Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• Bicyclic heterocycles medicaments containing these compounds, their use and processes for their preparation
• the present invention relates to bicyclic heterocycles of the general formula
• R a represents a hydrogen atom or a C 1-3 -alkyl group
• R b is a hydrogen, fluorine, chlorine, bromine or iodine atom
• R c is a hydrogen, fluorine, chlorine or bromine atom, or
• R d is a cyclobutyl, cyclopentyl or cyclohexyl group, each substituted by a group R 1 -NR 2 , wherein
• R 1 represents a hydrogen atom or a Ci -3 alkyl group
• R 2 represents a hydroxy-Ci -4 alkyl-carbonyl group
• R e is a hydrogen atom or a fluorine, chlorine or bromine atom
• R 3 is a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidine-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 -CC- 3- alkyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-cyclo- 3- alkyl-hexahydropyrimidin-1-yl; and
• R 4 is a hydroxy, C 1-3 -alkyloxy, CW-cycloalkyloxy, amino, C 1-3 -alkylamino, di (C 1-3 -alkyl) amino, bis (2-methoxyethyl) amino , Pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl, 8-oxa-3-aza-bicyclo - [3.2.1] oct-3-yl, Piperazine-1 -yl, 4-C 1-3 -alkylpiperazine-1-yl, homopiperazine-1-yl or c 1-3 -alkyl-homopiperazine-1-yl-group, or
• R 5 is a hydrogen or a C atom represents -3 alkyl group, or a C, which substituted by a 4-position by the radical R 5 is substituted morpholinyl -4 alkoxy group, wherein R 5 is defined as mentioned above, and
• X represents a methine group substituted by a cyano group or a nitrogen atom
• pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl -3 alkyl groups may each be substituted by one or two Ci, and
• alkyl groups may be straight-chain or branched
• R a is a hydrogen atom
• R b is a fluorine, chlorine or bromine atom
• R c is a hydrogen or fluorine atom
• R d is a cyclopentyl group which is substituted in the 3-position by a group R 1 -NR 2 , wherein
• R 1 represents a hydrogen atom or a C 1-3 -alkyl group
• R 2 represents a hydroxy-Ci -3 alkyl-carbonyl group
• a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R 1 -NR 2 , wherein R 1 and R 2 are defined as mentioned above, a pyrrolidin-3-yl group which is substituted in the 1-position by the radical R 2 , where R 2 is defined as mentioned above,
• R e is a hydrogen atom
• R 3 is a 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl,
• 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidine Represents 1 -yl group
• R 4 is a hydroxy, Ci -3 alkyloxy, amino, Ci -3 alkylamino, di- (Ci -3 alkyl) amino,
• Ci -4 alkylcarbonylamino Ci -3 alkyloxy-Ci -3 alkyl carbonylamino, Ci -4 -Alkyloxycarbonylamino-, aminocarbonylamino, Ci -3 - alkylaminocarbonylamino, di- (Ci -3 - alkyl) aminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidine-1-ylcarbonylamino, piperazine-1-ylcarbonylamino, 4-Ci- 3 alkyl-piperazin-1 -ylcarbonylamino- morpholin-4-ylcarbonylamino- or a Ci -4 alkylsulfonylamino group,
• R 3 or R 4 a butoxy group which is substituted in the 4-position by a radical R 3 or R 4 , wherein R 3 and R 4 are defined as mentioned above, and
• X is a nitrogen atom
• alkyl groups may be straight-chain or branched
• R b is a fluorine, chlorine or bromine atom
• R c is a hydrogen or fluorine atom
• R d is a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R 1 -NR 2 , wherein
• R 1 represents a hydrogen atom, a methyl or ethyl group
• R 2 represents a hydroxy-Ci -3 alkyl-carbonyl group, a pyrrolidin-3-yl group which is substituted in the 1-position by the radical R 2 , where R 2 is defined as mentioned above,
• R e is a hydrogen atom
• R 3 is a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidine-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidine-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl; and
• R 4 is a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4 yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 3-oxa-8-azabicyclo [3.2.1] oct-8-yl , 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4
• R 3 or R 4 a butoxy group substituted in the position by a radical R 3 or R 4 , wherein R 3 and R 4 are as defined above, and
• X is a nitrogen atom
• alkyl groups may be straight-chain or branched
• R a is a hydrogen atom
• the phenyl radical substituted by R b and R c represents a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group,
• R d is a cyclohexyl group which is substituted in the 4-position by a hydroxyacetylamino or N- (hydroxyacetyl) -methylamino group,
• R e is a hydrogen atom, a methoxy or ethyloxy group
• R 4 is a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazine-1-yl, 4 Represents methylpiperazine-1-yl or 4-ethylpiperazine-1-yl group,
• R 4 a propyloxy group which is substituted at the 3-position by a radical R 4 , wherein R 4 is defined as mentioned above, and
• X is a nitrogen atom
• the phenyl radical substituted by R 4 and FP is a 3-chloro-4-fluorophenyl group or a 3-ethynylphenyl group,
• R d is a cyclohexyl group which is substituted in the 4-position by a hydroxyacetylamino or N- (hydroxyacetyl) -methylamino group,
• X is a nitrogen atom
• R d represents a 4-substituted cyclohexyl group
• R d represents a 1-substituted pyrrolidin-3-yl group
• R d represents a 1-substituted-piperidin-3-yl group
• R d represents a 1-substituted-piperidin-4-yl group
• R a , R b , R c , R e and X are each defined as mentioned above.
• R a , Ff, Ff 'Ff and X are as defined above, with a compound of the general formula
• R d is defined as mentioned above and Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
• Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative, for example triphenylphosphine / diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or Ethylenglycoldiethylether at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C performed.
• Ci -4 alkyl group a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a substituted by a radical R 3 or Ff C 2-4 alkyl group, wherein R 3 and Ff are defined as mentioned above, a C ⁇ -4 -alkyl group which is substituted by a substituted in the 1-position by the radical R 5 pyrrolidinyl, piperidinyl or Homopiperidinyl distr, or a Ci -4 alkyl group, by one in 4 Substituted by the radical R 5 substituted morpholinyl group, wherein R 5 is in each case defined as mentioned above, represents and
• Z 2 represents a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group.
• the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, Sodium hydride or N-ethyl-diisopropylamine performed.
• an organic or inorganic base such as potassium carbonate, Sodium hydride or N-ethyl-diisopropylamine performed.
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative, for example triphenylphosphine / diethyl azodicarboxylate.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative, for example triphenylphosphine / diethyl azodicarboxylate.
• R a , R b , R c , R d and X are defined as mentioned above and Z 3 is a
• Leaving group such as a halogen atom, e.g. a chlorine or bromine atom or a
• Sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group
• Ammonia a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives, such as morpholine.
• Ff is a group which can be converted into a hydroxy group, for example an optionally substituted benzyloxy group, a trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.
• the cleavage of the protecting group is carried out, for example, hydrolytically 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 base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
• an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
• an alkali base such
• the cleavage of a benzyl or methoxybenzyl radical is carried out, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon 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 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
• cleavage of a tert-butyl or benzyl radical is carried out, for example, by treatment with an acid, such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid, or by treatment with iodotrimethylsilane, if appropriate using a solvent such as methylene chloride, doxan, methanol or diethyl ether.
• an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid
• iodotrimethylsilane if appropriate using a solvent such as methylene chloride, doxan, methanol or diethyl ether.
• the reaction with a hydroxyalkyl carboxylic acid in the presence of an activating agent such as N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azabenzotriazoM -yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), conveniently in a solvent such as methylene chloride, dimethylformamide, acetonitrile, tetrahydrofuran, doxane or ethylene glycol diethyl ether at temperatures between -50 and 100 ° C, but preferably at temperatures between -20 and 60 ° C performed.
• an activating agent such as N, N'-carbonyldiimidazole, N, N'-dicy
• acylation or sulfonylation Isocyanates carbamoyl chlorides, carboxylic acid halides, carboxylic anhydrides and carboxylic acids with activating agents such as N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or O- (benzotriazol-1-yl) -N, N, N 'N'-tetramethyluronium tetrafluoroborate and as sulfonylating sulfonyl halides come into question, and / or
• a compound of general formula I which contains an amino, alkylamino or imino group, it may be converted by alkylation or eduktive alkylation into a corresponding alkyl compound of general formula I and / or
• a compound of general formula I which contains a tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or an N-tert-butyloxycarbonylimino group, this may be obtained by treatment with an acid such as hydrochloric acid or Trifluoroacetic acid are converted into a corresponding amino, alkylamino or imino compound of general formula I.
• optionally present reactive groups such as hydroxyl, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.
• the Tri methylsi IyI, tert-butyl-dimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group into consideration.
• Protective radicals for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
• the optionally subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example 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 Presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
• an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
• an alkali metal base such as sodium
• cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical is for example effected by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon 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 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• the cleavage of a 2,4-dimethoxy-benzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
• cleavage of a tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using egg nes solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• an acid such as trifluoroacetic acid or hydrochloric acid
• iodotrimethylsilane optionally using egg nes solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. ,
• the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
• cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.
• the cis- / trans mixtures obtained can be purified by chromatography into their cis and trans isomers, the compounds of the general formula I which are obtained in racemates, by methods known per se (see Allinger N. L and Eliel E L in “Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) into their optical antipodes and compounds of general formula I having at least 2 asymmetric carbon atoms due to their physicochemical differences according to known methods, for example by chromatography and / or fractional crystallization, in their diastereomers, which, if they are in racemic form can then be separated into the enantiomers as mentioned above.
• the enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such.
• Particularly common optically active acids are e.g.
• optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
• the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids.
• suitable acids are 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 the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), which is inhibited, for example ligand binding, receptor dimerization or the tyrosine kinase itself can be effected.
• EGF-R epidermal growth factor receptor
• the inhibition of human EGF receptor kinase is determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1 186 based on the sequence published in Nature 309 (1984), 418). To do this, the protein is expressed in Sf9 insect cells as a GST fusion protein using the baculovirus expression system.
• the measurement of the enzyme activity is carried out in the presence or absence of the test compounds in serial dilutions.
• the polymer pEY (4: 1) from SIGMA is used as a substrate.
• Biotinylated pEY (bio-pEY) is added as a tracer substrate.
• Each 100 ⁇ l reaction solution contains 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 enzyme preparation.
• the enzyme reaction was started by adding 50 ⁇ l of a 100 ⁇ M ATP solution in 10 mM magnesium chloride.
• the dilution of the enzyme preparation is adjusted so that the phosphate incorporation into the bio-pEY is linear in terms of time and amount of enzyme.
• the enzyme preparation is diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM saline, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
• the enzyme assays are carried out at room temperature over a period of 30 minutes and terminated by addition of 50 ⁇ l of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 ⁇ l are placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate is washed with 200 ⁇ l of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 ⁇ l of an HRPO-labeled anti-PY antibody (PY20H anti-PTynHRP from Transduction Laboratories, 250 ng / ml) is incubated for 60 minutes.
• a stop solution 250 mM EDTA in 20 mM HEPES pH 7.4
• 100 ⁇ l are placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate is washed with 200 ⁇ l of a washing solution (
• microtiter plate is washed three times with 200 ul of washing solution.
• the data is fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Päd Prism Version 3.0) with variable hill slope. All released iteration data have a correlation coefficient of more than 0.9 and the upper and lower values of the curves show a spread of at least a factor of 5.
• the curves deduce the active substance concentration which inhibits the activity of the EGF receptor kinase by 50% (IC50) ,
• the compounds according to the invention have IC 50 values below 1000 nM, preferably below 100 nM.
• the compounds of the general formula I according to the invention inhibit the signal transduction by tyrosine kinases, such as the human EGF receptor and are therefore useful for the treatment of pathophysiological processes that are caused by hyperfunction of tyrosine kinases.
• tyrosine kinases such as the human EGF receptor
• pathophysiological processes that are caused by hyperfunction of tyrosine kinases.
• Tumors in particular tumors of epithelial and neuroepithelial origin,
• vascular endothelial cells Metastasis and abnormal proliferation of vascular endothelial cells (neoangiogenesis).
• the compounds of the present invention are also useful for the prevention and treatment of respiratory and pulmonary diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1 -anti-trypsin deficiency, or cough, pulmonary emphysema, pulmonary fibrosis and hyper-reactive airways.
• inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1 -anti-trypsin deficiency, or cough, pulmonary emphysema, pulmonary fibros
• the compounds are also useful in the treatment of disorders of the gastrointestinal tract and bile ducts and bladder associated with disrupted tyrosine kinase activity, such as those found in chronic inflammatory changes such as cholecystitis, Crohn's disease, Ulcerative colitis, and Ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
• disrupted tyrosine kinase activity such as those found in chronic inflammatory changes such as cholecystitis, Crohn's disease, Ulcerative colitis, and Ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
• the compounds of general formula I and their physiologically acceptable salts can be used to treat other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc.
• tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc.
• the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adriamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc.
• topoisomerase inhibitors eg etoposide
• mitotic inhibitors eg, vinblastine
• nucleic acid-interacting compounds eg, cisplatin, cyclophosphamide, adriamycin
• hormone antagonists eg, tamoxifen
• inhibitors of metabolic processes eg, 5-FU, etc.
• these compounds alone or in combination with other respiratory therapies, such as secretolytically (e.g., ambroxol, N-acetylcysteine), broncholytically (e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g., theophylline or glucocorticoids) substances.
• secretolytically e.g., ambroxol, N-acetylcysteine
• broncholytically e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
• anti-inflammatory e.g., theophylline or glucocorticoids
• the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
• these are mixed with one or more conventional inert Carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures in common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories incorporated.
• novel compounds of the formula (I) can be obtained by methods known per se and analogously to the following synthesis examples.
• the preparation of the starting compounds is described in WO 03/82290 or is carried out by methods known per se.
• the following examples are intended to illustrate the present invention without limiting it:
• 1 drag core contains:
• the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
• a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
• the coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
• the finished film dragees are shined with beeswax. Dragee weight: 245 mg.
• Composition 1 tablet contains:
• Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a tray drying oven at 50 ° C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
• Diameter 10 mm, biplan with facet on both sides and one-sided part notch.
• Composition 1 tablet contains:
• the active substance mixed with milk sugar, corn starch and silicic acid is mixed with a
• Composition 1 capsule contains:
• Corn starch drink about 180.0 mg
• the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device. The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg capsule shell: hard gelatine capsule size 1. E) Suppositories with 150 mg active substance
• Composition 1 suppository contains: active ingredient 150.0 mg
• Polyethylene glycol 1500 550.0 mg
• the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
• composition 100 ml Suspension contain: active substance 1.00 g
• Carboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
• Distilled water is heated to 70 ° C.
• p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
• 5 ml of suspension contain 50 mg of active ingredient.
• composition active substance 10.0 mg
• the active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.
• 1 capsule contains: Active substance 5.0 mg
• the active substance is mixed with lactose for inhalation purposes.
• the mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).
• 1 hub contains:
• the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
• the pH of the solution is adjusted with 1 N hydrochloric acid.
• the adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).

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• 2006
  • 2006-08-03 US US11/996,886 patent/US20100234371A1/en not_active Abandoned
  • 2006-08-03 JP JP2008527427A patent/JP2009506990A/ja active Pending
  • 2006-08-03 CA CA002619037A patent/CA2619037A1/en not_active Abandoned
  • 2006-08-03 WO PCT/EP2006/065000 patent/WO2007023073A2/de active Application Filing
  • 2006-08-03 EP EP06778135A patent/EP1919900A2/de not_active Withdrawn
• 2011
  • 2011-02-15 US US13/027,669 patent/US20110136806A1/en not_active Abandoned

Non-Patent Citations (1)

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