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US20110046168A1 - Methods of treating diseases using quinazoline derivatives and pharmaceutical compositions containing them - Google Patents

Methods of treating diseases using quinazoline derivatives and pharmaceutical compositions containing them Download PDF

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Publication number
US20110046168A1
US20110046168A1 US12/914,003 US91400310A US2011046168A1 US 20110046168 A1 US20110046168 A1 US 20110046168A1 US 91400310 A US91400310 A US 91400310A US 2011046168 A1 US2011046168 A1 US 2011046168A1
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Prior art keywords
amino
tetrahydrofuran
buten
oxo
chloro
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US12/914,003
Inventor
Frank Himmelsbach
Elke Langkopf
Stefan Blech
Birgit Jung
Anke Baum
Flavio Solca
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE10063435A external-priority patent/DE10063435A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to quinazoline derivatives of general formula
  • R a denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group
  • R b denotes a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and
  • R c denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyran-4-ylmethoxy group,
  • R a , R b , and R c are as hereinbefore defined, but with the exception of the compounds
  • R a denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl group
  • R b denotes a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and
  • R c denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyran-4-ylmethoxy group,
  • the compounds of general formula I may be prepared by the following methods, for example:
  • R a and R c are as hereinbefore defined, with a compound of general formula
  • R b is as hereinbefore defined; and Z 1 denotes a leaving group such as a halogen atom, e.g., a chlorine or bromine atom, or a hydroxy group.
  • a halogen atom e.g., a chlorine or bromine atom, or a hydroxy group.
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, expediently at temperatures between ⁇ 50° C. and 150° C., preferably at temperatures between ⁇ 20° C. and 80° C.
  • a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane
  • a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzen
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 4-dimethylaminopyridine, in the presence of N-ethyldiisopropylamine (Hünig base), whilst these organic bases may simultaneously also act as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, expediently at temperatures between ⁇ 50° C. and 150° C., preferably at temperatures between ⁇ 20° C. and 80° C.
  • solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran
  • the reaction is preferably carried out in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 1-hydroxybenzotriazole, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, ethylene glycol diethylether or
  • R a and R c are as hereinbefore defined; and Z 2 denotes a leaving group such as a halogen atom, a substituted hydroxy or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of general formula:
  • R b is as hereinbefore defined.
  • the reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethylether, ethylene glycol diethylether or sulfolane or mixtures thereof, optionally in the presence of an inorganic or tertiary organic base, e.g., sodium carbonate or potassium hydroxide, a tertiary organic base, e.g., triethylamine or N-ethyldiisopropylamine (Hünig base), whilst these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide at temperatures between ⁇ 20° C. and 150° C., but preferably at temperatures between ⁇ 10° C. and 100° C.
  • a reaction accelerator such as an alkal
  • the secondary amino group bound to the quinazoline of general formula II or IV may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • protecting groups include the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group.
  • Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g., in the presence of iodotrimethylsilane, at temperatures between 0° C. and 120° C., preferably at temperatures between 10° C. and 100° C.
  • an aqueous solvent e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g., with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0° C. and 100° C., but preferably at ambient temperatures between 20° C. and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50° C. and 120° C. or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0° C. and 50° C.
  • the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
  • the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. N. L. Allinger and E. L. Eliel in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g., by chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • an optically active substance which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salt
  • Optically active acids in common use are, e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • An optically active alcohol may be for example (+) or ( ⁇ )-menthol and an optically active acyl group in amides, for example, may be a (+)- or ( ⁇ )-menthyloxycarbonyl.
  • the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
  • a starting compound of general formula II is obtained by reacting a 7-fluoro-6-nitro compound correspondingly substituted in the 4 position with a corresponding allcoxide and subsequently reducing the nitro compound thus obtained or
  • a starting compound of general formula III is obtained, for example, by reacting a suitable bromocrotonic acid derivative with one of the amines of general formula V known from the literature, or
  • a starting compound of general formula IV is obtained by acylating a compound of general formula II with a suitable crotonic acid derivative.
  • the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerization or tyrosine kinase itself. It is also possible to block the transmission of signals to components located further down.
  • EGF-R Epidermal Growth Factor receptor
  • EGF-receptor kinase The inhibition of human EGF-receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186, based on the sequence published in Nature 309 (1984), 418). To do this, the protein was expressed in Sf9 insect cells as a GST fusion protein using the Baculovirus expression system.
  • the enzyme activity was measured in the presence or absence of the test compounds in serial dilutions.
  • the polymer pEY (4:1) produced by SIGMA was used as the substrate.
  • Biotinylated pEY (bio-pEY) was added as the tracer substrate. Every 100 ⁇ l of reaction solution contained 10 ⁇ l of the inhibitor in 50% DMSO, 20 ⁇ l of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 ⁇ g/ml bio-pEY) and 20 ⁇ l of enzyme preparation.
  • the enzyme reaction was started by the addition of 50 ⁇ l of a 100 ⁇ M ATP solution in 10 mM magnesium chloride.
  • the dilution of the enzyme preparation was adjusted so that the incorporation of phosphate into the bio-pEY was linear in terms of time and quantity of enzyme.
  • the enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
  • the enzyme assays were carried out at ambient temperature over a period of 30 minutes and were ended by the addition of 50 ⁇ l of a stopping solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 ⁇ l were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at ambient temperature. Then the plate was washed with 200 ⁇ l of a washing solution (50 mM Tris, 0.05% Tween 20). After the addition of 100 ⁇ l of a HRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP produced by Transduction Laboratories, 250 ng/ml), it was incubated for 60 minutes.
  • a stopping solution 250 mM EDTA in 20 mM HEPES pH 7.4
  • 100 ⁇ l were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at ambient temperature. Then the plate was washed with 200 ⁇ l of a washing solution (
  • microtiter plate was washed three times with 200 ⁇ l of washing solution.
  • the compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases e.g., benign or malignant tumors, particularly tumors of epithelial and neuroepithelial origin, metastasization and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g., in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
  • inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or coughs, pulmonary emphysema,
  • the compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found, e.g., in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier's disease, secreting adenomas and protein loss syndrome.
  • diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found, e.g., in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier's disease, secreting adenomas and protein
  • the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat other diseases caused by abnormal function of tyrosine kinases, such as, e.g., epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.
  • diseases caused by abnormal function of tyrosine kinases such as, e.g., epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.
  • the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g., etoposide), mitosis inhibitors (e.g., vinblastine), compounds which interact with nucleic acids (e.g., cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g., tamoxifen), inhibitors of metabolic processes (e.g., 5-FU etc.), cytokines (e.g., interferons), antibodies, etc.
  • topoisomerase inhibitors e.g., etoposide
  • mitosis inhibitors e.g., vinblastine
  • nucleic acids e.g., cis-platin, cyclophosphamide, adriamycin
  • hormone antagonists
  • these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity.
  • these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion. These combinations may be administered either simultaneously or sequentially.
  • These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
  • the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg.
  • they are formulated with one or more conventional inert carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
  • conventional inert carriers and/or diluents e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stea
  • the crude bromocrotonic acid chloride is taken up in 30 ml of methylene chloride and, while cooling with an ice bath, added dropwise to a solution of 7.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-cyclopropylmethoxyquinazoline and 10.20 ml of Hünig base in 150 ml of tetrahydrofuran.
  • the reaction mixture is stirred for about 1.5 hours while cooling with an ice bath and then for another two hours at ambient temperature.
  • 5.20 g of N-(2-methoxyethyl)-N-methylamine are added and the reaction mixture is stirred overnight at ambient temperature.
  • active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate.
  • Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
  • Weight of core 230 mg; die: 9 mm, convex.
  • the tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film-coated tablets are polished with beeswax.
  • Weight of coated tablet 245 mg.
  • the active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone.
  • the moist composition After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C., it is screened again (1.5 mm mesh size) and the lubricant is added.
  • the finished mixture is compressed to form tablets.
  • Weight of tablet 220 mg; diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
  • active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
  • the active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm
  • the granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
  • the active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • the active substance is homogeneously distributed therein and the melt is poured into chilled molds.
  • active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavoring 0.30 g dist. water ad 100 ml
  • the distilled water is heated to 70° C.
  • the methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring.
  • the solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
  • the suspension is evacuated with stirring to eliminate air. 5 ml of suspension contains 50 mg of active substance.
  • the active substance is dissolved in the requisite amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
  • the active substance is mixed with lactose for inhalation.
  • the mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg). Weight of capsule: 70.0 mg; size of capsule: 3.
  • the active substance and benzalkonium chloride are dissolved in ethanol/water (50/50).
  • the pH of the solution is adjusted with 1N hydrochloric acid.
  • the resulting solution is filtered and transferred into suitable containers for use in hand-held nebulizers (cartridges). Contents of the container: 4.5 g.

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Abstract

A compound of general formula I
Figure US20110046168A1-20110224-C00001
    • wherein:
    • Ra is a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group;
    • Rb is a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino, or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and
    • Rc is a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group,
    • or a tautomer, stereoisomer, or salt thereof,
      particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and airways, and the preparation thereof.

Description

    SUMMARY OF THE INVENTION
  • The present invention relates to quinazoline derivatives of general formula
  • Figure US20110046168A1-20110224-C00002
  • the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
  • In the above general formula I
  • Ra denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,
  • Rb denotes a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and
  • Rc denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyran-4-ylmethoxy group,
  • with the exception of the compounds
    • (1) 3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (5) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (8) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (9) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (10) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (11) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (12) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (13) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (14) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (15) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (16) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (17) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (18) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
    • (19) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline,
    • (20) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline and
    • (21) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline.
  • Preferred compounds of the above general formula I are those wherein
  • Ra, Rb, and Rc are as hereinbefore defined, but with the exception of the compounds
    • (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (5) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (8) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (9) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (10) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (11) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (12) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (13) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (14) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (15) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (16) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (17) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (18) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
    • (19) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline,
    • (20) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (21) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (22) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (23) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (24) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (25) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (26) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (27) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (28) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline,
    • (29) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline,
    • (30) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoline,
    • (31) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazoline,
    • (32) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline and
    • (33) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
      the tautomers, the stereoisomers and the salts thereof.
  • Particularly preferred compounds of general formula I are those wherein
  • Ra denotes a 1-phenylethyl or 3-chloro-4-fluorophenyl group,
  • Rb denotes a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group and
  • Rc denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy or tetrahydropyran-4-ylmethoxy group,
  • with the exception of the compounds
    • (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (5) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (6) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (7) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (8) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (9) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (10) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (11) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
    • (12) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (13) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (14) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (15) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (16) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (17) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (18) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
    • (19) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline,
    • (20) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (21) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (22) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (23) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (24) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (25) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (26) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline,
    • (27) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoline,
    • (28) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazoline,
    • (29) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline,
    • (30) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (31) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (32) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline and
    • (33) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline,
      the tautomers, the stereoisomers and the salts thereof.
  • The following particularly preferred compounds of general formula I may be mentioned by way of example:
    • (a) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline;
    • (b) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
    • (c) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis(2-methoxyethyl)amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (d) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-ethylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (e) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (f) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (g) 4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydrofuran-3-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,
    • (h) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-(4-{N-[(tetrahydrofuran-3-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline,
    • (i) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline,
    • (j) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline,
    • (k) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(tetrahydropyran-4-yloxy)quinazoline,
    • (l) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (m) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline,
    • (o) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline,
    • (p) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
    • (q) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (r) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
    • (s) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline; and
    • (t) 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,
      the tautomers, the stereoisomers and the salts thereof.
  • The compounds of general formula I may be prepared by the following methods, for example:
  • a) Reacting a Compound of General Formula
  • Figure US20110046168A1-20110224-C00003
  • wherein:
    Ra and Rc are as hereinbefore defined, with a compound of general formula
  • Figure US20110046168A1-20110224-C00004
  • wherein:
    Rb is as hereinbefore defined; and
    Z1 denotes a leaving group such as a halogen atom, e.g., a chlorine or bromine atom, or a hydroxy group.
  • The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, expediently at temperatures between −50° C. and 150° C., preferably at temperatures between −20° C. and 80° C.
  • With a compound of general formula III wherein Z1 denotes a leaving group, the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 4-dimethylaminopyridine, in the presence of N-ethyldiisopropylamine (Hünig base), whilst these organic bases may simultaneously also act as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, expediently at temperatures between −50° C. and 150° C., preferably at temperatures between −20° C. and 80° C.
  • With a compound of general formula III wherein Z1 denotes a hydroxy group, the reaction is preferably carried out in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 1-hydroxybenzotriazole, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, ethylene glycol diethylether or sulfolane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between −50° C. and 150° C., but preferably at temperatures between −20° C. and 80° C.
    • b) Reacting a Compound of General Formula
  • Figure US20110046168A1-20110224-C00005
  • wherein:
    Ra and Rc are as hereinbefore defined; and
    Z2 denotes a leaving group such as a halogen atom, a substituted hydroxy or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of general formula:

  • H—Rb  (V)
  • wherein Rb is as hereinbefore defined.
  • The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethylether, ethylene glycol diethylether or sulfolane or mixtures thereof, optionally in the presence of an inorganic or tertiary organic base, e.g., sodium carbonate or potassium hydroxide, a tertiary organic base, e.g., triethylamine or N-ethyldiisopropylamine (Hünig base), whilst these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide at temperatures between −20° C. and 150° C., but preferably at temperatures between −10° C. and 100° C. The reaction may, however, also be carried out without a solvent or in an excess of the compound of general formula V used.
  • In the reactions described above, the secondary amino group bound to the quinazoline of general formula II or IV may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. Examples of protecting groups include the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group.
  • Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g., in the presence of iodotrimethylsilane, at temperatures between 0° C. and 120° C., preferably at temperatures between 10° C. and 100° C.
  • However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g., with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0° C. and 100° C., but preferably at ambient temperatures between 20° C. and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50° C. and 120° C. or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0° C. and 50° C.
  • Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
  • Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. N. L. Allinger and E. L. Eliel in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g., by chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • The enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are, e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (−)-menthyloxycarbonyl.
  • Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
  • The compounds of general formulae II to V used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.
  • For example, a starting compound of general formula II is obtained by reacting a 7-fluoro-6-nitro compound correspondingly substituted in the 4 position with a corresponding allcoxide and subsequently reducing the nitro compound thus obtained or
  • a starting compound of general formula III is obtained, for example, by reacting a suitable bromocrotonic acid derivative with one of the amines of general formula V known from the literature, or
  • a starting compound of general formula IV is obtained by acylating a compound of general formula II with a suitable crotonic acid derivative.
  • As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerization or tyrosine kinase itself. It is also possible to block the transmission of signals to components located further down.
  • The biological properties of the new compounds were investigated as follows:
  • The inhibition of human EGF-receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186, based on the sequence published in Nature 309 (1984), 418). To do this, the protein was expressed in Sf9 insect cells as a GST fusion protein using the Baculovirus expression system.
  • The enzyme activity was measured in the presence or absence of the test compounds in serial dilutions. The polymer pEY (4:1) produced by SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) was added as the tracer substrate. Every 100 μl of reaction solution contained 10 μl of the inhibitor in 50% DMSO, 20 μl of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 μg/ml bio-pEY) and 20 μl of enzyme preparation. The enzyme reaction was started by the addition of 50 μl of a 100 μM ATP solution in 10 mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the incorporation of phosphate into the bio-pEY was linear in terms of time and quantity of enzyme. The enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
  • The enzyme assays were carried out at ambient temperature over a period of 30 minutes and were ended by the addition of 50 μl of a stopping solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at ambient temperature. Then the plate was washed with 200 μl of a washing solution (50 mM Tris, 0.05% Tween 20). After the addition of 100 μl of a HRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP produced by Transduction Laboratories, 250 ng/ml), it was incubated for 60 minutes. Then the microtiter plate was washed three times with 200 μl of washing solution. The samples were then combined with 100 μl of a TMB-peroxidase solution (A:B=1:1, Kirkegaard Perry Laboratories). After 10 minutes, the reaction was stopped. The extinction was measured at OD450nm with an ELISA reader. All data points were measured three times.
  • The data were matched by means of an iterative calculation using an analytical program for sigmoidal curves (Graph Pad Prism Version 3.0) with variable Hill pitch. All the iteration data released showed a correlation coefficient of more 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. The concentration of active substance which inhibits the activity of EGF-receptor kinase by 50% (IC50) was derived from the curves.
  • The following results were obtained:
  • Compound Inhibition of EGF-Receptor
    (Example No.) Kinase IC50 [nM]
    1 0.7
    1 (2)  0.6
    1 (3)  4.0
    1 (5)  3.0
    1 (10) 0.5
    1 (22) 1.0
    1 (32) 0.3
    1 (33) 0.5
    1 (34) 0.4
  • The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are, e.g., benign or malignant tumors, particularly tumors of epithelial and neuroepithelial origin, metastasization and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g., in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
  • The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found, e.g., in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier's disease, secreting adenomas and protein loss syndrome.
  • In addition, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat other diseases caused by abnormal function of tyrosine kinases, such as, e.g., epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.
  • By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g., etoposide), mitosis inhibitors (e.g., vinblastine), compounds which interact with nucleic acids (e.g., cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g., tamoxifen), inhibitors of metabolic processes (e.g., 5-FU etc.), cytokines (e.g., interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion. These combinations may be administered either simultaneously or sequentially.
  • These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
  • For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
  • The following Examples are intended to illustrate the present invention without restricting it.
    • Preparation of the Starting Compounds Example I 3-methylaminotetrahydrofuran
  • 3.43 g of lithium aluminium hydride are added batchwise to 50 ml of tetrahydrofuran while cooling with an ice bath. Then a solution of 5.00 g of 3-[(benzyloxycarbonyl)-amino]tetrahydrofuran in 20 ml tetrahydrofuran is added dropwise, while the temperature remains below 10° C. After 10 minutes, the cooling bath is removed and the reaction mixture is refluxed for about three hours. For working up, 3.7 ml of water, 3.7 ml of 15% sodium hydroxide solution, and another 3 ml of water are carefully added dropwise to the reaction mixture while cooling with an ice bath. Then some tetrahydrofuran is added and the mixture is stirred for another 15 minutes. The aluminium hydroxide slurry precipitated is suction filtered and washed with a total of 150 ml of tetrahydrofuran. The filtrate is evaporated down using the rotary evaporator. A colorless oil remains, which is reacted without any further purification. Mass spectrum (ESI+): m/z=102 [M+H]+; Rf value: 0.20 (silica gel, methylene chloride/methanol=9:1).
    • Example II 3-[(benzyloxycarbonyl)amino]tetrahydrofuran
  • 12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of diphenylphosphorylazide in 500 ml of dioxane are combined with 41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The reaction mixture is heated to 100° C. for about seven hours. After cooling to ambient temperature, the reaction mixture is evaporated down using the rotary evaporator. The residue is taken up in 500 ml of methylene chloride and washed twice with 100 ml of 1 N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (3:1 to 1:2) as eluant. Yield: 15.60 g (55% of theory); mass spectrum (ESI−): m/z=220 [M−H]−; Rf value: 0.78 (silica gel, methylene chloride/methanol=9:1).
    • Example III 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((R)-tetrahydrofuran-3-yloxy)quinazoline
  • A mixture of 12.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-(R)-tetrahydrofuran-3-yloxy)quinazoline, 200 ml of ethanol, 100 ml of water, and 17.20 ml of glacial acetic acid is heated to reflux temperature. Then a total of 7.00 g of iron powder is added in batches. The reaction mixture is refluxed for about four hours and then cooled to ambient temperature overnight. For working up, the reaction mixture is evaporated using the rotary evaporator. The residue is taken up in methylene chloride/methanol (9:1), mixed with 20 ml of concentrated ammonia solution and filtered through a layer of silica gel. It is washed with copious amounts of methylene chloride/methanol (9:1) and the combined filtrates are evaporated down. The residue is stirred with diethylether and suction filtered. Yield: 8.59 g (73% of theory); mass spectrum (ESI−): m/z=373, 375 [M−H]−; Rf value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
  • The following compounds are obtained analogously to Example III:
  • (1) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy)quinazoline
    Mass spectrum (ESL): m/z=373, 375 [M−H]−; Rf value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
    (2) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-(tetrahydropyran-4-yloxy)quinazoline
    Mass spectrum (ESI−): m/z=387, 389 [M−H]−; Rf value: 0.20 (silica gel, ethyl acetate).
    (3) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=387, 389 [M−H]−; Rf value: 0.55 (silica gel, ethyl acetate/methanol=9:1).
    (4) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=387, 389 [M−H]−; Rf value: 0.40 (silica gel, ethyl acetate/methanol=9:1).
    • Example IV 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((R)-tetrahydrofuran-3-yloxy)quinazoline
  • 13.80 g of potassium tert-butoxide are added batchwise to a solution of 10.80 g of (R)-3-hydroxytetrahydrofuran in 100 ml of N,N-dimethylformamide while cooling with an ice bath. The reaction mixture is stirred for about one hour, then 10.40 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are added batchwise. The cooling bath is then removed and the deep red reaction mixture is stirred for two hours at ambient temperature. For working up the reaction mixture is poured onto about 500 ml of water and neutralized with 2 N hydrochloric acid. The yellowish precipitate formed is suction filtered and dried at 70° C. in a circulating air drier. Yield: 12.80 g; melting point: 244° C.; mass spectrum (ESI−): m/z=403, 405 [M−H]−.
  • The following compounds are obtained analogously to Example IV:
  • (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)quinazoline
    Mass spectrum (ESI−): m/z=403, 405 [M−H]−; Rf value: 0.45 (silica gel, ethyl acetate).
    (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-(tetrahydropyran-4-yloxy)quinazoline
    Mass spectrum (ESI−): m/z=417, 419 [M−H]−; Rf value: 0.42 (silica gel, ethyl acetate).
    (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=417, 419 [M−H]−; Rf value: 0.47 (silica gel, ethyl acetate).
    (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=417, 419 [M−H]−; Rf value: 0.41 (silica gel, ethyl acetate).
    (5) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=433, 435 [M+H]+; Rf value: 0.79 (silica gel, ethyl acetate/methanol=9:1).
    (6) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=419, 421 [M+H]+; Rf value: 0.44 (silica gel, ethyl acetate).
    (7) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=419, 421 [M+H]+; Rf value: 0.44 (silica gel, ethyl acetate).
    • Example V (R)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamine
  • 21.10 g of (R)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine (crude product from Example VI) are dissolved in 200 ml of methanol and hydrogenated in the presence of 4.00 g of palladium on activated charcoal (10% Pd) at ambient temperature until the uptake of hydrogen has ended. For working up the catalyst is filtered off and the filtrate is evaporated using the rotary evaporator. A thin yellow oil is left, which is further reacted without any more purification. Yield: 8.60 g (73% of theory); mass spectrum (ESI+): m/z=116 [M+H]+.
  • The following compounds are obtained analogously to Example V:
  • (1) (S)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamine
    Mass spectrum (ESI+): m/z=116 [M+H]+.
    (2) N-[(tetrahydropyran-4-yl)methyl]-N-methylamine
    Mass spectrum (ESI+): m/z=130 [M+H]+.
    • Example VI (R)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine
  • A solution of 24.60 g of (R)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methylamide in 90 ml tetrahydrofuran is added dropwise to 17.00 g of lithium aluminium hydride in 150 ml of tetrahydrofuran. The reaction mixture is refluxed for two hours. For working up it is cooled to 0° C. in an ice bath, mixed with 20 ml of water and 10 ml of 15 N sodium hydroxide solution and stirred for another 20 minutes. Then it is filtered through a layer of magnesium sulfate and washed with a total of about 500 ml of tetrahydrofuran. The filtrate is evaporated down in vacuo, leaving a yellowish oil which is further reacted without any more purification. Yield: 21.10 g (92% of theory); mass spectrum (ESI+): m/z=206 [M+H]+.
  • The following compounds are obtained analogously to Example VI:
  • (1) (S)-N-[(tetrahydrofuran-2-yl)methyl]-N-benzyl-N-methylamine
    Rf value: 0.20 (silica gel, ethyl acetate/methanol=9:1).
    (2) N-[(tetrahydropyran-4-yl)methyl]-N-benzyl-N-methylamine
    Mass spectrum (ESI+): m/z=220 [M+H]+.
    • Example VII (R)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methylamide
  • 25.30 g of N-benzyl-N-methylamine are added to a solution of 20.00 ml of (R)-tetrahydrofuran-2-carboxylic acid in 200 ml tetrahydrofuran. Then a total of 67.10 g of 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are added batchwise while cooling with an ice bath and the reaction mixture is then stirred for about 48 hours at ambient temperature. The precipitate formed is suction filtered, the filtrate is evaporated, mixed with water and filtered again. The filtrate obtained is made alkaline with sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated down. A yellowish oil remains, which is further reacted without any further purification. Yield: 24.60 g (54% of theory); mass spectrum (ESI+): m/z=220 [M+H]+; Rf value: 0.62 (silica gel, ethyl acetate).
  • The following compounds are obtained analogously to Example VII:
  • (1) (S)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methylamide
    Mass spectrum (ESI+): m/z=242 [M+Na]+; Rf value: 0.62 (silica gel, ethyl acetate).
    (2) tetrahydropyran-4-carboxylic acid-N-benzyl-N-methylamide
    The amide coupling is carried out with 1,1′-carbonyldiimidazole in tetrahydrofuran. Mass spectrum (ESI+): m/z=256 [M+Na]+; Rf value: 0.45 (silica gel, ethyl acetate).
    • Example VIII 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
  • 22.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)methoxy]quinazoline are hydrogenated in 300 ml of tetrahydrofuran in the presence of 3.50 g of platinum dioxide at ambient temperature until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated to dryness using the rotary evaporator. The residue is stirred with diethylether, suction filtered, washed with diethylether and dried at ambient temperature. Yield: 19.95 g (93% of theory); mass spectrum (ESI+): m/z=403, 405 [M+H]+; melting point: 221° C.
  • The following compounds are obtained analogously to Example VIII:
  • (1) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=389, 391 [M+H]+; Rf value: 0.11 (silica gel, ethyl acetate).
    (2) 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=389, 391 [M+H]+; Rf value: 0.33 (silica gel, ethyl acetate/methanol=9:1).
    • Preparation of the Final Compounds Example 1 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
  • 4.70 ml of oxalyl chloride are added dropwise to a solution of 4.50 g of bromocrotonic acid in 60 ml of methylene chloride. Then one drop of N,N-dimethylformamide is added. After about 30 minutes, the development of gas has ended and the reaction mixture is evaporated using the rotary evaporator. The crude bromocrotonic acid chloride is taken up in 30 ml of methylene chloride and, while cooling with an ice bath, added dropwise to a solution of 7.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-amino-7-cyclopropylmethoxyquinazoline and 10.20 ml of Hünig base in 150 ml of tetrahydrofuran. The reaction mixture is stirred for about 1.5 hours while cooling with an ice bath and then for another two hours at ambient temperature. Then 5.20 g of N-(2-methoxyethyl)-N-methylamine are added and the reaction mixture is stirred overnight at ambient temperature. For working up, it is diluted with methylene chloride and washed thoroughly with water. The organic phase is dried over magnesium sulfate and evaporated down. The crude product is purified by chromatography over a silica gel column with ethyl acetate followed by ethyl acetate/methanol (19:1) as eluant. Yield: 5.07 g (51% of theory); mass spectrum (ESI−): m/z=512, 514 [M−H]−; Rf value: 0.25 (silica gel, ethyl acetate/methanol=9:1).
  • The following compounds are obtained analogously to Example 1:
  • (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline
    Mass spectrum (ESI−): m/z=468, 470 [M−H]−; Rf value: 0.09 (silica gel, ethyl acetate/methanol=9:1).
    (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
    Mass spectrum (ESL): m/z=482, 484 [M−H]−; Rf value: 0.11 (silica gel, ethyl acetate/methanol=9:1).
    (3) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis(2-methoxyethyl)amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI−): m/z=532 [M−H]−; Rf value: 0.40 (silica gel, ethyl acetate/methanol=9:1).
    (4) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-ethylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESL): m/z=502 [M−H]−; Rf value: 0.20 (silica gel, ethyl acetate/methanol=9:1).
    (5) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI−): m/z=488 [M−H]−; Rf value: 0.25 (silica gel, ethyl acetate/methanol=9:1).
    (6) 4-[(R)-(1-phenylethyl)amino]-6-({-4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI−): m/z=514 [M−H]−; Rf value: 0.15 (silica gel, ethyl acetate/methanol=9:1).
    (7) 4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydrofuran-3-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI−): m/z=500 [M−H]−; Rf value: 0.18 (silica gel, ethyl acetate/methanol=9:1).
    (8) 4-[(3-chloro-4-fluorophenyl)amino]-6[(4-(4-{N-[(tetrahydrofuran-3-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI−): m/z=538, 540 [M−H]−; Rf value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
    (9) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline; mass spectrum (ESI+): m/z=486, 488 [M+H]+.
    (10) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline
    Mass spectrum (ESI+): m/z=486, 488 [M+H]+; Rf value: 0.45 (silica gel, methylene chloride/methanol=5:1).
    (11) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(tetrahydropyran-4-yloxy)quinazoline
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; Rf value: 0.55 (silica gel, methylene chloride/methanol=5:1).
    (12) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; Rf value: 0.60 (silica gel, methylene chloride/methanol=5:1).
    (13) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; Rf value: 0.50 (silica gel, methylene chloride/methanol=5:1).
    (14) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=528, 530 [M+H]+; Rf value: 0.31 (silica gel, ethyl acetate/methanol=9:1).
    (15) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI+): m/z=446 [M+H]+; Rf value: 0.11 (silica gel, ethyl acetate/methanol=9:1).
    (16) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=588, 590 [M+H]+; Rf value: 0.55 (silica gel, methylene chloride/methanol=9:1).
    (17) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=542, 544 [M+H]+; Rf value: 0.55 (silica gel, methylene chloride/methanol=9:1).
    (18) 4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI+): m/z=528, 530 [M+H]+; Rf value: 0.25 (silica gel, ethyl acetate/methanol=9:1).
    (19) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(R)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI+): m/z=540, 542 [M+H]+; melting point: 149° C.-153° C.
    (20) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(S)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI+): m/z=540, 542 [M+H]+; Rf value: 0.29 (silica gel, ethyl acetate/methanol=9:1).
    (21) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI+): m/z=560 [M+H]+; Rf value: 0.17 (silica gel, ethyl acetate/methanol=9:1).
    (22) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI−): m/z=508, 510 [M−H]−; melting point: 140° C.
    • (23) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
  • Mass spectrum (ESI+): m/z=496, 498 [M+H]+; Rf value: 0.42 (silica gel, ethyl acetate/methanol=9:1).
  • (24) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI+): m/z=554, 556 [M+H]+; melting point: 141° C.
    (25) 4-[(R)-(1-phenylethyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    Mass spectrum (ESI+): m/z=530 [M+H]+; Rf value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:0.5).
    (26) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(R)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI+): m/z=554, 556 [M+H]+; melting point: 117° C.-121° C.
    (27) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{(S)-N-[(tetrahydrofuran-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI+): m/z=554, 556 [M+H]+; Rf value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:0.5).
    (28) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=514, 516 [M+H]+; Rf value: 0.19 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=95:5:0.05).
    (29) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=554, 556 [M−H]−; melting point: 174° C.
    (30) 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=602, 604 [M+H]+; melting point: 100° C.-102° C.
    (31) 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
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; melting point: 110° C.-112° C.
    (32) 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
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; Rf value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:0.1).
    (33) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-ethyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
    Mass spectrum (ESI+): m/z=500, 502 [M+H]+; melting point: 154° C.-157° C.
    (34) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
    Mass spectrum (ESI+): m/z=514, 516 [M+H]+; Rf value: 0.34 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:1).
    (35) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline
    Mass spectrum (ESI+): m/z=528, 530 [M+H]+; melting point: 184° C.-185° C.
    (36) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline
    Mass spectrum (ESI+): m/z=512, 514 [M+H]+; Rf value: 0.53 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:0.5).
    (37) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-ethyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=512, 514 [M−H]−; Rf value: 0.15 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia=90:10:1).
    (38) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI−): m/z=526, 528 [M−H]−; Rf value: 0.27 (silica gel, methylene chloride/methanol=9:1).
    (39) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-isopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline
    Mass spectrum (ESI+): m/z=528, 530 [M+H]+; Rf value: 0.31 (silica gel, methylene chloride/methanol=9:1).
  • The following compounds may also be prepared analogously to the foregoing Examples and other methods known from the literature:
    • (1) 4-benzylamino-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
    • (2) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(tetrahydropyran-4-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    • (3) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)methoxy]quinazoline
    • (4) 4-[(R)-(1-phenylethyl)amino]-6-[(4-(4-{N-[(tetrahydrofuran-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline
    • (5) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    • (6) 4-[(R)-(1-phenylethyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    • (7) 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline
    Example 2 Coated Tablets Containing 75 Mg Of Active Substance 1 Tablet Core Contains:
  • active substance 75.0 mg
    calcium phosphate 93.0 mg
    corn starch 35.5 mg
    polyvinylpyrrolidone 10.0 mg
    hydroxypropylmethylcellulose 15.0 mg
    magnesium stearate 1.5 mg
    230.0 mg
    • Preparation:
  • The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. Weight of core: 230 mg; die: 9 mm, convex. The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax. Weight of coated tablet: 245 mg.
    • Example 3 Tablets Containing 100 Mg of Active Substance Composition: 1 Tablet Contains:
  • active substance 100.0 mg
    lactose 80.0 mg
    corn starch 34.0 mg
    polyvinylpyrrolidone 4.0 mg
    magnesium stearate 2.0 mg
    220.0 mg
    • Preparation:
  • The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C., it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg; diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
    • Example 4 Tablets Containing 150 Mg of Active Substance Composition: 1 Tablet Contains:
  • active substance 150.0 mg
    powdered lactose 89.0 mg
    corn starch 40.0 mg
    colloidal silica 10.0 mg
    polyvinylpyrrolidone 10.0 mg
    magnesium stearate 1.0 mg
    300.0 mg
    • Preparation:
  • The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Weight of tablet: 300 mg; die: 10 mm, flat.
    • Example 5 Hard Gelatine Capsules Containing 150 Mg of Active Substance 1 Capsule Contains:
  • active substance 50.0 mg
    corn starch (dried) approx. 80.0 mg
    lactose (powdered) approx. 87.0 mg
    magnesium stearate 3.0 mg
    approx. 420.0 mg
    • Preparation:
  • The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg; capsule shell: size 1 hard gelatine capsule.
    • Example 6 Suppositories Containing 150 Mg of Active Substance 1 Suppository Contains:
  • active substance 150.0 mg
    polyethyleneglycol 1500 550.0 mg
    polyethyleneglycol 6000 460.0 mg
    polyoxyethylene sorbitan monostearate 840.0 mg
    2,000.0 mg
    • Preparation:
  • After the suppository mass has been melted, the active substance is homogeneously distributed therein and the melt is poured into chilled molds.
    • Example 7 Suspension Containing 50 Mg of Active Substance 100 ml of Suspension Contains:
  • active substance 1.00 g
    carboxymethylcellulose-Na-salt 0.10 g
    methyl p-hydroxybenzoate 0.05 g
    propyl p-hydroxybenzoate 0.01 g
    glucose 10.00 g
    glycerol 5.00 g
    70% sorbitol solution 20.00 g
    flavoring 0.30 g
    dist. water ad 100 ml
    • Preparation:
  • The distilled water is heated to 70° C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution, and the flavoring have been added and dissolved, the suspension is evacuated with stirring to eliminate air. 5 ml of suspension contains 50 mg of active substance.
    • Example 8 Ampoules Containing 10 Mg Active Substance Composition:
  • active substance 10.0 mg
    0.01 N hydrochloric acid q.s.
    double-distilled water ad 2.0 ml
    • Preparation:
  • The active substance is dissolved in the requisite amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
    • Example 9 Ampoules Containing 50 Mg of Active Substance Composition:
  • active substance 50.0 mg
    0.01 N hydrochloric acid q.s.
    double-distilled water ad 10.0 ml
    • Preparation:
  • The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
    • Example 10 Capsules for Powder Inhalation Containing 5 Mg of Active Substance 1 Capsule Contains:
  • active substance  5.0 mg
    lactose for inhalation 15.0 mg
    20.0 mg
    • Preparation:
  • The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg). Weight of capsule: 70.0 mg; size of capsule: 3.
    • Example 11 Solution for Inhalation for Hand-Held Nebulizers Containing 2.5 Mg Active Substance 1 Spray Contains:
  • active substance 2.500 mg
    benzalkonium chloride 0.001 mg
    1N hydrochloric acid q.s.
    ethanol/water (50/50) ad 15.000 mg
    • Preparation:
  • The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and transferred into suitable containers for use in hand-held nebulizers (cartridges). Contents of the container: 4.5 g.

Claims (13)

1. A method of treating benign or malignant tumors, diseases of the airways and lungs, and diseases of the gastrointestinal tract, bile duct, and gall bladder in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula I
Figure US20110046168A1-20110224-C00006
wherein
Ra is a 3-chloro-4-fluorophenyl group;
Rb is a dimethylamino group; and
Rc is a tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group,
or a stereoisomer or physiologically acceptable salt thereof.
2. The method according to claim 1, wherein:
Rc is a tetrahydrofuran-3-yloxy,
or a steroisomer or physiologically acceptable salt thereof.
3. The method according to claim 1, wherein the compound is:
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline or physiologically acceptable salt thereof.
4. The method according to claim 1, wherein the compound is a physiologically acceptable salt comprising the combination of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline with an organic or inorganic acid.
5. The method according to claim 4, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
6. The method according to claim 5, wherein the acid is maleic acid.
7. The method according to claim 1, wherein the compound is:
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-(tetrahydrofuran-3-yl)oxy)quinazoline or physiologically acceptable salt thereof.
8. The method according to claim 1, wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
9. The method according to claim 5, wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
10. The method according to claim 9, wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin.
11. The method according to claim 1, wherein the diseases of the airways and lungs is chosen from chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
12. The method according to claim 1, wherein the diseases of the gastrointestinal tract, bile duct, and gall bladder is chosen from cholecystitis, Crohn's disease, ulcerative colitis, ulcers in the gastrointestinal tract, Ménétrier's disease, secreting adenomas and protein loss syndrome.
13. The method according to claim 1, wherein the disease is psoriasis.
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US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
US20110039863A1 (en) * 2003-04-29 2011-02-17 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis
US20110142929A1 (en) * 2008-06-06 2011-06-16 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising bibw 2992
US20110207929A1 (en) * 2006-01-26 2011-08-25 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US8735409B2 (en) 2009-12-21 2014-05-27 Qiang Zhang Quinazoline derivatives
US8828391B2 (en) 2011-05-17 2014-09-09 Boehringer Ingelheim International Gmbh Method for EGFR directed combination treatment of non-small cell lung cancer
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US9556191B2 (en) 2013-04-28 2017-01-31 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158196A1 (en) * 2002-02-16 2003-08-21 Boehringer Ingelheim Pharma Gmbh Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
US7776315B2 (en) * 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
US20100310477A1 (en) * 2000-11-28 2010-12-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg. Pharmaceutical compositions based on anticholingerics and additional active ingredients
DE10204462A1 (en) * 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
TWI324597B (en) * 2002-03-28 2010-05-11 Astrazeneca Ab Quinazoline derivatives
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20040044014A1 (en) * 2002-04-19 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
US20030225079A1 (en) * 2002-05-11 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
US20040048887A1 (en) * 2002-07-09 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
WO2004006846A2 (en) 2002-07-15 2004-01-22 Exelixis, Inc. Receptor-type kinase modulators and methods of use
US7223749B2 (en) * 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
DE10334226A1 (en) * 2003-07-28 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20050059661A1 (en) * 2003-07-28 2005-03-17 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
KR20060054388A (en) * 2003-07-29 2006-05-22 아스트라제네카 아베 Piperidyl-quinazolin Derivatives as Tyrosine Kinase Inhibitors
GB0317665D0 (en) * 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
DK1667991T3 (en) * 2003-09-16 2008-08-18 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
PT1667992E (en) * 2003-09-19 2007-04-30 Astrazeneca Ab Quinazoline derivatives
ES2281007T3 (en) * 2003-09-19 2007-09-16 Astrazeneca Ab DERIVATIVES OF QUINAZOLINA.
JP2007506716A (en) * 2003-09-25 2007-03-22 アストラゼネカ アクチボラグ Quinazoline derivatives
ES2466818T3 (en) 2003-09-26 2014-06-11 Exelixis, Inc. C-Met modulators and methods of use
US20050096332A1 (en) * 2003-10-30 2005-05-05 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20050203088A1 (en) * 2004-01-09 2005-09-15 Boehringer Ingelheim International Gmbh Medicament combinations based on scopine- or tropene acid esters with EGFR-kinase inhibitors
AU2005239878B9 (en) * 2004-05-06 2010-01-07 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
US20060032853A1 (en) * 2004-07-27 2006-02-16 Freeman Jimmy L Pressure vessel door
CA2599210A1 (en) * 2005-02-26 2006-08-31 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
KR100832594B1 (en) * 2005-11-08 2008-05-27 한미약품 주식회사 Quinazoline derivatives as an multiplex inhibitor and method for the preparation thereof
EP1921070A1 (en) * 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
WO2008095847A1 (en) * 2007-02-06 2008-08-14 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
KR20100111291A (en) * 2008-02-07 2010-10-14 베링거 인겔하임 인터내셔날 게엠베하 Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production
EA019183B1 (en) 2008-05-13 2014-01-30 Астразенека Аб Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
EP2313397B1 (en) * 2008-08-08 2016-04-20 Boehringer Ingelheim International GmbH Cyclohexyloxy substituted heterocycles, medicine containing these connections, their application and production method
KR20170052702A (en) 2009-01-16 2017-05-12 엑셀리시스, 인코포레이티드 The end of N- (4 - {[6,7-bis (methyloxy) quinolin-4-yl] oxy} phenyl) -N '- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide Acid salts and their crystalline forms
CN104906582A (en) 2009-02-13 2015-09-16 勃林格殷格翰国际有限公司 Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a further antidiabetic agent and uses thereof
JP5793428B2 (en) 2009-03-11 2015-10-14 オークランド ユニサーヴィスィズ リミテッド Prodrug form of kinase inhibitors and their use in therapy
WO2010130758A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of cancer and fibrotic diseases
UA108618C2 (en) 2009-08-07 2015-05-25 APPLICATION OF C-MET-MODULATORS IN COMBINATION WITH THEMOSOLOMID AND / OR RADIATION THERAPY FOR CANCER TREATMENT
CN102020639A (en) 2009-09-14 2011-04-20 上海恒瑞医药有限公司 6-amido quinazoline or 3-cyano quinoline derivative, preparation method thereof and application of derivative to medicament
UY32919A (en) 2009-10-02 2011-04-29 Boehringer Ingelheim Int Pharmaceutical composition, pharmaceutical dosage form, procedure for its preparation, methods for its treatment and its uses
EP2608792B1 (en) 2010-08-26 2017-10-11 Boehringer Ingelheim International GmbH Methods of administering an egfr inhibitor
AR085689A1 (en) 2011-03-07 2013-10-23 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITIONS OF METFORMIN, LINAGLIPTINE AND AN SGLT-2 INHIBITOR
CN102898386B (en) 2011-07-27 2015-07-29 上海医药集团股份有限公司 Quinazoline derivant, its preparation method, intermediate, composition and application thereof
JP2014532063A (en) 2011-10-12 2014-12-04 テリジェン リミテッドＴｅｌｉｇｅｎｅ Ｌｔｄ Quinazoline derivatives as kinase inhibitors and methods of use thereof
UA111010C2 (en) 2012-01-17 2016-03-10 Астеллас Фарма Інк. PIRASINCARBOXAMID COMPOUND
CN104350049B (en) 2012-05-07 2016-07-13 苏州韬略生物科技有限公司 Substituted-amino quinazoline as inhibitors of kinases
JP2015524400A (en) 2012-07-19 2015-08-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Fumarate salt of 9- [4- (3-chloro-2-fluoro-phenylamino) -7-methoxy-quinazolin-6-yloxy] -1,4-diaza-spiro [5.5] undecan-5-one , Its use and preparation as drugs
CA2812519A1 (en) 2013-04-05 2014-10-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HRP20190101T1 (en) 2013-04-05 2019-03-08 Boehringer Ingelheim International Gmbh THERAPEUTIC USES OF EMPAGLIFLOZINE
HK1213818A1 (en) 2013-04-05 2016-07-15 勃林格殷格翰国际有限公司 Therapeutic uses of empagliflozin
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HK1215378A1 (en) 2013-04-18 2016-08-26 勃林格殷格翰国际有限公司 Pharmaceutical composition, methods for treating and uses thereof
CN103304492B (en) * 2013-06-20 2015-12-23 湖南欧亚生物有限公司 The synthetic method of a kind of EGFR inhibitor Dacomitinib
EP3089976B1 (en) 2014-01-02 2019-08-14 Teva Pharmaceuticals International GmbH Crystalline forms of afatinib dimaleate
WO2015186065A1 (en) 2014-06-02 2015-12-10 Sun Pharmaceutical Industries Limited Process for the preparation of 4-dimethylaminocrotonic acid
EP3201190A4 (en) 2014-10-01 2018-03-14 Sun Pharmaceutical Industries Ltd Crystalline form of afatinib dimaleate
CN105801568B (en) 2015-01-15 2019-07-30 杭州普晒医药科技有限公司 One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition
WO2016166720A2 (en) 2015-04-17 2016-10-20 Hetero Research Foundation Polymorphs and process for the preparation of quinazolinyl derivatives
KR20180018551A (en) 2015-06-12 2018-02-21 프레세니어스 카비 온콜로지 리미티드 Polymorphic forms of afatinib free base and afatinib dimaleate
US10525059B2 (en) 2015-08-21 2020-01-07 Fresenius Kabi Oncology, Ltd. Pharmaceutical compositions comprising Afatinib
US20170076349A1 (en) * 2015-09-15 2017-03-16 Katherine Rohach Miller Kiosk-based in-store custom stationery fulfillment system
US20180125813A1 (en) 2016-11-10 2018-05-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
TWI808958B (en) 2017-01-25 2023-07-21 美商特普醫葯公司 Combination therapy involving diaryl macrocyclic compounds
JP2020513006A (en) 2017-04-06 2020-04-30 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ New form of afatinib zimare art
US10421734B1 (en) * 2018-08-31 2019-09-24 Sami Labs Limited Process for the preparation of enantiopure 3-amino tetrahydrofuran and its salts
TW202317126A (en) 2021-06-15 2023-05-01 美商建南德克公司 Egfr inhibitor and perk activator in combination therapy

Citations (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866572A (en) * 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US6127374A (en) * 1997-07-29 2000-10-03 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6153617A (en) * 1997-07-29 2000-11-28 Warner-Lambert Company Irreversible bicyclic inhibitors of tyrosine kinases
US6251912B1 (en) * 1997-08-01 2001-06-26 American Cyanamid Company Substituted quinazoline derivatives
US6297258B1 (en) * 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
US20010044435A1 (en) * 2000-04-08 2001-11-22 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6344459B1 (en) * 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US20020032208A1 (en) * 1995-12-18 2002-03-14 Zeneca Limited Chemical compounds
US6403580B1 (en) * 2000-08-26 2002-06-11 Boehringer Ingelheim Pharma Kg Quinazolines, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20020077330A1 (en) * 2000-08-26 2002-06-20 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20020082270A1 (en) * 2000-08-26 2002-06-27 Frank Himmelsbach Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US20020169180A1 (en) * 1999-06-21 2002-11-14 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20020173509A1 (en) * 2000-12-20 2002-11-21 Frank Himmelsbach Quinazoline derivatives and phamaceutical compositions containing them
US20030149062A1 (en) * 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US6617329B2 (en) * 2000-08-26 2003-09-09 Boehringer Ingelheim Pharma Kg Aminoquinazolines and their use as medicaments
US20030191308A1 (en) * 2000-04-07 2003-10-09 Hennequin Laurent Francois Andre Quinazoline compounds
US6656946B2 (en) * 2000-08-26 2003-12-02 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US20030225079A1 (en) * 2002-05-11 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
US6673803B2 (en) * 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US20040024019A1 (en) * 2000-06-02 2004-02-05 Norihiko Tanimoto Drug composition antagonistic to both pgd2/txa2 receptors
US6740651B2 (en) * 2000-08-26 2004-05-25 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US20040158065A1 (en) * 2003-02-05 2004-08-12 Hubert Barth Preparation of substituted quinazolines
US20050043233A1 (en) * 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20050085495A1 (en) * 2003-10-17 2005-04-21 Boehringer Ingelheim International Gmbh Process for preparing amino crotonyl compounds
US6924285B2 (en) * 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20050215574A1 (en) * 2002-03-28 2005-09-29 Bradbury Robert H 4-anilino quinazoline derivatives as antiproliferative agents
US6972288B1 (en) * 1999-02-27 2005-12-06 Boehringer Ingelheim Pharma Kg 4-amino-quinazoline and quinoline derivatives having an inhibitory effect on signal transduction mediated by tyrosine kinases
US20060058311A1 (en) * 2004-08-14 2006-03-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
US7196091B2 (en) * 2003-06-06 2007-03-27 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20070078091A1 (en) * 1998-06-09 2007-04-05 Doris Hubler Pharmaceutical combinations for compensating for a testosterone deficiency in men while simultaneously protecting the prostate
US7223749B2 (en) * 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20080103161A1 (en) * 2002-04-19 2008-05-01 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
US7456189B2 (en) * 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
US20090203683A1 (en) * 2000-03-14 2009-08-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20090306378A1 (en) * 2006-01-26 2009-12-10 Juergen Schroeder Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6442472A (en) 1987-08-10 1989-02-14 Kanebo Ltd Quinazoline derivative, production thereof and brain function disorder improving agent containing said derivative as active ingredient
GB9300059D0 (en) 1992-01-20 1993-03-03 Zeneca Ltd Quinazoline derivatives
GB9401182D0 (en) 1994-01-21 1994-03-16 Inst Of Cancer The Research Antibodies to EGF receptor and their antitumour effect
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
SI9620103A (en) 1995-07-06 1998-10-31 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
IL120302A0 (en) 1996-03-27 1997-06-10 Pfizer Use of alpha1-adrenoreceptor antagonists in the prevention and treatment of benign prostatic hyperplasia
UA73073C2 (en) 1997-04-03 2005-06-15 Уайт Холдінгз Корпорейшн Substituted 3-cyan chinolines
GB9715892D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
TW436485B (en) * 1997-08-01 2001-05-28 American Cyanamid Co Substituted quinazoline derivatives
AU2093499A (en) 1997-12-30 1999-07-19 Chiron Corporation Members of tnf and tnfr families
RS49779B (en) 1998-01-12 2008-06-05 Glaxo Group Limited, BICYCLIC HETEROAROMATIC COMPOUNDS AS PROTEIN TYROSINE KINASE INHIBITORS
EP1950201A1 (en) 1998-09-29 2008-07-30 Wyeth Holdings Corporation Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors
US6262088B1 (en) 1998-11-19 2001-07-17 Berlex Laboratories, Inc. Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants
US6344455B1 (en) 1998-11-19 2002-02-05 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, and irreversible inhibitor of tyrosine kinases
DE19908567A1 (en) 1999-02-27 2000-08-31 Boehringer Ingelheim Pharma New 4-amino-quinazoline or quinoline derivatives, are tyrosine kinase-mediated signal transduction inhibitors useful e.g. for treating tumors, polyps or respiratory or gastrointestinal diseases
DE19911366A1 (en) 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma New 4-amino-quinazoline or quinoline derivatives, are tyrosine kinase-mediated signal transduction inhibitors useful e.g. for treating tumors, polyps or respiratory or gastrointestinal diseases
DE19911509A1 (en) 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
UA74803C2 (en) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use
IL141235A (en) 2000-02-09 2012-04-30 Novartis Int Pharm Ltd Combined use of an alpha-adrenoceptor antagonist and a muscarinic antagonist in the manufacture of a medicament for the treatment of benign prostatic hyperplasia
AU4545201A (en) 2000-03-13 2001-09-24 American Cyanamid Co Method of treating or inhibiting colonic polyps
DE10017539A1 (en) 2000-04-08 2001-10-11 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE50111799D1 (en) 2000-04-08 2007-02-15 Boehringer Ingelheim Pharma BICYCLIC HETEROCYCLES, MEDICAMENTS CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF
DE10042064A1 (en) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Chinazolines, medicaments containing these compounds, their use and processes for their preparation
DE10042058A1 (en) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10042060A1 (en) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10042062A1 (en) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and methods of preparation
DE10042059A1 (en) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
EP1810715A3 (en) 2000-11-22 2009-12-16 Novartis AG Combination comprising an agent decreasing VEGF activity and an agent decreasing EGF activity
DE10063435A1 (en) 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazoline derivatives, pharmaceuticals containing these compounds, their use and process for their preparation
BR0308902A (en) 2002-03-30 2005-01-04 Boehringer Ingelheim Pharma 4- (n-phenylamino) -quinazolines / quinolines as tyrosine kinase inhibitors
DE10217689A1 (en) 2002-04-19 2003-11-13 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10307165A1 (en) 2003-02-20 2004-09-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10345875A1 (en) 2003-09-30 2005-04-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, pharmaceutical compositions containing them, their use and methods of preparation
PE20100252A1 (en) 2008-06-06 2010-04-12 Boehringer Ingelheim Int NEW SOLID PHARMACEUTICAL FORMULATIONS INCLUDING 4 - [(3-CHLORO-4-FLUOROPHENYL) AMINO DIMALEATE] -6 - {[4- (N, N-DIMETHYLAMINO) -1-OXO-2-BUTEN-1-IL] AMINO } -7 - ((S) -TETRAHIDROFURAN-3-ILOXI) -QUINAZOLINA
US20120157472A1 (en) * 2009-01-14 2012-06-21 Boehringer Ingelheim International Gmbh Method for treating colorectal cancer
DK2451445T3 (en) 2009-07-06 2019-06-24 Boehringer Ingelheim Int PROCEDURE FOR DRYING BIBW2992, IT'S SALTS AND SOLID PHARMACEUTICAL FORMULATIONS INCLUDING THIS ACTIVE INGREDIENT
JP2013512882A (en) 2009-12-07 2013-04-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング BIBW2992 for use in the treatment of triple negative breast cancer

Patent Citations (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6362336B1 (en) * 1995-12-18 2002-03-26 Zeneca Limited Chemical compounds
US20020032208A1 (en) * 1995-12-18 2002-03-14 Zeneca Limited Chemical compounds
US5866572A (en) * 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US6344459B1 (en) * 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6673803B2 (en) * 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6153617A (en) * 1997-07-29 2000-11-28 Warner-Lambert Company Irreversible bicyclic inhibitors of tyrosine kinases
US6127374A (en) * 1997-07-29 2000-10-03 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6251912B1 (en) * 1997-08-01 2001-06-26 American Cyanamid Company Substituted quinazoline derivatives
US20070078091A1 (en) * 1998-06-09 2007-04-05 Doris Hubler Pharmaceutical combinations for compensating for a testosterone deficiency in men while simultaneously protecting the prostate
US6297258B1 (en) * 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
US6972288B1 (en) * 1999-02-27 2005-12-06 Boehringer Ingelheim Pharma Kg 4-amino-quinazoline and quinoline derivatives having an inhibitory effect on signal transduction mediated by tyrosine kinases
US7220750B2 (en) * 1999-06-21 2007-05-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20070185091A1 (en) * 1999-06-21 2007-08-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic Heterocycles, Pharmaceutical Compositions Containing These Compounds, Their Use and Processes for Preparing Them
US20020169180A1 (en) * 1999-06-21 2002-11-14 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20090203683A1 (en) * 2000-03-14 2009-08-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20030191308A1 (en) * 2000-04-07 2003-10-09 Hennequin Laurent Francois Andre Quinazoline compounds
US7160889B2 (en) * 2000-04-07 2007-01-09 Astrazeneca Ab Quinazoline compounds
US6627634B2 (en) * 2000-04-08 2003-09-30 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20010044435A1 (en) * 2000-04-08 2001-11-22 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20040024019A1 (en) * 2000-06-02 2004-02-05 Norihiko Tanimoto Drug composition antagonistic to both pgd2/txa2 receptors
US7084136B2 (en) * 2000-06-02 2006-08-01 Shionogi & Co., Ltd. Drug composition antagonistic to both PGD2/TXA2 receptors
US20020082270A1 (en) * 2000-08-26 2002-06-27 Frank Himmelsbach Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6740651B2 (en) * 2000-08-26 2004-05-25 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6656946B2 (en) * 2000-08-26 2003-12-02 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6653305B2 (en) * 2000-08-26 2003-11-25 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6617329B2 (en) * 2000-08-26 2003-09-09 Boehringer Ingelheim Pharma Kg Aminoquinazolines and their use as medicaments
US20020077330A1 (en) * 2000-08-26 2002-06-20 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6403580B1 (en) * 2000-08-26 2002-06-11 Boehringer Ingelheim Pharma Kg Quinazolines, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20020173509A1 (en) * 2000-12-20 2002-11-21 Frank Himmelsbach Quinazoline derivatives and phamaceutical compositions containing them
US7019012B2 (en) * 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20060100223A1 (en) * 2000-12-20 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20030149062A1 (en) * 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20090306072A1 (en) * 2002-02-05 2009-12-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20050215574A1 (en) * 2002-03-28 2005-09-29 Bradbury Robert H 4-anilino quinazoline derivatives as antiproliferative agents
US20080269487A1 (en) * 2002-03-28 2008-10-30 Astrazeneca Ab 4-anilino quinazoline derivatives as antiproliferative agents
US7119084B2 (en) * 2002-03-30 2006-10-10 Boehringer Ingelheim International Gmbh Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20060270672A1 (en) * 2002-03-30 2006-11-30 Frank Himmelsbach Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US6924285B2 (en) * 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20090036676A1 (en) * 2002-03-30 2009-02-05 Frank Himmelsbach Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20080103161A1 (en) * 2002-04-19 2008-05-01 Frank Himmelsbach Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
US20070099918A1 (en) * 2002-05-11 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy
US20030225079A1 (en) * 2002-05-11 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
US20040158065A1 (en) * 2003-02-05 2004-08-12 Hubert Barth Preparation of substituted quinazolines
US7223749B2 (en) * 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20080254040A1 (en) * 2003-04-29 2008-10-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20050043233A1 (en) * 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US7196091B2 (en) * 2003-06-06 2007-03-27 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US7456189B2 (en) * 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
US20050085495A1 (en) * 2003-10-17 2005-04-21 Boehringer Ingelheim International Gmbh Process for preparing amino crotonyl compounds
US20090238828A1 (en) * 2004-08-14 2009-09-24 Boehringer Ingelheim International Gmbh Combinations for the Treatment of Diseases involving Cell Proliferation
US20060058311A1 (en) * 2004-08-14 2006-03-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20090306378A1 (en) * 2006-01-26 2009-12-10 Juergen Schroeder Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8722694B2 (en) 1999-06-21 2014-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
USRE43431E1 (en) 2000-12-20 2012-05-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US8586608B2 (en) 2000-12-20 2013-11-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US8431585B2 (en) 2002-05-11 2013-04-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
US20110039863A1 (en) * 2003-04-29 2011-02-17 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis
US8426586B2 (en) 2003-10-17 2013-04-23 Boehringer Ingelheim International Gmbh Process for preparing amino crotonyl compounds
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
US8404697B2 (en) 2005-11-11 2013-03-26 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US9089571B2 (en) 2005-11-11 2015-07-28 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US9539258B2 (en) 2005-11-11 2017-01-10 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20110207929A1 (en) * 2006-01-26 2011-08-25 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US8188274B2 (en) 2006-01-26 2012-05-29 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US8067593B2 (en) 2006-01-26 2011-11-29 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20110207932A1 (en) * 2006-01-26 2011-08-25 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US8877764B2 (en) 2006-09-18 2014-11-04 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
US8545884B2 (en) 2008-06-06 2013-10-01 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising BIBW 2992
US20110142929A1 (en) * 2008-06-06 2011-06-16 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising bibw 2992
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US10004743B2 (en) 2009-07-06 2018-06-26 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US8735409B2 (en) 2009-12-21 2014-05-27 Qiang Zhang Quinazoline derivatives
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US9556191B2 (en) 2013-04-28 2017-01-31 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors

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