EP1845992A1 - Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis - Google Patents

Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis

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Publication number
EP1845992A1
EP1845992A1 EP06707722A EP06707722A EP1845992A1 EP 1845992 A1 EP1845992 A1 EP 1845992A1 EP 06707722 A EP06707722 A EP 06707722A EP 06707722 A EP06707722 A EP 06707722A EP 1845992 A1 EP1845992 A1 EP 1845992A1
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EP
European Patent Office
Prior art keywords
amino
quinazoline
chloro
phenyl
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP06707722A
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German (de)
French (fr)
Inventor
Birgit Jung
Bernd Disse
Gerald Pohl
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE102005005505A external-priority patent/DE102005005505A1/en
Priority claimed from DE102005036216A external-priority patent/DE102005036216A1/en
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1845992A1 publication Critical patent/EP1845992A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

Definitions

  • Part of the active ingredients La - 1.j and 1.1 - 1.101 contains a hydrolysis-sensitive ester or lactone group.
  • substantially anhydrous dosage forms and application forms are selected for these compounds.
  • nasal administration is preferably as a powder for intranasal deposition.
  • the adjuvants used in nasal powders are carriers (which carry a finely micronized active), gelling agents (which promote the removal of the Slow down active agent from the nasal cavity), fillers (to bring low-dose drugs to a manageable volume) or enhancers (which improve the absorption of the drug), where an excipient can also perform several functions at the same time.
  • Cyclodextrins and derivatives for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin;
  • candidate excipients are: human serum albumin, polyalcohols (e.g., mannitol, sorbitol, xylitol), trehalose, amino acids, monosaccharides (e.g., glucose or arabinose), casein, salts (e.g., sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
  • polyalcohols e.g., mannitol, sorbitol, xylitol
  • trehalose amino acids
  • monosaccharides e.g., glucose or arabinose
  • casein casein
  • salts e.g., sodium chloride, calcium carbonate
  • the propellant-containing aerosols which can be used in the context of the use according to the invention can dissolve the active substance or the active substance combination in the propellant gas or contain it in dispersed form.
  • the propellant gases which can be used to produce the aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butcine or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-containing aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and agents for aerosols Adjustment of pH included. All of these ingredients are known in the art.
  • the nasal application of the active ingredient according to the invention or the active ingredient combination in the form of propellant-free solutions or suspensions come as a solution or suspending aqueous, oily or alcoholic, for example ethanolic solutions into consideration.
  • the solvent may be water only or it may be a mixture of water and ethanol.
  • sterile aqueous solutions of the corresponding pharmaceutically acceptable salts may be used.
  • solutions or suspensions of the active compounds in aqueous propylene glycol, in sesame or peanut oil into consideration.
  • Aqueous solutions should be suitably buffered if necessary and the liquid diluent made isotonic with, for example, sufficient salt or glucose.
  • the formulations described in Examples 1-5 and 7 contain any active ingredient selected from Group 1.
  • the formulation of Example 6 contains an active ingredient selected from Group 1 which has no hydrolysis-sensitive group, such as an ester or lactone group.
  • the active ingredient and any excipient present are each micronised using conventional techniques, optionally spheronised and sieved, and optionally then mixed in the desired ratio.
  • an average particle size (aerodynamic diameter) lying between 5 and 200 ⁇ m is set, for example in the range between 10 to 25 ⁇ m, the average particle size of the excipient is expediently selected in the range 10 to 350 ⁇ m, for example between 15 to 80 ⁇ m.
  • Method of preparation The active ingredient in the form of a physiologically acceptable salt and the excipients are dissolved in water and filled into a corresponding container.
  • the active ingredient is dissolved in sesame oil and filled into a corresponding container.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to the use of selected EGFR kinase inhibitors, especially selected quinazolines, quinolines, and pyrimidopyrimidines, for treating nasal polyposis and chronic rhinosinusitis.

Description

Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung der chronischen Rhinosinusitis Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis
Gegenstand der vorliegenden Erfindung ist die Verwendung von ausgewählten EGf-R Kinase Inhibitoren, insbesondere von ausgewählten Chinazolinen, Chinolinen und Pyrimido-pyrimidinen, zur Herstellung eines Arzneimittels zur Vorbeugung und Behandlung, insbesondere zur Behandlung von nasaler Polyposis, der Rhinosinusitis, insbesondere der chronischen Rhinosinusitis. Tautomere, Racemate, Stereoisomere, z.B. Enantiomere oder Diastereomere, Solvate bzw. Hydrate, Salze, insbesondere physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, der ausgewählten EGFR Kinase Inhibitoren sind ebenso Gegenstand der erfindungsgemäßen Verwendung. Patienten mit einer chronischen Rhinosinusitis leiden an einer verringerten Lebensqualität und dieses Krankheitsbild ist oft mit anderen schwerwiegenden Krankheiten wie beispielsweise Asthma, Ekzeme und Ohrenentzündungen (Otitis media) verbunden. Nasale Polyposis ist in vielen Fällen die Ursache für Rhinosinusitis und chronische Rhinosinusitis. Nasale Polypen können beispielsweise durch eine allergische Rhinitis, akute und chronische Rhinitis oder durch virale oder bakterielle Infektionen; durch Reizstoffe, Nebel und Dämpfe entstehen.The present invention is the use of selected EGf-R kinase inhibitors, in particular selected quinazolines, quinolines and pyrimido-pyrimidines, for the preparation of a medicament for the prevention and treatment, in particular for the treatment of nasal polyposis, rhinosinusitis, in particular chronic rhinosinusitis. Tautomers, racemates, stereoisomers, e.g. Enantiomers or diastereomers, solvates or hydrates, salts, in particular physiologically tolerable salts with inorganic or organic acids or bases, of the selected EGFR kinase inhibitors are likewise subject matter of the use according to the invention. Patients with chronic rhinosinusitis suffer from a reduced quality of life and this condition is often associated with other serious illnesses such as asthma, eczema and otitis media. Nasal polyposis is the cause of rhinosinusitis and chronic rhinosinusitis in many cases. Nasal polyps may be caused, for example, by allergic rhinitis, acute and chronic rhinitis or by viral or bacterial infections; caused by irritants, mist and vapors.
Überraschenderweise führen die ausgewählten EGFR Kinase Inhibitoren zu einer Verkleinerung (Abschwellen) von vergrößerten nasalen Polypen und sind somit zur Behandlung der nasalen Polyposis und/oder chronischer Rhinosinusitis sowie präventiv zur Verhinderung von Rezidiven nach konventioneller Therapie, etwa operativer Polypektomie, geeignet.Practice r surprisingly cause the selected EGFR kinase inhibitors to a reduction (decongestion) of enlarged nasal polyps and thus for the treatment of nasal polyposis and / or chronic rhinosinusitis and preventive for preventing recurrence after conventional therapy, such as surgical polypectomy suitable.
Zur erfindungsgemäßen Verwendung kommen beispielsweise die folgenden Verbindungen 1 ausgewählt aus der Gruppe bestehend aus den Verbindungen 1.a bis 1.j und 1.1 bis 1.101 zum Einsatz:For the use according to the invention, for example, the following compounds 1 selected from the group consisting of the compounds 1.a to 1.j and 1.1 to 1.101 are used:
(La) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)- carbonyl]-piperazin-1 -yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin, (1.b) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- θthoxy]-6-[(vinylcarbonyl)amino]-chinazolin, (1.c) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin, (1^d) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin, (1.e) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(La) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine 1 -yl} -ethoxy) -6 - [(vinylcarbonyl) amino] quinazoline, (1.b) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -thio] - 6 - [(vinylcarbonyl) amino] quinazoline, (1.c) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo -morpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, (1 ^ d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- ( (S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, (1.e) 4 - [(3-chloro-4-fluoro) phenyl) amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] quinazoline,
(U) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropyl- methoxy-chinazolin, (1.q) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(U) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N- [(ethoxycarbonyl) methyl] amino} -1- oxo-2-buten-1-yl) -amino] -7-cyclopropyl-methoxy-quinazoline, (1.q) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- ( morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy-quinazoline,
(1.hι 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]- 1-OXO-2- buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(1.hι 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-OXO-2-butene-1-yl } amino) -7-cyclopropylmethoxy-quinazoline,
(U) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo- morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin, (U) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5 ,4-d]pyrimidin , (U.) 4-[(3-Chlor-4-fluorphθnyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- aminoJ-7-cyclopropylmethoxy-chinazolin,(U) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxomorpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (U) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] - pyrimido [5,4-d] pyrimidine, (U.) 4 - [(3-Chloro-4-fluoro-phosphoryl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene 1-yl] -aminoJ-7-cyclopropylmethoxy quinazoline,
(1.2) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-cyclopropylmethoxy-chinazolin,(1.2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(1.3) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopropylmethoxy-chinazolin,(1.3) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(1.4) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopentyloxy-chinazolin,(1.4) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} - 7-cyclopentyloxy-quinazoline,
(1.5) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo^-buten-i-yllaminoj^-cyclopropylmethoxy-chinazolin, (1;6) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(1.5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo ^ -butene-i-ylamino] -cyclopropylmethoxy-quinazoline, (1 ; 6) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2 oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(1.7) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpho- lin^-yO-i -oxo^-buten-i -y^aminoJ^-cyclopropylmethoxy-chinazolin, (1.8) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,(1.7) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholino] -yO-i-oxo ^ -butene-i-aminoethylcyclopropylmethoxyquinazoline, (1.8) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
(1.9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1-oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin, (IJO) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yllaminoj^-cyclopentyloxy-chinazolin,(1.9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy quinazoline, (IJO) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -butene-1-ylamino] -cyclopentyloxy-quinazoline,
(1.11 ) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1 -oxo- 2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin,(1.11) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo-2-] butene-1-yl] amino} -7-cyclopropylmethoxy quinazoline,
(1.12) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1 - oxo^-buten-i-yljamino^-cyclopropylmethoxy-chinazolin,(1.12) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-butyne -i-yljamino ^ -cyclopropylmethoxy-quinazoline,
(1.13) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 - oxo^-buten-i -yljamino^-cyclopropylmethoxy-chinazolin,(1.13) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-butyne -i -ylamino ^ -cyclopropylmethoxy-quinazoline,
(1.1 4) 4-[(R)-(1 -Phenyl-θthyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-ami- no]-1 -oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin, (U.5) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin,(1.1 4) 4 - [(R) - (1-Phenylthio) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -1-oxo -2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (U.5) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino ) -1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline,
(1.16) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin,(1.16) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (S) -tetrahydrofuran-3-yloxy) -quinazoline,
(1.17) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopentyloxy-chinazolin,(1.17) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopentyloxy-quinazoline,
(1.13) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo-(1.13) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo]
2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin, (1.19) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dim9thylamino)-1 -oxo-2-buten-1 - yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, (1^j)) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, (1.19) 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1 -oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, (1 → j)) 4 - [(3-chloro-4-fluorophenyl ) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] - quinazoline,
(1.2 1 ) 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin,(1.2 1) 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline,
(1.22) 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazolin, CL23) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimi- din,(1.22) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, CL23) 4 [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(1.24) 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2- buten-1 -yl]amino}-7-ethoxy-chinolin, (1.25) 3-Cyano-4-[(3-chlor-4-(pyridin-2-yl-methoxy)-phenyl)amino]-6-{[4-(N,N-di- methylamino)-1 -oxo-2-buten-1 -yl]amino}-7-ethoxy-chinolin,(1.24) 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1-yl] amino} -7-ethoxy-quinoline, (1.25) 3-Cyano-4 - [(3-chloro-4- (pyridin-2-yl-methoxy) -phenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1 - oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline,
(1.26) 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin, (LiZ) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo-2-buten-1 -yl]amino}-7-methoxy-chinazolin,(1.26) 4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl ) quinazoline, (LiZ) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -1 - oxo-2-buten-1-yl] amino} -7-methoxy-quinazoline,
(1.28) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.28) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.29) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1 - oxo-2-buten-1 -yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.29) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene 1 -yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline,
(1.30) 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1 -oxo- 2-buten-1 -yl]amino}-chinazolin,(1.30) 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-butene-1 - yl] amino} -quinazoline,
(1.31 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin, (Ll2J 4-[(3-Chlor-4-f luor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.31) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy quinazoline, (LI 2 J 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.33) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.33) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -6 - [( S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.34) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1 - yl]-ethoxy}-7-methoxy-chinazolin,(1.34) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} - 7-methoxy-quinazoline,
(1.35) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4- yloxy]-7-methoxy-chinazolin,(1.35) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
(1.36) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1 -yloxy)-7- methoxy-chinazolin, (L3_7) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclo- hexan-1 -yloxy)-7-methoxy-chinazolin,(1.36) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-ylxy) -7-methoxy-quinazoline, (L3_7) 4 - [(3 -Chloro-4-fluoro-phenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexane-1-ylxy) -7-methoxy-quinazoline,
(L3Jl) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- chinazolin,(L 3 JI) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline,
(1.39) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.39) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxy-quinazoline,
(1.40) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,(1.40) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.41) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(methoxymethyl)carbonyl]-pipericlin-4- yloxy}-7-methoxy-chinazolin, (1.42) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy- chinazolin,(1.41) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -pipericlin-4-yloxy} -7-methoxy-quinazoline, (1.42) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline
(1.43) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(2-acetylamino-ethyl)-piperidin-4-yl- oxy]-7-methoxy-chinazolin, (L44) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy- chinazolin,(1.43) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yl-oxy] -7-methoxy-quinazoline, (L44 ) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline,
(1.45) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy- chinazolin,(1.45) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxyquinazoline,
(1.46) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy- ethoxy)-chinazolin,(1.46) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline,
(1.47) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]- cyclohexan-1 -yloxy}-7-methoxy-chinazolin,(1.47) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) -sulfonylamino] -cyclohexane-1-ynyloxy} -7-methoxy-quinazoline,
(1.48) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-1-yloxy}-7-methoxy-chinazolin, (1:49) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]- cyclohexan-i -yloxyJ-7-mθthoxy-chinazolin,(1.48) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline , (1:49) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) -sulfonylamino] -cyclohexane-i-yyloxy-7-methoxy -quinazoline,
(1.50) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylami- no-ethoxy)-chinazolin,(1.50) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline,
(1.51) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methan- sulfonylamino-ethoxy)-chinazolin,(1.51) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline,
(1.52) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(piperidin-1 -yl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,(1.52) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.53) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -aminocarbonylmethyl-piperidin-4-yl- oxy)-7-methoxy-chinazolin, (L54) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]- N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,(1.53) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yl-oxy) -7-methoxy-quinazoline, (L54) 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] - N -methyl-amino} -cyclohexan-1-ylxy) -7-methoxy -quinazoline,
(1.55) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N- methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,(1.55) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane 1-oxy) -7-methoxyquinazoline,
(1.56) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N- methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,(1.56) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane 1-oxy) -7-methoxyquinazoline,
(1.57) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan- 1 -yloxy)-7-methoxy-chinazolin,(1.57) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexane-1-yloxy) -7-methoxy-quinazoline,
(1.5B) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7- ethoxy-chinazolin, (1.59) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazolin,(1.5B) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline, (1.59) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxyethoxy) -quinazoline,
(1.60) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4-yloxy]- 7-(2-methoxy-ethoxy)-chinazolin, (IAi) 4-[(3-Chlor-4-f luor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1 -yloxy)- 7-methoxy-chinazolin,(1.60) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) - quinazoline, (IAi) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline,
(1.62) 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin,(1.62) 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
(1.63) 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy- chinazolin,(1.63) 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxyquinazoline,
(1.64) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1 -yl)carbonyl]-N-me- thyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,(1.64) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} - cyclohexane-1-yloxy) -7-methoxy-quinazoline,
(1.65) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1 -yl)- carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin, (1J5I3) 4-[(3-Chlor-4-f luor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-1 -yloxy}-7-methoxy-chinazolin,(1.65) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N-methyl- amino} -cyclohexan-1-ylxy) -7-methoxy-quinazoline, (1J5I3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholine-4- yl) carbonylamino] - cyclohexane-1-ylxy} -7-methoxy-quinazoline,
(1.67) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxopyrrolidin-1 -yl)ethyl]-piperidin- 4-yloxy}-7-methoxy-chinazolin,(1.67) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy -quinazoline,
(1.68) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy}-7-(2-methoxy-ethoxy)-chinazolin,(1.68) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxy) ethoxy) -quinazoline,
(1.69) 4-[(3-Ethinyl-phenyl)amino]-6-(1 -acetyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.69) 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.70) 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7-methoxy- chinazolin, (1.711 ) 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-me- thoxy-chinazolin,(1.70) 4 - [(3-Ethynyl-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, (1.711) 4 - [(3-ethynyl-phenyl) -amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.72) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7(2-methoxy- ethoxy)-chinazolin,(1.72) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxyethoxy) quinazoline,
(1.73) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -isopropyloxycarbonyl-piperidin-4-yl- oxy)-7-methoxy-chinazolin,(1.73) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yl-oxy) -7-methoxy-quinazoline,
(1.74) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1 -yloxy)- 7-methoxy-chinazolin,(1.74) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline,
(1.75) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl- amino]-cyclohexan-1 -yloxy}-7-methoxy-chinazolin, CLZl-.) 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin, (1.77) 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7- methoxy-chinazolin,(1.75) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yxyxy } -7-methoxy-quinazoline, CLZl- . ) 4 - [(3-Ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, (1.77) 4 - [(3-ethynyl-phenyl) -amino] -6- [1 - (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxyquinazoline,
(1.7B) 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-chinazolin,(1.7B) 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.79) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(cis-2,6-dimethyl-morpholin-4-yl)car- bonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, (1.8D) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(2-methyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, (Ml) 4-[(3-Chlor-4-f luor-phenyl)amino]-6-{1 -[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1 ]- hept5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.79) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidine-4- yloxy} -7-methoxy-quinazoline, (1.8D) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] - piperidin-4-yloxy} -7-methoxy-quinazoline, (Ml) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa -5-azabicyclo [2.2.1] -hept5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.82) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(N-methyl-N-2-methoxyethyl-amino)- carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.82) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} - 7-methoxy-quinazoline,
(1.83) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.83) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.84) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(2-methoxyethyl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,(1.84) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.85) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(3-methoxypropyl-amino)-carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, (U£6) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-ami- noj-cyclohexan-i-yloxyj^-methoxy-chinazolin,(1.85) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, (U £ 6) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy -quinazoline,
(1.87) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclo- hexan-1-yloxy]-7-methoxy-chinazolin,(1.87) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7- methoxy-quinazoline,
(1.88) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yl- oxy)-7-methoxy-chinazolin(1.88) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yl-oxy) -7-methoxy-quinazoline
(1.89) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl- aminoj-cyclohexan-i-yloxyl^-methoxy-chinazolin,(1.89) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy-quinazoline,
(1.90) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimθthylamino-cyclohθxan-1 - yloxy)-7-methoxy-chinazolin (L9_l) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N- methyl-aminoj-cyclohexan-i -yloxyj^-methoxy-chinazolin,(1.90) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylthio-amino-cyclo-ethane-1-yloxy) -7-methoxy-quinazoline (L9_l) 4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino-cyclohexane-1-ylxy) -methoxy-quinazoline,
(1.92) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxo-3-methyl-imidazolidin-1 -yl)- θthyl]-piperidin-4-yloxy}-7-mθthoxy-chinazolin (1.93) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxo-hexahydropyrimidin-1 -yl)- ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.92) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [2- (2-oxo-3-methyl-imidazolidin-1-yl) -thyl] -piperidine-4 yloxy} -7-mθthoxy-quinazoline (1.93) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-hexahydropyrimidin-1-yl) -ethyl] -piperidin-4-yloxy} - 7-methoxy-quinazoline,
(1.94) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(S)-(tθtrahydrofuran-2-yl)methoxy]-chinazolin, QJΪ5) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7- methoxy-chinazolin,(1.94) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [( S) - (t-thrahydrofuran-2-yl) methoxy] quinazoline, QJΪ5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- methoxy-quinazoline,
(1.96) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -cyano-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.96) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.97) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy- chinazolin,(1.97) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline,
(1.9B) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methylcarbonyl-piperidin-4-yloxy)-7- methoxy-chinazolin, (1.99) 4-[(3-Ch)or-4-f luor-phenyl)amino]-6-( 1 -dimethylaminoacetyl-piperidin-4- yloxy)-7-methoxy-chinazolin, (1.100) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(dimethylamino)carbonylmethyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, (1.101) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)- chinazolin,(1.9B) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylcarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, (1.99) 4 - [(3 Ch) or-4-fluoro-phenyl) amino] -6- (1-dimethylaminoacetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, (1,100) 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- {1 - [(dimethylamino) carbonylmethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, (1.101) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (1-methanesulfonyl-piperidin-4-yloxy) -quinazoline,
oder deren Salze.or their salts.
Die Verbindungen sind als solche aus dem Stand der Technik bekannt, derenThe compounds are known as such from the prior art, whose
Herstellung ist beispielsweise in folgenden Druckschriften beschrieben:Production is described, for example, in the following publications:
WO 96/30347; WO 97/02266; WO 97/32880, WO 99/35146; WO 00/31048; WO 00/51991 , WO 00/78735; WO 01/34574; WO 01/61816; WO 01/77104; WO 02/18351 ; WO 02/18370, WO 02/18372; WO 02/18373; WO 02/18375, WO 02/13376; WO 02/50043; WO 03/082290; Cancer Research 2004, 64:11 (3958- 3965); Am J Health-Syst Pharm 2000, 57(15), 2063-2076; Clinical Therapeutics 1999, 21 (2), 309-318; WO 98/50433; und WO 95/20045.WO 96/30347; WO 97/02266; WO 97/32880, WO 99/35146; WO 00/31048; WO 00/51991, WO 00/78735; WO 01/34574; WO 01/61816; WO 01/77104; WO 02/18351; WO 02/18370, WO 02/18372; WO 02/18373; WO 02/18375, WO 02/13376; WO 02/50043; WO 03/082290; Cancer Research 2004, 64:11 (3958-3965); Am J Health-Syst Pharm 2000, 57 (15), 2063-2076; Clinical Therapeutics 1999, 21 (2), 309-318; WO 98/50433; and WO 95/20045.
In allen Ausführungsformen oder Aspekten der Erfindung sind die EGFR Kinase Inhibitoren U. bis 1.101 bevorzugt, insbesondere die EGFR Kinase Inhibitoren 11 14, !§> 18> Ii- IH, 1/17, 1/19, 121, 123, 124, 127, 128, 1.30. 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43. 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1,71 , 1.72, 1.78, 1.82, 1.83, 1.84, 1.8», 1.90, 1.91 , 194 und 1.95In all embodiments or aspects of the invention, the EGFR kinase inhibitors U. to 1.101 are preferred, in particular the EGFR kinase inhibitors 11 14,! §> 18 > Ii-IH, 1/17, 1/19, 121, 123, 124, 127, 128, 1.30. 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43. 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.8 », 1.90, 1.91, 194, and 1.95
oder deren Salze.or their salts.
Physiologisch verträgliche Säureadditionssalze der Verbindungen der Gruppe 1 sind beispielsweise das Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonate, Hydronitrat, Hydromaleinate, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrate, Hydrolactate, Hydrooxalate, Hydrosuccinate, Hydrobenzoate und Hydro-p-toluolsulfonate.Physiologically acceptable acid addition salts of the compounds of group 1 are, for example, the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonates, hydronitrate, hydromaleinates, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrates, hydrolactates, hydroxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulfonates ,
Ein weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Vorbeugung oder/und Behandlung der chronischen Rhinosinusitis, der nasalenAnother object of the present invention is a method for the prevention and / or treatment of chronic rhinosinusitis, the nasal
Polyposis sowie der chronischen Rhinosinusitis mit nasaler Polyposis, vorzugsweise der chronischen Rhinosinusitis mit nasaler Polyposis, umfassend die Verabreichung einer wirksamen Menge einer oder mehrerer der vorstehend genanntenPolyposis and nasal polyposis chronic rhinosinusitis, preferably chronic nasal polyposis rhinosinusitis comprising administering an effective amount of one or more of the foregoing
Verbindungen (1.a) bis (1.0 oder (1.1) bis (1.101) oder gegebenenfalls eines deren physiologisch verträglichen Salze an einen Patienten, der einer solchen Behandlung bedarf. Die Verbindungen werden in einer geeigneten Arzneimittelform verabreicht, vorzugsweise in einer für die nasale Anwendung geeigneten Zubereitung, beispielsweise in Form einer Lösung, einer Suspension, eines Aerosols oder einesCompounds (1.a) to (1.0 or (1.1) to (1.101) or, where appropriate, one of their physiologically acceptable salts to a patient in need of such treatment The compounds are administered in a suitable pharmaceutical form, preferably in one for nasal use suitable preparation, for example in the form of a solution, a suspension, an aerosol or a
Pulvers. Bevorzugt ist die Monotherapie, femer bevorzugt ist das Verfahren zur Behandlung.Powder. Preferably, the monotherapy, furthermore preferred is the method of treatment.
Unter dem Ausdruck "Vorbeugung", "Prävention" oder "vorbeugende Behandlung" ist eine Behandlung zum Zweck der Reduktion des Risikos zu verstehen, eine der genannten Indikationen zu entwickeln, insbesondere bei Patienten mit erhöhtem Risiko für diese Indikationen, bei bereits bestehender Vorgeschichte bzw. entsprechender Anamnese, beispielsweise bei Patienten nach bereits erfolgter konventioneller Therapie, etwa operativer Polypektomie. Statistisch nachweisbar ist der Erfolg der präventiven Behandlung durch Reduktion des Auftretens der betreffenden Indikationen in einer entsprechenden Risikopatientenpopulation im Vergleich mit einer Risikopatientenpopulation ohne vorbeugende Behandlung.By the term "prevention", "prevention" or "preventive treatment" is meant a treatment for the purpose of reducing the risk of developing one of the mentioned indications, in particular in patients with an increased risk for these indications, in the case of existing history or appropriate history, for example in patients after conventional therapy has already taken place, such as surgical polypectomy. Statistically verifiable is the success of the preventive treatment by reduction of the occurrence of the relevant indications in a corresponding high-risk population compared with a high-risk population without preventive treatment.
Unter dem Ausdruck "Behandlung" ist eine therapeutische Behandlung von Patienten mit manifester, akuter oder chronischer Indikation zu verstehen, wobei einerseits die symptomatische (palliative) Behandlung zur Linderung der Krankheitssymptome und andererseits die kausale oder kurative Behandlung der Indikation mit dem Ziel, den pathologischen Zustand zu beenden, den Schweregrad des pathologischenThe term "treatment" is to be understood as a therapeutic treatment of patients with a manifest, acute or chronic indication, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim of the pathological condition to terminate the severity of the pathological
Zusiands zu vermindern oder die Progression des pathologischen Zustands zu verzögern, abhängig von der Art oder Schwere der Indikation, eingeschlossen sind.Contraindications to reduce or delay the progression of the pathological condition, depending on the type or severity of the indication, are included.
Bei dem erfindungsgemäßen Verfahren werden die genannten Verbindungen in Dosierungen von 0.001-500 mg pro Anwendung, vorzugsweise bei 0.01 -50 mg, insbesondere bevorzugt 0.02 bis 10 mg eingesetzt, wobei die Gabe zweckmäßigerweise 1 bis 3 mal täglich erfolgt.In the method according to the invention, the compounds mentioned are used in dosages of 0.001-500 mg per application, preferably at 0.01-50 mg, particularly preferably 0.02 to 10 mg, wherein the administration is expediently carried out 1 to 3 times a day.
Die nasale Applikation der Wirkstoffe kann beispielsweise durch Darreichung von Nasentropfen oder, unter Verwendung bekannter Dosiersysteme, in Form von Nasalspray (Lösung oder Suspension), aus wässrigen Lösungen oder Suspensionen als Aerosol oder mittels Pulver für die intranasale Deposition erfolgen.The nasal administration of the active ingredients can be carried out, for example, by administering nasal drops or, using known dosing systems, in the form of nasal spray (solution or suspension), aqueous solutions or suspensions as aerosol or by powder for intranasal deposition.
Ein Teil der Wirkstoffe La - 1.j und 1.1 - 1.101 enthält eine hydrolyseempfindliche Ester- oder Lactongruppe. Zweckmäßigerweise werden für diese Verbindungen im wesentlichen wasserfreie Darreichungs- und Applikationsformen gewählt. In diesen Fällen erfolgt die nasale Verabreichung bevorzugt als Pulver für die intranasale Deposition.Part of the active ingredients La - 1.j and 1.1 - 1.101 contains a hydrolysis-sensitive ester or lactone group. Appropriately, substantially anhydrous dosage forms and application forms are selected for these compounds. In these cases, nasal administration is preferably as a powder for intranasal deposition.
Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren Pulverformulierungen für die nasale Applikation können den Wirkstoff oder die Wirk stoff kombination entweder allein oder im Gemisch mit geeigneten, vorzugsweise physiologisch unbedenklichen Hilfsstoffen enthalten.The powder formulations for nasal administration which can be used in the context of the use according to the invention may contain the active substance or the active substance combination either alone or in admixture with suitable, preferably physiologically acceptable excipients.
Die bei Nasalpulvern zur Verwendung kommenden Hilfsstoffe sind Träger (die einen fein mikronisierten Wirkstoff transportieren), Gelbildner (die den Abtransport des Wirkstoffs aus der Nasenhöhle verlangsamen), Füllstoffe (um niedrig dosierte Wirkstoffe auf ein handhabbares Volumen zu bringen) oder Enhancer (die die Resorption des Wirkstoffs verbessern), wobei ein Hilfsstoff auch mehrere Funktionen zugleich erfüllen kann.The adjuvants used in nasal powders are carriers (which carry a finely micronized active), gelling agents (which promote the removal of the Slow down active agent from the nasal cavity), fillers (to bring low-dose drugs to a manageable volume) or enhancers (which improve the absorption of the drug), where an excipient can also perform several functions at the same time.
Als Träger kommen beispielsweise die folgenden Hilfsstoffe, einschließlich deren Mischungen, in Frage (wobei ein Teil dieser Träger gleichzeitig eine Wirkung als Enhancer aufweist):Suitable carriers are, for example, the following auxiliaries, including mixtures thereof (part of these carriers having at the same time an action as enhancer):
Cellulose oder deren -ester- und -etherderivate: mikrokristalline Cellulose, mikrofeine Cellulose, Methylcellulose, Ethylcellulose, Hydroxymethylcellulose, Hydroxyethyl- cellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Natrium-Carboxy- methylcellulose;Cellulose or its ester and ether derivatives: microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose;
Disaccharide wie Lactose oder Lactosemonohydrat, Saccharose, Maltose;Disaccharides such as lactose or lactose monohydrate, sucrose, maltose;
Stärke: Stärke-Mikropartikel, quervernetzte Stärke, (quervernetzte) Stärkederivate;Starch: starch microparticles, cross-linked starch, (cross-linked) starch derivatives;
Oligo- und Polysaccharide wie Dextran-Mikropartikel (Sephadex®); Cyclodextrine, beispielsweise ß-Cyclodextrin oder Dimethyl-ß-Cyclodextrin; (quervemetztes) Polyvinylpyrollidon; Gelatine, Chitin, Chitosan, Tragantgummi, Polyacrylate, Alginsäure, Polyethylenglycole (Mol. gewicht ca. 1000-8000 Da).Oligo- and polysaccharides such as dextran microparticles (Sephadex ®); Cyclodextrins, for example, β-cyclodextrin or dimethyl-β-cyclodextrin; (crosslinked) polyvinyl pyrollidone; Gelatin, chitin, chitosan, tragacanth, polyacrylates, alginic acid, polyethylene glycols (mol. Weight about 1000-8000 Da).
Je nach ihren Eigenschaften kommen als Enhancer für die jeweiligen Formulierungswege beispielsweise die folgenden Hilfsstoffe, einschließlich deren Mischungen, in Frage:Depending on their properties, suitable enhancers for the respective formulation routes are, for example, the following auxiliaries, including mixtures thereof:
Tenside: nicht-ionische, ionische und amphotere Tenside, beispielsweise Polyoxyethylene-9-laurylether, Poloxamer 407, Brij 35, Brij 96, Polysorbat 80, Sojabohnen-Sterylglucosid (soybean-derived sterylglucoside);Surfactants: nonionic, ionic and amphoteric surfactants, for example polyoxyethylene-9-lauryl ether, poloxamer 407, Brij 35, Brij 96, polysorbate 80, soybean-steryl glucoside (soybean-derived sterylglucoside);
Gallensalze bzw. -derivate, beispielsweise Na-deoxycholat, Na-glycocholat, Natrium- tauro-24,25-dihydrofusidat (Sodium-tauro-24,25-dihydrofusidate [STDHF]); Fettsäure-Derivate, beispielsweise Ölsäure, Lauroylcarnitine, Acylcarnitin, Palmitoyl- DL-carnitine;Bile salts or derivatives, for example Na-deoxycholate, Na-glycocholate, sodium tauro-24,25-dihydrofusidate (sodium tauro-24,25-dihydrofusidate [STDHF]); Fatty acid derivatives, for example oleic acid, lauroylcarnitines, acylcarnitine, palmitoyl-DL-carnitines;
Phospholipide, beispielsweise Didecanoyl-L-alpha-phosphatidylcholin, Dimyristoyl- phosphatidylglycerol, Lysophosphatidylcholin, semisynthetische Lysophosphatidyl- cholin-Varianten, Dipalmitoyl-phosphatidlycholin;Phospholipids, for example didecanoyl-L-alpha-phosphatidylcholine, dimyristoylphosphatidylglycerol, lysophosphatidylcholine, semisynthetic lysophosphatidylcholine variants, dipalmitoylphosphatidylcholine;
Cyclodextrine und -derivate, beispielsweise α-, ß- oder γ-Cyclodextrin, Dimethyl-ß- Cyclodextrin, Hydroxypropyl-ß-Cyclodextrin;Cyclodextrins and derivatives, for example α-, β- or γ-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin;
Chitosan und -derivate, beispielsweise Poly-L-arginin-Chitosan, Hyaluronan Chitosan;Chitosan and derivatives, for example poly-L-arginine-chitosan, hyaluronan chitosan;
Diethylaminoethyl-Dextran, Glycyrrhetinic acid, EDTA, Hyaluronsäureester.Diethylaminoethyl-dextran, glycyrrhetinic acid, EDTA, hyaluronic acid ester.
Als spezielle Hilfsstoffe kommen in Frage:As special auxiliaries are:
Mucolytika, beispielsweise N-Acetylcystein oder Ambroxol, zur Herabsetzung der Viskosität des Mucus, wodurch die Diffusion und Resorption des Wirkstoffs verbessert werden können (beschrieben in WO 04078211);Mucolytics, for example N-acetylcysteine or ambroxol, for reducing the viscosity of the mucus, whereby the diffusion and absorption of the active ingredient can be improved (described in WO 04078211);
Weitere, in Frage kommende Hilfsstoffe sind: humanes Serum Albumin, Polyalkohole (z.B. Mannitol, Sorbitol, Xylit), Trehalose, Aminosäuren, Monosaccharide (z.B. Glucose oder Arabinose), Casein, Salze (z.B. Natriumchlorid, Calciumcarbonat) oder Mischungen dieser Hilfsstoffe miteinander.Other candidate excipients are: human serum albumin, polyalcohols (e.g., mannitol, sorbitol, xylitol), trehalose, amino acids, monosaccharides (e.g., glucose or arabinose), casein, salts (e.g., sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
Die für die nasale Deposition geeigneten Partikelgrößen des Wirkstoffs sowie gegebenfalls verwendeter Hilfsstoffe sind im Stand der Technik beschrieben, ebenso geeignete Techniken zur Einstellung entsprechender Partikelgrößenverteilungen, etwa durch Vermahlung, Mikronisierung oder durch Sprühtrocknung. Nur exemplarisch seien in diesem Zusammenhang folgende Dokumente genannt: EP 1124544; US 2005019411 ; EP 1 036 562; WO 95/05805; Farmacopea Europea, III Edition 1997, Paragraph 2.9.18., Seite 143. Angaben zu Partikelgrößen oder Parti <elgrößeverteilungen beziehen sich, sofern nichts anderes angegeben ist, immer auf den aerodynamischen Durchmesser, bestimmt für Partikelgrößen kleiner oder gleich 10 μm mittels Kaskadenimpaktor, für Partikelgrößen größer 10 μm mittels Laserbeugung. Beide Bestimmungsmethoden sind im Stand der Technik beschrieben. Für die nasale Deposition geeignete Partikelgrößen (aerodynamischer Durchmesser) liegen im Bereich zwischen etwa 10 und 200 μm. Bei Partikelgrößen unterhalb 10 μm, insbesondere unterhalb etwa 5 μm, werden die Teilchen inhalierbar und gelangen in die Lunge.The suitable for the nasal deposition particle sizes of the active ingredient and optionally used adjuvants are described in the prior art, as well as suitable techniques for setting appropriate particle size distributions, such as by grinding, micronization or by spray drying. By way of example only, the following documents may be mentioned in this connection: EP 1124544; US 2005019411; EP 1 036 562; WO 95/05805; Farmacopea Europea, III Edition 1997, Paragraph 2.9.18., Page 143. Particle sizes or particle size distributions, unless stated otherwise, always refer to the aerodynamic diameter determined for particle sizes smaller or equal to 10 μm by means of cascade impactor, for particle sizes greater than 10 μm by means of laser diffraction. Both methods of determination are described in the prior art. For nasal deposition suitable particle sizes (aerodynamic diameter) are in the range between about 10 and 200 microns. With particle sizes below 10 microns, especially below about 5 microns, the particles are inhaled and enter the lungs.
In geeigneten Nasal-Pulvern besitzen die Hilfsstoffe eine durchschnittliche Parlikelgröße von bis zu 350 μm, vorzugsweise zwischen 10 und 150 μm, besonders bevorzugt zwischen 15 and 80 μm. Der Wirkstoff wird mit einer durchschnittlichen Parlikelgröße von 0,1 bis 200 μm, vorzugsweise 5 bis 25 μm, besonders bevorzugt 10 bis 25 μm, dem Hilfsstoff beigemischt. Wirkstoff mit einer durchschnittlichen Partikelgröße von 0,1 bis 5 μm wird mit einem Träger, der ein für die nasale Deposition geeignetes Partikelgrößenspektrum aufweist, formuliert. Wirkstoff mit einer durchschnittlichen Partikelgröße von 5 bis 10 μm wird vorzugsweise, jedoch nicht zwingend, mit einem Träger, der ein für die nasale Deposition geeignetes Partikelgrößenspektrum aufweist, formuliert. Die Pulver können z.B. aus Kapseln mit geeigneten, im Stand der Technik beschriebenen Inhalatoren appliziert werden.In suitable nasal powders, the auxiliaries have an average particle size of up to 350 .mu.m, preferably between 10 and 150 .mu.m, particularly preferably between 15 and 80 .mu.m. The active ingredient is mixed with an average particle size of 0.1 to 200 .mu.m, preferably 5 to 25 .mu.m, particularly preferably 10 to 25 .mu.m, the excipient. Active ingredient having an average particle size of 0.1 to 5 microns is formulated with a carrier having a suitable for nasal deposition particle size spectrum. Active ingredient with an average particle size of 5 to 10 μm is preferably, but not necessarily, formulated with a carrier which has a particle size spectrum suitable for nasal deposition. The powders may e.g. from capsules with suitable inhalers described in the prior art.
Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Aerosole können den Wirkstoff oder die Wirkstoffkombination im Treibgas gelöst oder in dispergierter Form enthalten. Die zur Herstellung der Aerosole einsetzbaren Treibgase sind aus dem Stand der Technik bekannt. Geeignete Treibgase sind ausgewählt aus der Gruppe bestehend aus Kohlenwasserstoffen wie n-Propan, n- Butcin oder Isobutan und Halogenkohlenwasserstoffen wie bevorzugt fluorierten Derivaten des Methans, Ethans, Propans, Butans, Cyclopropans oder Cyclobutans. Die vorstehend genannten Treibgase können dabei allein oder in Mischungen derselben zur Verwendung kommen. Besonders bevorzugte Treibgase sind fluorierte Alkanderivate ausgewählt aus TG134a (1 ,1 ,1 ,2-Tetrafluorethan), TG227 (1 ,1 ,1 ,2,3,3,3-Heptafluorpropan) und Mischungen derselben.The propellant-containing aerosols which can be used in the context of the use according to the invention can dissolve the active substance or the active substance combination in the propellant gas or contain it in dispersed form. The propellant gases which can be used to produce the aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butcine or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
Die m Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Aerosole können ferner weitere Bestandteile wie Kosolventien, Stabilisatoren, oberflächenaktive Mittel (Surfactants), Antioxidantien, Schmiermittel sowie Mittel zur Einstellung des pH-Werts enthalten. All diese Bestandteile sind im Stand der Technik bekannt.The propellant-containing aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and agents for aerosols Adjustment of pH included. All of these ingredients are known in the art.
Erfolgt die nasale Applikation des erfindungsgemäßen Wirkstoffs oder der Wirkstoffkombination in Form von treibgasfreien Lösungen oder Suspensionen kommen als Lösungs- oder Suspendiermittel wässrige, ölige oder alkoholische, beispielsweise ethanolische Lösungen in Betracht. Das Lösungsmittel kann ausschließlich Wasser sein oder es ist ein Gemisch aus Wasser und Ethanol. Ebenso können sterile wässrige Lösungen der entsprechenden pharmazeutisch annehmbaren Salze zum Einsatz kommen. Des weiteren kommen Lösungen oder Suspensionen der Wirkstoffe in wässrigem Propylenglykol, in Sesam- oder Erdnussöl in Betracht. Wässrige Lösungen sollten nötigenfalls auf geeignete Weise gepuffert und der flüssige Verdünner beispielsweise mit genügend Salz oder Glucose isotonisch gemacht werden. Abhängig vom Stabilitätsoptimum und der Verträglichkeit können die den Wirkstoff oder die Wirkstoff kombination enthaltenden Lösungen oder Suspensionen mit geeigneten physiologisch verträglichen Säuren oder Basen auf einen pH-Wert von 2 bis 9, bevorzugt von 2 bis 7, insbesondere 2 bis 5 eingestellt werden. Zur Einstellung dieses pH-Werts können Säuren ausgewählt aus anorganischen oder organischen Säuren Verwendung finden. Beispiele für besonders geeignete anorganische Säuren sind Salzsäure, Bromwasserstoff säure, Salpetersäure, Schwefelsäure und/oder Phosphorsäure. Beispiele für besonders geeignete organische Säuren sind: Ascorbinsäure, Zitronensäure, Äpfelsäure, Weinsäure, Maleinsäure, Bernsteinsäure, Fumarsäure, Essigsäure, Ameisensäure und/oder Propionsäure und andere. Bevorzugte anorganische Säuren sind Salzsäure, Schwefelsäure. Unter den organischen Säuren sind Ascorbinsäure, Fumarsäure und Zitronensäure bevorzugt. Gegebenenfalls können auch Gemische der genannten Säuren eingesetzt werden, insbesondere in Fällen von Säuren, die neben ihren Säuerungseigenschaften auch andere Eigenschaften, z.B. als Antioxidantien oder Komplexbildner besitzen, wie beispielsweise Zitronensäure oder Ascorbinsäure. Als Basen kommen hierbei beispielsweise Natriumhydroxid, Kaliumhydroxid, Arginin, Cyclohexylamin, Ethanolamin, Diethanolamin und Triethanolamin in Betracht. Wie bereits eingangs erwähnt, weisen die Verbindungen 1 und deren Salze wertvolle Eigenschaften auf, insbesondere können sie zur Behandlung der nasalen Polyposis, der Rhinosinusitis, vorzugsweise der chronischen Rhinosinusitis oder der chronischen Rhinosinusitis mit nasaler Poyposis eingesetzt werden.If the nasal application of the active ingredient according to the invention or the active ingredient combination in the form of propellant-free solutions or suspensions come as a solution or suspending aqueous, oily or alcoholic, for example ethanolic solutions into consideration. The solvent may be water only or it may be a mixture of water and ethanol. Likewise, sterile aqueous solutions of the corresponding pharmaceutically acceptable salts may be used. Furthermore, solutions or suspensions of the active compounds in aqueous propylene glycol, in sesame or peanut oil into consideration. Aqueous solutions should be suitably buffered if necessary and the liquid diluent made isotonic with, for example, sufficient salt or glucose. Depending on the stability optimum and the compatibility, the solutions or suspensions containing the active substance or the active compound can be adjusted to a pH of 2 to 9, preferably 2 to 7, in particular 2 to 5, with suitable physiologically tolerated acids or bases. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Optionally, it is also possible to use mixtures of the abovementioned acids, in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as antioxidants or complexing agents, for example citric acid or ascorbic acid. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. As already mentioned, the compounds 1 and their salts have valuable properties, in particular they can be used for the treatment of nasal polyposis, rhinosinusitis, preferably chronic rhinosinusitis or chronic rhinosinusitis with nasal pooyposis.
Beispielsweise wurden die VerbindungenFor example, the compounds were
La. 1.b. 1.C 1.d. 1-e. 1.5. 1.6, 1.7. 1.8, 1.27, 1.30. 1.31. 1.32, 1.33, 1.34 undLa. 1.b. 1.C 1.d. 1-e. 1.5. 1.6, 1.7. 1.8, 1.27, 1.30. 1.31. 1.32, 1.33, 1.34 and
1.94.1.94.
als nasale Formulierungen für eine topische Applikation zubereitet.prepared as nasal formulations for topical application.
Beispiele für FormulierungenExamples of formulations
Die nachfolgenden Beispiele dienen der Erläuterung der Erfindung, ohne den Gegenstand der Erfindung zu beschränken. Beispiele für pharmazeutische Darreichungsformen von Verbindungen der Gruppe 1 können auch dem Stand der Technik entnommen werden, beispielsweise den vorstehend genannten Druckschriften.The following examples serve to illustrate the invention without limiting the scope of the invention. Examples of pharmaceutical dosage forms of compounds of group 1 can also be taken from the prior art, for example the abovementioned publications.
Die in den Beispiele 1 bis 5 und 7 beschriebenen Formulierungen enthalten einen beliebigen Wirkstoff ausgewählt aus der Gruppe 1. Die Formulierung des Beispiels 6 enthält einen Wirkstoff ausgewählt aus der Gruppe 1 , der keine hydrolyseempfindliche Gruppe, etwa eine Ester-oder Lactongruppe, besitzt.The formulations described in Examples 1-5 and 7 contain any active ingredient selected from Group 1. The formulation of Example 6 contains an active ingredient selected from Group 1 which has no hydrolysis-sensitive group, such as an ester or lactone group.
A) Pulver für die intranasale Applikation: Beispiel 1 :A) powder for intranasal administration: Example 1
Beispiel 2:Example 2:
Beispiel 3: Example 3:
Beispiel 4:Example 4:
Beispiel 5:Example 5:
Allgemeine Angaben zu den Beispielen 1 bis 5:General information on Examples 1 to 5:
Der Wirkstoff und der gegebenenfalls vorhanden Hilfsstoff (Lactosemonohydrat) werden, sofern erforderlich, jeweils mittels konventioneller Techniken mikronisiert, gegebenenfalls sphäronisiert und gesiebt, und gegebenenfalls anschließend im gewünschten Mengenverhältnis gemischt. Für den Wirkstoff wird eine zwischen 5 unc 200 μm liegende durchschnittliche Partikelgröße (aerodynamischer Durchmesser) eingestellt, beispielsweise im Bereich zwischen 10 bis 25 μm, die durchschnittliche Partikelgröße des Hilfsstoffs wird zweckmäßigerweise im Bereich 10 bis 350 μm gewählt, beispielsweise zwischen 15 bis 80 μm.If necessary, the active ingredient and any excipient present (lactose monohydrate) are each micronised using conventional techniques, optionally spheronised and sieved, and optionally then mixed in the desired ratio. For the active ingredient, an average particle size (aerodynamic diameter) lying between 5 and 200 μm is set, for example in the range between 10 to 25 μm, the average particle size of the excipient is expediently selected in the range 10 to 350 μm, for example between 15 to 80 μm.
B) Lösungen für die intranasale Applikation:B) Solutions for intranasal administration:
Beispiel 6Example 6
Nasalspray mit 1 mg Wirkstoff Zusammensetzung:Nasal spray with 1 mg of active ingredient Composition:
Wirkstoff 1.0 mg (bezogen auf die freie Base)Active ingredient 1.0 mg (based on the free base)
Natriumchlorid q.s. zur Isotonisierung Benzalkoniumchlorid 0.025 mgSodium chloride q.s. for isotonization benzalkonium chloride 0.025 mg
Dinatriumedetat 0.05 mgDisodium edetate 0.05 mg
Waε.ser gereinigt ad 0.1 mlWaε.ser cleaned ad 0.1 ml
Herstellungsverfahren: Der Wirkstoff in Form eines physiologisch verträglichen Salzes und die Hilfsstoffe werden in Wasser gelöst und in ein entsprechendes Behältnis abgefüllt.Method of preparation: The active ingredient in the form of a physiologically acceptable salt and the excipients are dissolved in water and filled into a corresponding container.
Beispiel 7Example 7
Nasalspray mit 1 mg WirkstoffNasal spray with 1 mg of active ingredient
Zusammensetzung:Composition:
Wirkstoff 1.0 mg (bezogen auf die freie Base)Active ingredient 1.0 mg (based on the free base)
Sesamöl ad 0.1 mlSesame oil ad 0.1 ml
Herstellungsverfahren:Production method:
Der Wirkstoff wird in Sesamöl gelöst und in ein entsprechendes Behältnis abgefüllt. The active ingredient is dissolved in sesame oil and filled into a corresponding container.

Claims

Patentansprüche claims
1. Verwendung von Verbindungen 1 ausgewählt aus der Gruppe bestehend aus den Verbindungen La bis Lj und 1.1 bis 1.1011. Use of compounds 1 selected from the group consisting of the compounds La to Lj and 1.1 to 1.101
(LS • 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)- carbonyl]-piperazin-1 -yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin, (Ub) 4-[(3-Chlor-4-f luor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin, d .c'i 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(LS) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine 1 -yl} -ethoxy) -6 - [(vinylcarbonyl) amino] quinazoline, (Ub) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) - 6-methyl-2-oxo-morpholin-4-yl) - ethoxy] -6 - [(vinylcarbonyl) amino] -quinazoline, d .c 'i 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline,
(1.d) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-m9thyl-2-oxo-morphoiin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(1.d) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morphoiin-4-yl) -butyloxy] - 6 - [(vinylcarbonyl) amino] -quinazoline,
(Le i 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin, (U) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-(Le i 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [( vinylcarbonyl) amino] quinazoline, (U) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N-
[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1 -yl)amino]-7-cyclopropyl- methoxy-chinazolin,[(ethoxycarbonyl) methyl] amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline,
(Lg) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin, (Lh] 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin, (Lj) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo- morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin, (Li) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(Lg) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} - 7-cyclopropylmethoxy quinazoline, (Lh] 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2 buten-1-yl} -amino) -7-cyclopropylmethoxy-quinazoline, (Lj) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl- 6-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, (Li) 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6 - [(4-dimethylamino-cyclohexyl) amino] pyrimido [5,4-d] pyrimidine,
(1.1) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(1.1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(1.2) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1 - yl]amino}-7-cyclopropylmethoxy-chinazolin,(1.2) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(1.3) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-cyclopropylmethoxy-chinazolin, (1.4) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-ylj- amino}-7-cyclopentyloxy-chinazolin, (1.51 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo^-buten-i-yljamino^-cyclopropylmethoxy-chinazolin, (IJS) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo-2-buten-1 -yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin, CLZ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpho- lin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin, (1.81 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,(1.3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline, (1.4) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl-amino} -7 -cyclopentyloxy-quinazoline, (1.51 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl] - 1-oxo-buten-i-yl-amino-cyclopropyl-methoxy-quinazoline, (IJS) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl -2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, CLZ) 4- [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-butene 1 -yl] amino} -7-cyclopropylmethoxy-quinazoline, (1.81 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo -morpholin-4-yl) -ethoxy] -7-methoxyquinazoline,
(1.9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(1.9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino]-1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy quinazoline,
(1.10) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yljaminoj^-cyclopentyloxy-chinazolin, (UJJ 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1 -oxo- 2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin,(1.10) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl-amino-1-cyclopentyloxy-quinazoline, ( UJJ 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1 -yl] amino} -7-cyclopropylmethoxyquinazoline,
(1.12) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1 - oxo^-buten-i -yljaminoj^-cyclopropylmethoxy-chinazolin,(1.12) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-butyne -i -ylamino) cyclopropylmethoxy quinazoline,
(1.13) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1- oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(1.13) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline,
(1.14) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-ami- nol-i -oxo^-buten-i -yljaminoj^-cyclopropylmethoxy-chinazolin,(1.14) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino-i-oxo] - buten-1-ylamino] cyclopropylmethoxyquinazoline,
(UiD 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin, (Ui>) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin, (1.17) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-annino]-(UiD 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - (( R) -tetrahydrofuran-3-yloxy) quinazoline, (Ui) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -butene-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline, (1.17) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-Annino] -
1 -oxo-2-buten-1 -yljaminoj^-cyclopentyloxy-chinazolin,1 -oxo-2-buten-1-yl-amino-1-cyclopentyloxy-quinazoline,
(1.1 tt) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo- 2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin,(1.1 t) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino } -7-cyclopentyloxy-quinazoline,
(1.19) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.19) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.20) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, (1.21) 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin, (JL2J=) 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazolin,(1.20) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, (1.21) 4 - [(3-Ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, (JL 2 J =) 4 - [(3-Chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline,
(1.23) 4-[(R)-(1 -Phenyl-θthyl)arτnino]-6-(4-hyclroxy-phenyl)-7H-pyrrolo[2,3-cl]pyrimi- din,(1.23) 4 - [(R) - (1-phenylthio) arnino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-cl] pyrimidine,
(1.24) 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2- buten-1 -yl]amino}-7-ethoxy-chinolin,(1.24) 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1-yl] amino} -7-ethoxy-quinoline,
(L2Ji) 3-Cyano-4-[(3-chlor-4-(pyridin-2-yl-methoxy)-phenyl)amino]-6-{[4-(N,N-di- methylamino)-1 -oxo-2-buten-1 -yl]amino}-7-ethoxy-chinolin, CL£i>) 4-{[3-Chlor-4-(3-f luor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin,(L 2 Ji) 3-cyano-4 - [(3-chloro-4- (pyridin-2-yl-methoxy) -phenyl) -amino] -6 - {[4- (N, N-dimethylamino) - 1-oxo-2-buten-1-yl] amino} -7-ethoxy-quinoline, Cl-1) 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} - 6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) quinazoline,
(1.27) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo-2-buten-1-yl]amino}-7-methoxy-chinazolin,(1.27) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-methoxy-quinazoline,
(1.28) 4-[(3-Chlor-4-fiuorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-[(tetrahydrof uran-2-yl)methoxy]-chinazolin,(1.28) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- [(tetrahydrofuran-2-yl) methoxy] quinazoline,
(1.29) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1 - oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.29) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene 1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.30) 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo- 2-buten-1 -yljamino}-chinazolin, CL3JL) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,(1.30) 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-butene-1 - yljamino} -quinazoline, CL3JL) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] - 7-methoxy-quinazoline,
(1.32) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.32) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [( R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.33) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-y!)- ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.33) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -6- [ (S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(1.34) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1- yl]-ethoxy}-7-methoxy-chinazolin,(1.34) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} - 7-methoxy-quinazoline,
(1.35) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4- yloxy]-7-methoxy-chinazolin, (Lßji) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1 -yloxy)-7- methoxy-chinazolin,(1.35) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, (Lβji) 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-ylxy) -7-methoxy-quinazoline,
(1.37) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclo- hexan-1 -yloxy)-7-methoxy-chinazolin, (1.3») 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- chinazolin, (1.39) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7-methoxy- chinazolin, (L4JD 4-[(3-Chlor-4-f luor-phenyl)amino]-6-{1 -[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin, (1.411) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(methoxymethyl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin, (L4J-) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy- chinazolin,(1.37) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline, (1.3 ») 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, (1.39) 4 - [(3-chloro-4- fluorophenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, (L 4 JD 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, (1,411) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, (L 4 J-) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidine 3-yloxy) -7-methoxyquinazoline,
(1.43) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yl- oxy]-7-methoxy-chinazolin,(1.43) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yl-oxy] -7-methoxy-quinazoline,
(1.44) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy- chinazolin, (L4J-) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy- chinazolin, (L4J.) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tθtrahydropyran-4-yloxy)-7-(2-methoxy- ethoxy)-chinazolin, (L4J'.) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]- cyclohexan-1 -yloxy}-7-methoxy-chinazolin,(1.44) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, (L 4 J-) 4 - [(3-chloro) 4-fluoro-phenyl) amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, (4 L J.) 4 - [(3-chloro-4-fluoro-phenyl) amino ] -6- (t-thrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) quinazoline, (L 4 J '.) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexane-1-oxy} -7-methoxy-quinazoline,
(L4Ji) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-1-yloxy}-7-methoxy-chinazolin, (1.49) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]- cyclohexan-1 -yloxy}-7-methoxy-chinazolin, (L5(l) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylami- no-ethoxy)-chinazolin,(L 4 Ji) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy quinazoline, (1.49) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) -sulfonylamino] -cyclohexane-1-yloxy} -7- methoxy-quinazoline, (L5 (I) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline,
(1.51 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methan- sulfonylamino-ethoxy)-chinazolin,(1.51) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline,
(1.52) 4-[(3-Chlor-4-f luor-phenyl)amino]-6-{1 -[(piperidin-1 -yl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,(1.52) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.53) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -aminocarbonylmethyl-piperidin-4-yl- oxy)-7-methoxy-chinazolin,(1.53) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yl-oxy) -7-methoxy-quinazoline
(1.54) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]- N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin, (UL'.,) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N- methyl-aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin,(1.54) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane 1-yloxy) -7-methoxy-quinazoline, (UL '.,) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} cyclohexan-i-yloxy ^ -methoxy-quinazoline,
(1.5B) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N- methyl-aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin, (1.57) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan- 1 -yloxy)-7-methoxy-chinazolin,(1.5B) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino-cyclohexane i-yloxy ^ -methoxy-quinazoline, (1.57) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonyl-amino-cyclohexane-1-yloxy) -7-methoxy-quinazoline .
(1.58) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7- ethoxy-chinazolin,(1.58) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline,
(1.59) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazolin,(1.59) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxyethoxy) -quinazoline,
(1.60) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4-yloxyj- 7-(2-methoxy-ethoxy)-chinazolin,(1.60) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy-7- (2-methoxy-ethoxy) -quinazoline .
(1.61) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)- 7-methoxy-chinazolin, CL62) 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7- methoxy-chinazolin,(1.61) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, CL62) 4 - [(3 Ethynylphenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
(1.63) 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy- chinazolin,(1.63) 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxyquinazoline,
(1.64) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-me- thyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,(1.64) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N-methyl-amino} - cyclohexane-1-yloxy) -7-methoxy-quinazoline,
(1.65) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1 -yl)- carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin,(1.65) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] -N-methyl- amino} -cyclohexane-1-yloxy) -7-methoxy-quinazoline,
(1.6(>) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-1-yloxy}-7-methoxy-chinazolin, (U>7) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxopyrrolidin-1 -yl)ethyl]-piperidin- 4-yloxy}-7-methoxy-chinazolin,(1.6 (>) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy -quinazoline, (U> 7) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy } -7-methoxy-quinazoline,
(1.68) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4- yloxy}-7-(2-methoxy-ethoxy)-chinazolin,(1.68) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxy) ethoxy) -quinazoline,
(1.69) 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.69) 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.70) 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.70) 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline,
(1.711) 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-me- thoxy-chinazolin, (1.72) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-pipeπdin-4-yloxy)-7(2-methoxy- ethoxy)-chinazolin,(1.711) 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, (1.72) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidine-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline,
(1.73) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yl- oxy)-7-methoxy-chinazolin, (-LZf-D 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1 -yloxy)-(1.73) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yl-oxy) -7-methoxy-quinazoline, (-LZf-D 4- [ (3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexane-1-yloxy) -
7-methoxy-chinazolin, (1.75) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl- amino]-cyclohexan-1 -yloxy}-7-methoxy-chinazolin, (LTiI) 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin, (UJ.) 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4-yloxy]-7- methoxy-chinazolin,7-methoxy-quinazoline, (1.75) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-ylxy} -7-methoxy-quinazoline, (LTiI) 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, (UJ.) 4 - [(3-ethynylphenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
(1.78) 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-chinazolin,(1.78) 4 - [(3-ethynyl-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.79) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)car- bonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.79) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidine-4- yloxy} -7-methoxy-quinazoline,
(1.80) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(2-methyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin,(1.80) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy -quinazoline,
(1.811) 4-[(3-Chlor-4-f luor-ρhenyl)amino]-6-{1 -[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1 ]- hept5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, (1Λ2) 4-[(3-Chlor-4-fluor-ρhenyl)amino]-6-{1 -[(N-methyl-N-2-methoxyethyl-amino)- carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.811) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-azabicyclo [2.2.1] -hept5 -yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, (1Λ2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl- N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline,
(1.83) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -ethyl-piperidin-4-yloxy)-7-methoxy- chinazolin,(1.83) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.84) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,(1.84) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.85) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin,(1.85) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.86) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-ami- no)-cyclohexan-1-yloxy]-7-methoxy-chinazolin, (IJBj') 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclo- hexan-1-yloxy]-7-methoxy-chinazolin,(1.86) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7- methoxy-quinazoline, (IJBj ') 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexane-1 yloxy] -7-methoxy-quinazoline,
(1.88) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yl- oxy)-7-methoxy-chinazolin (1.89) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl- amino)-cyclohexan-1 -yloxy]-7-methoxy-chinazolin,(1.88) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yl-oxy) -7-methoxy-quinazoline (1.89) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy quinazoline,
(1.90) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1 - yloxy)-7-methoxy-chinazolin(1.90) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline
5 (L9JL) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N- methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-chinazolin,5 (L 9 JL) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} cyclohexane-1-ylxy) -7-methoxyquinazoline,
(1.92) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxo-3-methyl-imidazolidin-1 -yl)- ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin(1.92) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-3-methyl-imidazolidin-1-yl) -ethyl] -piperidine-4 yloxy} -7-methoxy-quinazoline
(1.93) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxo-hθxahydropyrimidin-1 -yl)- o ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin,(1.93) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-hydroxy-pyrimidin-1-yl) -o-ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
(1.94) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(1.94) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [( S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
QJ)J)) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7- methoxy-chinazolin, 5 (1_JH>) 4-[(3-Chlor-4-f luor-phenyl)amino]-6-(1 -cyano-piperidin-4-yloxy)-7-methoxy- chinazolin,QJ) J)) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 5 (1-yH) 4- [ (3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.97) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy- chinazolin,(1.97) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline,
(1.98) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methylcarbonyi-piperidin-4-yloxy)-7- 0 methoxy-chinazolin,(1.98) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylcarbonyi-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.99) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -dimethylaminoacetyl-piperidin-4- yloxy)-7-methoxy-chinazolin,(1.99) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-dimethylamino-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
(1.100) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(dimethylamino)carbonylmethyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, 5 (1.101) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)- chinazolin,(1,100) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(dimethylamino) -carbonyl-methyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 5 (1.101) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -quinazoline,
deren Tautomere, deren Stereoisomere oder deren Salze, zur Herstellung eines Medikamentes zur Vorbeugung oder Behandlung einer Indikation ausgewählt aus 0 der Gruppe bestehend aus chronischer Rhinosinusitis, nasaler Polyposis und der chronischen Rhinosinusitis mit nasaler Polyposis.their tautomers, their stereoisomers or their salts, for the manufacture of a medicament for the prevention or treatment of an indication selected from the group consisting of chronic rhinosinusitis, nasal polyposis and chronic rhinosinusitis with nasal polyposis.
2. Verwendung einer der Verbindungen U., 1^4, U>, UJ, JL9, 1.14, 1.17, 1.19. 1.21 , 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71 , 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91. 1.94 und 1.95, deren Tautomere, deren Stereoisomere oder deren Salze, gemäß Anspruch 1.2. Use of one of the compounds U., 1 ^ 4, U>, UJ, JL9, 1.14, 1.17, 1.19. 1.21, 1.23, 1.24, 1.27, 1.28, 1.30, 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43, 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.88, 1.90, 1.91. 1.94 and 1.95, their tautomers, their stereoisomers or salts thereof, according to claim 1.
5 3. Vorwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass die Indikation chronische Rhinosinusitis ist.5 3. Vorvor according to one of claims 1 or 2, characterized in that the indication is chronic rhinosinusitis.
4. Vorwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass die Indikation nasale Polyposis ist. o4. Avor according to one of claims 1 or 2, characterized in that the indication is nasal polyposis. O
5. Vorwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass die Indikation chronische Rhinosinusitis mit nasaler Polyposis ist.5. Vorwend according to one of claims 1 or 2, characterized in that the indication is chronic rhinosinusitis with nasal polyposis.
6. Vorwendung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass es 5 sich um ein Medikament zur Vorbeugung handelt.6. Vorwend according to one of claims 1 to 5, characterized in that it is 5 is a medicament for the prevention.
7. Vorwendung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass es sich um ein Medikament zur Behandlung handelt.7. Vorwend according to one of claims 1 to 5, characterized in that it is a medicament for treatment.
0 8. Verwendung eine der in Anspruch 1 oder 2 genannten Verbindungen zur Herstellung eines Medikamentes, um vergrößerte nasale Polypen zu verkleinern.0 8. Use of the compounds mentioned in claim 1 or 2 for the manufacture of a medicament to reduce enlarged nasal polyps.
9. Verwendung einer der in Anspruch 1 oder 2 genannten Verbindungen zur Herstellung eines Arzneimittels für die nasale Anwendung. 59. Use of any of the compounds mentioned in claim 1 or 2 for the manufacture of a medicament for nasal application. 5
10. Arzneimittel in Form eines Pulvers für die nasale Applikation enthaltend mindestens eine der in Anspruch 1 genannten Verbindungen mit einer mittleren Partikelgröße im Bereich zwischen etwa 0,1 und 200 μm und optional einen oder mehrere Hilfsstoffe. 010. Drugs in the form of a powder for nasal administration containing at least one of the compounds mentioned in claim 1 with an average particle size in the range between about 0.1 and 200 microns and optionally one or more excipients. 0
11. Arzneimittel für die nasale Applikation in Form einer Suspension enthaltend mindestens eine der in Anspruch 1 genannten Verbindungen, ein Suspensionmittel und optional einen oder mehrere Hilfsstoffe. 11. Medicament for nasal administration in the form of a suspension comprising at least one of the compounds mentioned in claim 1, a suspension agent and optionally one or more excipients.
12. Arzneimittel für die nasale Applikation in Form einer Lösung enthaltend mindestens eine der in Anspruch 1 genannten Verbindungen, mindestens ein Lösungsmittel und optional einen oder mehrere Hilfsstoffe.12. Drugs for nasal administration in the form of a solution containing at least one of the compounds mentioned in claim 1, at least one solvent and optionally one or more excipients.
13. Verfahren zur Vorbeugung oder Behandlung einer Indikation ausgewählt aus der13. A method for the prevention or treatment of an indication selected from
Gruppe bestehend aus chronischer Rhinosinusitis, nasaler Polyposis und der chronischen Rhinosinusitis mit nasaler Polyposis umfassend die Verabreichung einer wirksamen Menge einer oder mehrerer der in Anspruch 1 oder 2 genannten Verbindungen oder eines deren physiologisch verträglichen Salze an einen Patienten, der einer solchen Behandlung bedarf.A group consisting of chronic rhinosinusitis, nasal polyposis and chronic nasal polyposis rhinosinusitis comprising administering to a patient in need of such treatment an effective amount of one or more of the compounds recited in claim 1 or 2 or one of their physiologically acceptable salts.
14. Verfahren nach Anspruch 13, dadurch gekennzeichnet, dass die Indikation chronische Rhinosinusitis ist.14. The method according to claim 13, characterized in that the indication is chronic rhinosinusitis.
15. Verfahren nach Anspruch 13, dadurch gekennzeichnet, dass die Indikation nasale Polyposis ist.15. The method according to claim 13, characterized in that the indication is nasal polyposis.
16. Verfahren nach Anspruch 13, dadurch gekennzeichnet, dass die Indikation chronische Rhinosinusitis mit nasaler Polyposis ist.16. The method according to claim 13, characterized in that the indication is chronic rhinosinusitis with nasal polyposis.
17. Verfahren zur Verkleinerung vergrößerter Nasenpolypen umfassend die Verabreichung einer wirksamen Menge einer oder mehrerer der in Anspruch 1 oder 2 genannten Verbindungen oder eines deren physiologisch verträglichen Salze an einen Patienten, der einer solchen Behandlung bedarf. 17. A method of reducing enlarged nasal polyps comprising administering to a patient in need of such treatment an effective amount of one or more of the compounds recited in claim 1 or 2 or one of their physiologically tolerable salts.
EP06707722A 2005-02-04 2006-01-16 Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis Withdrawn EP1845992A1 (en)

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DE102005005505A DE102005005505A1 (en) 2005-02-04 2005-02-04 Use of quinazoline derivatives e.g. 4-((3-chloro-4-fluoro-phenyl)amino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, which are tyrosine kinase inhibitors, to prevent or treat symptoms of e.g. chronic rhinosinusitis
DE102005036216A DE102005036216A1 (en) 2005-08-02 2005-08-02 Use of quinazoline derivatives e.g. 4-((3-chloro-4-fluoro-phenyl)amino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, which are tyrosine kinase inhibitors, to prevent or treat symptoms of e.g. chronic rhinosinusitis
PCT/EP2006/050215 WO2006082129A1 (en) 2005-02-04 2006-01-16 Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis

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