WO2003089439A1 - Bicyclic heterocycles, medicaments containing these compounds, their use, and method for the production thereof - Google Patents

Bicyclic heterocycles, medicaments containing these compounds, their use, and method for the production thereof Download PDF

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WO2003089439A1
WO2003089439A1 PCT/EP2003/003828 EP0303828W WO03089439A1 WO 2003089439 A1 WO2003089439 A1 WO 2003089439A1 EP 0303828 W EP0303828 W EP 0303828W WO 03089439 A1 WO03089439 A1 WO 03089439A1
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carbon atoms
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amino
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PCT/EP2003/003828
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Frank Himmelsbach
Birgit Jung
Flavio Solca
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to CA2484395A priority patent/CA2484395C/en
Priority to EP03746824A priority patent/EP1499619A1/en
Priority to JP2003586159A priority patent/JP4527406B2/en
Publication of WO2003089439A1 publication Critical patent/WO2003089439A1/en

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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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    • C07D405/14—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 three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

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 -alkyl group
  • R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 to R 3 is substituted, wherein
  • R 1 and R 2 which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • R 3 is a hydrogen, fluorine, chlorine or bromine atom
  • R c is a hydrogen atom or a fluorine, chlorine or bromine atom
  • R 4 is a hydroxy, C ⁇ -3 alkyloxy-, C 3 _ 6 cycloalkyloxy, C 3 _ 6 cycloalkyl, C ⁇ -3-alkyloxy, amino, C ⁇ -3 alkylamino, di- (C ⁇ - 3- alkyl) amino, bis (2-C 1, 3 -alkyloxyethyl) amino, bis (3-C 3 -alkyloxy-propyl) amino, pyrrolidin-1-yl, Pipe - ridin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4- (C 1-3 alkyl) -piperazine-1 -yI-, homopiperazin-1-yl or 4- (C ⁇ -3 -AlkyI) - represents homopiperazine-1-yl group,
  • R 5 is a hydrogen atom or a -C. Represents 3 ⁇ alkyl group
  • B is a carbonyl or sulfonyl group
  • C is a 1, 3-allenylene, 1, 1-vinylene or 1, 2-vinylene group, which may each be substituted by one or two methyl groups or by a trifluoromethyl group,
  • a 1,3-butadiene-1,4-ylene group which may be substituted by one or two methyl groups or by a trifluoromethyl group,
  • D is a straight-chain or branched C 1-4 -alkylene group
  • E is a pyrrolidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 5 carbon atoms, if the two hydrogen atoms are on adjacent carbon atoms, or contains 2 to 4 carbon atoms, when there are two hydrogen atoms on carbon atoms which are separated by an atom, whilst the abovementioned pyrrolidin-1-yl groups each additionally by one or two C- ⁇ - 3 Alkyl groups may be substituted,
  • a piperidin-1-yl or homopiperidin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached are carbon atoms, which are separated by two atoms, wherein the above-mentioned piperidine-1 yl and homopiperidin-1-yl groups each additionally by one or two C ⁇ -3 alkyl groups may be substituted,
  • X is a methine group substituted by a cyano group or a nitrogen atom
  • aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as meaning a phenyl group which is monosubstituted or disubstituted by R 6 , where the substituents may be identical or different and
  • R 6 is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C ⁇ methoxy- -3 alkyl, hydroxy, C- ⁇ - 3 alkyloxy, difluoromethyl, trifluoromethyl, difluoro-, trifluoromethoxy or cyano group,
  • heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the abovementioned heteroaryl groups being in each case mono- or disubstituted by the radical R 6 , where the substituents are identical or may be different and R 6 is as defined above, and
  • alkyl groups may be straight-chain or branched.
  • Preferred compounds of the above general formula I are those in which R a is a hydrogen atom
  • R b is a substituted by the radicals R 1 to R 3 phenyl group, wherein
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom
  • phenyloxy or phenylmethoxy group wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or
  • a pyridinyloxy or pyndinylmethoxy group wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,
  • R 2 is a hydrogen, fluorine or chlorine atom
  • R 3 represents a hydrogen atom
  • R ° is a hydrogen atom
  • R 4 is a hydroxy, C ⁇ -3 -alkyloxy-, amino, C ⁇ -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, piperazin-1-yl, 4- (C -3 alkyl) -piperazin-1-yl, homopiperazin-1-yl, or 4- (C ⁇ 3- alkyl) homopiperazin-1-yl group,
  • R 4 a propyloxy group which is substituted in the 3-position by a radical R 4 , wherein R 4 is defined as mentioned above, or
  • R 4 a butoxy group substituted in the 4-position by a radical R 4 , wherein R 4 is defined as mentioned above,
  • A is an imino group
  • B is a carbonyl or sulfonyl group
  • C is a 1, 1-vinylene, 1, 2-vinylene or ethynylene group
  • D is a methylene, 1, 1-ethylene or 1, 2-ethylene group
  • E is a piperidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms represented by two atoms are separated, whereby the above-mentioned piperidin-1-yl groups each additionally by one or two C ⁇ -3 alkyl groups may be substituted,
  • a piperazin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing from 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing from 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms, or contain 1 to 3 carbon atoms, when the two hydrogen atoms on carbon atoms are, which are separated by an atom, or contains 1 or 2 carbon atoms, when the two hydrogen atoms are on carbon atoms which are separated by two atoms, wherein the above-mentioned piperazin-1-yl groups each additionally by one or two C 3 Alkyl groups may be substituted, or
  • a morpholin-4-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms separated by two atoms are, with the above-mentioned morpholin-4-yl groups may each additionally by one or two C ⁇ -3 alkyl groups,
  • X is a nitrogen atom
  • alkyl groups may be straight-chain or branched
  • R a is a hydrogen atom
  • R b is a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group,
  • R c is a hydrogen atom, a methoxy, ethyloxy, 2- (methoxy) ethyloxy, 3- (morpholin-4-yl) propoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy , Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy or tetrahydropyran-4-ylmethoxy group,
  • A is an imino group
  • B is a carbonyl group
  • C is a 1, 2-vinylene group
  • E is a 2-azabicyclo [2.2.1] hept-2-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diaza-bicyclo 2.2.1] hept-2-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 2-azabicyclo [2.2.2] oct-2-yl, 3 -Aza-bicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-8-yl, 3,8-diazabicyclo [3.2.1] oct-3-yl -, 8-methyl-3,8-diaza-bicyclo [3.2.1] oct-3-yl, 3,8-diaza-bicyclo [3.2.1] oct-8-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1] oct-8-yl, 3-oxa-8-
  • X is a nitrogen atom
  • R a is a hydrogen atom
  • R is a 3-chloro-4-fluoro-phenyl group
  • R c is a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy group
  • A is an imino group
  • B is a carbonyl group
  • C is a 1, 2-vinylene group
  • E is a 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl group, a 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl group or an 8- Oxa-3-azabicyclo [3.2.1] oct-3-yl group and
  • X is a nitrogen atom
  • the compounds of general formula I can be prepared, for example, by the following processes:
  • R a , R b , R c , A, B and X are as defined above and R 7 and R 8 , which may be the same or different, C ⁇ . 4 alkyl groups, with a compound of general formula
  • reaction is conveniently carried out in a solvent or solvent mixture such as tetrahydrofuran, tetrahydrofuran / water, acetonitrile, acetonitrile, water, dioxane, ethylene glycol dimethyl ether, isopropanol, methylene chloride, dimethylformamide or sulfolane optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium hydroxide or 1, 8 Diazabicyclo [5.4.0] undec-7-ene and. optionally in the presence of a lithium salt such as lithium chloride at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C carried out.
  • a lithium salt such as lithium chloride at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C carried out.
  • the reaction may also be carried out with a reactive derivative of the compound of general formula III, for example the hydrate or a hemiacetal.
  • R a , R b , R c , A, B, C, D and X are as defined above and Z 1 is a leaving group such as a halogen atom or a substituted sulphonyloxy group such as a chlorine or bromine atom, a Methansulfonyloxy- or p- Toluolsulfonyloxy distr, with a compound of general formula
  • the reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, sulfolane, toluene or methylene chloride or mixtures thereof optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium carbonate, potassium hydroxide, triethylamine or N-ethyl diisopropylamine and optionally in the presence of a reaction accelerator such as an alkali metal iodide at temperatures between -20 and 150 ° C, but preferably at temperatures between 0 and 100 ° C carried out leads.
  • a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, sulfolane, toluene or methylene chloride or mixtures thereof
  • an inorganic or organic base for example sodium carbon
  • 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.
  • a protective group for a hydroxy group the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group into consideration.
  • Suitable protecting groups 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 optional subsequent cleavage of a protective moiety used 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 metal 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
  • 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 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.
  • Trifluoracetylrestes The cleavage of a Trifluoracetylrestes is preferably carried out 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 at temperatures between 0 and 50 ° C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid
  • sodium hydroxide optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • the compounds of the general formula I obtained can, as already mentioned at the beginning, 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 resolved into their enantiomers.
  • the cis- / trans mixtures obtained can be purified by chromatography into their cis and trans isomers, the compounds of general formula I which are obtained in racemates, by methods known per se (see Allinger NL and Eliel EL in “ Topics in Stereochemistry “, Vol. 6, Wiley Interscience, 1971)) in 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, eg by chromatography and / or fractional crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers 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 as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • suitable agents Especially - 1.5 -
  • optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
  • 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 according to the invention of the general formula I 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, by inhibition of the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected.
  • EGF-R epidermal growth factor receptor
  • the inhibition of the human EGF receptor kinase was determined with the aid of the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418).
  • the protein was expressed in Sf9 insect cells as a GST fusion protein using the baculovirus expression system.
  • the measurement of enzyme activity was carried out in the presence or absence of the test compounds in serial dilutions.
  • the polymer pEY (4: 1) from SIGMA was used as a substrate.
  • Biotinylated pEY (bio-pEY) was added as a tracer substrate.
  • Each 100 ⁇ l 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 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 became so. adjusted that the phosphate incorporation into the bio-pEY was linear in terms of time and amount of enzyme.
  • the enzyme preparation was 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 were performed at room temperature for 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 was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was 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-pty ⁇ HRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes.
  • a stop solution 250 mM EDTA in 20 mM HEPES pH 7.4
  • 100 ⁇ l was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was washed with 200 ⁇ l of a washing solution (
  • microtiter plate was washed three times with 200 ul of washing solution.
  • the data was fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable hill slope. All released iteration data showed a correlation coefficient of over 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. From the curves, the drug concentration was derived, which inhibits the activity of EGF receptor kinase by 50% (ICso) ,
  • the compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases e.g. Benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds of the 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, 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, emphysema, pulmonary fibrosis and hyper-reactive air
  • the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder, which are associated with a disrupted activity of tyrosine kinases, 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.
  • tyrosine kinases 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 tolerable salts can be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyper proliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the Immune system, hyperproliferation of hematopoietic cells etc.
  • diseases caused by aberrant function of tyrosine kinases such as epidermal hyper proliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the Immune system, hyperproliferation of hematopoietic cells 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).
  • Mitosis inhibitors eg vinblastine
  • compounds interacting with nucleic acids eg cisplatin, cyclophosphamide, adriamycin
  • hormone antagonists eg tamoxifen
  • inhibitors of metabolic processes eg 5-FU etc.
  • cytokines eg interferons
  • Antibodies etc.
  • these compounds may be used alone or in combination with other respiratory therapeutics, 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 at 0.1-15 mg / kg.
  • these are administered with one or more conventional inert carrier - 10 -
  • substances and / or diluents e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty 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.
  • This solution is added dropwise with ice-bath cooling to a mixture of 7.00 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-amino-7-cyclopropylmethoxy-quinazoline and 9.60 ml of Hünig base in 80 ml of tetrahydrofuran.
  • the reaction solution is stirred for one hour in an ice bath and for a further hour at room temperature. Now one-fifth of this solution is removed and 740 mg (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride and 1 ml Hünig base are added.
  • the reaction mixture is stirred overnight at 60 ° C and then concentrated in vacuo.
  • the flask residue is taken up with ethyl acetate and a little methanol and extracted with water.
  • the organic phase is applied to silica gel and chromatographed on a silica gel column with ethyl acetate / methanol (95: 5 to 70:30) as the eluent.
  • the product obtained is crystallized from diisopropyl ether and filtered off with suction.
  • composition 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.
  • coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax.
  • 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.
  • Tablet weight 220 mg 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 silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm.
  • the granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
  • 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 gelatin capsule size 1.
  • 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.
  • Carboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
  • Dest. Water is heated to 70 ° C. P-hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethylcellulose
  • the active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • 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:
  • 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 1N hydrochloric acid.
  • the adjusted solution is filtered and filled into suitable containers for the hand-operated sprayer (cartridges).

Abstract

The invention relates to bicyclic heterocycles of general formula (I), in which Ra, Rb, Rc, A, B, C, D, E and X are defined as in Claim 1, to tautomers, stereoisomers, mixtures and salts thereof, particularly their physiologically compatible salts with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory action on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of these compounds for treating diseases, particularly tumor diseases and benign prostatic hyperplasia (BPH), diseases of the lungs and of the respiratory passages and to the production thereof.

Description

Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
Gegenstand der vorliegenden Erfindung sind bicyclische Heterocyclen der allgemeinen FormelThe present invention relates to bicyclic heterocycles of the general formula
Figure imgf000002_0001
Figure imgf000002_0001
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine Hemmwirkung auf die durch Tyrosinkinasen vermittelte Signaltransduktion, deren Verwendung zur Behandlung von Krankheiten, insbesondere von Tumorerkrankungen sowie der benignen Prostatahyperplasie (BPH), von Erkrankungen der Lunge und der Atemwege und deren Herstellung.their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically acceptable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for the treatment of diseases, especially of tumor diseases and benign prostatic hyperplasia (BPH), lung and respiratory diseases and their production.
In der obigen allgemeinen Formel I bedeutetIn the above general formula I means
Ra ein Wasserstoffatom oder eine Cι- -Alkylgruppe,R a represents a hydrogen atom or a C 1 -alkyl group,
Rb eine Phenyl-, Benzyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 bis R3 substituiert ist, wobeiR b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 to R 3 is substituted, wherein
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
eine C1-4-Alkyl-, Hydroxy-, C1-4-Alkoxy-, C2-3-Alkenyl- oder C2-3-Alkinylgruppe,C 1-4 alkyl, hydroxy, C 1-4 alkoxy, C 2-3 alkenyl or C 2-3 alkynyl,
eine Aryl-, Aryloxy-, Arylmethyl- oder Arylmethoxygruppe, eine , Heteroaryl-, Heteroaryloxy-, Heteroarylmethyl- oder Heteroarylmethoxy- gruppe,an aryl, aryloxy, arylmethyl or arylmethoxy group, a, heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group,
eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe odera substituted by 1 to 3 fluorine atoms methyl or methoxy group or
eine Cyano-, Nitro- oder Aminogruppe, unda cyano, nitro or amino group, and
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 3 is a hydrogen, fluorine, chlorine or bromine atom,
eine Methyl- oder Trifluormethylgruppe darstellen,represent a methyl or trifluoromethyl group,
Rc ein Wasserstoff atom oder ein Fluor-, Chlor- oder Bromatom,R c is a hydrogen atom or a fluorine, chlorine or bromine atom,
eine Hydroxy- oder Cι- -Alkyloxygruppe,a hydroxy or C 1 -alkyloxy group,
eine durch 1 bis 3 Fluoratome substituierte Methoxygruppe,a methoxy group substituted by 1 to 3 fluorine atoms,
eine durch 1 bis 5 Fluoratome substituierte Ethyloxygruppe,an ethyloxy group substituted by 1 to 5 fluorine atoms,
eine C2-4-Alkyloxygruppe, die durch einen Rest R4 substituiert ist, wobeia C 2-4 alkyloxy group substituted by a radical R 4 , wherein
R4 eine Hydroxy-, Cι-3-Alkyloxy-, C3_6-Cycloalkyloxy-, C3_6-Cycloalkyl- Cι-3-alkyloxy-, Amino-, Cι-3-Alkylamino-, Di-(Cι-3-alkyl)amino-, Bis-(2-C1.3- alkyloxy-ethyl)-amino-, Bis-(3-Cι.3-alkyloxy-propyl)-amino-, Pyrrolidin-1-yl-, Pipe- ridin-1-yl-, Homopiperidin-1-yl-, Morpholin-4-yl-, Homomorpholin-4-yI-, Piperazin- 1-yl-, 4-(C1-3-Alkyl)-piperazin-1-yI-, Homopiperazin-1-yl- oder 4-(Cι-3-AlkyI)- homopiperazin-1-ylgruppe darstellt,R 4 is a hydroxy, Cι -3 alkyloxy-, C 3 _ 6 cycloalkyloxy, C 3 _ 6 cycloalkyl, Cι-3-alkyloxy, amino, Cι -3 alkylamino, di- (Cι - 3- alkyl) amino, bis (2-C 1, 3 -alkyloxyethyl) amino, bis (3-C 3 -alkyloxy-propyl) amino, pyrrolidin-1-yl, Pipe - ridin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4- (C 1-3 alkyl) -piperazine-1 -yI-, homopiperazin-1-yl or 4- (Cι -3 -AlkyI) - represents homopiperazine-1-yl group,
eine C2- -Alkyloxygruppe, die durch die Gruppe E substituiert ist, wobei E wie nachstehend erwähnt definiert ist,a C 2- alkyloxy group substituted by the group E, wherein E is defined as mentioned below,
eine C3-7-Cycloalkyloxy- oder C3-7-Cycloalkyl-Cι_4-alkyloxygruppe, eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy- oder Tetrahydropyran-4-yloxy- gruppe,a C 3-7 alkyloxy group cycloalkyloxy or C 3- 7 cycloalkyl Cι_ 4, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,
eine Tetrahydrofuranyl-Cι-4-alkyloxy- oder Tetrahydropyranyl-Cι-4-alkyloxygruppe,a tetrahydrofuranyl Cι -4 alkyloxy or tetrahydropyranyl Cι alkyloxy -4,
eine Pyrrolidin-3-yloxy-, Piperidin-3-yloxy- oder Piperidin-4-yloxy-Gruppe,a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,
eine 1-(Cι-3-Alkyl)-pyrrolidin-3-yloxy-, 1-(Cι-3-Alkyl)-piperidin-3-yloxy- oder 1-(Cι_3-Alkyl)- piperidin-4-yloxy-Gruppe,a 1- (Cι -3 alkyl) -pyrrolidin-3-yloxy, 1- (3 Cι- alkyl) -piperidin-3-yloxy or 1- (3 Cι_ alkyl) - piperidin-4-yloxy Group,
eine Cι-4-Alkoxygruppe, die durch eine in 1 -Stellung durch den Rest R5 substituierte Pyrrolidinyl-, Piperidinyl- oder Homopiperidinylgruppe substituiert ist, wobeia Cι -4 alkoxy group which is substituted by a substituted in the 1 position by the group R 5 pyrrolidinyl, piperidinyl or homopiperidinyl group wherein
R5 ein Wasserstoffatom oder eine Cι.3~Alkylgruppe darstellt,R 5 is a hydrogen atom or a -C. Represents 3 ~ alkyl group,
oder eine Cι-4-AIkoxygruppe, die durch eine in 4-Stellung durch den Rest R5 substituierte Morpholinyl- oder Homomorpholinylgruppe substituiert ist, wobei R5 wie vorstehend erwähnt definiert ist,or Cι -4 -AIkoxygruppe which is substituted by a 4-position by the radical R 5 substituted morpholinyl or homomorpholinyl group, wherein R 5 is defined as mentioned above,
A eine Imino- oder Cι-4-Alkyliminogruppe,A one imino or Cι -4 -alkylimino,
B eine Carbonyl- oder Sulfonylgruppe,B is a carbonyl or sulfonyl group,
C eine 1 ,3-Allenylen-, 1 ,1-Vinylen- oder 1 ,2-Vinylengruppe, die jeweils durch eine oder zwei Methylgruppen oder durch eine Trifluormethylgruppe substituiert sein kann,C is a 1, 3-allenylene, 1, 1-vinylene or 1, 2-vinylene group, which may each be substituted by one or two methyl groups or by a trifluoromethyl group,
eine Ethinylengruppe oderan ethynylene group or
eine 1 ,3-Butadien-1 ,4-ylengruppe, die durch eine oder zwei Methylgruppen oder durch eine Trifluormethylgruppe substituiert sein kann,a 1,3-butadiene-1,4-ylene group which may be substituted by one or two methyl groups or by a trifluoromethyl group,
D eine geradkettige oder verzweigte C1-4-Alkylengruppe, E eine Pyrrolidin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 2 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, wobei die vorstehend erwähnten Pyrrolidin-1-ylgruppen jeweils zusätzlich durch eine oder zwei C-ι-3-Alkylgruppen substituiert sein können,D is a straight-chain or branched C 1-4 -alkylene group, E is a pyrrolidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 5 carbon atoms, if the two hydrogen atoms are on adjacent carbon atoms, or contains 2 to 4 carbon atoms, when there are two hydrogen atoms on carbon atoms which are separated by an atom, whilst the abovementioned pyrrolidin-1-yl groups each additionally by one or two C-ι- 3 Alkyl groups may be substituted,
eine Piperidin-1-yl- oder Homopiperidin-1-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperidin-1-yl- und Homopiperidin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,a piperidin-1-yl or homopiperidin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached are carbon atoms, which are separated by two atoms, wherein the above-mentioned piperidine-1 yl and homopiperidin-1-yl groups each additionally by one or two Cι -3 alkyl groups may be substituted,
eine Piperazin-1 -yl- oder Homopiperazin-1-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperazin-1-yl- und Homopiperazin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können, eine Morpholin-4-yl- oder Homomorpholin-4-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Morpholin-4-yl- und Homomorpholin-4-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,a piperazine-1-yl or homopiperazin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached are carbon atoms, which are separated by two atoms, whilst the abovementioned piperazin-1-yl and homopiperazin-1-yl groups each additionally by one or two Cι -3 alkyl groups may be substituted, a morpholin-4-yl or homomorpholin-4-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached carbon atoms are separated by two atoms, whilst the abovementioned morpholin-4-yl-4-yl groups and Homomorpholin each additionally by one or two Cι -3 alkyl groups may be substituted,
undand
X eine durch eine Cyanogruppe substituierte Methingruppe oder ein Stickstoffatom,X is a methine group substituted by a cyano group or a nitrogen atom,
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen jeweils eine Phenylgruppe zu verstehen ist, die durch R6 mono- oder disubstituiert ist, wobei die Substituenten gleich oder verschieden sein können undwherein the aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as meaning a phenyl group which is monosubstituted or disubstituted by R 6 , where the substituents may be identical or different and
R6 ein Wasserstoffatom, ein Fluor-, Chlor-, Brom- oder lodatom oder eine Cι-3-Alkyl-, Hydroxy-, C-ι-3-Alkyloxy-, Difluormethyl-, Trifluormethyl-, Difluor- methoxy-, Trifluormethoxy- oder Cyanogruppe darstellt,R 6 is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a Cι methoxy- -3 alkyl, hydroxy, C-ι- 3 alkyloxy, difluoromethyl, trifluoromethyl, difluoro-, trifluoromethoxy or cyano group,
unter den bei der Definition der vorstehend genannten Reste erwähnten Hetero- arylgruppen eine Pyridinyl-, Pyridazinyl-, Pyrimidinyl- oder Pyrazinylgruppe zu verstehen ist, wobei die vorstehend erwähnten Heteroarylgruppen jeweils durch den Rest R6 mono- oder disubstituiert sind, wobei die Substituenten gleich oder verschieden sein können und R6wie vorstehend erwähnt definiert ist, undthe heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the abovementioned heteroaryl groups being in each case mono- or disubstituted by the radical R 6 , where the substituents are identical or may be different and R 6 is as defined above, and
soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen gerad- kettig oder verzweigt sein können.Unless otherwise mentioned, the abovementioned alkyl groups may be straight-chain or branched.
Bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denen Ra ein Wasserstoff atom,Preferred compounds of the above general formula I are those in which R a is a hydrogen atom,
Rb eine durch die Reste R1 bis R3 substituierte Phenylgruppe, wobeiR b is a substituted by the radicals R 1 to R 3 phenyl group, wherein
R1 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 1 is a hydrogen, fluorine, chlorine or bromine atom,
eine Methyl-, Trifluormethyl- oder Ethinylgruppe,a methyl, trifluoromethyl or ethynyl group,
eine Phenyloxy- oder Phenylmethoxygruppe, wobei der Phenylteil der vorstehend erwähnten Gruppen gegebenenfalls durch ein Fluor- oder Chloratom substituiert ist, odera phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or
eine Pyridinyloxy- oder Pyndinylmethoxygruppe, wobei der Pyridinylteil der vorstehend erwähnten Gruppen gegebenenfalls durch eine Methyl- oder Trifluormethylgruppe substituiert ist,a pyridinyloxy or pyndinylmethoxy group, wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,
R2ein Wasserstoff-, Fluor- oder Chloratom undR 2 is a hydrogen, fluorine or chlorine atom and
R3 ein Wasserstoffatom darstellen,R 3 represents a hydrogen atom,
R° ein Wasserstoffatom,R ° is a hydrogen atom,
eine C1-3-Alkyloxygruppe,a C 1-3 -alkyloxy group,
eine C4-6-Cycloalkyloxy- oder C3-6-Cycloalkyl-Cι-2-alkyloxy-Gruppe,a C 4-6 cycloalkyloxy or C 3-6 cycloalkyl-Cι -2 alkyloxy group,
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy-, Tetrahydrofuranyl-Cι-2-alkyloxy - oder Tetrahydropyranyl~Cι..2-alkyloχy-Gjruppe,a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C 2 -alkyloxy or tetrahydropyranyl-C 1 -C 2 -alkyl- o- y-gamma group,
) eine Ethyloxygruppe, die in 2-Stellung durch einen Rest R4 substituiert ist, wobei) an ethyloxy group which is substituted in the 2-position by a radical R 4 , wherein
R4 eine Hydroxy-, Cι-3-Alkyloxy-, Amino-, Cι-3-Alkylamino-, Di-(C1-3-alkyl)amino-, Bis-(2-methoxyethyI)-amino-, Pyrrolidin-1-yl-, Piperidin-1-yl-, Homopiperidin-1-yl-, Morpholin-4-yl-, Homomorpholin-4-yl-, Piperazin-1-yl-, 4-(C -3-Alkyl)-piperazin-1- yl-, Homopiperazin-1-yl-, oder 4-(Cι-3-Alkyl)-homopiperazin-1-yl-Gruppe darstellt,R 4 is a hydroxy, Cι -3 -alkyloxy-, amino, Cι -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, piperazin-1-yl, 4- (C -3 alkyl) -piperazin-1-yl, homopiperazin-1-yl, or 4- (Cι 3- alkyl) homopiperazin-1-yl group,
eine Propyloxygruppe, die in 3-Stellung durch einen Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist, odera propyloxy group which is substituted in the 3-position by a radical R 4 , wherein R 4 is defined as mentioned above, or
eine Butyloxygruppe, die in 4-Stellung durch einen Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,a butoxy group substituted in the 4-position by a radical R 4 , wherein R 4 is defined as mentioned above,
A eine Iminogruppe,A is an imino group,
B eine Carbonyl- oder Sulfonylgruppe,B is a carbonyl or sulfonyl group,
C eine 1 ,1-Vinylen-, 1 ,2-Vinylen- oder Ethinylengruppe,C is a 1, 1-vinylene, 1, 2-vinylene or ethynylene group,
D eine Methylen-, 1 , 1 -Ethylen- oder 1 ,2-Ethylengruppe,D is a methylene, 1, 1-ethylene or 1, 2-ethylene group,
E eine Piperidin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoff atome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperidin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,E is a piperidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms represented by two atoms are separated, whereby the above-mentioned piperidin-1-yl groups each additionally by one or two Cι -3 alkyl groups may be substituted,
eine Piperazin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperazin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können, odera piperazin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing from 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing from 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms, or contain 1 to 3 carbon atoms, when the two hydrogen atoms on carbon atoms are, which are separated by an atom, or contains 1 or 2 carbon atoms, when the two hydrogen atoms are on carbon atoms which are separated by two atoms, wherein the above-mentioned piperazin-1-yl groups each additionally by one or two C 3 Alkyl groups may be substituted, or
eine Morpholin-4-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Morpholin-4-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,a morpholin-4-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms separated by two atoms are, with the above-mentioned morpholin-4-yl groups may each additionally by one or two Cι -3 alkyl groups,
undand
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
Besonders bevorzugte Verbindungen der obigen allgemeinen Formel I sind diejenigen, in denenParticularly preferred compounds of the above general formula I are those in which
Ra ein Wasserstoffatom,R a is a hydrogen atom,
Rb eine 3-Ethinylphenyl-, 3-Bromphenyl-, 3,4-Difluorphenyl- oder 3-Chlor-4-fluor-phenyl- gruppe,R b is a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group,
Rc ein Wasserstoffatom, eine Methoxy-, Ethyloxy-, 2-(Methoxy)ethyloxy-, 3-(Morpholin~4-yl)propyIoxy-, Cyclo- butyloxy-, Cyclopentyloxy-, Cyclohexyloxy-, Cyclopropylmethoxy-, Cyclopentylmethoxy-, Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy-, Tetra- hydrofuran-2-ylmethoxy-, Tetrahydrofuran-3-ylmethoxy- oder Tetrahydropyran-4-yl- methoxy-Gruppe,R c is a hydrogen atom, a methoxy, ethyloxy, 2- (methoxy) ethyloxy, 3- (morpholin-4-yl) propoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy , Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy or tetrahydropyran-4-ylmethoxy group,
A eine Iminogruppe,A is an imino group,
B eine Carbonylgruppe,B is a carbonyl group,
C eine 1 ,2-Vinylengruppe,C is a 1, 2-vinylene group,
D eine Methylengruppe,D is a methylene group,
E eine 2-Aza-bicyclo[2.2.1]hept-2-yl-, 2,5-Diaza-bicyclo[2.2.1]hept-2-yl-, 5-Methyl-2,5-diaza-bicyclo[2.2.1 ]hept-2-yl-, 2-Oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl-, 2-Aza-bicyclo[2.2.2]oct-2-yl-, 3-Aza-bicyclo[3.2.1]oct-3-yl-, 8-Aza-bicyclo[3.2.1]oct-8-yl-, 3,8-Diaza-bicyclo[3.2.1]oct-3-yl-, 8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl-, 3,8-Diaza-bicyclo[3.2.1]oct-8-yl-, 3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl-, 3-Oxa-8-aza-bicyclo[3.2.1joct-8-yl- oder 8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl-Gruppe undE is a 2-azabicyclo [2.2.1] hept-2-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diaza-bicyclo 2.2.1] hept-2-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 2-azabicyclo [2.2.2] oct-2-yl, 3 -Aza-bicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-8-yl, 3,8-diazabicyclo [3.2.1] oct-3-yl -, 8-methyl-3,8-diaza-bicyclo [3.2.1] oct-3-yl, 3,8-diaza-bicyclo [3.2.1] oct-8-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1] oct-8-yl, 3-oxa-8-aza-bicyclo [3.2.1joct-8-yl or 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl group and
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
Ganz besonders bevorzugte Verbindungen der allgemeinen Formel I sind diejenigen, in denenVery particularly preferred compounds of general formula I are those in which
Ra ein Wasserstoffatom,R a is a hydrogen atom,
R eine 3-Chlor-4-fluor-phenylgruppe, Rc eine Tetrahydrofuran-3-yloxy-, Cyclopentyloxy- oder Cyclopropylmethoxygruppe,R is a 3-chloro-4-fluoro-phenyl group, R c is a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy group,
A eine Iminogruppe,A is an imino group,
B eine Carbonylgruppe,B is a carbonyl group,
C eine 1 ,2-Vinylengruppe,C is a 1, 2-vinylene group,
D eine Methylengruppe,D is a methylene group,
E eine 2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl-Gruppe, eine 3-Oxa-8-aza-bicyclo[3.2.1]oct-8-yl-Gruppe oder eine 8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl-Gruppe undE is a 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl group, a 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl group or an 8- Oxa-3-azabicyclo [3.2.1] oct-3-yl group and
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
Beispielsweise seien folgende besonders bevorzugte Verbindungen der allgemeinen Formel I erwähnt:For example, the following particularly preferred compounds of general formula I may be mentioned:
(a) 4-[(3-Chlor-4-fluor-phenyI)amino]-6-{[4-((1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin,(a) 4 - [(3-Chloro-4-fluoro-phenyl) amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy quinazoline,
(b) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1 -oxo-2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin,(b) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(c) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(c) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(d) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-1-oxo- 2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin, - 1.1 -(d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, - 1.1 -
(e) 4-[(3-ChIor-4-fluor-phenyl)amino]-6-{[4-((1 R,4f?)-2-oxa-5-aza-bicyclo[2.2.1 jhept- 5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(e) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4f-2) -oxa-5-aza-bicyclo [2.2.1] 5-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline,
(f) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-oxo- 2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(f) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(9) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1R,4 )-2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-1-oxo-2-buten-1-yl]amino}-7-[( :?)-(tetrahydrofuran-3-yl)oxy]-chinazolin und(9) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [( : ?) - (tetrahydrofuran-3-yl) oxy] quinazoline and
(h) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(h) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline,
sowie deren Salze.and their salts.
Die Verbindungen der allgemeinen Formel I lassen sich beispielsweise nach folgenden Verfahren herstellen:The compounds of general formula I can be prepared, for example, by the following processes:
a) Umsetzung einer Verbindung der allgemeinen Formela) reaction of a compound of the general formula
Figure imgf000012_0001
in der
Figure imgf000012_0001
in the
Ra, Rb, Rc, A, B und X wie eingangs erwähnt definiert sind und R7 und R8, die gleich oder verschieden sein können, Cι.4-Alkylgruppen darstellen, mit einer Verbindung der allgemeinen FormelR a , R b , R c , A, B and X are as defined above and R 7 and R 8 , which may be the same or different, Cι. 4 alkyl groups, with a compound of general formula
OHC - D - E, (III) in derOHC - D - E, (III) in the
D und E wie eingangs erwähnt definiert sind. Die Umsetzung wird zweckmäßigerweise in einem Lösungsmittel oder Lösungsmittelgemisch wie Tetrahydrofuran, Tetrahydrofuran/Wasser, Acetonitril, Acetonitril Wasser, Dioxan, Ethylenglycoldimethylether, Isopropanol, Methylenchlorid, Dimethylformamid oder Sulfolan gegebenenfalls in Gegenwart einer anorganischen oder organischen Base, z.B. Natriumcarbonat, Kaliumhydroxid oder 1 ,8-Diazabicyclo[5.4.0]undec-7-en und. gegebenenfalls in Gegenwart eines Lithiumsalzes wie Lithiumchlorid bei Temperaturen zwischen -50 und 150°C, vorzugsweise jedoch bei Temperaturen zwischen -20 und 80°C, durchgeführt. Die Reaktion kann auch mit einem reaktiven Derivat der Verbindung der allgemeinen Formel lli durchgeführt werden, beispielsweise dem Hydrat oder einem Hemiacetal.D and E are defined as mentioned above. The reaction is conveniently carried out in a solvent or solvent mixture such as tetrahydrofuran, tetrahydrofuran / water, acetonitrile, acetonitrile, water, dioxane, ethylene glycol dimethyl ether, isopropanol, methylene chloride, dimethylformamide or sulfolane optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium hydroxide or 1, 8 Diazabicyclo [5.4.0] undec-7-ene and. optionally in the presence of a lithium salt such as lithium chloride at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C carried out. The reaction may also be carried out with a reactive derivative of the compound of general formula III, for example the hydrate or a hemiacetal.
b) Umsetzung einer Verbindung der allgemeinen Formelb) reaction of a compound of the general formula
Figure imgf000013_0001
Figure imgf000013_0001
in der Ra, Rb, Rc, A, B, C, D und X wie eingangs erwähnt definiert sind und Z1 eine Austrittsgruppe wie ein Halogenatom oder eine substituierte Sulfonyloxygruppe wie ein Chlor- oder Bromatom, eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe darstellt, mit einer Verbindung der allgemeinen Formelin which R a , R b , R c , A, B, C, D and X are as defined above and Z 1 is a leaving group such as a halogen atom or a substituted sulphonyloxy group such as a chlorine or bromine atom, a Methansulfonyloxy- or p- Toluolsulfonyloxygruppe, with a compound of general formula
H - E, (V)H - E, (V)
in der E wie eingangs erwähnt definiert ist.is defined in the E as mentioned above.
Die Umsetzung wird zweckmäßigerweise in einem Lösungsmittel wie Isopropanol, Butanol, Tetrahydrofuran, Dioxan, Acetonitril, Dimethylformamid, Sulfolan, Toluol oder Methylenchlorid oder deren Gemischen gegebenenfalls in Gegenwart einer anorganischen oder organischen Base, z.B. Natriumcarbonat, Kaliumcarbonat, Kaliumhydroxid, Triethylamin oder N-Ethyl-diisopropylamin und gegebenenfalls in Gegenwart eines Reaktionsbeschleunigers wie einem Alkalijodid bei Temperaturen zwischen -20 und 150°C, vorzugsweise jedoch bei Temperaturen zwischen 0 und 100°C, durchge- führt. Die Umsetzung kann jedoch auch ohne Lösungsmittel oder in einem Überschuß der eingesetzten Verbindung der allgemeinen Formel V durchgeführt werden.The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, sulfolane, toluene or methylene chloride or mixtures thereof optionally in the presence of an inorganic or organic base, for example sodium carbonate, potassium carbonate, potassium hydroxide, triethylamine or N-ethyl diisopropylamine and optionally in the presence of a reaction accelerator such as an alkali metal iodide at temperatures between -20 and 150 ° C, but preferably at temperatures between 0 and 100 ° C carried out leads. However, the reaction can also be carried out without a solvent or in an excess of the compound of general formula V used.
Bei den vorstehend beschriebenen Umsetzungen können gegebenenfalls vorhandene reaktive Gruppen wie Hydroxy-, Amino-, Alkylamino- oder Iminogruppen während der Umsetzung durch übliche Schutzgruppen geschützt werden, welche nach der Umsetzung wieder abgespalten werden.In the reactions described above, 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.
Beispielsweise kommen als Schutzrest für eine Hydroxygruppe die Trimethylsilyl-, Acetyl-, Trityl-, Benzyl- oderTetrahydropyranylgruppe in Betracht.For example, as a protective group for a hydroxy group, the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group into consideration.
Als Schutzreste für eine Amino-, Alkylamino- oder Iminogruppe kommen beispielsweise die Formyl-, Acetyl-, Trifluoracetyl-, Ethoxycarbonyl-, tert.-Butoxycarbonyl-, Benzyloxy- carbonyl-, Benzyl-, Methoxybenzyl- oder 2,4-Dimethoxybenzylgruppe in Betracht.Suitable protecting groups 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 ,
Die gegebenenfalls anschließende Abspaltung eines verwendeten Schutzrestes erfolgt beispielsweise hydrolytisch in einem wässrigen Lösungsmittel, z.B. in Wasser, Iso- propanol/Wasser, Essigsäure/Wasser, Tetrahydrofu ran/Wasser oder Dioxan/Wasser, in Gegenwart einer Säure wie Trifluoressigsäure, Salzsäure oder Schwefelsäure oder in Gegenwart einer Alkalibase wie Natriumhydroxid oder Kaliumhydroxid oder aprotisch, z.B. in Gegenwart, von Jodtrimethylsilan, bei Temperaturen zwischen 0 und 120°C, vorzugsweise bei Temperaturen zwischen 10 und 100°C.The optional subsequent cleavage of a protective moiety used 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 metal 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.
Die Abspaltung eines Benzyl-, Methoxybenzyl- oder Benzyloxycarbonylrestes erfolgt jedoch beispielsweise hydrogenolytisch, z.B. mit Wasserstoff in Gegenwart eines Katalysators wie Palladium/Kohle in einem geeigneten Lösungsmittel wie Methanol, Ethanol, Essigsäureethylester oder Eisessig gegebenenfalls unter Zusatz einer Säure wie Salzsäure bei Temperaturen zwischen 0 und 100°C, vorzugsweise jedoch bei Raumtemperaturen zwischen 20 und 60°C, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar. Die Abspaltung eines 2,4-^Dimethoxy- benzylrestes erfolgt jedoch vorzugsweise in Trifluoressigsäure in Gegenwart von Anisol.However, 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, however, is preferably carried out in trifluoroacetic acid in the presence of anisole.
Die Abspaltung eines tert.-Butyl- oder tert.-Butyloxycarbonylrestes erfolgt vorzugsweise durch Behandlung mit einer Säure wie Trifluoressigsäure oder Salzsäure oder durch Behandlung mit Jodtrimethylsilan gegebenenfalls unter Verwendung eines Lösungsmittels wie Methylenchlorid, Dioxan, Methanol oder Diethylether.The 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 a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Die Abspaltung eines Trifluoracetylrestes erfolgt vorzugsweise durch Behandlung mit einer Säure wie Salzsäure gegebenenfalls in Gegenwart eines Lösungsmittels wie Essigsäure bei Temperaturen zwischen 50 und 120°C oder durch Behandlung mit Natronlauge gegebenenfalls in Gegenwart eines Lösungsmittels wie Tetrahydrofuran bei Temperaturen zwischen 0 und 50°C.The cleavage of a Trifluoracetylrestes is preferably carried out 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 at temperatures between 0 and 50 ° C.
Femer können die erhaltenen Verbindungen der allgemeinen Formel I, wie bereits eingangs erwähnt wurde, in ihre Enantiomeren und/oder Diastereomeren aufgetrennt werden. So können beispielsweise cis-/trans-Gemische in ihre eis- und trans-lsomere, und Verbindungen mit mindestens einem optisch aktiven Kohlenstoffatom in ihre Enantiomeren aufgetrennt werden.Furthermore, the compounds of the general formula I obtained can, as already mentioned at the beginning, be separated into their enantiomers and / or diastereomers. Thus, for example, cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be resolved into their enantiomers.
So lassen sich beispielsweise die erhaltenen cis-/trans-Gemische durch Chromatographie in ihre eis- und trans-lsomeren, die erhaltenen Verbindungen der allgemeinen Formel I, welche in Racematen auftreten, nach an sich bekannten Methoden (siehe Allinger N. L. und Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in ihre optischen Antipoden und Verbindungen der allgemeinen Formel I mit mindestens 2 asymmetrischen Kohlenstoffatomen auf Grund ihrer physikalischchemischen Unterschiede nach an sich bekannten Methoden, z.B. durch Chromatographie und/oder fraktionierte Kristallisation, in ihre Diastereomeren auftrennen, die, falls sie in racemischer Form anfallen, anschließend wie oben erwähnt in die Enantiomeren getrennt werden können.Thus, for example, the cis- / trans mixtures obtained can be purified by chromatography into their cis and trans isomers, the compounds of general formula I which are obtained in racemates, by methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971)) in 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, eg by chromatography and / or fractional crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
Die Enantiomerentrennung erfolgt vorzugsweise durch Säulentrennung an chiralen Phasen oder durch Umkristallisieren aus einem optisch aktiven Lösungsmittel oder durch Umsetzen mit einer, mit der racemischen Verbindung Salze oder Derivate wie z.B. Ester oder Amide bildenden optisch aktiven Substanz, insbesondere Säuren und ihre aktivierten Derivate oder Alkohole, und Trennen des auf diese Weise erhaltenen diastereomeren Salzgemisches oder Derivates, z.B. auf Grund von verschiedenen Löslichkeiten, wobei aus den reinen diastereomeren Salzen oder Derivaten die freien Antipoden durch Einwirkung geeigneter Mittel freigesetzt werden können. Besonders - 1.5 -The separation of enantiomers 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 as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents. Especially - 1.5 -
gebräuchliche, optisch aktive Säuren sind z.B. die D- und L-Formen von Weinsäure oder Dibenzoylweinsäure, Di-o-Tolylweinsäure, Äpfelsäure, Mandelsäure, Campher- sulfonsäure, Glutaminsäure, Asparaginsäure oder Chinasäure. Als optisch aktiver Alkohol kommt beispielsweise (+)- oder (-)-Menthol und als optisch aktiver Acylrest in Amiden beispielsweise (+)-oder (-)-Menthyloxycarbonyl in Betracht.Common optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
Desweiteren können die erhaltenen Verbindungen der Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze mit anorganischen oder organischen Säuren, übergeführt werden. Als Säuren kommen hierfür beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure oder Maleinsäure in Betracht.Furthermore, 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. Examples of 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.
Wie bereits eingangs erwähnt, weisen die erfindungsgemäßen Verbindungen der allgemeinen Formel I und ihre physiologisch verträglichen Salze wertvolle pharmakologische Eigenschaften auf, insbesondere eine Hemmwirkung auf die durch den Epidermal Growth Factor-Rezeptor (EGF-R) vermittelte Signaltransduktion, wobei diese beispielsweise durch eine Inhibition der Ligandenbindung, der Rezeptordimerisierung oder der Tyrosinkinase selbst bewirkt werden kann. Außerdem ist es möglich, daß die Signalübertragung an weiter abwärtsliegenden Komponenten blockiert wird.As already mentioned, the compounds according to the invention of the general formula I 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, by inhibition of the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission is blocked at further downstream components.
Die biologischen Eigenschaften der neuen Verbindungen wurden wie folgt geprüft:The biological properties of the new compounds were tested as follows:
Die Hemmung der humanen EGF-Rezeptorkinase wurde mit Hilfe der cyto- plasmatischen Tyrosinkinase-Domäne (Methionin 664 bis Alanin 1186 basierend auf der in Nature 309 (1984), 418 publizierten Sequenz) bestimmt. Hierzu wurde das Protein in Sf9 Insektenzellen als GST-Fusionsprotein unter Verwendung des Baculovirus-Expressionssystems exprimiert.The inhibition of the human EGF receptor kinase was determined with the aid of the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this, the protein was expressed in Sf9 insect cells as a GST fusion protein using the baculovirus expression system.
Die Messung der Enzymaktivität wurde in Gegenwart oder Abwesenheit der Testverbindungen in seriellen Verdünnungen durchgeführt. Das Polymer pEY (4:1) von SIGMA wurde als Substrat verwendet. Biotinyliertes pEY (bio-pEY) wurde als Tracer-Substrat zugesetzt. Jede 100 μl Reaktionslösung enthielt 10 μl des Inhibitors in 50% DMSO, 20 μl der Substrat-Lösung (200 mM HEPES pH 7.4, 50 mM Magnesiumacetat, 2.5 mg/ml poly(EY), 5 μg/ml bio-pEY) und 20 μl Enzympräparation. Die Enzymreaktion wurde durch Zugabe von 50μl einer 100 μM ATP Lösung in 10 mM Magnesiumchlorid gestartet. Die Verdünnung der Enzympräparation wurde so . eingestellt, daß der Phosphat-Einbau in das bio-pEY hinsichtlich Zeit und Enzymmenge linear war. Die Enzympräparation wurde in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM Kochsalz, 0.05% Triton X-100, 1 mM DTT und 10% Glycerin verdünnt.The measurement of enzyme activity was carried out in the presence or absence of the test compounds in serial dilutions. The polymer pEY (4: 1) from SIGMA was used as a substrate. Biotinylated pEY (bio-pEY) was added as a tracer substrate. Each 100 μl 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 enzyme preparation. The enzyme reaction was started by adding 50 μl of a 100 μM ATP solution in 10 mM magnesium chloride. The dilution of the enzyme preparation became so. adjusted that the phosphate incorporation into the bio-pEY was linear in terms of time and amount of enzyme. The enzyme preparation was 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.
Die Enzymassays wurden bei Raumtemperatur über einen Zeitraum von 30 Minuten ausgeführt und durch Zugabe von 50 μl einer Stopplösung (250 mM EDTA in 20 mM HEPES pH 7.4) beendet. 100 μl wurden auf eine Streptavidin-beschichtete Mikrotiterplatte gebracht und 60 Minuten bei Raumtemperatur inkubiert. Danach wurde die Platte mit 200 μl einer Waschlösung (50 mM Tris, 0.05% Tween 20) gewaschen. Nach Zugabe von 100 μl eines HRPO-gelabelten anti-PY Antikörpers (PY20H Anti- PtyπHRP von Transduction Laboratories, 250 ng/ml) wurde 60 Minuten inkubiert. Danach wurde die Mikrotiterplatte dreimal mit je 200 μl Waschlösung gewaschen. Die Proben wurden dann mit 100 μl einer TMB-Peroxidase-Lösung (A:B = 1:1, Kirkegaard Perry Laboratories) versetzt. Nach 10 Minuten wurde die Reaktion gestoppt. Die Extinktion wurde bei OD450nm mit einem ELISA-Leser gemessen. Alle Datenpunkte wurden als Triplikate bestimmt.The enzyme assays were performed at room temperature for a period of 30 minutes and terminated by addition of 50 μl of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl was placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. Thereafter, the plate was washed with 200 μl of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 μl of an HRPO-labeled anti-PY antibody (PY20H anti-ptyπHRP from Transduction Laboratories, 250 ng / ml) was incubated for 60 minutes. Thereafter, the microtiter plate was washed three times with 200 ul of washing solution. The samples were then spiked with 100 μl of a TMB peroxidase solution (A: B = 1: 1, Kirkegaard Perry Laboratories). After 10 minutes, the reaction was stopped. The absorbance was measured at OD4 50nm with an ELISA reader. All data points were determined as triplicates.
Die Daten wurden mittels einer iterativen Rechnung unter Verwendung eines Analysen- programmes für sigmoidale Kurven (Graph Pad Prism Version 3.0) mit variabler Hill- Steigung angepaßt. Alle freigegebenen Iterationsdaten wiesen einen Korrelationskoeffizienten von über 0.9 auf und die Ober- und Unterwerte der Kurven zeigten eine Spreizung von mindestens einem Faktor von 5. Aus den Kurven wurde die Wirkstoffkonzentration abgeleitet, die die Aktivität der EGF-Rezeptorkinase zu 50% hemmt (ICso).The data was fit by means of an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with variable hill slope. All released iteration data showed a correlation coefficient of over 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. From the curves, the drug concentration was derived, which inhibits the activity of EGF receptor kinase by 50% (ICso) ,
Folgende Ergebnisse wurden erhalten:The following results were obtained:
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000017_0001
Figure imgf000018_0001
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I hemmen somit die Signaltransduktion durch Tyrosinkinasen, wie am Beispiel des humanen EGF- Rezeptors gezeigt wurde, und sind daher nützlich zur Behandlung pathophysiologischer Prozesse, die durch Überfunktion von Tyrosinkinasen hervorgerufen werden. Das sind z.B. benigne oder maligne Tumoren, insbesondere Tumoren epithelialen und neuro- epithelialen Ursprungs, Metastasierung sowie die abnorme Proliferation vaskulärer Endothelzellen (Neoangiogenese).The compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases. These are e.g. Benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
Die erfindungsgemäßen Verbindungen sind auch nützlich zur Vorbeugung und Behandlung von Erkrankungen der Atemwege und der Lunge, die mit einer vermehrten oder veränderten Schleimproduktion einhergehen, die durch Stimulation von Tyrosinkinasen hervorgerufen wird, wie z.B. bei entzündlichen Erkrankungen der Atemwege wie chronische Bronchitis, chronisch obstruktive Bronchitis, Asthma, Bronchiektasien, allergische oder nicht-allergische Rhinitis oder Sinusitis, zystische Fibröse, α1-Anti- trypsin-Mangel, oder bei Husten, Lungenemphysem, Lungenfibrose und hyperreaktiven Atemwegen.The compounds of the 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, α1-anti-trypsin deficiency, or cough, emphysema, pulmonary fibrosis and hyper-reactive airways.
Die Verbindungen sind auch geeignet für die Behandlung von Erkrankungen des Magen-Darm-Traktes und der Gallengänge und -blase, die mit einer gestörten Aktivität der Tyrosinkinasen einhergehen, wie sie z.B. bei chronisch entzündlichen Veränderungen zu finden sind, wie Cholezystitis, M. Crohn, Colitis uicerosa, und Geschwüren im Magen-Darm-Trakt oder wie sie bei Erkrankungen des Magen-Darm- Traktes, die mit einer vermehrten Sekretion einhergehen, vorkommen, wie M. Menetrier, sezernierende Adenome und Proteinverlustsyndrome. Außerdem können die Verbindungen der allgemeinen Formel I und deren physiologisch verträglichen Salze zur Behandlung anderer Krankheiten verwendet werden, die durch aberrante Funktion von Tyrosinkinasen verursacht werden, wie z.B. epidermaler Hyper- proliferation (Psoriasis), benigner Prostatahyperplasie (BPH), inflammatorischer Prozesse, Erkrankungen des Immunsystems, Hyperproliferation hämatopoetischer Zellen etc..The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder, which are associated with a disrupted activity of tyrosine kinases, 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. In addition, the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyper proliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the Immune system, hyperproliferation of hematopoietic cells etc.
Auf Grund ihrer biologischen Eigenschaften können die erfindungsgemäßen Verbindungen allein oder in Kombination mit anderen pharmakologisch wirksamen Verbindungen angewendet werden, beispielsweise in der Tumortherapie in Mono- therapie oder in Kombination mit anderen Anti-Tumor Therapeutika, beispielsweise in Kombination mit Topoisomerase-Inhibitoren (z.B. Etoposide), Mitoseinhibitoren (z.B. Vinblastin), mit Nukleinsäuren interagierenden Verbindungen (z.B. cis-Platin, Cyclo- phosphamid, Adriamycin), Hormon-Antagonisten (z.B. Tamoxifen), Inhibitoren meta- bolischer Prozesse (z.B. 5-FU etc.), Zytokinen (z.B. Interferonen), Antikörpern etc. Für die Behandlung von Atemwegserkrankungen können diese Verbindungen allein oder in Kombination mit anderen Atemwegstherapeutika, wie z.B. sekretolytisch (z.B. Ambroxol, N-Acetylcystein), broncholytisch (z.B. Tiotropium oder Ipratropium oder Fenoterol, Salmeterol, Salbutamol) und/oder entzündungshemmend (z.B. Theophylline oder Glucocorticoide) wirksamen Substanzen angewendet werden. Für die Behandlung von Erkrankungen im Bereich des Magen-Darm-Traktes können diese Verbindungen ebenfalls alleine oder in Kombination mit Motilitäts- oder Sekretions-beeinflussenden Substanzen gegeben werden. Diese Kombinationen können entweder simultan oder sequentiell verabreicht werden.Because of their biological properties, 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). , Mitosis inhibitors (eg vinblastine), compounds interacting with nucleic acids (eg cisplatin, cyclophosphamide, adriamycin), hormone antagonists (eg tamoxifen), inhibitors of metabolic processes (eg 5-FU etc.), cytokines (eg interferons ), Antibodies, etc. For the treatment of respiratory diseases, these compounds may be used alone or in combination with other respiratory therapeutics, 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. For the treatment of diseases in the region of the gastrointestinal tract, these compounds can also be given alone or in combination with motility or secretion-influencing substances. These combinations can be administered either simultaneously or sequentially.
Die Anwendung dieser Verbindungen entweder alleine oder in Kombination mit anderen Wirkstoffen kann intravenös, subkutan, intramuskulär, intraperitoneal, intranasal, durch Inhalation oder transdermal oder oral erfolgen, wobei zur Inhalation insbesondere Aerosolformulierungen geeignet sind.The use of these compounds, either alone or in combination with other active substances, may be intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, by inhalation or transdermally or orally, in particular aerosol formulations being suitable for inhalation.
Bei der pharmazeutischen Anwendung werden die erfindungsgemäßen Verbindungen in der Regel bei warmblütigen Wirbeltieren, insbesondere beim Menschen, in Dosierungen von 0.01-100 mg/kg Körpergewicht, vorzugsweise bei 0.1-15 mg/kg verwendet. Zur Verabreichung werden diese mit einem oder mehreren üblichen inerten Träger- - 10 -In the pharmaceutical application, 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 at 0.1-15 mg / kg. For administration, these are administered with one or more conventional inert carrier - 10 -
stoffen und/oder Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Zellulose, Magnesiumstearat, Polyvinylpyrrolidon, Zitronensäure, Weinsäure, Wasser, Wasser/Ethanol, Wasser/Glycerin, Wasser/Sorbit, Wasser/Poly- ethylenglykol, Propylenglykol, Stearylalkohol, Carboxymethylcellulose oder fetthaltigen Substanzen wie Hartfett oder deren geeigneten Gemischen in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen, Lösungen, Sprays oder Zäpfchen eingearbeitet.substances and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty 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.
Die nachfolgenden Beispiele sollen die vorliegende Erfindung näher erläutern ohne diese zu beschränken:The following examples are intended to illustrate the present invention without limiting it:
Herstellung der Ausgangsverbindungen:Preparation of the starting compounds:
Beispiel IExample I
4-f(3-Chlor-4-fluor-phenyl)aminol-6-f(diethoxy-phosphoryl)-acetylamino1-7-r(S)-(tetra- hydrofuran-3-yl)oxy1-chinazolin4-f (3-chloro-4-fluoro-phenyl) -aminol-6-f (diethoxy-phosphoryl) -acetylamino 1-7-r (S) - (tetrahydrofuran-3-yl) oxy-1-quinazoline
60.07 g Diethoxyphophorylessigsäure werden in 750 ml N,N-Dimethylformamid vorgelegt und bei Raumtemperatur mit 48.67 g N,N'-Carbonyldiimidazol versetzt. Nach beendeter Gasentwicklung werden 90.00 g 4-[(3-Chlor-4-fluor-phenyl)amino]-6-amino-[(S)- (tetrahydrofuran-3-yl)oxy]-chinazolin zugegeben und das Reaktionsgemisch. wird etwa 4-5 Stunden bei Raumtemperatur gerührt, bis die Umsetzung vollständig ist. Nun wird das Reaktionsgemisch im Wasserbad leicht erwärmt und es werden zweimal je 750 ml Wasser zugegeben. Die dicke Suspension wird über Nacht nachgerührt und am nächsten Morgen werden nochmals 350 ml Wasser zugegeben. Die Suspension wird im Eisbad abgekühlt, eine Stunde nachgerührt und abgesaugt. Der Filterkuchen wird mit 240 ml N,N-Dimethylforrnamid/Wasser (1 :2) und 240 ml Diisopropylether nachgewaschen und im Umlufttrockenschrank bei 40°C getrocknet. Ausbeute: 117.30 g (88 % der Theorie) Rf-Wert: 0.37 (Kieselgel, Methylenchlorid/Methanol = 9:1 ) Massenspektrum (ESI+): m/z = 553, 555 [M+H]+ 60.07 g Diethoxyphophorylessigsäure be presented in 750 ml of N, N-dimethylformamide and treated at room temperature with 48.67 g of N, N'-carbonyldiimidazole. After completion of gas evolution 90.00 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-amino - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline are added and the reaction mixture . is stirred for about 4-5 hours at room temperature until the reaction is complete. Now, the reaction mixture is heated slightly in a water bath and it is added twice per 750 ml of water. The thick suspension is stirred overnight and the next morning, 350 ml of water are added again. The suspension is cooled in an ice bath, stirred for an hour and filtered with suction. The filter cake is washed with 240 ml of N, N-dimethylformamide / water (1: 2) and 240 ml of diisopropyl ether and dried in a circulating air dryer at 40 ° C. Yield: 117.30 g (88% of theory) R f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESI + ): m / z = 553, 555 [M + H] +
Analog Beispiel I wird folgende Verbindung erhalten: (1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylamino]-7-[(R)-Analogously to Example I, the following compound is obtained: (1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(diethoxy-phosphoryl) -acetylamino] -7 - [(R) -
(tetrahydrofuran-3-yl)oxy]-chinazolin(Tetrahydrofuran-3-yl) oxy] -quinazoline
Massenspektrum (ESI+): m/z = 553, 555 [M+H]+ Mass spectrum (ESI + ): m / z = 553, 555 [M + H] +
Beispiel IIExample II
(1S,4S)-(2-Oxa-5-aza-bicvclof2.2.1lhept-5-yl)-acetaldehvd-hvdrochlorid hergestellt durch Behandeln von (1S,4S)-5-(2,2-Dimethoxy-ethyl)-2-oxa-5-aza- bicyclo[2.2.1]heptan mit konz. Salzsäure in Wasser bei 80°C. Die erhaltene Lösung wird direkt unter Bsp. 2 und Bsp. 2(5) weiter umgesetzt.(1S, 4S) - (2-Oxa-5-aza-bicyclof2.2.1lhept-5-yl) -acetaldehyde hydrochloride prepared by treating (1S, 4S) -5- (2,2-dimethoxy-ethyl) - 2-oxa-5-azabicyclo [2.2.1] heptane with conc. Hydrochloric acid in water at 80 ° C. The solution obtained is reacted further directly under Ex. 2 and Ex. 2 (5).
Analog Beispiel II werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example II:
(1 ) (3-Oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-acetaldehyd-hydrochlorid Die erhaltene Lösung wird direkt unter Bsp. 2(1) weiter umgesetzt.(1) (3-Oxa-8-azabicyclo [3.2.1] oct-8-yl) -acetaldehyde hydrochloride The resulting solution is further reacted directly under Ex. 2 (1).
(2) (1R,4R)-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-acetaldehyd-hydrochlorid(2) (1R, 4R) - (2-Oxa-5-azabicyclo [2.2.1] hept-5-yl) -acetaldehyde hydrochloride
Die erhaltene Lösung wird direkt unter Bsp. 2(2) und Bsp. 2(4) weiter umgesetzt.The resulting solution is reacted further directly under Ex. 2 (2) and Ex. 2 (4).
(3) (8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-acetaldehyd-hydrochlorid Die erhaltene Lösung wird direkt unter Bsp. 2(3) weiter umgesetzt.(3) (8-Oxa-3-azabicyclo [3.2.1] oct-3-yl) -acetaldehyde hydrochloride The resulting solution is further reacted directly under Ex. 2 (3).
Beispiel IIIExample III
(1S,4SV5-(2,2-Dimethoxy-ethvn-2-oxa-5-aza-bicvclor2.2.nheptan hergestellt durch Umsetzung von (1 S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]heptan-hydro- chlorid mit Bromacetaldehyd-dimethylacetal in Gegenwart von Kaliumcarbonat in N-(1S, 4SV5- (2,2-Dimethoxy-ethyn-2-oxa-5-aza-bicyclo) -2.nheptane prepared by reacting (1S, 4S) -2-oxa-5-aza-bicyclo [2.2. 1] heptane hydrochloride with bromoacetaldehyde dimethyl acetal in the presence of potassium carbonate in N 2
Methylpyrrolidinon bei 100°C.Methylpyrrolidinone at 100 ° C.
Rf-Wert: 0.35 (Kieselgel, Methylenchlorid/Methanol/konz. wässriges Ammoniak =R f value: 0.35 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia logo CNRS logo INIST
90:10:1 )90: 10: 1)
Massenspektrum (ESl+): m/z = 188 [M+H]+ Mass spectrum (ESl + ): m / z = 188 [M + H] +
Analog Beispiel III werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example III:
(1 ) 8-(2,2-Dimethoxy-ethyl)-3-oxa-8-aza-bicyclo[3.2.1]octan - 2.1 -(1) 8- (2,2-Dimethoxy-ethyl) -3-oxa-8-aza-bicyclo [3.2.1] octane - 2.1 -
Rf-Wert: 0.81 (Kieselgel, Methylenchlorid/Methanol/konz. wässriges Ammoniak = 90:10:1)R f value: 0.81 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 1)
(2) (1R,4R)-5-(2,2-Dimethoxy-ethyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan(2) (1R, 4R) -5- (2,2-dimethoxy-ethyl) -2-oxa-5-aza-bicyclo [2.2.1] heptane
Rf-Wert: 0.23 (Kieselgel, Essigester/Methanol/konz. wässriges Ammoniak = 90:10:1)R f value: 0.23 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)
Massenspektrum (ESl+): m/z = 188 [M+H]+ Mass spectrum (ESl + ): m / z = 188 [M + H] +
Das eingesetzte (1R,4R)-2-Oxa-5~aza-bicyclo[2.2.1]heptan-hydrochlorid wird durchThe used (1R, 4R) -2-oxa-5 ~ aza-bicyclo [2.2.1] heptane hydrochloride is by
Umsetzung von (2R,4R)-1 -(tert.-Butyloxycarbonyl)-2-[(4-methylphenyl-sulfonyloxy)- methyl]-4-hydroxy-pyrrolidin (s. J. Org. Chem., 1992, 57, 3783-3789) mit Natriumhydrid in Tetrahydrofuran und anschließender Behandlung mit Salzsäure in Dioxan hergestellt.Reaction of (2R, 4R) -1- (tert-butyloxycarbonyl) -2 - [(4-methylphenylsulfonyloxy) methyl] -4-hydroxy-pyrrolidine (see J. Org. Chem., 1992, 57, 3783-3789) with sodium hydride in tetrahydrofuran and subsequent treatment with hydrochloric acid in dioxane.
(3) 3-(2,2-Dimethoxy-ethyl)-8-oxa-3-aza-bicyclo[3.2.1]octan(3) 3- (2,2-Dimethoxy-ethyl) -8-oxa-3-azabicyclo [3.2.1] octane
Rf-Wert: 0.84 (Kieselgel, Essigester/Methanol/konz. wässriges Ammoniak = 90:10:1)R f value: 0.84 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1)
Herstellung der Endverbindungen:Preparation of the end compounds:
Beispiel 1example 1
4-r(3-Chlor-4-fluor-phenyl)amino1-6-fr4-((1 S.4S)-2-oxa-5-aza-bicvclor2.2.nhept-5-yl)-1 - oxo-2-buten-1-vπamino}-7-cvclopropylmethoxy-chinazolin4-r (3-chloro-4-fluoro-phenyl) -amino 1-6-fr4 - ((1 S.4S) -2-oxa-5-aza-bicvclor2.2-hept-5-yl) -1-oxo -2-buten-1-vπamino} -7-cvclopropylmethoxy-quinazoline
Figure imgf000022_0001
Figure imgf000022_0001
4.50 g Bromerotonsäure werden in 40 ml Methylenchlorid gelöst und mit 4.70 ml Oxalyl- chlorid versetzt. Nach Zugabe von 0.02 ml N,N-Dimethylformamid setzt heftige Gasentwicklung ein, welche nach etwa zwei Stunden beendet ist. Das Reaktionsgemisch wird im Vakuum eingeengt und der Kolbenrückstand in 40 ml Methylenchlorid gelöst. Diese Lösung wird unter Eisbad-Kühlung zu einem Gemisch aus 7.00 g 4-[(3-Chlor-4- fluor-phenyI)amino]-6-amino-7-cyclopropylmethoxy-chinazolin und 9.60 ml Hünigbase in 80 ml Tetrahydrofuran getropft. Die Reaktionslösung wird eine Stunde im Eisbad und i eine weiter Stunde bei Raumtemperatur gerührt. Nun wird ein Fünftel dieser Lösung abgenommen und mit 740 mg (1 S,4S)-2-Oxa-5-aza- bicycIo[2.2.1]heptan-hydrochiorid und 1 ml Hünigbase versetzt. Das Reaktionsgemisch wird über Nacht bei 60°C gerührt und anschließend im Vakuum eingeengt. Der Kolben- rückstand wird mit Essigester und wenig Methanol aufgenommen und mit Wasser extrahiert. Die organische Phase wird auf Kieselgel aufgezogen und über eine Kieselgelsäule mit Essigester/Methanol (95:5 bis 70:30) als Laufmittel chromatographiert. Das erhaltene Produkt wird aus Diisopropylether kristallisiert und abgesaugt. Ausbeute: 850 mg (42 % der Theorie) Rf-Wert: 0.36 (Kieselgel, Essigester/Methanol = 9:1 ) Massenspektrum (ESI+): m/z = 524, 526 [M+H]+ 4.50 g of bromoteronic acid are dissolved in 40 ml of methylene chloride and treated with 4.70 ml of oxalyl chloride. After addition of 0.02 ml of N, N-dimethylformamide begins vigorous evolution of gas, which is complete after about two hours. The reaction mixture is concentrated in vacuo and the flask residue dissolved in 40 ml of methylene chloride. This solution is added dropwise with ice-bath cooling to a mixture of 7.00 g of 4 - [(3-chloro-4-fluoro-phenyl) amino] -6-amino-7-cyclopropylmethoxy-quinazoline and 9.60 ml of Hünig base in 80 ml of tetrahydrofuran. The reaction solution is stirred for one hour in an ice bath and for a further hour at room temperature. Now one-fifth of this solution is removed and 740 mg (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride and 1 ml Hünig base are added. The reaction mixture is stirred overnight at 60 ° C and then concentrated in vacuo. The flask residue is taken up with ethyl acetate and a little methanol and extracted with water. The organic phase is applied to silica gel and chromatographed on a silica gel column with ethyl acetate / methanol (95: 5 to 70:30) as the eluent. The product obtained is crystallized from diisopropyl ether and filtered off with suction. Yield: 850 mg (42% of theory) R f value: 0.36 (silica gel, ethyl acetate / methanol = 9: 1) Mass spectrum (ESI + ): m / z = 524, 526 [M + H] +
Analog Beispiel 1 wird folgende Verbindung erhalten:Analogously to Example 1, the following compound is obtained:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-yI)- 1 -oxo-2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino] -7-cyclopentyloxy-quinazoline
Figure imgf000023_0001
Figure imgf000023_0001
Rf-Wert: 0.40 (Reversed Phase DC-Fertigplatte (E. Merck), Acetonitril/Wasser/ Trifluoressigsäure = 50:50:1) Massenspektrum (ESL): m/z = 536, 538 [M-H]" R f value: 0.40 (Reversed phase DC precast plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) Mass spectrum (ESL): m / z = 536, 538 [MH] "
Beispiel 2Example 2
4-r(3-Chlor-4-fluor-phenyl)amino1-6-(r4-((1 S.4S)-2-oxa-5-aza-bicvclor2.2.nhept-5-yl)-1- oxo-2-buten-1-vnaminoV7-r(S)-(tetrahvdrofuran-3-yl)oxy1-chinazolin
Figure imgf000024_0001
4-r (3-chloro-4-fluoro-phenyl) -amino 1-6- (r 4 - ((1 S. 4 S) -2-oxa-5-aza-bicyclopror2.2-hept-5-yl) -1- oxo-2-buten-1-vnaminoV7-r (S) - (tetrahvdrofuran-3-yl) oxy1-quinazoline
Figure imgf000024_0001
Zu einer Lösung aus 340 mg Lithiumchlorid in 22 ml Wasser wird bei Raumtemperatur eine Lösung aus 4.44 g 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(diethoxy-phosphoryl)- acetylamino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin in 22 ml Tetrahydrofuran gegeben. Dann werden 2.73 g Kaliumhydroxid-Plätzchen zugesetzt und das Reaktionsgemisch wird im Eis/Aceton-Kühlbad auf -3°C abgekühlt. Nun wird die unter Beispiel II erhaltene Lösung des (1S,4S)-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-acetaldehyd-hydro- chlorids innerhalb von 5 min bei einer Temperatur von 0°C zugetropft. Nach beendeter Zugabe wird das Reaktionsgemisch noch 10 min bei 0°C und weitere 20 min bei Raumtemperatur gerührt. Zur Aufarbeitung werden 100 ml Essigester zugegeben und wässri- ge Phase wird abgetrennt. Die organische Phase wird mit gesättigter Natriumchlorid- Lösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wird chromatographisch über eine Kieselgelsäule mit Methylenchlorid/Methanol/konz. methanolischem Ammoniak (980:18:2 auf 750:225:25) als Laufmittel gereinigt. Das erhaltene Produkt wird mit wenig Diisopropylether zur Kristallisation gebracht. Ausbeute: 2.60 g (60 % der Theorie)A solution of 4.44 g of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (diethoxy-phosphoryl) -acetylamino] at room temperature is added to a solution of 340 mg of lithium chloride in 22 ml of water at room temperature. Add 7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline in 22 ml of tetrahydrofuran. Then 2.73 g of potassium hydroxide pellets are added and the reaction mixture is cooled to -3 ° C in the ice / acetone cooling bath. Now the obtained under Example II solution of (1S, 4S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) acetaldehyde hydrochloride within 5 min at a temperature of 0 ° C added dropwise. After completion of the addition, the reaction mixture is stirred for 10 min at 0 ° C and a further 20 min at room temperature. For workup, 100 ml of ethyl acetate are added and the aqueous phase is separated off. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is chromatographed on a silica gel column with methylene chloride / methanol / conc. methanolic ammonia (980: 18: 2 to 750: 225: 25) as the eluent. The product obtained is crystallized with a little diisopropyl ether. Yield: 2.60 g (60% of theory)
Rf-Wert: 0.33 (Kieselgel, Methylenchlorid/Methanol/konz. wässriges Ammoniak = 90:10:1) Massenspektrum (ESI+): m/z = 540, 542 [M+H]+ R f value: 0.33 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia = 90: 10: 1) Mass spectrum (ESI + ): m / z = 540, 542 [M + H] +
Analog Beispiel 2 werden folgende Verbindungen erhalten:Analogously to Example 2, the following compounds are obtained:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-1 -oxo-2- buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin (1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -1 - oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
Figure imgf000025_0001
Figure imgf000025_0001
Massenspektrum (ESI+): m/z = 554, 556 [M+H]+ Mass Spectrum (ESI + ): m / z = 554, 556 [M + H] +
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1R,4R)-2-oxa-5-aza-bicycIo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin(2) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
Figure imgf000025_0002
Figure imgf000025_0002
Rf-Wert: 0.08 (Kieselgel, Essigester/Methanol/konz. wässriges Ammoniak = 90:10:1) Massenspektrum (ESI"): m/z = 538, 540 [M-H]" ~R f value: 0.08 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia = 90: 10: 1) Mass spectrum (ESI " ): m / z = 538, 540 [MH] "
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-oxo-2- buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
Figure imgf000025_0003
Figure imgf000025_0003
Rf-Wert: 0.77 (Aluminiumoxid, Essigester/Methanol = 95:5) Massenspektrum (ESI+): m/z = 554, 556 [M+H]+ R f value: 0.77 (alumina, ethyl acetate / methanol = 95: 5) Mass spectrum (ESI + ): m / z = 554, 556 [M + H] +
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]-chinazolin
Figure imgf000026_0001
(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline
Figure imgf000026_0001
Massenspektrum (ESI+): m/z = 540, 542 [M+H]+ Mass spectrum (ESI + ): m / z = 540, 542 [M + H] +
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)- 1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]-chinazolin(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) - 1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline
Figure imgf000026_0002
Figure imgf000026_0002
Massenspektrum (ESI+): m/z = 540, 542 [M+H]+ Mass spectrum (ESI + ): m / z = 540, 542 [M + H] +
Analog den vorstehend genannten Beispielen und anderen literaturbekannten Verfahren können auch folgende Verbindungen hergestellt werden:Analogously to the abovementioned examples and other processes known from the literature, the following compounds can also be prepared:
Figure imgf000026_0003
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000026_0003
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000033_0001
Figure imgf000034_0001
Beispiel 3Example 3
Dragees mit 75 mg WirksubstanzDragees with 75 mg active substance
Zusammensetzung: 1 Drageekern enthält:Composition: 1 drag core contains:
Wirksubstanz 75.0 mgActive substance 75.0 mg
Calciumphosphat 93.0 mgCalcium phosphate 93.0 mg
Maisstärke 35.5 mgCornstarch 35.5 mg
Polyvinylpyrrolidon 10.0 mgPolyvinylpyrrolidone 10.0 mg
Hydroxypropylmethylcellulose 15.0 mgHydroxypropylmethylcellulose 15.0 mg
Magnesiumstearat 1.5 mgMagnesium stearate 1.5 mg
230.0 mg230.0 mg
Herstellung:production:
Die Wirksubstanz wird mit Calciumphosphat, Maisstärke, Polyvinylpyrrolidon, Hydroxypropylmethylcellulose und der Hälfte der angegebenen Menge Magnesiumstearat gemischt. Auf einer Tablettiermaschine werden Preßlinge mit einem Durchmesser von ca. 13 mm hergestellt, diese werden auf einer geeigneten Maschine durch ein Sieb mit 1.5 mm-Maschenweite gerieben und mit der restlichen Menge Magnesiumstearat vermischt. Dieses Granulat wird auf einer Tablettiermaschine zu Tabletten mit der gewünschten Form gepreßt.The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On 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.
Kerngewicht: 230 mgCore weight: 230 mg
Stempel: 9 mm, gewölbtStamp: 9 mm, curved
Die so hergestellten Drageekerne werden mit einem Film überzogen, der im wesentlichen aus Hydroxypropylmethylcellulose besteht. Die fertigen Filmdragees werden mit Bienenwachs geglänzt.The coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax.
Drageegewicht: 245 mg.Dragee weight: 245 mg.
Beispiel 4Example 4
Tabletten mit 100 mg WirksubstanzTablets with 100 mg active substance
Zusammensetzung: 1 Tablette enthält:Composition: 1 tablet contains:
Wirksubstanz 100.0 mg - 36 -Active substance 100.0 mg - 36 -
Milchzucker 80.0 mg Maisstärke 34.0 mg Polyvinylpyrrolidon 4.0 mg Magnesiumstearat 2.0 mg 220.0 mgMilk sugar 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg
Herstellungverfahren:Production process:
Wirkstoff, Milchzucker und Stärke werden gemischt und mit einer wäßrigen Lösung des Polyvinylpyrrolidons gleichmäßig befeuchtet. Nach Siebung der feuchten Masse (2.0 mm-Maschenweite) und Trocknen im Hordentrockenschrank bei 50°C wird erneut gesiebt (1.5 mm-Maschenweite) und das Schmiermittel zugemischt. Die preßfertige Mischung wird zu Tabletten verarbeitet.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.
Tablettengewicht: 220 mg Durchmesser. 10 mm, biplan mit beidseitiger Facette und einseitiger Teilkerbe.Tablet weight: 220 mg diameter. 10 mm, biplan with facet on both sides and one-sided part notch.
Beispiel 5Example 5
Tabletten mit 150 mg WirksubstanzTablets with 150 mg active substance
Zusammensetzung: 1 Tablette enthält:Composition: 1 tablet contains:
Wirksubstanz 150.0 mg Milchzucker pulv. 89.0 mg Maisstärke 40.0 mgActive ingredient 150.0 mg lactose powdered 89.0 mg cornstarch 40.0 mg
Kolloide Kieselgelsäure 10.0 mg Polyvinylpyrrolidon 10.0 mg Magnesiumstearat 1.0 mg 300.0 mgColloidal silicic acid 10.0 mg Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 mg 300.0 mg
Herstellung: Die mit Milchzucker, Maisstärke und Kieselsäure gemischte Wirksubstanz wird mit einer 20%igen wäßrigen Polyvinylpyrrolidonlösung befeuchtet und durch ein Sieb mit 1.5 mm-Maschenweite geschlagen.production: The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve with a mesh size of 1.5 mm.
Das bei 45°C getrocknete Granulat wird nochmals durch dasselbe Sieb gerieben und mit der angegebenen Menge Magnesiumstearat gemischt. Aus der Mischung werden Tabletten gepreßt.The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
Tablettengewicht: 300 mgTablet weight: 300 mg
Stempel: 10 mm, flachStamp: 10 mm, flat
Beispiel 6Example 6
Hartgelatine-Kapseln mit 150 mg WirksubstanzHard gelatine capsules with 150 mg active substance
Zusammensetzung: 1 Kapsel enthält:Composition: 1 capsule contains:
Wirkstoff. 150.0 mgActive ingredient. 150.0 mg
Maisstärke getr. ca. 180.0 mgCorn starch drink. about 180.0 mg
Milchzucker pulv. ca. 87.0 mgMilk sugar powder approx. 87.0 mg
Magnesiumstearat 3.0 mg ca. 420.0 mgMagnesium stearate 3.0 mg approx. 420.0 mg
Herstellung:production:
Der Wirkstoff wird mit den Hilfsstoffen vermengt, durch ein Sieb von 0.75 mm-Maschenweite gegeben und in einem geeigneten Gerät homogen gemischt. Die Endmischung wird in Hartgelatine-Kapseln der Größe 1 abgefüllt. Kapselfüllung: ca. 320 mgThe 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
Kapselhülle: Hartgelatine-Kapsel Größe 1.Capsule shell: hard gelatin capsule size 1.
Beispiel 7Example 7
Suppositorien mit 150 mg WirksubstanzSuppositories with 150 mg active substance
Zusammensetzung: 1 Zäpfchen enthält: Wirkstoff 150.0 mgComposition: 1 suppository contains: Active ingredient 150.0 mg
Polyäthylenglykol 1500 550.0 mgPolyethylene glycol 1500 550.0 mg
Polyäthylenglykol 6000 460.0 mgPolyethylene glycol 6000 460.0 mg
Polyoxyäthylensorbitanmonostearat 840.0 mgPolyoxyethylene sorbitan monostearate 840.0 mg
2000.0 mg2000.0 mg
Herstellung:production:
Nach dem Aufschmelzen der Suppositorienmasse wird der Wirkstoff darin homogen verteilt und die Schmelze in vorgekühlte Formen gegossen.After the suppository mass has melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
Beispiel 8Example 8
Suspension mit 50 mg WirksubstanzSuspension with 50 mg active substance
Zusammensetzung:Composition:
100 ml Suspension enthalten:100 ml suspension contain:
Wirkstoff 1.00 gActive ingredient 1.00 g
Carboxymethylcellulose-Na-Salz 0.10 g p-Hydroxybenzoesäuremethylester 0.05 g p-Hydroxybenzoesäurepropylester 0.01 gCarboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
Rohrzucker 10.00 gCane sugar 10.00 g
Glycerin 5.00 gGlycerol 5.00 g
Sorbitlösung 70%ig 20.00 gSorbitol solution 70% 20.00 g
Aroma 0.30 gAroma 0.30 g
Wasser dest.ad 100.00 mlWater dest.ad 100.00 ml
Herstellung:production:
Dest. Wasser wird auf 70°C erhitzt. Hierin wird unter Rühren p-Hydroxybenzoe- säuremethylester und -propylester sowie Glycerin und Carboxymethylcellulose-Dest. Water is heated to 70 ° C. P-hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethylcellulose
Natriumsalz gelöst. Es wird auf Raumtemperatur abgekühlt und unter Rühren derDissolved sodium salt. It is cooled to room temperature and with stirring
Wirkstoff zugegeben und homogen dispergiert. Nach Zugabe und Lösen des Zuckers, der Sorbitlösung und des Aromas wird die Suspension zur Entlüftung unter Rühren evakuiert.Active ingredient added and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
5 ml Suspension enthalten 50 mg Wirkstoff. Beispiel 95 ml of suspension contain 50 mg of active ingredient. Example 9
Ampullen mit 10 mg WirksubstanzAmpoules with 10 mg active substance
Zusammensetzung:Composition:
Wirkstoff 10.0 mgActive ingredient 10.0 mg
0.01 n Salzsäure s.q.0.01 n hydrochloric acid s.q.
Aqua bidest ad 2.0 mlAqua bidest ad 2.0 ml
Herstellung:production:
Die Wirksubstanz wird in der erforderlichen Menge 0.01 n HCI gelöst, mit Kochsalz isotonisch gestellt, sterilfiltriert und in 2 ml Ampullen abgefüllt.The active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
Beispiel 10Example 10
Ampullen mit 50 mg WirksubstanzAmpoules with 50 mg active substance
Zusammensetzung:Composition:
Wirkstoff 50.0 mgActive ingredient 50.0 mg
0.01 n Salzsäure s.q.0.01 n hydrochloric acid s.q.
Aqua bidest ad 10.0 mlAqua bidest ad 10.0 ml
Herstellung:production:
Die Wirksubstanz wird in der erforderlichen Menge 0.01 n HCI gelöst, mit Kochsalz isotonisch gestellt, sterilfiltriert und in 10 ml Ampullen abgefüllt.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.
Beispiel 11Example 11
Kapseln zur Pulverinhalation mit 5 mg WirksubstanzCapsules for powder inhalation with 5 mg active substance
1 Kapsel enthält:1 capsule contains:
Wirksubstanz 5.0 mg Lactose für Inhalationszwecke 15.0 mgActive substance 5.0 mg Lactose for inhalation 15.0 mg
20.0 mg20.0 mg
Herstellung:production:
Die Wirksubstanz wird mit Lactose für Inhalationszwecke gemischt. Die Mischung wird auf einer Kapselmaschine in Kapseln (Gewicht der Leerkapsel ca. 50 mg) abgefüllt.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).
Kapselgewicht: 70.0 mg Kapselgröße: 3Capsule weight: 70.0 mg Capsule size: 3
Beispiel 12Example 12
Inhalationslösung für Handvemebler mit 2.5 mg WirksubstanzInhalation solution for handheld nebulizers with 2.5 mg active substance
1 Hub enthält:1 hub contains:
Wirksubstanz 2.500 mgActive substance 2,500 mg
Benzalkoniumchlorid 0.001 mg 1N-Salzsäure q.s.Benzalkonium chloride 0.001 mg 1N hydrochloric acid q.s.
Ethanol/Wasser (50/50) ad 15.000 mgEthanol / water (50/50) ad 15,000 mg
Herstellung:production:
Die Wirksubstanz und Benzalkoniumchlorid werden in Ethanol/Wasser (50/50) gelöst. Der pH-Wert der Lösung wird mit 1N-Salzsäure eingestellt. Die eingestellte Lösung wird filtriert und in für den Handvemebler geeignete Behälter (Kartuschen) abgefüllt.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 adjusted solution is filtered and filled into suitable containers for the hand-operated sprayer (cartridges).
Füllmasse des Behälters: 4.5 g Fill weight of the container: 4.5 g

Claims

Patentansprüche claims
1. Bicyclische Heterocyclen der allgemeinen Formel1. Bicyclic heterocycles of the general formula
Figure imgf000041_0001
in denen
Figure imgf000041_0001
in which
Ra ein Wasserstoffatom oder eine Cι-4-Alkylgruppe,R a is a hydrogen atom or a Cι -4 alkyl group,
Rb eine Phenyl-, Benzyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 bis R3 substituiert ist, wobeiR b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 to R 3 is substituted, wherein
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
eine Cι_ -Alkyl-, Hydroxy-, Cι-4-Alkoxy-, C2-3-Alkenyl- oder C2-3-Alkinylgruppe,a Cι_ alkyl, hydroxy, Cι -4 alkoxy, C 2-3 -alkenyl or C 2-3 -alkynyl,
eine Aryl-, Aryloxy-, Arylmethyl- oder Arylmethoxygruppe,an aryl, aryloxy, arylmethyl or arylmethoxy group,
eine Heteroaryl-, Heteroaryloxy-, Heteroarylmethyl- oder Heteroarylmethoxy- gruppe,a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group,
eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe odera substituted by 1 to 3 fluorine atoms methyl or methoxy group or
eine Cyano-, Nitro- oder Aminogruppe, unda cyano, nitro or amino group, and
R3 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 3 is a hydrogen, fluorine, chlorine or bromine atom,
eine Methyl- oder Trifluormethylgruppe darstellen,represent a methyl or trifluoromethyl group,
Rc ein Wasserstoffatom oder ein Fluor-, Chlor- oder Bromatom, eine Hydroxy- oder Cι-4-Alkyloxygruppe,R c is a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy or Cι -4 alkyloxy,
eine durch 1 bis 3 Fluoratome substituierte Methoxygruppe,a methoxy group substituted by 1 to 3 fluorine atoms,
eine durch 1 bis 5 Fluoratome substituierte Ethyloxygruppe,an ethyloxy group substituted by 1 to 5 fluorine atoms,
eine C2-4-Alkyloxygruppe, die durch einen Rest R4 substituiert ist, wobeia C 2-4 alkyloxy group substituted by a radical R 4 , wherein
R4 eine Hydroxy-, C1-3-Alkyloxy-, C3-6-Cycloalkyloxy-, C3-6-Cycloalkyl- C1-3-alkyloxy-, Amino-, Cι-3-Alkylamino-, Di-(C1-3-alkyl)amino-, Bis-(2-C1-3- alkyloxy-ethyl)-amino-, Bis-(3-C1-3-alkyloxy-propyl)-amino-, Pyrrolidin-1 -yl-, Piperidin-1-yl-, Homopiperidin-1-yl-, Morpholin-4-yl-, Homomorpholin-4-yl-, Piperazin-1-yl-, 4-(Cι-3-Alkyl)-piperazin-1-yl-, Homopiperazin-1-yl- oder 4- (Cι-3-Alkyl)-homopiperazin-1 -ylgruppe darstellt,R 4 is hydroxy, C 1-3 alkyloxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl C 1-3 alkyloxy, amino, Cι -3 alkylamino, di- ( C 1-3 alkyl) amino, bis (2-C 1-3 alkyloxyethyl) amino, bis (3-C 1-3 alkyloxypropyl) amino, pyrrolidine-1 yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, Homomorpholin-4-yl, piperazin-1-yl, 4- (Cι -3 alkyl) -piperazine Represents 1-yl, homopiperazin-1-yl or 4- (C 3 -alkyl) homopiperazine-1-yl group,
eine C2- -Alkyloxygruppe, die durch die Gruppe E substituiert ist, wobei E wie nachstehend erwähnt definiert ist,a C 2- alkyloxy group substituted by the group E, wherein E is defined as mentioned below,
eine C3_7-Cycloalkyloxy- oder C3-7-Cycloalkyl-Cι-4-alkyloxygruppe,a C 3 _ 7 alkyloxy cycloalkyloxy or C 3-7 cycloalkyl-Cι- 4,
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy- oder Tetrahydropyran-4-yloxy- gruppe,a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,
eine Tetrahydrofuranyl-Cι-4-alkyloxy- oder Tetrahydropyranyl-Cι- -alkyloxygruppe,a tetrahydrofuranyl Cι -4 alkyloxy alkyloxy or tetrahydropyranyl Cι-,
eine Pyrrolidin-3-yloxy-, Piperidin-3-yloxy- oder Piperidin-4-yloxy-Gruppe,a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,
eine 1-(Cι-3-Alkyl)-pyrrolidin-3-yloxy-, 1-(Cι.3-Alkyl)-piperidin-3-yloxy- oder 1 ~(Cι-3-Alkyl)- piperidin-4-yloxy-Gruppe,a 1- (Cι -3 alkyl) -pyrrolidin-3-yloxy, 1- (. Cι-C3 alkyl) -piperidin-3-yloxy or 1 ~ (Cι -3 alkyl) - piperidin-4-yloxy -Group,
eine Cι-4-Alkoxygruppe, die durch eine in 1 -Stellung durch den Rest R5 substituierte Pyrrolidinyl-, Piperidinyl- oder Homopiperidinylgruppe substituiert ist, wobei R5 ein Wasserstoffatom oder eine C-ι-3-Alkylgruppe darstellt,a Cι -4 alkoxy group which is substituted by a substituted in the 1 position by the group R 5 pyrrolidinyl, piperidinyl or homopiperidinyl group wherein R 5 represents a hydrogen atom or a C-ι -3 alkyl group,
oder eine Cι-4-Alkoxygruppe, die durch eine in 4-Stellung durch den Rest R5 substituierte Morpholinyl- oder Homomorpholinylgruppe substituiert ist, wobei R5 wie vorstehend erwähnt definiert ist,or Cι -4 alkoxy group which is substituted by a 4-position by the radical R 5 substituted morpholinyl or homomorpholinyl group, wherein R 5 is defined as mentioned above,
A eine Imino- oder Cι-4-Alkyliminogruppe,A one imino or Cι -4 -alkylimino,
B eine Carbonyl- oder Sulfonylgruppe,B is a carbonyl or sulfonyl group,
C eine 1 ,3-Allenylen-, 1 ,1-Vinylen- oder 1 ,2-Vinylengruppe, die jeweils durch eine oder zwei Methylgruppen oder durch eine Trifluormethylgruppe substituiert sein kann,C is a 1, 3-allenylene, 1, 1-vinylene or 1, 2-vinylene group, which may each be substituted by one or two methyl groups or by a trifluoromethyl group,
eine Ethinylengruppe oderan ethynylene group or
eine 1 ,3-Butadien-1 ,4-ylengruppe, die durch eine oder zwei Methylgruppen oder durch eine Trifluormethylgruppe substituiert sein kann,a 1,3-butadiene-1,4-ylene group which may be substituted by one or two methyl groups or by a trifluoromethyl group,
D eine geradkettige oder verzweigte Cι-4-Alkylengruppe,D represents a linear or branched Cι -4 alkylene,
E eine Pyrrolidin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 2 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, wobei die vorstehend erwähnten Pyrrolidin- 1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,E is a pyrrolidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 5 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain 2 to 4 carbon atoms, when the two hydrogen atoms are on carbon atoms which are separated by an atom, wherein the abovementioned pyrrolidin-1-yl groups each additionally by one or two C 1-3 alkyl groups can be substituted
eine Piperidin-1-yl- oder Homopiperidin-1-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperidin-1-yl- und Homopiperidin-1-ylgruppen jeweils zusätzlich durch eine oder zwei C-|.3-Alkylgruppen substituiert sein können,a piperidin-1-yl or homopiperidin-1-yl group in which in each case two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to 5 Contains carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms on carbon atoms which are separated by two atoms, wherein the above-mentioned piperidin-1-yl and homopiperidin-1-yl groups each additionally by one or two C-. 3- alkyl groups may be substituted,
eine Piperazin-1-yl- oder Homopiperazin-1-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperazin-1-yl- und Homopiperazin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Ct-3-Alkylgruppen substituiert sein können,a piperazin-1-yl or homopiperazin-1-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached Carbon atoms which are separated by two atoms, wherein the abovementioned piperazin-1-yl and homopiperazin-1-yl groups may each be additionally substituted by one or two C t-3- alkyl groups,
eine Morpholin-4-yl- oder Homomorpholin-4-ylgruppe, in denen jeweils zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 6 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Morpholin-4-yl- und Homomorpholin-4-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,a morpholin-4-yl or homomorpholin-4-yl group in which each two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 6 carbon atoms, if the two hydrogen atoms are on the same carbon atom, or 1 to Contains 5 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms or contains 1 to 4 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contains 1 to 3 carbon atoms when the two hydrogen atoms are attached carbon atoms are separated by two atoms, whilst the abovementioned morpholin-4-yl-4-yl groups and Homomorpholin each additionally by one or two Cι -3 alkyl groups may be substituted,
und X eine durch eine Cyanogruppe substituierte Methingruppe oder ein Stickstoffatom bedeuten,and X is a methine group substituted by a cyano group or a nitrogen atom,
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen jeweils eine Phenylgruppe zu verstehen ist, die durch R6 mono- oder disubstituiert ist, wobei die Substituenten gleich oder verschieden sein können undwherein the aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as meaning a phenyl group which is monosubstituted or disubstituted by R 6 , where the substituents may be identical or different and
R6 ein Wasserstoffatom, ein Fluor-, Chlor-, Brom- oder lodatom oder eine Cι- -Alkyl-, Hydroxy-, C-ι-3-Alkyloxy-, Difluormethyl- Trifluormethyl-, Difluor- methoxy-, Trifluormethoxy- oder Cyanogruppe darstellt,R 6 is a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a Cι- alkyl, hydroxy, C-ι -3 alkyloxy, difluoromethyl trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group represents,
unter den bei der Definition der vorstehend genannten Reste erwähnten Hetero- arylgruppen eine Pyridinyl-, Pyridazinyl-, Pyrimidinyl- oder Pyrazinylgruppe zu verstehen ist, wobei die vorstehend erwähnten Heteroarylgruppen jeweils durch den Rest R6 mono- oder disubstituiert sind, wobei die Substituenten gleich oder verschieden sein können und R6 wie vorstehend erwähnt definiert ist, undthe heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the abovementioned heteroaryl groups being in each case mono- or disubstituted by the radical R 6 , where the substituents are identical or may be different and R 6 is as defined above, and
soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen gerad- kettig oder verzweigt sein können,Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
2. Bicyclische Heterocyclen der allgemeinen Formel I gemäß Anspruch 1 , in denen2. bicyclic heterocycles of the general formula I according to claim 1, in which
Ra ein Wasserstoffatom,R a is a hydrogen atom,
Rb eine durch die Reste R1 bis R3 substituierte Phenylgruppe, wobeiR b is a substituted by the radicals R 1 to R 3 phenyl group, wherein
R1 ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 1 is a hydrogen, fluorine, chlorine or bromine atom,
eine Methyl-, Trifluormethyl- oder Ethinylgruppe, eine Phenyloxy- oder Phenylmethoxygruppe, wobei der Phenylteil der vorstehend erwähnten Gruppen gegebenenfalls durch ein Fluor- oder Chloratom substituiert ist, odera methyl, trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group, wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or
eine Pyridinyloxy- oder Pyridinylmethoxygruppe, wobei der Pyridinylteil der vorstehend erwähnten Gruppen gegebenenfalls durch eine Methyl- oder Trifluormethylgruppe substituiert ist,a pyridinyloxy or pyridinylmethoxy group, wherein the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,
R2 ein Wasserstoff-, Fluor- oder Chloratom undR 2 is a hydrogen, fluorine or chlorine atom and
R3 ein Wasserstoffatom darstellen,R 3 represents a hydrogen atom,
Rc ein Wasserstoffatom,R c is a hydrogen atom,
eine Cι-3-Alkyloxygruppe,a Cι -3 alkyloxy,
eine
Figure imgf000046_0001
oder C3-6-Cycloalkyl-C1-2-alkyloxy-Gruppe,a
Figure imgf000046_0001
or C 3-6 -cycloalkyl-C 1-2 -alkyloxy group,
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy-, Tetrahydrofuranyl-Cι,2-alkyloxy - oder Tetrahydropyranyl-Cι-2-alkyloxy-Gruppe,a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C 1, 2 -alkyloxy or tetrahydropyranyl-C 2 -alkyloxy group,
eine Ethyloxygruppe, die in 2-Stellung durch einen Rest R4 substituiert ist, wobeian ethyloxy group which is substituted in the 2-position by a radical R 4 , wherein
R4 eine Hydroxy-, Cι-3-Alkyloxy-, Amino-, C^s-Alkylamino-, Di-(Cι-3-alkyl)amino-, Bis-(2-methoxyethyl)-amino-, Pyrrolidin-1-yl-, Piperidin-1-yl-, Homopiperidin-1-yl-, Morpholin-4-yl-, Homomorpholin-4-yl-, Piperazin-1-yl-, 4-(Cι-3-Alkyl)-piperazin-1- yl-, Homopiperazin-1-yl- oder 4-(Cι-3-Alkyl)-homopiperazin-1-yl-Gruppe darstellt,R 4 is a hydroxy, Cι -3 alkyloxy, amino, C ^ s-alkylamino, di- (Cι -3 alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1 yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, Homomorpholin-4-yl, piperazin-1-yl, 4- (Cι -3 alkyl) -piperazine 1- yl, homopiperazin-1-yl or 4- (Cι -3 alkyl) homopiperazine-1-yl-group,
eine Propyloxygruppe, die in 3-Stellung durch einen Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist, odera propyloxy group which is substituted in the 3-position by a radical R 4 , wherein R 4 is defined as mentioned above, or
eine Butyloxygruppe, die in 4-Stellung durch einen Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist, A eine Iminogruppe,a butoxy group substituted in the 4-position by a radical R 4 , wherein R 4 is defined as mentioned above, A is an imino group,
B eine Carbonyl- oder Sulfonylgruppe,B is a carbonyl or sulfonyl group,
C eine 1 ,1-Vinylen-, 1 ,2-Vinylen- oder Ethinylengruppe,C is a 1, 1-vinylene, 1, 2-vinylene or ethynylene group,
D eine Methylen-, 1 ,1-Ethylen- oder 1 ,2-Ethylengruppe,D is a methylene, 1, 1-ethylene or 1, 2-ethylene group,
E eine Piperidin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperidin-1-ylgruppen jeweils zusätzlich durch eine oder zwei C1-3-Alkylgruppen substituiert sein können,E is a piperidin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms that are represented by two atoms each of which the above-mentioned piperidin-1-yl groups may additionally be substituted by one or two C 1-3 alkyl groups,
eine Piperazin-1-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Piperazin-1-ylgruppen jeweils zusätzlich durch eine oder zwei Cι_3-Alkylgruppen substituiert sein können, odera piperazin-1-yl group in which two hydrogen atoms on the carbon skeleton are replaced by a straight-chain alkylene bridge, this bridge containing 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing 1 to 4 carbon atoms when the two hydrogen atoms are on adjacent carbon atoms, or contain 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain 1 or 2 carbon atoms when the two hydrogen atoms are on carbon atoms separated by two atoms are, wherein the above-mentioned piperazin-1-yl groups may each be additionally substituted by one or two Cι_ 3 alkyl groups, or
eine Morpholin-4-ylgruppe, in der zwei Wasserstoffatome am Kohlenstoffgerüst durch eine geradkettige Alkylenbrücke ersetzt sind, wobei diese Brücke 2 bis 5 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich am selben Kohlenstoffatom befinden, oder 1 bis 4 Kohlenstoffatome enthält, wenn die zwei Wasserstoffatome sich an benachbarten Kohlenstoffatomen befinden, oder 1 bis 3 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch ein Atom getrennt sind, oder 1 oder 2 Kohlenstoffatome enthält, wenn sich die zwei Wasserstoffatome an Kohlenstoffatomen befinden, die durch zwei Atome getrennt sind, wobei die vorstehend erwähnten Morpholin-4-ylgruppen jeweils zusätzlich durch eine oder zwei Cι-3-Alkylgruppen substituiert sein können,a morpholin-4-yl group in which two hydrogen atoms on the carbon backbone are replaced by a straight-chain alkylene bridge, this bridge containing from 2 to 5 carbon atoms when the two hydrogen atoms are on the same carbon atom or containing from 1 to 4 carbon atoms, if the two Are hydrogen atoms on adjacent carbon atoms, or contain from 1 to 3 carbon atoms when the two hydrogen atoms are on carbon atoms separated by an atom or contain one or two carbon atoms when the two hydrogen atoms are on carbon atoms through two atoms are separated, whereby the above-mentioned morpholin-4-yl groups each additionally by one or two Cι -3 alkyl groups may be substituted,
undand
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
3. Bicyclische Heterocyclen der allgemeinen Formel 1 gemäß Anspruch 1 , in denen3. bicyclic heterocycles of the general formula 1 according to claim 1, in which
Ra ein Wasserstoffatom,R a is a hydrogen atom,
Rb eine 3-Ethinylphenyl-, 3-Bromphenyl-, 3,4-Difluorphenyl- oder 3-Chlor-4-fluor-phenyl- gruppe,R b is a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group,
Rc ein Wasserstoffatom,R c is a hydrogen atom,
eine Methoxy-, Ethyloxy-, 2-(Methoxy)ethyloxy-, 3-(Morpholin-4-yl)propyloxy-, Cyclo- butyloxy-, Cyclopentyloxy-, Cyclohexyloxy-, Cyclopropylmethoxy-, Cyclopentylmethoxy-, Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yIoxy-, Tetra- hydrofuran-2-ylmethoxy-, Tetrahydrofuran-3-ylmethoxy- oder Tetrahydropyran-4-yl- methoxy-Gruppe,a methoxy, ethyloxy, 2- (methoxy) ethyloxy, 3- (morpholin-4-yl) propyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy , Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy or tetrahydropyran-4-yl-methoxy group,
A eine Iminogruppe,A is an imino group,
B eine Carbonylgruppe, C eine 1,2-Vinylengruppe,B is a carbonyl group, C is a 1,2-vinylene group,
D eine Methylengruppe,D is a methylene group,
E eine 2-Aza-bicyclo[2.2.1]hept-2-yl-, 2,5-Diaza-bicyclo[2.2.1]hept-2-yl-, 5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-, 2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl-, 2-Aza-bicyclo[2.2.2]oct-2-yl-, 3-Aza-bicyclo[3.2.1]oct-3-yl-, 8-Aza-bicyclo[3.2.1 ]oct-8-yl-, 3,8-Diaza-bicyclo[3.2.1]oct-3-yl-, 8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl-, 3,8~Diaza-bicyclo[3.2.1]oct-8-yl-, 3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl-, 3-Oxa-8-aza-bicyclo[3.2.1]oct-8-yl- oder 8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl-Gruppe undE is a 2-azabicyclo [2.2.1] hept-2-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diaza-bicyclo 2.2.1] hept-2-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl, 2-azabicyclo [2.2.2] oct-2-yl, 3 -Aza-bicyclo [3.2.1] oct-3-yl, 8-azabicyclo [3.2.1] oct-8-yl, 3,8-diazabicyclo [3.2.1] oct-3-yl -, 8-methyl-3,8-diaza-bicyclo [3.2.1] oct-3-yl, 3,8-diaza-bicyclo [3.2.1] oct-8-yl, 3-methyl-3, 8-diaza-bicyclo [3.2.1] oct-8-yl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl or 8-oxa-3-aza-bicyclo [3.2. 1] oct-3-yl group and
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
4. Bicyclische Heterocyclen der allgemeinen Formel I gemäß Anspruch 1 , in denen4. bicyclic heterocycles of the general formula I according to claim 1, in which
Ra ein Wasserstoffatom,R a is a hydrogen atom,
Rb eine 3-Chlor-4-fluor-phenylgruppe,R b is a 3-chloro-4-fluoro-phenyl group,
Rc eine Tetrahydrofuran-3-yloxy-, Cyclopentyloxy- oder Cyclopropylmethoxygruppe,R c is a tetrahydrofuran-3-yloxy, cyclopentyloxy or cyclopropylmethoxy group,
A eine Iminogruppe,A is an imino group,
B eine Carbonylgruppe,B is a carbonyl group,
C eine 1 ,2-Vinylengruppe,C is a 1, 2-vinylene group,
D eine Methylengruppe,D is a methylene group,
E eine 2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl-Gruppe, eine 3-Oxa-8-aza-bicyclo[3.2.1]oct-8-yl-Gruppe oder eine 8-Oxa-3-aza-bicyclö[3.2.1]oct-3-yl-GruppeundE is a 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl group, a 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl group or an 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl group;
X ein Stickstoffatom bedeuten,X is a nitrogen atom,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.their tautomers, their stereoisomers, their mixtures and their salts.
5. Folgende Verbindungen der allgemeinen Formel I gemäß Anspruch 1 :5. The following compounds of general formula I according to claim 1:
(a) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1 ]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin,(a) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline,
(b) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1 ]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin,(b) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(c) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(c) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] heptane 5-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(d) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-1-oxo- 2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(d) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(e) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(e) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline,
(f) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-oxo- 2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(f) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -1- oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline,
(g) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1 ,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]-chinazolin und(g) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1,4-R) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline and
(h) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5- yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]-chinazolin,(h) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((1S, 4S) -2-oxa-5-aza-bicyclo [2.2.1] hept-5 - yl) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-3-yl) oxy] quinazoline,
sowie deren Salze. and their salts.
6. Physiologisch verträgliche Salze der Verbindungen nach mindestens einem der Ansprüche 1 bis 5 mit anorganischen oder organischen Säuren oder Basen.6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases.
7. Arzneimittel, enthaltend eine Verbindung nach mindestens einem der Ansprüche 1 bis 5 oder ein physiologisch verträgliches Salz gemäß Anspruch 6 neben gegebenenfalls einem oder mehreren inerten Trägerstoffen und/oder Verdünnungsmitteln.7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt according to claim 6, optionally together with one or more inert carriers and / or diluents.
8. Verwendung einer Verbindung nach mindestens einem der Ansprüche 1 bis 6 zur Herstellung eines Arzneimittels, das zur Behandlung von benignen oder malignen Tumoren, zur Vorbeugung und Behandlung von Erkrankungen der Atemwege und der Lunge sowie zur Behandlung von Erkrankungen des Magen-Darm-Traktes und der Gallengänge und -blase geeignet ist.8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of respiratory and pulmonary diseases and for the treatment of diseases of the gastrointestinal tract and the bile duct and bladder is suitable.
9. Verfahren zur Herstellung eines Arzneimittels gemäß Anspruch 7, dadurch gekennzeichnet, daß auf nicht-chemischem Wege eine Verbindung nach mindestens einem der Ansprüche 1 bis 6 in einen oder mehrere inerte Trägerstoffe und/oder Verdünnungsmittel eingearbeitet wird.9. A process for the preparation of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated into one or more inert carriers and / or diluents by non-chemical means.
10. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I gemäß den Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß10. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that
a) eine Verbindung der allgemeinen Formela) a compound of the general formula
Figure imgf000051_0001
in der
Figure imgf000051_0001
in the
Ra, Rb, Rc, A, B und X wie in Anspruch 1 erwähnt definiert sind und R7 und R8, die gleich oder verschieden sein können, C1-4-Alkylgruppen darstellen, mit einer Verbindung der allgemeinen Formel OHC - D - E , (lll) in derR a , R b , R c , A, B and X are as defined in claim 1 and R 7 and R 8 , which may be the same or different, represent C 1-4 alkyl groups, with a compound of the general formula OHC - D - E, (III) in the
D und E wie eingangs erwähnt definiert sind, umgesetzt wird oderD and E are defined as mentioned above, or is implemented
b) eine Verbindung der allgemeinen Formelb) a compound of the general formula
Figure imgf000052_0001
in der
Figure imgf000052_0001
in the
Ra, Rb, Rc, A, B, C, D und X wie in Anspruch 1 erwähnt definiert sind und Z1 eine Austrittsgruppe wie ein Halogenatom oder eine substituierte Sulfonyloxygruppe wie ein Chlor- oder Bromatom, eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe darstellt, mit einer Verbindung der allgemeinen FormelR a , R b , R c , A, B, C, D and X are as defined in claim 1 and Z 1 is a leaving group such as a halogen atom or a substituted sulphonyloxy group such as a chlorine or bromine atom, a Methansulfonyloxy- or p- Toluolsulfonyloxygruppe, with a compound of general formula
H - E, (V)H - E, (V)
in der E wie eingangs erwähnt definiert ist, umgesetzt wird undis defined in the E as mentioned above, is implemented and
erforderlichenfalls ein bei den vorstehend beschriebenen Umsetzungen verwendeter Schutzrest wieder abgespalten wird und/oderif necessary, a protective moiety used in the reactions described above is split off again and / or
gewünschtenfalls eine so erhaltene Verbindung der allgemeinen Formel I in ihre Stereoisomere aufgetrennt wird und/oderif desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or
eine so erhaltene Verbindung der allgemeinen Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze, übergeführt wird. a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application into its physiologically tolerated salts.
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AR039571A1 (en) 2005-02-23

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