der Naseneinführbereich des Nasenstückes elliptisch geformt. Die Öffnung im Naseneinführbereich ist kleiner als die Öffnung im Aufsteckbereich bemessen. Nach einer Weiterbildung verengt sich der Querschnitt des Nasenstückes vom Aufsteckbereich bis zum Naseneinführbereich kontinuierlich.For adapting the nose piece to the shape of a human nostril, the nose insertion area of the nosepiece is preferably elliptically shaped. The opening in the Naseneinführbereich is smaller than the opening dimensioned in Aufsteckbereich. According to a development, the cross section of the nose piece narrows continuously from the attachment area to the nasal insertion area.
Bevorzugt umfasst der einen Kolben umfassende Druckerzeuger eine Halterung für den Vorratsbehälter, eine zugeordnete Antriebsfeder mit einer Lösetaste und ein Förderrohr, wobei ein axiales Spannen der Antriebsfeder die Halterung mit dem Vorratsbehälter und dem Förderrohr in einer dem Nasenstück entgegen gesetzte Richtung verlagert und Fluid aus einem Vorratsbehälter in die Druckkammer saugt. In weiterer Ausgestaltung ist die bestimmte Menge einstellbar.Preferably, the pressure generator comprising a piston comprises a holder for the reservoir, an associated drive spring with a release button and a conveyor tube, wherein axial tensioning of the drive spring displaces the support with the reservoir and the delivery tube in a direction opposite the nosepiece and sucks fluid from a reservoir into the pressure chamber. In a further embodiment, the specific amount is adjustable.
Vorzugsweise bewirkt eine Beaufschlagung der Lösetaste eine Entspannung der gespannten Antriebsfeder, die das Förderrohr in Richtung des Nasenstücks bewegt und dabei das Fluid zum Austrag durch die Düse mit Druck beaufschlagt. Um beim Zerstäuben ein Zurückströmen von Flüssigkeit aus der Druckkammer in den Vorratsbehälter zu verhindern, ist dem Förderrohr ein Rückschlagventil zugeordnet.Preferably, an actuation of the release button causes a relaxation of the tensioned drive spring, which moves the delivery tube in the direction of the nosepiece and thereby pressurizes the fluid for discharge through the nozzle. In order to prevent backflow of liquid from the pressure chamber into the reservoir during atomization, a non-return valve is associated with the delivery pipe.
Zum Gebrauch des Zerstäubers für eine Vielzahl von Arzneimitteln verbrauchenden Anwendungen ist ein Vorratsbehälter für das Fluid innerhalb eines Gehäuses austauschbar angeordnet. Vorteilhafterweise umfasst die Düse ein Düsenkanälen zur Erzeugung von zwei aufeinander treffenden Sprühstrahlen zur Erzeugung einer Sprühwolke zugeordnetes Filtersystem. Die Düsenkanäle sind derart ausgebildet, dass zwei annähernd in einem rechten Winkel aufeinander treffende Sprühstrahlen gebildet werden. Das den Düsenkanälen zugeordnete Filtersystem bewirkt ein Zurückhalten fester Partikel und verhindert ein Verstopfen der Düsenkanäle. Vorzugsweise umfasst die Düse ein Filtersystem und mindes- tens zwei Düsenkanäle zur Erzeugung von mindestens zwei aufeinander treffenden Sprüstrahlen zur Erzeugung einer Sprühwolke.For use of the nebulizer for a variety of drug-consuming applications, a reservoir for the fluid is interchangeably disposed within a housing. Advantageously, the nozzle comprises a nozzle channels for generating two spray jets meeting one another for producing a spray system associated with a spray cloud. The nozzle channels are designed such that two approximately at a right angle to each other impinging spray jets are formed. The filter system associated with the nozzle channels causes retention of solid particles and prevents clogging of the nozzle channels. Preferably, the nozzle comprises a filter system and at least two nozzle channels for generating at least two spray jets meeting one another to produce a spray cloud.
Es versteht sich, dass die vorstehend genannten und nachstehend noch zu erläuternden Merkmale nicht nur in der jeweils angegebenen Kombination, sondern auch in anderen Kombinationen verwendbar sind. Der Rahmen der Erfindung ist nur durch die Ansprüche definiert.It goes without saying that the features mentioned above and those yet to be explained below can be used not only in the respectively specified combination but also in other combinations. The scope of the invention is defined only by the claims.
Die Erfindung wird im Folgenden anhand eines Ausführungsbeispieles unter Bezugnahme auf die zugehörige Zeichnung näher erläutert. Die einzige Fig. der Zeichnung zeigt:The invention will be explained in more detail below with reference to an embodiment with reference to the accompanying drawings. The only Fig. The drawing shows:
Fig. 1 eine Schnittdarstellung eines erfindungsgemäßen Zerstäubers undFig. 1 is a sectional view of an atomizer according to the invention and
Fig. 2 eine schematische Draufsicht auf ein Nasenstück des Zerstäubers nach Fig. 1. Der Zerstäuber 1 dient zur Zerstäubung eines Fluids 2, insbesondere eines hochwirksamen Arzneimittels, und ist als tragbarer Inhalator ausgebildet, der ohne Treibgas arbeitet. Bei der Zerstäubung des Fluids 2, vorzugsweise einer Flüssigkeit, wird ein Aerosol gebildet, das von einem nicht dargestellten Benutzer eingeatmet werden kann.FIG. 2 shows a schematic plan view of a nose piece of the atomizer according to FIG. 1. FIG. The nebulizer 1 is used for nebulizing a fluid 2, in particular a highly effective drug, and is designed as a portable inhaler, which operates without propellant gas. In the atomization of the fluid 2, preferably a liquid, an aerosol is formed, which can be inhaled by a user, not shown.
Der Zerstäuber 1 weist einen wechselbaren Vorratsbehälter 3 mit dem Fluid 2 auf, der im Wesentlichen einen zylindrischen Aufbau aufweist und von unten in den geöffneten Zerstäuber 1 einsetzbar ist. In dem starren Vorratsbehälter 3 befindet sich ein das Fluid 2 auf- nehmender Beutel 4. Zur Zerstäubung des Fluids 2 in einer vorbestimmten einstellbaren Menge umfasst der Zerstäuber 1 einen einen Kolben 24 umfassenden Druckerzeuger 5 mit einer Halterung 6 für den Behälter 3, einer Antriebsfeder 7 mit einer zur Entspannung manuell zu betätigenden Lösetaste 8, einem Förderrohr 9 mit einem eingesetzten Rückschlagventil 10, einer Druckkammer 11 und einer Düse 12, der ein Mundstück 13 zugeordnet ist.The atomizer 1 has an exchangeable storage container 3 with the fluid 2, which has a substantially cylindrical structure and can be inserted from below into the opened atomizer 1. In order to atomise the fluid 2 in a predetermined adjustable amount, the atomizer 1 comprises a pressure generator 5 comprising a piston 24 with a holder 6 for the container 3, a drive spring 7 with a release button 8 which can be manually actuated for relaxation, a delivery tube 9 with an inserted non-return valve 10, a pressure chamber 11 and a nozzle 12 to which a mouthpiece 13 is assigned.
Beim axialen Spannen der Antriebsfeder 7 durch ein Drehen eines Gehäuseunterteils 18 mit einem daran lösbar befestigten Innenteil 17 relativ zu einem an dem Mundstück 13 angeformten Gehäuseoberteil 16 wird die Halterung 6 mit dem Vorratsbehälter 3 und dem Förderrohr 9 nach unten bewegt und Fluid aus dem Behälter 3 über das Rückschlagventil 10 in die dem Kolben 24 des Druckerzeugers 5 zugeordnete Druckkammer 11 gesaugt. Beim anschließenden schlagartigen Entspannen der Antriebsfeder 7 durch die Betätigung der Lösetaste 8 wird das Fluid 2 in der Druckkammer 11 von der das Förderrohr 9 nach oben verlagernden Antriebsfeder 7 unter Druck gesetzt und über die Düse 12 ausgegeben, wobei eine Zerstäubung stattfindet. Die Zerstäubung erfolgt beispielsweise in Partikel im μm-Bereich, vorzugsweise in Partikel mit einer Größe von etwa 20 μm, die eine Wolke bzw. einen Strahl eines Aerosols bilden. Ein Benutzer kann das Aerosol inhalieren, wobei Zuluft über Zuluftöffnungen 15 in dem Mundstück 13 ansaugbar ist.During axial tensioning of the drive spring 7 by rotating a lower housing part 18 with an inner part 17 detachably fastened thereto relative to an upper housing part 16 formed on the mouthpiece 13, the support 6 is moved downwards with the storage container 3 and the delivery pipe 9 and fluid from the container 3 sucked via the check valve 10 in the piston 24 of the pressure generator 5 associated pressure chamber 11. During the subsequent abrupt release of the drive spring 7 by the actuation of the release button 8, the fluid 2 is pressurized in the pressure chamber 11 of the conveyor tube 9 upwardly displacing the drive spring 7 and discharged through the nozzle 12, wherein a sputtering takes place. The atomization takes place, for example, in particles in the μm range, preferably in particles with a size of about 20 μm, which form a cloud or a jet of an aerosol. A user can inhale the aerosol, wherein supply air can be sucked into the mouthpiece 13 via supply air openings 15.
Um Fluid 2 als Aerosol durch die Nase zu verabreichen, damit es durch die Schleimhäute in der Nasenhöhle absorbiert wird, ist auf das Mundstück 13 ein Nasenstück 19 abnehmbar aufgesteckt. Das Nasenstück 19 weist in dem dem Mundstück 13 zugeordneten Aufsteckbereich 20 eine zum Mundstück 13 kongruente Geometrie auf und ist im Querschnitt sowohl im Aufsteckbereich 20 als auch im Naseneinführbereich 21 im Wesentlichen ellip- tisch geformt Die Öffnung 22 im Naseneinfuhrbereich 21 des Nasenstucks 19 ist kleiner als die Öffnung 23 im Aufsteckbereich 20 bemessen und weitet sich kontinuierlich bis zu dem abgedichtet an dem Mundstuck 13 anhegenden Aufsteckbereich 20 auf Die Abmessungen des Nasenstuckes 19 sind selbstverständlich an die Maße eines menschlichen Nasenlochs angepasst, wobei die Maße des größten und des kleinsten Außendurchmessers beispielsweise 16 mm und 10 mm betragen To administer fluid 2 as an aerosol through the nose so that it is absorbed by the mucous membranes in the nasal cavity, a nose piece 19 is detachably attached to the mouthpiece 13. In the attachment area 20 assigned to the mouthpiece 13, the nosepiece 19 has a geometry which is congruent to the mouthpiece 13 and is substantially elliptical in cross-section both in the attachment region 20 and in the nose insertion region 21. The opening 22 in the nasal introduction area 21 of the nose piece 19 is smaller than the opening 23 in the attachment area 20 and widens continuously up to the attachment area 20 which is sealed against the mouthpiece 13. The dimensions of the nosepiece 19 are, of course, the dimensions of a human nostril adapted, wherein the dimensions of the largest and the smallest outer diameter, for example, 16 mm and 10 mm

Claims

Patentansprüche claims
1 Zerstäuber zur Abgabe einer bestimmten Menge eines, insbesondere ein Arzneimittel aufweisenden, Fluids (2) als Aerosol durch eine Düse (12) aus einem Druckspeicher, wobei ein mechanischer Druckerzeuger (5) das abgemessene Fluid (2) in dem Druckspeicher beaufschlagt, der schlagartig zum Zerstauben freizugeben ist, dadurch gekennzeichnet, dass der Düse (12) ein Nasenstuck (19) zugeordnet ist1 atomizer for delivering a certain amount of, in particular having a drug, fluid (2) as an aerosol through a nozzle (12) from a pressure accumulator, wherein a mechanical pressure generator (5) acts on the measured fluid (2) in the pressure accumulator abruptly to release for atomizing, characterized in that the nozzle (12) is associated with a nose piece (19)
2 Zerstäuber nach Anspruch 1, dadurch gekennzeichnet, dass das Nasenstuck (19) abnehmbar befestigt ist2 atomizer according to claim 1, characterized in that the nose piece (19) is removably attached
3 Zerstäuber nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass die Düse (12) in einem Mundstuck (13) des Zerstäubers angeordnet ist, das das Nasenstuck (19) abgedichtet tragt3. An atomiser according to claim 1 or 2, characterized in that the nozzle (12) is arranged in a mouthpiece (13) of the atomizer, which carries the nose piece (19) sealed
4 Zerstäuber nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass das Nasenstuck (19) in dem dem Mundstuck (13) zugeordneten Aufsteckbereich (20) eine zum Mundstuck (13) kongruente Geometrie aufweist4 atomizer according to one of claims 1 to 3, characterized in that the nose piece (19) in the mouth piece (13) associated Aufsteckbereich (20) has a mouthpiece (13) congruent geometry
5 Zerstäuber nach Anspruch 4, dadurch gekennzeichnet, dass der Aufsteckbereich (20) des Nasenstuckes (19) im Querschnitt elliptisch ausgebildet ist5 atomizer according to claim 4, characterized in that the Aufsteckbereich (20) of the nose piece (19) is elliptical in cross-section
6 Zerstäuber nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass der Naseneinfuhrbereich (21) des Nasenstuckes (19) elliptisch geformt ist6. Atomiser according to one of claims 1 to 5, characterized in that the nasal insertion area (21) of the nose piece (19) is elliptical in shape
7 Zerstäuber nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass die Öffnung (22) im Naseneinfuhrbereich (21) kleiner als die Öffnung (23) im Aufsteckbereich (20) bemessen ist7. Atomiser according to one of claims 1 to 6, characterized in that the opening (22) in the nasal introduction region (21) is smaller than the opening (23) in the attachment area (20) is dimensioned
8 Zerstäuber nach Anspruch 7, dadurch gekennzeichnet, dass sich der Querschnitt des Nasenstuckes (19) vom Aufsteckbereich (20) bis zum Naseneinfuhrbereich (21) kontinuierlich verengt8 atomizer according to claim 7, characterized in that the cross section of the nose piece (19) from the Aufsteckbereich (20) narrows continuously to the nasal introduction area (21)
9 Zerstäuber nach Anspruch 1, dadurch gekennzeichnet, dass der a einen Kolben (24) umfassende der Druckerzeuger (5) eine Halterung (6) für den Vorratsbehälter (3), eine zugeordnete Antriebsfeder (7) mit einer Lösetaste (8) und ein Förderrohr (9) umfasst, wobei ein axiales Spannen der Antriebsfeder (7) die Halterung (6) mit dem Vorratsbehälter (3) und dem Förderrohr (9) in einer dem Nasenstück (19) ent- gegen gesetzte Richtung verlagert und Fluid (2) aus dem Vorratsbehälter (3) in eineAtomizer according to claim 1, characterized in that the a is a piston (24) comprising the pressure generator (5) comprises a holder (6) for the reservoir (3), an associated drive spring (7) with a release button (8) and a conveyor tube (9), wherein an axial clamping of the drive spring (7) the holder (6) with the storage container (3) and the delivery pipe (9) displaces in a direction opposite the nose piece (19) and fluid (2) from the storage container (3) into a
Druckkammer (11) saugt.Pressure chamber (11) sucks.
10. Zerstäuber nach Anspruch 1, dadurch gekennzeichnet, dass die bestimmte Menge des Fluids einstellbar ist.10. An atomiser according to claim 1, characterized in that the specific amount of the fluid is adjustable.
11. Zerstäuber nach Anspruch 10, dadurch gekennzeichnet, dass eine Beaufschlagung der Lösetaste (8) eine Entspannung der gespannten Antriebsfeder (7) bewirkt, die das Förderrohr (9) in Richtung des Nasenstücks (19) bewegt und dabei das Fluid11. An atomiser according to claim 10, characterized in that an actuation of the release button (8) causes a relaxation of the tensioned drive spring (7), which moves the delivery pipe (9) in the direction of the nose piece (19) and thereby the fluid
(2) zum Austrag durch die Düse (12) mit Druck beaufschlagt.(2) pressurized by the nozzle (12) for discharge.
12. Zerstäuber nach Anspruch 10 oder 12, dadurch gekennzeichnet, dass dem Förderrohr (9) ein Rückschlagventil (10) zugeordnet ist.12. Atomiser according to claim 10 or 12, characterized in that the delivery pipe (9) is associated with a check valve (10).
13. Zerstäuber nach Anspruch 1, dadurch gekennzeichnet, dass ein Vorratsbehälter13. Atomizer according to claim 1, characterized in that a storage container
(3) für das Fluid (2) innerhalb eines Gehäuses austauschbar angeordnet ist.(3) is arranged interchangeably for the fluid (2) within a housing.
14. Zerstäuber nach Anspruch 1, dadurch gekennzeichnet, dass die Düse (12) ein Düsenkanälen zur Erzeugung von zwei aufeinander treffenden Sprühstrahlen zur Erzeugung einer Sprühwolke zugeordnetes Filtersystem umfasst.14. An atomiser according to claim 1, characterized in that the nozzle (12) comprises a nozzle channels for generating two impinging spray jets for generating a spray cloud associated filter system.
15. Nasenstück als Adapter für einen Zerstäuber (1) nach einem der Ansprüche 1 bis 14. 15. nose piece as an adapter for a sprayer (1) according to one of claims 1 to 14.
PCT/EP2007/055383 2006-06-02 2007-06-01 Atomizer WO2007141203A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2009512611A JP2009538656A (en) 2006-06-02 2007-06-01 Atomizer
CA002653422A CA2653422A1 (en) 2006-06-02 2007-06-01 Atomizer
EP07729784A EP2029205A1 (en) 2006-06-02 2007-06-01 Atomizer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006025871A DE102006025871A1 (en) 2006-06-02 2006-06-02 atomizer
DE102006025871.1 2006-06-02

Publications (1)

Publication Number Publication Date
WO2007141203A1 true WO2007141203A1 (en) 2007-12-13

Family

ID=38472898

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/055383 WO2007141203A1 (en) 2006-06-02 2007-06-01 Atomizer

Country Status (5)

Country Link
EP (1) EP2029205A1 (en)
JP (1) JP2009538656A (en)
CA (1) CA2653422A1 (en)
DE (1) DE102006025871A1 (en)
WO (1) WO2007141203A1 (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009153049A1 (en) * 2008-06-20 2009-12-23 Boehringer Ingelheim International Gmbh Inhaler
US7837235B2 (en) 2004-01-08 2010-11-23 Boehringer Ingelheim International Gmbh Device for clamping a fluidic component
US7963955B2 (en) 1998-02-27 2011-06-21 Boehringer Ingelheim International Gmbh Container for a medicinal liquid
JP2012530567A (en) * 2009-06-25 2012-12-06 ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhaler
DE102013013397A1 (en) * 2013-08-13 2015-03-12 Epinamics Gmbh Aerosol dispenser for transdermal pharmaceutical compositions
US9545487B2 (en) 2012-04-13 2017-01-17 Boehringer Ingelheim International Gmbh Dispenser with encoding means
CN106456915A (en) * 2014-05-14 2017-02-22 技术合伙公司 Aerosolisation engine for liquid drug delivery background
US9682202B2 (en) 2009-05-18 2017-06-20 Boehringer Ingelheim International Gmbh Adapter, inhalation device, and atomizer
US9724482B2 (en) 2009-11-25 2017-08-08 Boehringer Ingelheim International Gmbh Nebulizer
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
US9757750B2 (en) 2011-04-01 2017-09-12 Boehringer Ingelheim International Gmbh Medicinal device with container
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
US9943654B2 (en) 2010-06-24 2018-04-17 Boehringer Ingelheim International Gmbh Nebulizer
US10004857B2 (en) 2013-08-09 2018-06-26 Boehringer Ingelheim International Gmbh Nebulizer
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
US10099022B2 (en) 2014-05-07 2018-10-16 Boehringer Ingelheim International Gmbh Nebulizer
US10124125B2 (en) 2009-11-25 2018-11-13 Boehringer Ingelheim International Gmbh Nebulizer
US10124129B2 (en) 2008-01-02 2018-11-13 Boehringer Ingelheim International Gmbh Dispensing device, storage device and method for dispensing a formulation
US10195374B2 (en) 2014-05-07 2019-02-05 Boehringer Ingelheim International Gmbh Container, nebulizer and use
US10722666B2 (en) 2014-05-07 2020-07-28 Boehringer Ingelheim International Gmbh Nebulizer with axially movable and lockable container and indicator
FR3121047A1 (en) * 2021-03-29 2022-09-30 Aptar France Sas Nasal powder delivery device

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL3035886T3 (en) 2013-08-20 2021-05-31 Boehringer Ingelheim Vetmedica Gmbh Inhaler
WO2015024652A1 (en) 2013-08-20 2015-02-26 Boehringer Ingelheim Vetmedica Gmbh Inhaler
ES2960809T3 (en) 2013-08-20 2024-03-06 Boehringer Ingelheim Vetmedica Gmbh Inhaler
CN113679910A (en) * 2020-05-19 2021-11-23 顾瑜 Atomization device

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3820698A (en) * 1971-08-31 1974-06-28 Boehringer Sohn Ingelheim Device for spraying liquid pharmaceuticals
WO1991014468A1 (en) * 1990-03-21 1991-10-03 Dmw (Technology) Limited Atomising devices and methods
GB2291135A (en) * 1994-07-06 1996-01-17 Boehringer Ingelheim Kg Device for dispensing fluid
WO1998039043A1 (en) * 1997-03-03 1998-09-11 Alfred Von Schuckmann Metered dispensing device for substances
WO2003002045A1 (en) * 2001-06-29 2003-01-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nebulizer for applying liquids on the cornea
US20030226907A1 (en) * 2002-05-16 2003-12-11 Boehringer Ingelheim International Gmbh System comprising a nozzle and a fixing means therefor
WO2005079997A1 (en) * 2004-02-24 2005-09-01 Boehringer Ingelheim International Gmbh Atomiser
US20050268915A1 (en) * 2004-06-07 2005-12-08 Willem Wassenaar Nasal adaptation of an oral inhaler device

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3820698A (en) * 1971-08-31 1974-06-28 Boehringer Sohn Ingelheim Device for spraying liquid pharmaceuticals
WO1991014468A1 (en) * 1990-03-21 1991-10-03 Dmw (Technology) Limited Atomising devices and methods
GB2291135A (en) * 1994-07-06 1996-01-17 Boehringer Ingelheim Kg Device for dispensing fluid
WO1998039043A1 (en) * 1997-03-03 1998-09-11 Alfred Von Schuckmann Metered dispensing device for substances
WO2003002045A1 (en) * 2001-06-29 2003-01-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nebulizer for applying liquids on the cornea
US20030226907A1 (en) * 2002-05-16 2003-12-11 Boehringer Ingelheim International Gmbh System comprising a nozzle and a fixing means therefor
WO2005079997A1 (en) * 2004-02-24 2005-09-01 Boehringer Ingelheim International Gmbh Atomiser
US20050268915A1 (en) * 2004-06-07 2005-12-08 Willem Wassenaar Nasal adaptation of an oral inhaler device

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7963955B2 (en) 1998-02-27 2011-06-21 Boehringer Ingelheim International Gmbh Container for a medicinal liquid
US9027967B2 (en) 2004-01-08 2015-05-12 Boehringer Ingelheim International Gmbh Device for clamping a fluidic component
US7837235B2 (en) 2004-01-08 2010-11-23 Boehringer Ingelheim International Gmbh Device for clamping a fluidic component
US10124129B2 (en) 2008-01-02 2018-11-13 Boehringer Ingelheim International Gmbh Dispensing device, storage device and method for dispensing a formulation
WO2009153049A1 (en) * 2008-06-20 2009-12-23 Boehringer Ingelheim International Gmbh Inhaler
JP2011524228A (en) * 2008-06-20 2011-09-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhaler
EP2135632A1 (en) * 2008-06-20 2009-12-23 Boehringer Ingelheim International Gmbh Inhalator
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
US9682202B2 (en) 2009-05-18 2017-06-20 Boehringer Ingelheim International Gmbh Adapter, inhalation device, and atomizer
JP2012530567A (en) * 2009-06-25 2012-12-06 ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhaler
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
US9724482B2 (en) 2009-11-25 2017-08-08 Boehringer Ingelheim International Gmbh Nebulizer
US10124125B2 (en) 2009-11-25 2018-11-13 Boehringer Ingelheim International Gmbh Nebulizer
US9943654B2 (en) 2010-06-24 2018-04-17 Boehringer Ingelheim International Gmbh Nebulizer
US9757750B2 (en) 2011-04-01 2017-09-12 Boehringer Ingelheim International Gmbh Medicinal device with container
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
US9545487B2 (en) 2012-04-13 2017-01-17 Boehringer Ingelheim International Gmbh Dispenser with encoding means
US10220163B2 (en) 2012-04-13 2019-03-05 Boehringer Ingelheim International Gmbh Nebuliser with coding means
US10004857B2 (en) 2013-08-09 2018-06-26 Boehringer Ingelheim International Gmbh Nebulizer
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
US10894134B2 (en) 2013-08-09 2021-01-19 Boehringer Ingelheim International Gmbh Nebulizer
US11642476B2 (en) 2013-08-09 2023-05-09 Boehringer Ingelheim International Gmbh Nebulizer
DE102013013397A1 (en) * 2013-08-13 2015-03-12 Epinamics Gmbh Aerosol dispenser for transdermal pharmaceutical compositions
US10716905B2 (en) 2014-02-23 2020-07-21 Boehringer Lngelheim International Gmbh Container, nebulizer and use
US10099022B2 (en) 2014-05-07 2018-10-16 Boehringer Ingelheim International Gmbh Nebulizer
US10195374B2 (en) 2014-05-07 2019-02-05 Boehringer Ingelheim International Gmbh Container, nebulizer and use
US10722666B2 (en) 2014-05-07 2020-07-28 Boehringer Ingelheim International Gmbh Nebulizer with axially movable and lockable container and indicator
CN106456915A (en) * 2014-05-14 2017-02-22 技术合伙公司 Aerosolisation engine for liquid drug delivery background
FR3121047A1 (en) * 2021-03-29 2022-09-30 Aptar France Sas Nasal powder delivery device
WO2022208014A1 (en) 2021-03-29 2022-10-06 Aptar France Sas Device for nasal delivery of powder

Also Published As

Publication number Publication date
DE102006025871A1 (en) 2007-12-06
EP2029205A1 (en) 2009-03-04
JP2009538656A (en) 2009-11-12
CA2653422A1 (en) 2007-12-13

Similar Documents

Publication Publication Date Title
WO2007141203A1 (en) Atomizer
EP3508239B1 (en) Adapter, inhalant apparatus and atomizer
JP5681492B2 (en) Nozzle, inhaler, and method of manufacturing nozzle
EP2015811B1 (en) Atomizer and method of atomizing fluid
JP5719291B2 (en) Inhaler
EP2023990A1 (en) Adapter with an attachment for an atomizer
EP2066380B1 (en) Inhaler
MX2011013077A (en) Inhaler.
EP2066382B1 (en) Piston dosing pump
ES2734501T3 (en) Mouthpiece for an inhaler
EP2007459A1 (en) Inhaler
JP5504156B2 (en) Inhaler
EP2424603B1 (en) Inhalation device
EP2066381A1 (en) Inhaler
WO2007110403A1 (en) Dosage aerosols for the administration of pharmaceutical preparations
EP2198972A1 (en) Reservoir and atomiser

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07729784

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2653422

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2007729784

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2009512611

Country of ref document: JP