WO2003089439A1 - Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production - Google Patents

Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production 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
atom
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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 AU2003226806A priority Critical patent/AU2003226806A1/en
Priority to EP03746824A priority patent/EP1499619A1/fr
Priority to JP2003586159A priority patent/JP4527406B2/ja
Priority to CA2484395A priority patent/CA2484395C/fr
Publication of WO2003089439A1 publication Critical patent/WO2003089439A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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).

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Abstract

La présente invention concerne des hétérocycles bicycliques de la formule générale (I), où Ra, Rb, Rc, A, B, C, D, E et X ont la définition donnée dans la revendication 1, leurs tautomères, leurs stéréo-isomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement compatibles avec des acides inorganiques ou organiques ayant de précieuses caractéristiques pharmacologiques, notamment une action inhibitrice sur la transduction de signaux transmise par la tyrosine-kinase. L'invention concerne également leur utilisation pour le traitement de maladies, notamment de maladies tumorales et de l'hypertrophie de la prostate (BPH), de maladies des poumons et des voies respiratoires, ainsi que leur production.
PCT/EP2003/003828 2002-04-19 2003-04-14 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production WO2003089439A1 (fr)

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AU2003226806A AU2003226806A1 (en) 2002-04-19 2003-04-14 Bicyclic heterocycles, medicaments containing these compounds, their use, and method for the production thereof
EP03746824A EP1499619A1 (fr) 2002-04-19 2003-04-14 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production
JP2003586159A JP4527406B2 (ja) 2002-04-19 2003-04-14 二環式ヘテロ環化合物、これら化合物を含有する医薬組成物、その使用及びその製造方法
CA2484395A CA2484395C (fr) 2002-04-19 2003-04-14 Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production

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DE10217689A DE10217689A1 (de) 2002-04-19 2002-04-19 Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
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JP2009514947A (ja) * 2005-11-08 2009-04-09 ハンミ ファーム． シーオー．， エルティーディー． 多重阻害剤としてのキナゾリン誘導体及びその製造方法
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US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
EP2448409A1 (fr) * 2009-07-02 2012-05-09 Newgen Therapeutics, Inc. Composés quinazoline contenant du phosphore et procédés d'utilisation
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US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
WO2013053206A1 (fr) 2011-10-12 2013-04-18 Teligene Ltd Dérivés de quinazoline en tant qu'inhibiteurs de kinases et leurs procédés d'utilisation
US8722694B2 (en) 1999-06-21 2014-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US8877764B2 (en) 2006-09-18 2014-11-04 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US9089571B2 (en) 2005-11-11 2015-07-28 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US9586939B2 (en) 2011-05-26 2017-03-07 Xuanzhu Pharma Co., Ltd. Quinazoline derivative as tyrosine-kinase inhibitor, preparation method therefor and application thereof
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11034672B1 (en) 2018-09-25 2021-06-15 Black Diamond Therapeutics, Inc. Tyrosine kinase inhibitor compositions, methods of making and methods of use
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use

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US8722694B2 (en) 1999-06-21 2014-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
USRE43431E1 (en) 2000-12-20 2012-05-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US8586608B2 (en) 2000-12-20 2013-11-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US7863281B2 (en) 2002-04-19 2011-01-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US10266518B2 (en) 2002-07-15 2019-04-23 Symphony Evolution, Inc. Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use
JP2009007363A (ja) * 2004-05-06 2009-01-15 Warner-Lambert Co Llc ４−フェニルアミノ−キナゾリン−６−イル−アミド
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8846699B2 (en) 2005-11-08 2014-09-30 Hanmi Pharm. Co., Ltd. Quinazoline derivatives as a multiplex inhibitor and method for the preparation thereof
JP4918097B2 (ja) * 2005-11-08 2012-04-18 ハンミ ファーム． シーオー．， エルティーディー． 多重阻害剤としてのキナゾリン誘導体及びその製造方法
JP2009514947A (ja) * 2005-11-08 2009-04-09 ハンミ ファーム． シーオー．， エルティーディー． 多重阻害剤としてのキナゾリン誘導体及びその製造方法
US9539258B2 (en) 2005-11-11 2017-01-10 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US9089571B2 (en) 2005-11-11 2015-07-28 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US8877764B2 (en) 2006-09-18 2014-11-04 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
US11091439B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11098015B2 (en) 2009-01-16 2021-08-24 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11091440B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
EP2448409A4 (fr) * 2009-07-02 2013-04-10 Newgen Therapeutics Inc Composés quinazoline contenant du phosphore et procédés d'utilisation
EP2448409A1 (fr) * 2009-07-02 2012-05-09 Newgen Therapeutics, Inc. Composés quinazoline contenant du phosphore et procédés d'utilisation
US8987284B2 (en) 2009-07-02 2015-03-24 Newgen Therapeutics, Inc. Phosphorus containing quinazoline compounds and methods of use
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US10004743B2 (en) 2009-07-06 2018-06-26 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
EP2479174A1 (fr) * 2009-09-14 2012-07-25 Jiangsu Hengrui Medicine Co., Ltd. Dérivés de la 6-amino-quinazoline ou de la 3-cyano-quinoline, leurs procédés de préparation et leurs utilisations pharmaceutiques
EP2479174A4 (fr) * 2009-09-14 2013-04-17 Jiangsu Hengrui Medicine Co Dérivés de la 6-amino-quinazoline ou de la 3-cyano-quinoline, leurs procédés de préparation et leurs utilisations pharmaceutiques
US8901140B2 (en) 2009-09-14 2014-12-02 Jiangsu Hengrui Medicine Co., Ltd. 6-amino quinazoline or 3-cyano quinoline derivatives, preparation methods and pharmaceutical uses thereof
US9358227B2 (en) 2009-09-14 2016-06-07 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical uses of 6-amino quinazoline or 3-cyano quinoline derivatives
US9956222B2 (en) 2011-05-26 2018-05-01 Xuanzhu Pharma Co., Ltd. Quinazoline derivative as tyrosine-kinase inhibitor, preparation method therefor and application thereof
US9586939B2 (en) 2011-05-26 2017-03-07 Xuanzhu Pharma Co., Ltd. Quinazoline derivative as tyrosine-kinase inhibitor, preparation method therefor and application thereof
CN103874696A (zh) * 2011-10-12 2014-06-18 苏州韬略生物科技有限公司 作为激酶抑制剂的喹唑啉衍生物及其使用方法
WO2013053206A1 (fr) 2011-10-12 2013-04-18 Teligene Ltd Dérivés de quinazoline en tant qu'inhibiteurs de kinases et leurs procédés d'utilisation
CN103874696B (zh) * 2011-10-12 2015-06-03 苏州韬略生物科技有限公司 作为激酶抑制剂的喹唑啉衍生物及其使用方法
US9388160B2 (en) 2011-10-12 2016-07-12 Teligene Ltd Quinazoline derivatives as kinases inhibitors and methods of use thereof
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
US11034672B1 (en) 2018-09-25 2021-06-15 Black Diamond Therapeutics, Inc. Tyrosine kinase inhibitor compositions, methods of making and methods of use

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PE20040171A1 (es) 2004-06-02
EP1499619A1 (fr) 2005-01-26
AU2003226806A1 (en) 2003-11-03
CA2484395A1 (fr) 2003-10-30
JP2005526837A (ja) 2005-09-08
CA2484395C (fr) 2011-11-22
UY27767A1 (es) 2003-11-28
AR039571A1 (es) 2005-02-23
DE10217689A1 (de) 2003-11-13
JP4527406B2 (ja) 2010-08-18

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