EP2313398A1 - Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof - Google Patents

Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof

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Publication number
EP2313398A1
EP2313398A1 EP09780994A EP09780994A EP2313398A1 EP 2313398 A1 EP2313398 A1 EP 2313398A1 EP 09780994 A EP09780994 A EP 09780994A EP 09780994 A EP09780994 A EP 09780994A EP 2313398 A1 EP2313398 A1 EP 2313398A1
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European Patent Office
Prior art keywords
amino
phenyl
quinazoline
methoxy
compounds
Prior art date
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EP09780994A
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German (de)
French (fr)
Inventor
Frank Himmelsbach
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority to EP09780994A priority Critical patent/EP2313398A1/en
Publication of EP2313398A1 publication Critical patent/EP2313398A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to cyclohexyloxy-substituted heterocycles of the general formula
  • the object of the present invention is to provide novel compounds which, because of their pharmaceutical activity as tyrosine kinase inhibitors, have therapeutic uses in the art, e.g. to treat pathophysiological processes caused by hyperfunction of tyrosine kinases.
  • R a represents an ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, 3-tetrahydrofuranyl, tetrahydrofuranylmethyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl and tetrahydropyranylmethyl group, and wherein, as far as nothing else is mentioned, the abovementioned alkyl groups may be straight-chain or branched,
  • R a is a radical selected from the group consisting of ethyl, butyl, cyclopropylmethyl and 4-tetrahydropyranyl group,
  • Another object of the invention are compounds of formula (I) for use as medicaments.
  • the compounds of formula (I) which is a disease selected from the group consisting of chronic Bronchitis, acute bronchitis, bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis , chronic sinusitis, cystic fibrosis or cystic fibrosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung disease, alveolitis, hyperreactive airways, nasal polyps, pulmonary edema, pneumonitis due to different causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus eryth, systemic scleroderma, sarcoidosis
  • COPD chronic
  • Another object of the invention is a pharmaceutical formulation containing a compound of formula (I).
  • Another object of the invention is a drug combination containing in addition to one or more compounds of formula (I) as another active ingredient one or more compounds selected from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists , EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors or two or three combinations thereof.
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterols, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol , Mabuterol, meluadrin, metaproterenol, milveterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, tiaramide, toluubuterol, zinterol and
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of: tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R) -1 -phenethyl-3- (9H-xanthene-9-carbonyloxy) -1 -azoniabicyclo [2.2.2] octane salts.
  • tiotropium salts preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts,
  • the cations are the pharmacologically active ingredients.
  • the above-mentioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
  • Preferred corticosteroids are compounds which are selected from the group consisting of: beclomethasone, betamethasone, budesonide, Butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, tipredane and
  • Steroids includes a reference to their optionally existing salts or derivatives
  • Alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphates,
  • Isonicotinates acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast pumafentrin, lirimilast, apremilast, arofylline, atizoram, oglemilast, tetomilast, and
  • N- (3,5-dichloro-1-oxido-pyridinyl-carboxamido- ⁇ -methoxy-trifluoromethyl-quinoline (D-4396 (Sch-351591)), N- (3,5-dichloropyrid-4-yl) - [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] glyoxylic acid amide (AWD-12-281 (GW-842470)), 9 - [(2-fluorophenyl) methyl] -N-methyl-2 - (trifluoromethyl) -9H-purine-6-amine (NCS-613),
  • Cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]
  • Cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
  • Preferred LTD4 receptor antagonists are compounds which are selected from the group consisting of montelukast, pranlukast, zafirlukast, and (E) -8- [2- [4- [4- (4-fluorophenyl) butoxy] phenyl ] ethenyl] -2- (1H-tetrazol-5-yl) -4H-1-benzopyran-4-one (MEN-91507)
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
  • the LTD4 receptor antagonists are optionally able to be understood, for example, alkali metal salts such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • alkali metal salts such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • the histamine H1 receptor antagonists used are preferably compounds selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, Chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, olopatadine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred PAF antagonists here are compounds which are selected from the group consisting of lexipafant and 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl ] -6H-thieno [3,2-f] - [1,2,4] triazolo [4,3-a] [1,4] diazepine
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention
  • Preferred dopamine receptor agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates, Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate
  • Preferred substances of preferred PI3 kinase antagonists are compounds which are selected from the group consisting of Quinoxalin-6-ylmethylene) thiazolidine-2,4-diones (AS-605240),
  • the term "optionally substituted” is understood to mean the abovementioned group which is optionally substituted by a lower-molecular radical.
  • Low-molecular radicals are understood to be chemically meaningful groups consisting of 1-25 atoms. Preferably, such groups have no negative effect on the pharmacological activity of the compounds.
  • the groups may include:
  • Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.
  • aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which can be replaced by one or more
  • Carbon chains optionally interrupted by heteroatoms, optionally substituted with heteroatoms or other common functional groups may be linked.
  • the compounds according to the invention including their salts, in which one or more hydrogen atoms, for example, one, two, three, four or five hydrogen atoms are replaced by deuterium.
  • Compounds of general formula (I) may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions.
  • Compounds of general formula (I) can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable Bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • alkali metal and alkaline earth metal salts of the compound of the formula (I) preference is given to the alkali metal hydroxides and alkaline earth hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium being preferred, sodium and potassium hydroxide being particularly preferred , (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 6 (3, 1-19)
  • the compounds of the general formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid.
  • suitable acids are succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid.
  • mixtures of the abovementioned acids can be used.
  • the invention relates to the respective compounds, optionally in the form of the individual diastereomers, mixtures of the individual diastereomers and / or the individual enantiomers, mixtures of the individual enantiomers or racemates, in the form of
  • hydrohalic acids for example, hydrochloric or hydrobromic acid - or organic acids - such as tartaric acid, fumaric acid, citric acid or methanesulfonic acid.
  • Protecting groups in the meaning of the present invention are to be understood as a collective term for such organic radicals with which certain functional groups of a molecule containing several active sites can be temporarily protected against the attack of reagents so that reactions take place only at the desired (unprotected) sites occur.
  • the protecting groups should be selectively introduced under mild conditions. They must be stable for the duration of the protection under all conditions of the reactions and cleaning operations to be performed; Racemizations and epimerizations must be suppressed. Protective groups should again be cleavable under mild conditions selectively and ideally with high yield.
  • an "organic solvent” is understood to mean an organic, low-molecular substance which can bring other organic substances to solution by physical means.
  • Prerequisite for the suitability as a solvent is that during the dissolution process, neither the solvent nor the solute chemically change, so that the components of the solution by physical separation methods such as distillation, crystallization, sublimation, evaporation, adsorption can be recovered in its original form.
  • physical separation methods such as distillation, crystallization, sublimation, evaporation, adsorption
  • Alcohols preferably methanol, ethanol, propanol, butanol, octanol, cyclohexanol;
  • Glycols preferably ethylene glycol, diethylene glycol;
  • Ether / glycol ethers preferably diethyl ether, tert-butyl methyl ether, dibutyl ether, anisole, dioxane, tetrahydrofuran, mono-, di-, tri-, polyethylene glycol ethers;
  • Ketones preferably acetone, butanone, cyclohexanone
  • Esters preferably acetic acid esters, glycol esters;
  • Nitrogen compounds preferably dimethylformamide, pyridine, N-methylpyrrolidone, acetonitrile;
  • Sulfur compounds preferably carbon disulfide, dimethylsulfoxide, sulfolane; Nitro compounds preferably nitrobenzene;
  • Halogenated hydrocarbons preferably dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, tetrachloroethene, 1,2-dichloroethane, chlorofluorocarbons;
  • Aliphatic or alicyclic hydrocarbons preferably benzines, petroleum ethers, cyclohexane, methylcyclohexane, decalin, terpene-L; or
  • Aromatic hydrocarbons preferably benzene, toluene, o-xylene, m-xylene, p-xylene; or corresponding mixtures thereof.
  • diastereomerically pure in the context of the present invention describes compounds of the formula (I) which are present in a diastereomeric purity of at least 85% de, preferably of at least 90% de, particularly preferably> 95% de.
  • de diastereomeric excess
  • de optical purity of diastereomeric compounds.
  • enantiomerically pure in the context of the present invention describes compounds of the formula (I) which are present in an enantiomeric purity of at least 85% ee, preferably of at least 90% ee, particularly preferably of> 95% ee.
  • ee enantiomeric excess
  • d- 6 alkyl (including those which are part of other groups) branched to and understood unbranched alkyl groups having 1 to 6 carbon atoms, and branched by the term "C-M-alkyl” and unbranched alkyl groups having 1 to 4 carbon atoms Understood. Preferred are alkyl groups having 1 to 4 carbon atoms, more preferably alkyl groups having 1 to 2 carbon atoms.
  • Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl
  • butyl includes / so-butyl, sec-butyl and te / f-butyl, etc.
  • C 3-7 -cycloalkyl means cyclic alkyl groups having 3 or 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with one or more multiple radicals selected from the group consisting of methyl, ethyl, / so-propyl, tert-butyl, hydroxy and fluorine.
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6, 10 or 14 carbon atoms. Examples include: phenyl, naphthyl, anthracenyl or phenanthrenyl, more preferably aryl is phenyl.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
  • Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a Methansulfonyloxy- or p-toluenesulfonyloxy or a hydroxy group.
  • the reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, preferably in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisopropylamine, at temperatures in the range of 20 0 C to 160 0 C, for example at temperatures in the range of 60 ° C to 140 ° C.
  • a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
  • a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisoprop
  • reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as
  • Triphenylphosphine / Azodicarbonklarediethylester conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures between -50 and 150 0 C, but preferably at temperatures between -20 and 80 ° C, carried out.
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether
  • R a is as defined above
  • a halogenating agent for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or triphenylphosphine / carbon tetrachloride or triphenylphosphine / N-chlorosuccinimide to give an intermediate compound of general formula (V),
  • an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or triphenylphosphine / carbon tetrachloride or triphenylphosphine / N-chlorosuccinimide
  • R a is defined as mentioned above and Z 2 represents a halogen atom, such as a chlorine or bromine atom,
  • the reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline, triethylamine or N-ethyl-diisopropylamine at temperatures in the range of 20 0 C to 160 0 C. , preferably carried out from 40 ° C to 120 0 C.
  • a solvent such as methylene chloride, chloroform, acetonitrile or toluene
  • a base such as N, N-diethylaniline, triethylamine or N-ethyl-diisopropylamine
  • the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture or with phosphorus oxychloride in acetonitrile in the presence of triethylamine at the boiling temperature of the reaction mixture or with triphenylphosphine / carbon tetrachloride or with triphenylphosphine / N-chlorosuccinimide in acetonitrile.
  • reaction of the compound of the general formula (VI) with the compound of the general formula (VII) or its salts is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, if appropriate in the presence of a base such as potassium carbonate, triethylamine or N- Ethyl diisopropylamine, at temperatures in the range of 20 ° C and 160 ° C, preferably from 60 0 C to 120 ° C.
  • the reaction is carried out in isopropanol at the boiling temperature of the reaction mixture.
  • the reaction of a compound of the general formula (IV) to give a compound of the general formula (I) can also be carried out as a one-pot reaction, for example in acetonitrile in the presence of triethylamine.
  • R a is as defined above, in the presence of a reducing agent.
  • the reductive amination is, for example, in a solvent such as dichloromethane, 1, 2 dichloroethane, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid, optionally in the presence of acetic acid at temperatures between 0 0 C and 80 0 C performed.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid
  • acetic acid at temperatures between 0 0 C and 80 0 C performed.
  • the reductive amination can also be carried out with hydrogen in the presence of a catalyst such as palladium on activated carbon or platinum oxide.
  • Another possibility is to form the enamine from the ketone of general formula VII and the amine of general formula VIII with elimination of water, for example with titanium (IV) isopropoxide, and then to reduce this, for example with sodium borohydride or hydrogen / palladium activated 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.
  • Protective radicals for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
  • the optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
  • an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence an alkali metal base
  • cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonyl restes takes place, for example hydrogenolytically, for example, 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 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid
  • an acid such as hydrochloric acid
  • the cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole, thioanisole, pentamethylbenzene or triethylsilane.
  • tert-butyl or tert. -Butyloxycarbonylrest.es is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • the cleavage of a Trifluoracetyl rest is preferably carried out by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be resolved into their enantiomers.
  • the resulting cis / trans mixtures can be purified by chromatography in their cis and trans isomers, the resulting compounds of general formula I, which in
  • the enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such.
  • Ester or amide-forming optically active substance in particular acids and their activated derivatives or
  • Derivatives e.g. due to different solubilities, wherein from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents.
  • Particularly common optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
  • acids examples include hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, phosphoric, fumaric, succinic, benzoic, salicylic, mandelic, lactic, malonic, citric, L-malic, L-tartaric or maleic acid ,
  • bases for this example, sodium hydroxide, potassium hydroxide, calcium hydroxide, diethanolamine or N-methyl-D-glucamine into consideration.
  • the compounds of the general formula (I) according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R) Inhibition of ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission to further downstream components is blocked.
  • EGF-R epidermal growth factor receptor
  • Reaction mixture refluxed for 2 hours.
  • the mixture is cooled to room temperature, with
  • the reaction mixture is dichloromethane and 1M sodium hydroxide solution, stirred briefly and extracted several times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. Purification on a silica gel column with ethyl acetate / methanol / aqueous ammonia (95: 5: 0.1 to 80: 20: 0.1) gives the two title compounds as a mixture.
  • the cis / trans mixture is separated by preparative HPLC (xBridge TM C18 from Waters, acetonitrile, water, aqueous ammonia). The assignment of the isomers via 1 H-NMR spectroscopy (400MHz, dimethyl sulfoxide-d6).
  • EGF-R mediated signal transduction may be e.g. with cells expressing human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha, respectively.
  • a murine hematopoietic cell line is genetically engineered to express functional human EGF-R. The proliferation of this cell line can therefore be stimulated by EGF.
  • the cells are cultured in RPMI / 1640 medium. Proliferation is stimulated with 20 ng / ml human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention, these compounds are dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration is 1%. The cultures are incubated for 48 hours at 37 ° C.
  • DMSO dimethyl sulfoxide
  • the relative cell count is determined using the Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation Assay
  • the relative cell count is calculated as a percentage of the control and the drug concentration, which inhibits the proliferation of the cells to 50% (IC50) derived.
  • the compounds of formula (I) are characterized by a variety of therapeutic applications. To emphasize are those applications for which the compounds of the formula (I) according to the invention can preferably be used as a tyrosine kinase inhibitor due to their pharmaceutical activity.
  • the compounds of general formula (I) according to the invention thus inhibit the signal transduction by tyrosine kinases, as exemplified by the human EGF receptor and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases as exemplified by the human EGF receptor and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases.
  • These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuro-epithelial 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-antitrypsin deficiency, or in cough, emphysema, pulmonary fibrosis and hyperreactive 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-antitrypsin deficiency, or in cough, emphysema, pulmonary fibrosis and hyperreactive airways.
  • the compounds are also useful in the treatment of disorders of the gastrointestinal tract and bile ducts and bladder associated with impaired activity of the tyrosine kinases, e.g. in chronic inflammatory disorders, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in disorders of the gastrointestinal tract associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
  • chronic inflammatory disorders such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in disorders of the gastrointestinal tract associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
  • the compounds of general formula (I) and their physiologically acceptable salts may be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc ..
  • tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc .
  • the compounds of the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adriamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc.
  • topoisomerase inhibitors eg etoposide
  • mitotic inhibitors eg, vinblastine
  • nucleic acid-interacting compounds eg, cisplatin, cyclophosphamide, adriamycin
  • hormone antagonists eg, tamoxifen
  • inhibitors of metabolic processes eg, 5-FU, etc.
  • these compounds may be used alone or in combination with other respiratory therapies, such as secretolytic (eg Ambroxol, N- acetylcysteine), broncholytic (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (eg theophylline or glucocorticoids) active substances.
  • secretolytic eg Ambroxol, N- acetylcysteine
  • broncholytic eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
  • anti-inflammatory eg theophylline or glucocorticoids
  • the compounds according to the invention can be administered orally, transdermally, by inhalation, parenterally or sublingually.
  • the compounds of the invention are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc.
  • An effective dose of the compounds according to the invention is between 0.1 and 5000, preferably between 1 and 500, more preferably between 5 and 300 mg / dose when administered orally during intravenous, subcutaneous or intramuscular administration 0.001 and 50, preferably between 0.1 and 10 mg / dose.
  • inhalation solutions are suitable according to the invention containing 0.01 to 1, 0, preferably 0.1 to 0.5% active ingredient.
  • the use of powders, ethanolic or aqueous solutions is preferred. It is likewise possible to use the compounds according to the invention as infusion solution, preferably in a physiological saline solution or nutrient salt solution.
  • the compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
  • Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example iner
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection solutions are prepared in a conventional manner, e.g. prepared with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid and filled into injection bottles or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • the compounds of the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.01-
  • these may be, for example, with one or more conventional inert carriers and / or
  • Diluents e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose,
  • Carboxymethylcellulose or fatty substances such as hard fat or their suitable Mixtures are incorporated in conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
  • 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.
  • 1 tablet contains:
  • Diameter 10 mm, biplan with facet on both sides and one-sided part notch.
  • 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:
  • 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.
  • Composition 1 suppository contains:
  • 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
  • Distilled water is heated to 70 0 C.
  • p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
  • 5 ml of suspension contain 50 mg of active ingredient.
  • the active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.
  • Composition Active ingredient 50.0 mg 0.01 n hydrochloric acid s.q.
  • 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 on one
  • Capsule machine in capsules (weight of the empty capsule about 50 mg) bottled.
  • 1 hub contains:
  • the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
  • the pH of the solution is adjusted with 1 N hydrochloric acid.
  • the adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).

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Abstract

The present invention relates to cyclohexylol-substituted heterocyclics of the general formula (I), to tautomers thereof, to stereoisomers thereof, to mixtures thereof and to salts thereof, in particular physiologically compatible salts thereof containing inorganic or organic acids and bases and having valuable pharmacological properties, in particular an inhibiting effect on the signal transduction mediated by tyrosine kinases, to the use thereof in the treatment of illnesses, in particular tumor diseases and benign prostate hyperplasia (BPH), diseases of the lungs and respiratory tracts, and to the production thereof.

Description

Cyclohexyloxy-substituierte Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung Cyclohexyloxy-substituted heterocycles, pharmaceutical compositions containing them, their use and processes for their preparation
Gegenstand der vorliegenden Erfindung sind Cyclohexyloxy-substituierte Heterocyclen der allgemeinen FormelThe present invention relates to cyclohexyloxy-substituted heterocycles of the general formula
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.
Aufgabe der vorliegenden Erfindung ist es, neue Verbindungen bereitzustellen, die aufgrund ihrer pharmazeutischen Wirksamkeit als Tyrosin-Kinase Hemmer zur Anwendung auf therapeutischem Gebiet, d.h. zur Behandlung von pathophysiologischen Prozessen, die durch Überfunktion von Tyrosinkinasen hervorgerufen werden, gelangen können.The object of the present invention is to provide novel compounds which, because of their pharmaceutical activity as tyrosine kinase inhibitors, have therapeutic uses in the art, e.g. to treat pathophysiological processes caused by hyperfunction of tyrosine kinases.
Detaillierte Beschreibung der ErfindungDetailed description of the invention
Überraschenderweise wurde gefunden, dass die vorstehend genannte Aufgabe durch Verbindungen der Formel (I), worin der Rest Ra die nachstehend genannten Bedeutungen hat, gelöst wird. Die vorliegende Erfindung betrifft daher Verbindungen der allgemeinen Formel (I), Surprisingly, it has been found that the above object is achieved by compounds of the formula (I) in which the radical R a has the meanings mentioned below. The present invention therefore relates to compounds of the general formula (I),
worinwherein
Ra eine Ethyl-, Propyl-, Butyl-, Cyclopropyl-, Cyclopropylmethyl-, Cyclobutyl-, Cyclobutylmethyl-, 3-Tetrahydrofuranyl-, Tetrahydrofuranylmethyl-, 3-Tetrahydropyranyl-, 4- Tetrahydropyranyl- und Tetrahydropyranylmethyl-Gruppe, und wobei, soweit nichts anderes erwähnt wird, die vorstehend genannten Alkylgruppen geradkettig oder verzweigt sein können,R a represents an ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, 3-tetrahydrofuranyl, tetrahydrofuranylmethyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl and tetrahydropyranylmethyl group, and wherein, as far as nothing else is mentioned, the abovementioned alkyl groups may be straight-chain or branched,
gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze, Solvate und Hydrate, bedeutet.optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates.
Bevorzugt sind Verbindungen der Formel (I), worinPreference is given to compounds of the formula (I) in which
Ra einen Rest ausgewählt aus der Gruppe bestehend aus Ethyl-, Butyl-, Cyclopropylmethyl- und 4-Tetrahydropyranyl-Gruppe bedeutet,R a is a radical selected from the group consisting of ethyl, butyl, cyclopropylmethyl and 4-tetrahydropyranyl group,
gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze, Solvate und Hydrate.optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts, solvates and hydrates.
Ein weiterer Gegenstand der Erfindung sind Verbindungen der Formel (I) zur Verwendung als Arzneimittel.Another object of the invention are compounds of formula (I) for use as medicaments.
Bevorzugt ist die Verwendung der Verbindungen der Formel (I), wobei es sich um entzündliche oder allergische Erkrankungen der Atemwege handelt.Preference is given to the use of the compounds of the formula (I), which are inflammatory or allergic diseases of the respiratory tract.
Besonders bevorzugt ist die Verwendung der Verbindungen der Formel (I), wobei es sich um eine Erkrankung handelt, die ausgewählt ist aus der Gruppe bestehend aus Chronischer Bronchitis, akuter Bronchitis, Bronchitis aufgrund bakterieller oder viraler Infektion oder Pilzen oder Helminthen, allergischer Bronchitis, toxischer Bronchitis, chronisch obstruktiver Bronchitis (COPD), Asthma (intrinsisch oder allergisch), pediatrischem Asthma, Bronchiektasien, allergischer Alveolitis, allergischer oder nicht-allergischer Rhinitis, chronischer Sinusitis, zystischer Fibrose oder Mukoviszidose, alpha-1-Antitrypsin-Mangel, Husten, Lungenemphysem, interstitieller Lungenerkrankungen, Alveolitis, hyperreaktiver Atemwege, Nasenpolypen, Lungenödemen, Pneumonitis aufgrund unterschiedlicher Genese wie Strahlen-induziert oder durch Aspiration oder infektiöse, Kollagenosen wie Lupus eryth, systemische Sklerodermie, Sarkoidose und M. Boeck. Weiterhin bevorzugt ist die Verwendung der Verbindungen der Formel (I), wobei es sich um entzündliche oder allergische Krankheitszustände handelt, bei denen Autoimmun-Reaktionen beteiligt sind.Particularly preferred is the use of the compounds of formula (I), which is a disease selected from the group consisting of chronic Bronchitis, acute bronchitis, bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis , chronic sinusitis, cystic fibrosis or cystic fibrosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung disease, alveolitis, hyperreactive airways, nasal polyps, pulmonary edema, pneumonitis due to different causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus eryth, systemic scleroderma, sarcoidosis and M. boeck. Further preferred is the use of the compounds of formula (I) which are inflammatory or allergic disease states in which autoimmune reactions are involved.
Weiterhin bevorzugt ist die Verwendung der Verbindungen der Formel (I), wobei es sich um eine Erkrankung in Form von benignen oder malignen Tumoren handelt. Ein weiterer Gegenstand der Erfindung ist eine pharmazeutische Formulierung enthaltend eine Verbindung der Formel (I).Further preferred is the use of the compounds of the formula (I), which is a disease in the form of benign or malignant tumors. Another object of the invention is a pharmaceutical formulation containing a compound of formula (I).
Bevorzugt ist eine oral applizierbare pharmazeutische Formulierung enthaltend eine Verbindung der Formel (I). Ein weiterer Gegenstand der Erfindung ist eine Arzneimittelkombinationen, die neben einer oder mehrerer Verbindungen der Formel (I) als weiteren Wirkstoff einen oder mehrere Verbindungen enthalten, die ausgewählt sind aus den Klassen der Betamimetika, Anticholinergika, Corticosteroiden, weitere PDE4-Inhibitoren, LTD4-Antagonisten, EGFR-Hemmern, Dopamin- Agonisten, H1-Antihistaminika, PAF-Antagonisten und PI3-Kinase Inhibitoren oder zwei- oder dreifach Kombinationen davon. Als Betamimetika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Arformoterol, Carmoterol, Formoterol, Indacaterol, Salmeterol, Albuterole, Bambuterol, Bitolterol, Broxaterol, Carbuterol, Clenbuterol, Fenoterol, Hexoprenalin, Ibuterol, Isoetharin, Isoprenalin, Levosalbutamol, Mabuterol, Meluadrin, Metaproterenol, Milveterol, Orciprenalin, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrin, Salmefamol, Soterenol, Sulphonterol, Terbutalin, Tiaramid, Tolubuterol, Zinterol undPreference is given to an orally administrable pharmaceutical formulation comprising a compound of the formula (I). Another object of the invention is a drug combination containing in addition to one or more compounds of formula (I) as another active ingredient one or more compounds selected from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists , EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors or two or three combinations thereof. Preferred betamimetics for this purpose are compounds selected from the group consisting of arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterols, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol , Mabuterol, meluadrin, metaproterenol, milveterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, tiaramide, toluubuterol, zinterol and
• 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1 ,1-dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one
• 8-{2-[2-(2,4-Difluor-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on • 8-{2-[2-(3,5-Difluor-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on • 8-{2-[2-(4-Ethoxy-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on• 8- {2- [2- (2,4-Difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3 -one • 8- {2- [2- (3,5-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazine -3-one • 8- {2- [2- (4-Ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• 8-{2-[2-(4-Fluor-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on • N-(5-{2-[3-(4,4-Diethyl-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-1 ,1-dimethyl-propylamino]-1- hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamid• 8- {2- [2- (4-Fluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one N- (5- {2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1-dimethyl-propylamino] - 1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide
• N-(5-{2-[3-(4,4-Diethyl-6-fluoro-2-oxo-4H-benzo[d][1 ,3]oxazin-1-yl)-1 ,1-dimethyl- propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamidN- (5- {2- [3- (4,4-diethyl-6-fluoro-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1,1-dimethyl - propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide
• N-(5-{2-[3-(4!4-Diethyl-6-methoxy-2-oxo-4H-benzo[d][1 !3]oxazin-1-yl)-1 ,1-dimethyl- propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamidN- (5- {2- [3- (4 : 4-diethyl-6-methoxy-2-oxo-4H-benzo [d] [1 ! 3] oxazin-1-yl) -1, 1-dimethyl - propylamino] -1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide
• N-(5-{2-[1 ,1-Dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1 ,3]oxazin-1-yl)-propylamino]-1- hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamidN- (5- {2- [1,1-dimethyl-3- (2-oxo-4,4-dipropyl-4H-benzo [d] [1,3] oxazin-1-yl) -propylamino] - 1-hydroxyethyl} -2-hydroxy-phenyl) -methanesulfonamide
• 8-{2-[1 ,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}- 6-hydroxy-4H-benzo[1 ,4]oxazin-3-on • 8-{2-[1 , 1 -Dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1 -yl)-propylamino]-1 - hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on• 8- {2- [1,1-Dimethyl-3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one • 8- {2- [1,1-dimethyl-3- (6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] - 1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one
• 8-{2-[1 ,1-Dimethyl-3-(2-oxo-5-trifluormethyl-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1- hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on• 8- {2- [1,1-dimethyl-3- (2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy 4H-benzo [1,4] oxazin-3-one
• 8-{2-[1 ,1-Dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1- hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on• 8- {2- [1,1-Dimethyl-3- (3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl) -propylamino] -1-hydroxyethyl} -6-hydroxy 4H-benzo [1,4] oxazin-3-one
• N-[2-Hydroxy-5-((1 R)-1 -hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-phenyl]-formamidN- [2-hydroxy-5 - ((1R) -1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl ] formamide
• 8-Hydroxy-5-((1 R)-1 -hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}- ethyl)-1 H-chinolin-2-on • 8-Hydroxy-5-[(1 R)-1 -hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-chinolin-2-on• 8-hydroxy-5 - ((1R) -1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1H-quinoline -2-one • 8-hydroxy-5 - [(1R) -1-hydroxy-2- (6-phenethylamino-hexylamino) -ethyl] -1H-quinolin-2-one
• 5-[(1 R)-2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1 -hydroxy- ethyl]-8-hydroxy-1 H-chinolin-2-on• 5 - [(1R) -2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxyethyl] -8- hydroxy-1H-quinolin-2-one
• [3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-5-methyl-phenyl]-harnstoff • 4-((1 R)-2-{6-[2-(2,6-Dichlor-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2- hydroxymethyl-phenol• [3- (4- {6 - [(2R) -2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methyl-phenyl] -urea • 4 - ((1R) -2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
• 3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)- benzenesulfonamid• 3- (4- {6 - [(2R) -2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzenesulfonamide
• 3-(3-{7-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}- propyl)-benzenesulfonamid • 4-((1 R)-2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1 -hydroxy-ethyl)-2- hydroxymethyl-phenol• 3- (3- {7 - [(2R) -2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzenesulfonamide • 4 - ((1R) -2- {6- [4- (3-cyclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol
• Λ/-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamid • (1 R)-5-{2-[6-(2,2-Difluor-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1 H- chinolin-2-on• Λ / -1-adamantanyl-2- {3 - [(2R) -2 - ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide • (1R) -5- {2- [6- (2,2-difluoro-2-phenyl-ethoxy) -hexylamino] -1-hydroxy-ethyl} -8-hydroxy-1H-quinoline 2-one
• (R,S)-4-(2-{[6-(2,2-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenol• (R, S) -4- (2 - {[6- (2,2-Difluoro-4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• (R,S)-4-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenol• (R, S) -4- (2 - {[6- (2,2-Difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• (R,S)-4-(2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenol• (R, S) -4- (2 - {[4,4-Difluoro-6- (4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• (R,S)-4-(2-{[6-(4,4-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenol • (R,S)-5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1 -hydroxy-ethyl)-8- hydroxychinolin- 2(1 H)-on• (R, S) -4- (2 - {[6- (4,4-Difluoro-4-phenylbutoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol • (R, S ) -5- (2 - {[6- (2,2-Difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxy-ethyl) -8-hydroxyquinoline-2 (1H) -one
• (R!S)-[2-({6-[2,2-Difluor-2-(3-methylphenyl)ethoxy]hexyl}amino)-1 - hydroxyethyl]-2- (hydroxymethyl)phenol• (R ! S) - [2 - ({6- [2,2-Difluoro-2- (3-methylphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol
• 4-(1 R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1 -hydroxyethyl)-2- (hydroxymethyl)phenol• 4- (1R) -2 - {[6- (2,2-Difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4!4,5l5-tetrafluor-6-(3-phenylpropoxy)- hexyl]amino}ethyl)phenol• (R, S) -2- (hydroxymethyl) -4- (1-hydroxy-2 - {[4 , 4,5l5-tetrafluoro-6- (3-phenylpropoxy) -hexyl] amino} ethyl) phenol
• (R,S)-[5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2- hydroxyphenyl]formamid • (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2!2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]- 2- (hydroxymethyl)phenol• (R, S) - [5- (2 - {[6- (2,2-Difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide • (R, S ) -4- [2 - ({6- [2- (3-bromophenyl) -2 2-difluoroethoxy] hexyl!} amino) -1-hydroxyethyl] - 2- (hydroxymethyl) phenol
• (R, S)-N-[3-(1 ,1 -Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethyl)phenyl]-harnstoff• (R, S) -N- [3- (1,1-Difluoro-2 - {[6 - ({2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} ethyl) phenyl] urea
• 3-[3-(1 ,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl}- amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dion3- [3- (1,1-Difluoro-2 - {[6- ({2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} -amino) hexyl] oxy} ethyl) phenyl] imidazolidine-2,4-dione
• (R!S)-4-[2-({6-[2,2-Difluor-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2- (hydroxymethyl)phenol• (R ! S) -4- [2 - ({6- [2,2-Difluoro-2- (3-methoxyphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol
• 5-((1 R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1 -hydroxyethyl)-8- hydroxychinolin- 2(1 H)-on • 4-((1 R)-2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenol• 5 - ((1R) -2 - {[6- (2,2-Difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxyquinoline-2 (1H) -one • 4 - ((1R) -2 - {[4,4-Difluoro-6- (4-phenylbutoxy) hexyl] amino} -1-hydroxy-ethyl) -2- (hydroxymethyl) -phenol
• (R,S)-4-(2-{[6-(3,3-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenol • (R,S)-(2-{[6-(2,2-Difluor-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2- (hydroxymethyl)phenol• (R, S) -4- (2 - {[6- (3,3-Difluoro-3-phenylpropoxy) hexyl] amino} -1-hydroxy-ethyl) -2- (hydroxymethyl) -phenol • (R, S ) - (2 - {[6- (2,2-Difluoro-2-phenylethoxy) -4,4-difluorohexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• (R,S)-4-(2-{[6-(2,2-Difluor-3-phenylpropoxy)hexyl]amino}-1 -hydroxy ethyl)-2- (hydroxymethyl)phenol• (R, S) -4- (2 - {[6- (2,2-Difluoro-3-phenylpropoxy) hexyl] amino} -1-hydroxyethyl) -2- (hydroxymethyl) phenol
• 3-[2-(3-Chlor-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro- benzothiazol-7-yl)-ethylamino]-ethyl}-propionamid3- [2- (3-chloro-phenyl) -ethoxy] -N- (2-diethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydroxy) benzothiazol-7-yl) -ethylamino] -ethyl} -propionamide
• N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)- ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamidN- (2-diethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl) -ethylamino] -ethyl} -3- ( 2-naphthalen-1-yl-ethoxy) -propionamide
• 7-[2-(2-{3-[2-(2-Chlor-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4- hydroxy-3H-benzothiazol-2-on gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p- toluolsulfonat.• 7- [2- (2- {3- [2- (2-Chloro-phenyl) -ethyl-amino] -propylsulfanyl} -ethyl-amino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Als Anticholinergika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus: Tiotropiumsalzen, bevorzugt das Bromidsalz, Oxitropiumsalzen, bevorzugt das Bromidsalz, Flutropiumsalzen, bevorzugt das Bromidsalz, Ipratropiumsalzen, bevorzugt das Bromidsalz, Aclidiniumsalze, bevorzugt das Bromidsalz, Glycopyrroniumsalzen, bevorzugt das Bromidsalz, Trospiumsalzen, bevorzugt das Chloridsalz, Tolterodin, (3R)-1 -Phenethyl-3-(9H-xanthen-9-carbonyloxy)-1 -azoniabicyclo[2.2.2]octan-Salze . In den vorstehend genannten Salzen stellen die Kationen die pharmakologisch aktiven Bestandteile dar. Als Anionen X" können die vorstehend genannten Salze bevorzugt enthalten Chlorid, Bromid, lodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat oder p-Toluolsulfonat, wobei Chlorid, Bromid, lodid, Sulfat, Methansulfonat oder p-Toluolsulfonat als Gegenionen bevorzugt sind. Von allen Salzen sind die Chloride, Bromide, lodide und Methansulfonate besonders bevorzugt. Weiterhin genannte Verbindungen sind:Preferred anticholinergic compounds here are compounds which are selected from the group consisting of: tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R) -1 -phenethyl-3- (9H-xanthene-9-carbonyloxy) -1 -azoniabicyclo [2.2.2] octane salts. In the above-mentioned salts, the cations are the pharmacologically active ingredients. As anions X " , the above-mentioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
• 2,2-Diphenylpropionsäuretropenolester-Methobromid • 2,2-Diphenylpropionsäurescopinester-Methobromid2,2-diphenylpropionic acid tropol ester methobromide 2,2-diphenylpropionic acid copoprene methobromide
• 2-Fluor-2,2-Diphenylessigsäurescopinester-Methobromid2-fluoro-2,2-diphenylacetic acid copoprene methobromide
• 2-Fluor-2,2-Diphenylessigsäuretropenolester-Methobromid2-fluoro-2,2-diphenylacetic acid tropol ester methobromide
• 3,3',4,4'-Tetrafluorbenzilsäuretropenolester-Methobromid • 3,3',4,4'-Tetrafluorbenzilsäurescopinester-Methobromid• 3,3 ', 4,4'-tetrafluorobenzylic acid tropol ester methobromide • 3,3', 4,4'-tetrafluorobenzilate copoprene methobromide
• 4,4'-Difluorbenzilsäuretropenolester-Methobromid4,4'-Difluorobenzylic acid tropol ester methobromide
• 4,4'-Difluorbenzilsäurescopinester-Methobromid4,4'-Difluorobenzic acid copoprene methobromide
• 3,3'-Difluorbenzilsäuretropenolester-Methobromid3,3'-Difluorobenzylic acid tropol ester methobromide
• S.S'-Difluorbenzilsäurescopinester-Methobromid • θ-Hydroxy-fluoren-θ-carbonsäuretropenolester-MethobromidS.S'-Difluorobenzilic Acid Copoester Methobromide • θ-Hydroxyfluorene-O-Carboxylic Acid Sterol Ester Methobromide
• θ-Fluor-fluoren-θ-carbonsäuretropenolester-Methobromid• θ-fluoro-fluorene-θ-carboxylic acid tropol ester methobromide
• θ-Hydroxy-fluoren-θ-carbonsäurescopinester-Methobromid• θ-Hydroxy-fluorene-θ-carboxylic acid copoprene methobromide
• θ-Fluor-fluoren-θ-carbonsäurescopinester-MethobromidΘ-fluoro-fluorene---carboxylic acid copo-ester methobromide
• θ-Methyl-fluoren-θ-carbonsäuretropenolester-Methobromid • θ-Methyl-fluoren-θ-carbonsäurescopinester-Methobromid• θ-methyl-fluorene---carboxylic acid-tropol ester-methobromide • θ-methyl-fluorene---carboxylic acid-co-ester methobromide
• Benzilsäurecyclopropyltropinester-MethobromidBenzylic acid cyclopropyltropine ester methobromide
• 2,2-Diphenylpropionsäurecyclopropyltropinester-Methobromid2,2-diphenylpropionic acid cyclopropyltropine ester methobromide
• θ-Hydroxy-xanthen-θ-carbonsäurecyclopropyltropinester-MethobromidΘ-hydroxy-xanthene-θ-carboxylic acid cyclopropyltropine ester methobromide
• θ-Methyl-fluoren-θ-carbonsäurecyclopropyltropinester-Methobromid • θ-Methyl-xanthen-θ-carbonsäurecyclopropyltropinester-Methobromid• θ-Methyl-fluorene-θ-carboxylic acid cyclopropyl-tropine ester methobromide • θ-methyl-xanthene-θ-carboxylic acid cyclopropyl-tropine ester methobromide
• θ-Hydroxy-fluoren-θ-carbonsäurecyclopropyltropinester-MethobromidΘ-Hydroxy-fluorene-θ-carboxylic acid cyclopropyltropine ester methobromide
• 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester-Methobromid4,4'-Difluorobenzilate methylcyclopropyltropine ester methobromide
• θ-Hydroxy-xanthen-θ-carbonsäuretropenolester-Methobromid• θ-hydroxy-xanthene---carboxylic acid tropol ester methobromide
• θ-Hydroxy-xanthen-θ-carbonsäurescopinester-Methobromid • θ-Methyl-xanthen-θ-carbonsäuretropenolester-MethobromidΘ-hydroxy-xanthene---carboxylic acid copo-ester-methobromide-methyl-xanthene---carboxylic acid-tropol ester-methobromide
• θ-Methyl-xanthen-θ-carbonsäurescopinester-Methobromid• θ-methyl-xanthene---carboxylic acid copo-ester methobromide
• θ-Ethyl-xanthen-θ-carbonsäuretropenolester-Methobromid• θ-ethyl-xanthene---carboxylic acid tropol ester methobromide
• θ-Difluormethyl-xanthen-θ-carbonsäuretropenolester-Methobromid• θ-difluoromethyl-xanthene---carboxylic acid tropol ester methobromide
• θ-Hydroxymethyl-xanthen-θ-carbonsäurescopinester-Methobromid Die vorstehend genannten Verbindungen sind im Rahmen der vorliegenden Erfindung auch als Salze einsetzbar, in denen statt des Methobromids, die Salze Metho-X zur Anwendung gelangen, wobei X die vorstehend für X" genannten Bedeutungen haben kann.• θ-hydroxymethyl-xanthene-θ-carbonsäurescopinester methobromide The above compounds are usable in the context of the present invention as salts in which instead of the methobromide reach the salts metho-X are used, wherein X mentioned above for X " Meanings can have.
Als Corticosteroide gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus: Beclomethason, Betamethason, Budesonid, Butixocort, Ciclesonid, Deflazacort, Dexamethason, Etiprednol, Flunisolid, Fluticason, Loteprednol, Mometason, Prednisolon, Prednison, Rofleponid, Triamcinolon, Tipredane undPreferred corticosteroids here are compounds which are selected from the group consisting of: beclomethasone, betamethasone, budesonide, Butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, tipredane and
• Pregna-1 ,4-diene-3,20-dione, 6-fluoro-11-hydroxy-16,17-[(1-methylethylidene) bis(oxy)]-21- [[4-[(nitrooxy)methyl]benzoyl]oxy]-, (6-alpha,11-beta,16-alpha)- (9Cl) (NCX-1024) • 16,17-butylidenedioxy-6,9-difluoro-1 1-hydroxy-17-(methylthio)androst-4-en-3-one (RPR- 106541 ),Pregna-1,4-diene-3,20-diones, 6-fluoro-11-hydroxy-16,17 - [(1-methylethylidenes) bis (oxy)] - 21 - [[4 - [(nitrooxy) methyl ] benzoyl] oxy] -, (6-alpha, 11-beta, 16-alpha) - (9Cl) (NCX-1024) • 16,17-butylidenedioxy-6,9-difluoro-1 1-hydroxy-17- methylthio) androst-4-en-3-one (RPR-106541),
• 6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-1 1 -hydroxy-16-methyl-3-oxo-androsta-1 ,4-dien-17- carbothionsäure (S)-fluoromethylester6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -1,1-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester
• 6,9-Difluor-1 1 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1 ,4-dien-17- carbothionsäure (S)-(2-oxo-tetrahydro-furan-3S-yl)ester,6,9-Difluoro-1 1 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-) yl) ester,
• 6-alpha,9-alpha-difluoro-11 -beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17beta-carbonsäure cyanomethyl ester , gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate. Jede Bezugnahme auf6-alpha, 9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha (2, 2,3,3-tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17beta carboxylic acid cyanomethyl esters, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to
Steroide schließt eine Bezugnahme auf deren gegebenenfalls existierende Salze oder Derivate,Steroids includes a reference to their optionally existing salts or derivatives,
Hydrate oder Solvate mit ein. Beispiele möglicher Salze und Derivate der Steroide können sein:Hydrates or solvates. Examples of possible salts and derivatives of steroids may be:
Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoate, Phosphate,Alkali metal salts, such as sodium or potassium salts, sulfobenzoates, phosphates,
Isonicotinate, Acetate, Dichloroacetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.Isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
Als PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, Ariflo (Cilomilast), Tofimilast Pumafentrin , Lirimilast , Apremilast, Arofyllin, Atizoram, Oglemilast, Tetomilast, undPreferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast pumafentrin, lirimilast, apremilast, arofylline, atizoram, oglemilast, tetomilast, and
• 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamid]-8-methoxy-Chinolin (D-4418),• 5 - [(N- (2,5-dichloro-3-pyridinyl) -carboxamide] -8-methoxy-quinoline (D-4418),
• N-(3,5-dichloro-1 -oxido^-pyridinyO-carboxamidl-δ-methoxy^trifluoromethyO-Chinolin (D- 4396 (Sch-351591 )),N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3- yl]glyoxylsäureamid (AWD-12-281 (GW-842470)), 9-[(2-fluorophenyl)methyl]-N-methyl-2- (trifluoromethyl)-9H-Purin-6-amine (NCS-613),N- (3,5-dichloro-1-oxido-pyridinyl-carboxamido-δ-methoxy-trifluoromethyl-quinoline (D-4396 (Sch-351591)), N- (3,5-dichloropyrid-4-yl) - [1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] glyoxylic acid amide (AWD-12-281 (GW-842470)), 9 - [(2-fluorophenyl) methyl] -N-methyl-2 - (trifluoromethyl) -9H-purine-6-amine (NCS-613),
• 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-Pyridine (CDP-840),4 - [(2R) -2- [3- (cyclopentyloxy) -4-methoxyphenyl] -2-phenylethyl] pyridine (CDP-840),
• N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1 ,4]benzodiazepin-3-yl]- 4-Pyridinecarboxamide (PD-168787),N- [(3R) -3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo [3,2,1-jk] [1,4] benzodiazepin-3-yl] - 4-pyridinecarboxamide (PD-168787),
• 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1 -naphthalenyl]-1 -(2-methoxyethyl)-2(1 H)-Pyridinone (T-440), • 2-[4-[6!7-diethoxy-2!3-bis(hydroxymethyl)-1 -naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1 (2H)- Phthalazinone (T-2585),4- [6,7-diethoxy-2,3-bis (hydroxymethyl) -1-naphthalenyl] -1- (2-methoxyethyl) -2 (1H) -pyridinone (T-440) • 2- [4- [6 ! 7-diethoxy-2 ! 3-bis (hydroxymethyl) -1 -naphthalenyl] -2-pyridinyl] -4- (3-pyridinyl) -1 (2H) - phthalazinone (T-2585),
• (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V- 1 1294A),• (3- (3-cyclopenyloxy-4-methoxybenzyl) -6-ethylamino-8-isopropyl-3H-purines (V-1294A),
• beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 ,3-dihydro-1 ,3-dioxo-2H-lsoindole-2- propanamid (CDC-801 ),Beta [3- (cyclopentyloxy) -4-methoxyphenyl] -1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),
• lmidazo[1 ,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl- (D- 22888)Imidazo [1,5-a] pyrido [3,2-e] pyrazine-6 (5H) -one, 9-ethyl-2-methoxy-7-methyl-5-propyl- (D-22888)
• 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-, (3S,5S)-2-Piperidinon (HT-0712), • 4-[1 -[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1 -oxido-4-pyridinyl)ethyl]-alpha,alpha- bis(trifluoromethyl)-Benzenemethanol (L-826141 )• 5- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-methylphenyl) methyl] -, (3S, 5S) -2-piperidinone (HT-0712), 4- [1- [3 , 4-bis (difluoro-methoxy) -phenyl] -2- (3-methyl-1-oxo-4-pyridinyl) -ethyl] -alpha, alpha- bis (trifluoromethyl) -benzene-methanol (L-826141)
• N-(3,5-Dichloro-1 -oxo-pyridin-4-yl)-4-difluormethoxy-3-cyclopropylmethoxybenzamidN- (3,5-dichloro-1-oxopyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide
• (-)p-[(4aR*,10öS*)-9-Ethoxy-1 ,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[s][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid • (R)-(+)-1 -(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon• (-) p - [(4aR * , 10oS * ) -9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [1, 6] naphthyridine 6-yl] -N, N-diisopropylbenzamide • (R) - (+) - 1 - (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone
• 3-(Cyclopentyloxy-4-methoxyphenyl)-1 -(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2- pyrrolidon• 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidone
• cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carbonsäure]Cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]
• 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 - on2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one
• cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-1 -ol]Cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]
• (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat• (R) - (+) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate
• (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat• (S) - (-) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate
• 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9/-/-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3-a]pyridin • 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(te/f-butyl)-9/-/-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3- a]pyridin, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9 / - / - pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a ] pyridine • 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (te / f-butyl) -9 / - / - pyrazolo [3,4-c] -1, 2,4-triazolo [4 , 3- a] pyridine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Cetuximab, Trastuzumab, Panitumumab ( = ABX-EGF), Mab ICR-62, Gefitinib, Canertinib, Erlotinib, undPreferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, panitumumab (= ABX-EGF), Mab ICR-62, gefitinib, canertinib, erlotinib, and
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-7- cyclopropylmethoxy-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -yl] -amino} -7-cyclopropylmethoxy-quinazoline .
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N -diethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline .
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline .
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-7- cyclopentyloxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 - yl]amino}-7-cyclopropylmethoxy-chinazolin• 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy -quinazoline, • 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo 2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1- yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazolin• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2] buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2- buten-1 -yOamino^-cyclopropylmethoxy-chinazolin• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2] butene-1-y-amino-cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-chinazolin• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten- 1-yl}amino)-7-cyclopropylmethoxy-chinazolin, • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- cyclopentyloxy-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1 -yl] amino} -7-cyclopentyloxy-quinazoline,
• 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1- yl]amino}-7-cyclopropylmethoxy-chinazolin,• 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) amino] -1-oxo-2-butene 1-yl] amino} -7-cyclopropylmethoxyquinazoline,
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1 -oxo-2-buten-1 - yl}amino)-7-cyclopropylmethoxy-chinazolin,• 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2-butene 1-yl) amino) -7-cyclopropylmethoxy quinazoline,
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2-buten-1 - yl}amino)-7-cyclopropylmethoxy-chinazolin,• 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl) amino) -7-cyclopropylmethoxy quinazoline,
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1 -oxo-2- buten-i-ylϊamino^-cyclopropylmethoxy-chinazolin, • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- ((R)-tetrahydrofuran-3-yloxy)-chinazolin,• 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-butene i-ylϊamino ^ -cyclopropylmethoxy-quinazoline, • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino} -7- ((R) -tetrahydrofuran-3-yloxy) quinazoline,
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- ((S)-tetrahydrofuran-3-yloxy)-chinazolin• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ((S. ) -tetrahydrofuran-3-yloxy) -quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten- 1 -yl}amino)-7-cyclopentyloxy-chinazolin, • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo-2-buten-1 - yl]amino}-7-cyclopentyloxy-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene-1 - yl} amino) -7-cyclopentyloxy-quinazoline, • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7 -cyclopentyloxy-quinazoline,
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- [(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- [(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [(R ) - (tetrahydrofuran-2-yl) methoxy] quinazoline, • 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-one] buten-1-yl] amino} -7- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin,• 4 - [(3-ethynyl-phenyl) -amino] -6,7-bis (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]- chinazolin, • 4-[(R)-(1 -Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,• 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, • 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine,
• 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-ethoxy-chinolin,3-Cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 ethoxy-quinoline,
• 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin, • 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 - yl]amino}-7-methoxy-chinazolin,• 4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline • 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2 -but-1-yl] amino} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-7- [(tetrahydrofuran-2-yl)methoxy]-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- [(tetrahydrofuran -2-yl) methoxy] -quinazoline,
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1- yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin,• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) -amino] -1-oxo-2-butene-1 yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 - yl]amino}-chinazolin,4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7- methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)- (tetrahydrofuran-2-yl)methoxy]-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)- (tetrahydrofuran-2-yl)methoxy]-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7- methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy- chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7- methoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro -phenyl) -amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino- ethoxy)-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy- chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl- aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro -phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] -N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}- cyclohexan-1 -yloxy)-7-methoxy-chinazolin ,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 - yloxy) -7-methoxyquinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}- cyclohexan-1 -yloxy)-7-methoxy- chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane-1 - yloxy) -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-ethoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy- ethoxy)-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy- ethoxy)-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy- chinazolin, • 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, • 4 - [(3-ethynyl-phenyl ) amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazolin,• 4 - [(3-ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}- cyclohexan-i-yloxy^-methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl- aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N-methyl-amino} -cyclohexane-i- yloxy-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) -carbonyl] - N-methyl-amino-cyclohexan-1-yloxy-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7- methoxy-chinazolin,• 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline .
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2- methoxy-ethoxy)-chinazolin,4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin,• 4 - [(3-ethynyl-phenyl) -amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin, • 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin,• 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-Methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy- chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1 -yloxy)-7-methoxy- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro -phenyl) amino] -6- (cis-4-methylamino-cyclohexan-1-ylxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexan-1-yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} - 7-methoxy-quinazoline,
• 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazolin, • 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, • 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy- chinazolin,• 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, • 4 - [(3-ethynyl-phenyl) -amino] -6- [1- ( 2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] piperidin-4-yloxy} -7-methoxyquinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin- 4-yloxy}-7-methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7 -methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} - 7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl ) carbonyl] - piperidin-4-yloxy} -7-methoxyquinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1- yloxy]-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1 -yloxy)-7-methoxy- chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, • 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methyl-amino-cyclohexane-1-oxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)- cyclohexan-1-yloxy]-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy- chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}- cyclohexan-1-yloxy)-7-methoxy-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexane-1 yloxy) -7-methoxy-quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)- (tetrahydrofuran-2-yl)methoxy]-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline .
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-chinazolin,4-[(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline,
• 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-ethoxy-chinolin ; • [4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}- 7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline ,3-Cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 -ethoxy-quinoline; • [4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (homomorpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} - 7 [(S) - (tetrahydrofuran-3-yl) oxy] quinazolines,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]- piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin, • 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6- [(vinylcarbonyl)amino]-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazin-1-yl } -ethoxy) -6 - [(vinylcarbonyl) amino] quinazoline, • 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2- oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6- [(vinylcarbonyl)amino]-chinazolin,• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [( vinylcarbonyl) amino] -quinazoline,
• 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6- [(vinylcarbonyl)amino]-chinazolin, und• 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [( vinylcarbonyl) amino] quinazoline, and
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-chinazolin, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate. Erfindungsgemäß bevorzugt sind Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.• 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N- [(ethoxycarbonyl) methyl] amino} -1-oxo 2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
Als LTD4-Rezeptor Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, und (E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1 H-tetrazol-5-yl)-4H-1 - benzopyran-4-one (MEN-91507)Preferred LTD4 receptor antagonists here are compounds which are selected from the group consisting of montelukast, pranlukast, zafirlukast, and (E) -8- [2- [4- [4- (4-fluorophenyl) butoxy] phenyl ] ethenyl] -2- (1H-tetrazol-5-yl) -4H-1-benzopyran-4-one (MEN-91507)
• 4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]- buttersäure (MN-O01 )4- [6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] -butyric acid (MN-O01)
• 1-(((R)-(3-(2-(6,7-Difluor-2-chinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2- propyl)phenyl)thio)methylcyclopropan-essigsäure,• 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,
• 1 -(((1 (R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1 -hydroxy-1 - methylethyl)phenyl)propyl)thio)methyl)cyclopropanessigsäure • [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]essigsäure gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat. Unter Salzen oder Derivaten zu deren Bildung die LTD4-Rezeptor Antagonisten gegebenenfalls in der Lage sind, werden beispielsweise verstanden: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Erdalkalisalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.• 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid • [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention. Among salts or derivatives to their Formation the LTD4 receptor antagonists are optionally able to be understood, for example, alkali metal salts such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
Als Histamin H1 Rezeptor Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Epinastin, Cetirizin, Azelastin, Fexofenadin, Levocabastin, Loratadin, Mizolastin, Ketotifen, Emedastin, Dimetinden, Clemastin, Bamipin, Cexchlorpheniramin, Pheniramin, Doxylamin, Chlorphenoxamin, Dimenhydrinat, Diphenhydramin, Promethazin, Ebastin, Olopatadine, Desloratidin und Meclozin, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind die Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat.The histamine H1 receptor antagonists used are preferably compounds selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, Chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, olopatadine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Als PAF-Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Lexipafant und 4-(2-Chlorphenyl)-9-methyl-2- [3(4-morpholinyl)-3-propanon-1 -yl]-6H-thieno-[3,2-f]-[1 ,2,4]triazolo[4,3-a][1 ,4]diazepinPreferred PAF antagonists here are compounds which are selected from the group consisting of lexipafant and 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl ] -6H-thieno [3,2-f] - [1,2,4] triazolo [4,3-a] [1,4] diazepine
• 6-(2-Chlorphenyl)-8,9-dihydro-1 -methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclo-penta-
[4,5]thieno-[3,2-f][1 ,2,4]triazolo[4,3-a][1 ,4]diazepin, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat[4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention
Als Dopamin-Rezeptor Agonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Bromocriptin, Cabergolin, Alpha-Dihydroergocryptin, Lisurid, Pergolid, Pramipexol, Roxindol, Ropinirol, Talipexol, Tergurid und Viozan, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate. Erfindungsgemäß bevorzugt sind Säureadditionssalze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat Als Substanzen bevorzugter PI3 Kinase Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus • 5-(Quinoxalin-6-ylmethylene)thiazolidine-2,4-dione (AS-605240),Preferred dopamine receptor agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates, Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate Preferred substances of preferred PI3 kinase antagonists are compounds which are selected from the group consisting of Quinoxalin-6-ylmethylene) thiazolidine-2,4-diones (AS-605240),
• 2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-Quinazolinone (C- 871 14),2-[(6-amino-9H-purin-9-yl) methyl] -5-methyl-3- (2-methylphenyl) -4 (3H) -quinazolinone (C-871 14),
• 2-Methyl-2-[4-[3-methyl-2-oxo-8-(chinolin-3-yl)-2,3-dihydroimidazo[4,5-c]chinolin-1- yl]phenyl]propionitrile (BEZ-235), gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Prodrugs, Solvate oder Hydrate.2-Methyl-2- [4- [3-methyl-2-oxo-8- (quinolin-3-yl) -2,3-dihydroimidazo [4,5-c] quinolin-1-yl] -phenyl] -propionitrile (BEZ-235), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.
Verwendete Begriffe und DefinitionenUsed terms and definitions
Unter dem Begriff "gegebenenfalls substituiert" wird im Rahmen der Erfindung die genannte Gruppe verstanden, die gegebenenfalls mit einem niedermolekularen Rest substituiert ist. Als niedermolekulare Reste werden als chemisch sinnvoll anzusehende Gruppen verstanden, bestehende aus 1-25 Atomen. Bevorzugt haben solche Gruppen keinen negativen Effekt auf die pharmakologische Wirksamkeit der Verbindungen. Beispielsweise können die Gruppen umfassen:In the context of the invention, the term "optionally substituted" is understood to mean the abovementioned group which is optionally substituted by a lower-molecular radical. Low-molecular radicals are understood to be chemically meaningful groups consisting of 1-25 atoms. Preferably, such groups have no negative effect on the pharmacological activity of the compounds. For example, the groups may include:
• Gerade oder verzweigte Kohlenstoffketten, gegebenenfalls unterbrochen durch Heteroatome, gegebenenfalls substituiert mit Ringen, Heteroatomen oder anderen gängigen funktionellen Gruppen.Straight or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups.
• Aromatische oder nicht-aromatische Ringsysteme bestehend aus Kohlenstoffatomen und gegebenenfalls Heteroatomen, die wiederum substituiert sein können mit funktionellen Gruppen.Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.
• Mehrere aromatische oder nicht-aromatische Ringsysteme bestehend aus Kohlenstoffatomen und gegebenenfalls Heteroatomen, die durch eine oder mehrereSeveral aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which can be replaced by one or more
Kohlenstoffketten, gegebenenfalls unterbrochen durch Heteroatome, gegebenenfalls substituiert mit Heteroatomen oder anderen gängigen funktionellen Gruppen verknüpft sein können.Carbon chains, optionally interrupted by heteroatoms, optionally substituted with heteroatoms or other common functional groups may be linked.
Ebenfalls mit vom Gegenstand dieser Erfindung umfasst sind die erfindungsgemäßen Verbindungen, einschließlich deren Salze, in denen ein oder mehrere Wasserstoffatome, beispielsweise ein, zwei, drei, vier oder fünf Wasserstoffatome, durch Deuterium ausgetauscht sind.Also included in the subject matter of this invention are the compounds according to the invention, including their salts, in which one or more hydrogen atoms, for example, one, two, three, four or five hydrogen atoms are replaced by deuterium.
Sofern in der Strukturformel eines Substituenten ein einseitig offener Bindestrich "-" verwendet wird, ist dieser Bindestrich als Verknüpfungspunkt zum Rest des Moleküls zu verstehen. Der Substituent tritt an die Stelle der entsprechenden Reste Ra, Rb, etc.. Sofern in der Bezeichnung oder Strukturformel eines Substituenten kein einseitig offener Bindestrich verwendet wird, ergibt sich der Verknüpfungspunkt zum Rest des Moleküls eindeutig aus der Bezeichnung oder Strukturformel selbst.If in the structural formula of a substituent a one-sided open hyphen "-" is used, this hyphen is to be understood as a connection point to the remainder of the molecule. The substituent takes the place of the corresponding radicals R a , R b , etc .. If in the name or structural formula of a substituent no unilaterally open hyphen is used, the point of attachment to the rest of the molecule clearly results from the name or structural formula itself.
Verbindungen der allgemeinen Formel (I) können Säuregruppen besitzen, hauptsächlich Carboxylgruppen, und/oder basische Gruppen wie z.B. Aminofunktionen. Verbindungen der allgemeinen Formel (I) können deshalb als innere Salze, als Salze mit pharmazeutisch verwendbaren anorganischen Säuren wie Salzsäure, Schwefelsäure, Phosphorsäure, Sulfonsäure oder organischen Säuren (wie beispielsweise Maleinsäure, Fumarsäure, Zitronensäure, Weinsäure oder Essigsäure) oder als Salze mit pharmazeutisch verwendbaren Basen wie Alkali- oder Erdalkalimetallhydroxiden oder Carbonaten, Zink- oder Ammoniumhydroxiden oder organischen Aminen wie z.B. Diethylamin, Triethylamin, Triethanolamin u.a. vorliegen. Zur Darstellung der Alkali- und Erdalkalimetallsalze der Verbindung der Formel (I), kommen vorzugsweise die Alkali- und Erdalkalihydroxide und - hydride in Betracht, wobei die Hydroxide und Hydride der Alkalimetalle, besonders des Natriums und Kaliums bevorzugt, Natrium- und Kaliumhydroxid besonders bevorzugt sind, (siehe auch Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sei., (1977), 6(3, 1-19)Compounds of general formula (I) may have acid groups, mainly carboxyl groups, and / or basic groups, e.g. Amino functions. Compounds of general formula (I) can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable Bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available. For the preparation of the alkali metal and alkaline earth metal salts of the compound of the formula (I), preference is given to the alkali metal hydroxides and alkaline earth hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium being preferred, sodium and potassium hydroxide being particularly preferred , (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 6 (3, 1-19)
Wie vorstehend genannt, können die Verbindungen der allgemeinen Formel (I) in ihre Salze, insbesondere für die pharmazeutische Anwendung, in ihre pharmakologisch unbedenklichen Säureadditionssalze mit einer anorganischen oder organischen Säure, überführt werden. Als Säuren kommen hierfür beispielsweise Bernsteinsäure, Bromwasserstoffsäure, Essigsäure, Fumarsäure, Maleinsäure, Methansulfonsäure, Milchsäure, Phosphorsäure, Salzsäure, Schwefelsäure, Weinsäure oder Zitronensäure in Betracht. Ferner können Mischungen der vorgenannten Säuren eingesetzt werden.As mentioned above, the compounds of the general formula (I) can be converted into their salts, in particular for the pharmaceutical application, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids are succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. Furthermore, mixtures of the abovementioned acids can be used.
Gegenstand der Erfindung sind die jeweiligen Verbindungen gegebenenfalls in Form der einzelnen Diastereomeren, Mischungen der einzelnen Diastereomeren und/oder der einzelnen Enantiomeren, Mischungen der einzelnen Enantiomeren oder Racemate, in Form derThe invention relates to the respective compounds, optionally in the form of the individual diastereomers, mixtures of the individual diastereomers and / or the individual enantiomers, mixtures of the individual enantiomers or racemates, in the form of
Tautomere sowie in Form der freien Basen oder der entsprechenden Säureadditionssalze mit pharmakologisch unbedenklichen Säuren - wie beispielsweise Säureadditionssalze mit Halogenwasserstoffsäuren - beispielsweise Chlor- oder Bromwasserstoffsäure - oder organischen Säuren - wie beispielsweise Weinsäure, Fumarsäure, Zitronensäure oder Methansulfonsäure.Tautomers and in the form of the free bases or the corresponding acid addition salts pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example, hydrochloric or hydrobromic acid - or organic acids - such as tartaric acid, fumaric acid, citric acid or methanesulfonic acid.
"Schutzgruppen" in Sinne der vorliegenden Erfindung sind als Sammelbezeichnung für solche organische Reste zu verstehen, mit denen bestimmte funktionelle Gruppen eines mehrere aktive Zentren enthaltenden Moleküls vorübergehend gegen den Angriff von Reagenzien geschützt werden können, so dass Reaktionen nur an den gewünschten (ungeschützten) Stellen stattfinden. Die Schutzgruppen sollen unter milden Bedingungen selektiv einzuführen sein. Sie müssen für die Dauer des Schutzes unter allen Bedingungen der durchzuführenden Reaktionen und Reinigungsoperationen stabil sein; Racemisierungen und Epimerisierungen müssen unterdrückt werden. Schutzgruppen sollen wieder unter milden Bedingungen selektiv und idealerweise mit hoher Ausbeute abspaltbar sein. Die Wahl einer geeigneten Schutzgruppe, die Bedingungen zur Umsetzung (Lösungsmittel, Temperatur, Dauer, etc.) aber auch die Möglichkeiten eine Schutzgruppe wieder zu entfernen sind im Stand der Technik bekannt (z.B. Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN: 3131370033)."Protecting groups" in the meaning of the present invention are to be understood as a collective term for such organic radicals with which certain functional groups of a molecule containing several active sites can be temporarily protected against the attack of reagents so that reactions take place only at the desired (unprotected) sites occur. The protecting groups should be selectively introduced under mild conditions. They must be stable for the duration of the protection under all conditions of the reactions and cleaning operations to be performed; Racemizations and epimerizations must be suppressed. Protective groups should again be cleavable under mild conditions selectively and ideally with high yield. The choice of a suitable protective group, the conditions for the reaction (solvent, temperature, duration, etc.) but also the possibilities to remove a protective group are known in the art (eg Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN: 3131370033).
Unter einem "organischen Lösungsmittel" wird im Rahmen der Erfindung ein organsicher, niedermolekularer Stoff verstanden, der andere organische Stoffe auf physikalischem Wege zur Lösung bringen kann. Voraussetzung für die Eignung als Lösungsmittel ist, dass sich beim Lösungsvorgang weder der lösende noch der gelöste Stoff chemisch verändern, dass also die Komponenten der Lösung durch physikalische Trenn verfahren wie Destillation, Kristallisation, Sublimation, Verdunstung, Adsorption in der Originalgestalt wieder gewonnen werden können. Aus verschiedenen Gründen können nicht nur die reinen Lösungsmittel, sondern Gemische, die die Lösungseigenschaften vereinigen verwendet werden. Beispielsweise seinen genannt:In the context of the invention, an "organic solvent" is understood to mean an organic, low-molecular substance which can bring other organic substances to solution by physical means. Prerequisite for the suitability as a solvent is that during the dissolution process, neither the solvent nor the solute chemically change, so that the components of the solution by physical separation methods such as distillation, crystallization, sublimation, evaporation, adsorption can be recovered in its original form. For various reasons, not only the pure solvents but mixtures that combine the dissolution properties can be used. For example, called his:
• Alkohole, bevorzugt Methanol, Ethanol, Propanol, Butanol, Octanol, Cyclohexanol;Alcohols, preferably methanol, ethanol, propanol, butanol, octanol, cyclohexanol;
• Glykole, bevorzugt Ethylenglykol, Diethylenglykol; • Ether / Glykolether, bevorzugt Diethylether, tert-Butylmethylether, Dibutylether, Anisol, Dioxan, Tetrahydrofuran, Mono-, Di-, Tri-, Polyethylenglykolether;Glycols, preferably ethylene glycol, diethylene glycol; Ether / glycol ethers, preferably diethyl ether, tert-butyl methyl ether, dibutyl ether, anisole, dioxane, tetrahydrofuran, mono-, di-, tri-, polyethylene glycol ethers;
• Ketone, bevorzugt Aceton, Butanon, Cyclohexanon;Ketones, preferably acetone, butanone, cyclohexanone;
• Ester, bevorzugt Essigsäureester, Glykolester;Esters, preferably acetic acid esters, glycol esters;
• Amide u.a. Stickstoff-Verbindungen, bevorzugt Dimethylformamid, Pyridin, N- Methylpyrrolidon, Acetonitril;• Amide and others Nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone, acetonitrile;
• Schwefel-Verbindungen, bevorzugt Schwefelkohlenstoff, Dimethylsulfoxid, Sulfolan; • Nitro-Verbindungen bevorzugt Nitrobenzol;Sulfur compounds, preferably carbon disulfide, dimethylsulfoxide, sulfolane; Nitro compounds preferably nitrobenzene;
• Halogenkohlenwasserstoffe, bevorzugt Dichlormethan, Chloroform, Tetrachlormethan, Tri-, Tetrachlorethen, 1 ,2-Dichlorethan, Chlorfluorkohlenstoffe;Halogenated hydrocarbons, preferably dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, tetrachloroethene, 1,2-dichloroethane, chlorofluorocarbons;
• aliphatische oder alicyclische Kohlenwasserstoffe, bevorzugt Benzine, Petrolether, Cyclohexan, Methylcyclohexan, Decalin, Terpen-L; oderAliphatic or alicyclic hydrocarbons, preferably benzines, petroleum ethers, cyclohexane, methylcyclohexane, decalin, terpene-L; or
• aromatische Kohlenwasserstoffe, bevorzugt Benzol, Toluol, o-Xylol, m-Xylol, p-Xylol; oder entsprechende Gemische davon.Aromatic hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene, p-xylene; or corresponding mixtures thereof.
Die Bezeichnung diastereomerenrein beschreibt im Rahmen der vorliegenden Erfindung Verbindungen der Formel (I), die in einer Diastereomerenreinheit von wenigstens 85%de, bevorzugt von wenigstens 90%de, besonders bevorzugt von > 95%de vorliegen. Die Bezeichnung de (diastereomeric excess) ist im Stand der Technik bekannt und beschreibt den optischen Reinheitsgrad diastereomerer Verbindungen.The term diastereomerically pure in the context of the present invention describes compounds of the formula (I) which are present in a diastereomeric purity of at least 85% de, preferably of at least 90% de, particularly preferably> 95% de. The term de (diastereomeric excess) is known in the art and describes the optical purity of diastereomeric compounds.
Die Bezeichnung enantiomerenrein beschreibt im Rahmen der vorliegenden Erfindung Verbindungen der Formel (I), die in einer Enantiomerenreinheit von wenigstens 85%ee, bevorzugt von wenigstens 90%ee, besonders bevorzugt von > 95%ee vorliegen. Die Bezeichnung ee (enantiomeric excess) ist im Stand der Technik bekannt und beschreibt den optischen Reinheitsgrad chiraler Verbindungen.The term enantiomerically pure in the context of the present invention describes compounds of the formula (I) which are present in an enantiomeric purity of at least 85% ee, preferably of at least 90% ee, particularly preferably of> 95% ee. The term ee (enantiomeric excess) is known in the art and describes the optical purity of chiral compounds.
Unter dem Begriff "d-6-Alkyl" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkylgruppen mit 1 bis 6 Kohlenstoffatomen verstanden und unter dem Begriff "C-M-Alkyl" verzweigte und unverzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen verstanden. Bevorzugt sind Alkylgruppen mit 1 bis 4 Kohlenstoffatomen, besonders bevorzugt Alkylgruppen mit 1 bis 2 Kohlenstoffatomen. Beispielsweise werden hierfür genannt: Methyl, Ethyl, n-Propyl, /so-Propyl, n-Butyl, /so-Butyl, sec-Butyl, te/f-Butyl, n- Pentyl, /so-Pentyl, neo-Pentyl oder Hexyl. Gegebenenfalls werden für die vorstehend genannten Gruppen auch die Abkürzungen Me, Et, n-Pr, /-Pr, n-Bu, /-Bu, t-Bu, etc. verwendet. Sofern nicht anders beschrieben, umfassen die Definitionen Propyl, Butyl, Pentyl und Hexyl alle denkbaren isomeren Formen der jeweiligen Reste. So umfasst beispielsweise Propyl n-Propyl und /so- Propyl, Butyl umfasst /so-Butyl, sec-Butyl und te/f-Butyl etc.The term "d- 6 alkyl" (including those which are part of other groups) branched to and understood unbranched alkyl groups having 1 to 6 carbon atoms, and branched by the term "C-M-alkyl" and unbranched alkyl groups having 1 to 4 carbon atoms Understood. Preferred are alkyl groups having 1 to 4 carbon atoms, more preferably alkyl groups having 1 to 2 carbon atoms. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise specified, the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / f-butyl, etc.
Unter dem Begriff "C3-7-Cycloalkyl" (auch soweit sie Bestandteil anderer Reste sind) werden cyclische Alkylgruppen mit 3 oder 7 Kohlenstoffatomen verstanden. Beispielsweise werden hierfür genannt: Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder Cycloheptyl. Soweit nicht anders beschrieben, können die cyclischen Alkylgruppen substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, tert- Butyl, Hydroxy und Fluor.The term "C 3-7 -cycloalkyl" (including those which are part of other groups) means cyclic alkyl groups having 3 or 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with one or more multiple radicals selected from the group consisting of methyl, ethyl, / so-propyl, tert-butyl, hydroxy and fluorine.
Unter dem Begriff "Aryl" (auch soweit sie Bestandteil anderer Reste sind) werden aromatische Ringsysteme mit 6, 10 oder 14 Kohlenstoffatomen verstanden. Beispielsweise werden hierfür genannt: Phenyl, Naphthyl, Anthracenyl oder Phenanthrenyl, bevorzugter Arylrest ist Phenyl.The term "aryl" (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6, 10 or 14 carbon atoms. Examples include: phenyl, naphthyl, anthracenyl or phenanthrenyl, more preferably aryl is phenyl.
"Halogen" steht im Rahmen der vorliegenden Erfindung für Fluor, Chlor, Brom oder lod. Sofern nicht gegenteilig angegeben, gelten Fluor, Chlor und Brom als bevorzugte Halogene."Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
Herstellungsverfahrenproduction method
Zur Herstellung von Verbindungen der allgemeinen Formel (I) sind beispielsweise folgende Verfahren geeignet:For the preparation of compounds of the general formula (I), for example, the following processes are suitable:
a) Umsetzung einer Verbindung der allgemeinen Formela) reaction of a compound of the general formula
mit einer Verbindung der allgemeinen Formel with a compound of the general formula
in der Ra wie eingangs erwähnt definiert ist und Z1 eine Austrittsgruppe wie ein Halogenatom, z.B. ein Chlor- oder Bromatom, eine Sulfonyloxygruppe wie eine Methansulfonyloxy- oder p- Toluolsulfonyloxygruppe oder eine Hydroxygruppe darstellt.in the R a is as defined above defined and Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group such as a Methansulfonyloxy- or p-toluenesulfonyloxy or a hydroxy group.
Mit einer Verbindung der allgemeinen Formel (III), in der Z1 ein Halogenatom oder eine Sulfonyloxygruppe darstellt, erfolgt die Umsetzung zweckmäßigerweise in einem Lösungsmittel wie Ethanol, Isopropanol, Acetonitril, Toluol, Tetrahydrofuran, Dioxan, Dimethylformamid, Dimethylsulfoxid oder N-Methylpyrrolidinon, vorzugsweise in Gegenwart einer Base wie Kaliumcarbonat, Kalium-tert-butylat, Natriumhydrid oder N-Ethyl-diisopropylamin, bei Temperaturen im Bereich von 200C bis 1600C, beispielsweise bei Temperaturen im Bereich von 60°C bis 140°C.With a compound of the general formula (III) in which Z 1 represents a halogen atom or a sulphonyloxy group, the reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, preferably in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisopropylamine, at temperatures in the range of 20 0 C to 160 0 C, for example at temperatures in the range of 60 ° C to 140 ° C.
Mit einer Verbindung der allgemeinen Formel III, in der Z1 eine Hydroxygruppe darstellt, wird die Umsetzung in Gegenwart eines wasserentziehenden Mittels, vorzugsweise in Gegenwart eines Phosphins und eines Azodicarbonsäurederivates wie z.B.With a compound of general formula III in which Z 1 represents a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as
Triphenylphosphin/Azodicarbonsäurediethylester, zweckmäßigerweise in einem Lösungsmittel wie Methylenchlorid, Acetonitril, Tetrahydrofuran, Dioxan, Toluol oder Ethylenglycoldiethylether bei Temperaturen zwischen -50 und 1500C, vorzugsweise jedoch bei Temperaturen zwischen -20 und 80°C, durchgeführt.Triphenylphosphine / Azodicarbonsäurediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or Ethylenglycoldiethylether at temperatures between -50 and 150 0 C, but preferably at temperatures between -20 and 80 ° C, carried out.
b) Umsetzung einer Verbindung der allgemeinen Formel (IV)b) Reaction of a compound of the general formula (IV)
in der Ra wie eingangs erwähnt definiert ist, mit einem Halogenierungsmittel, beispielsweise einem Säurehalogenid wie Thionylchlorid, Thionylbromid, Phosphortrichlorid, Phosphorpentachlorid, Phosphoroxychlorid, oder Triphenylphosphin/Tetrachlorkohlenstoff oder Triphenylphosphin/N-Chlorsuccinimid zu einer Zwischenverbindung der allgemeinen Formel (V), in which R a is as defined above, with a halogenating agent, for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, or triphenylphosphine / carbon tetrachloride or triphenylphosphine / N-chlorosuccinimide to give an intermediate compound of general formula (V),
in der Ra wie eingangs erwähnt definiert ist und Z2 ein Halogenatom wie ein Chlor- oder Bromatom darstellt,in which R a is defined as mentioned above and Z 2 represents a halogen atom, such as a chlorine or bromine atom,
und anschließender Umsetzung mit einer Verbindung der Formel (VI),and subsequent reaction with a compound of the formula (VI),
(VI), oder dessen Salzen. (VI), or its salts.
Die Umsetzung mit dem Halogenierungsmittel wird gegebenenfalls in einem Lösungsmittel wie Methylenchlorid, Chloroform, Acetonitril oder Toluol und gegebenfalls in Gegenwart einer Base wie N,N-Diethylanilin, Triethylamin oder N-Ethyl-diisopropylamin bei Temperaturen im Bereich von 200C bis 1600C, vorzugsweise von 40°C bis 1200C durchgeführt. Vorzugsweise wird die Reaktion jedoch mit Thionylchlorid und katalytischen Mengen an Dimethylformamid bei der Siedetemperatur des Reaktionsgemisches oder mit Phosphoroxychlorid in Acetonitril in Gegenwart von Triethylamin bei der Siedetemperatur des Reaktionsgemisches oder mit Triphenylphosphin/Tetrachlorkohlenstoff oder mit Triphenylphosphin/N-Chlorsuccinimid in Acetonitril durchgeführt.The reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline, triethylamine or N-ethyl-diisopropylamine at temperatures in the range of 20 0 C to 160 0 C. , preferably carried out from 40 ° C to 120 0 C. Preferably, however, the reaction is carried out with thionyl chloride and catalytic amounts of dimethylformamide at the boiling temperature of the reaction mixture or with phosphorus oxychloride in acetonitrile in the presence of triethylamine at the boiling temperature of the reaction mixture or with triphenylphosphine / carbon tetrachloride or with triphenylphosphine / N-chlorosuccinimide in acetonitrile.
Die Umsetzung der Verbindung der allgemeinen Formel (VI) mit der Verbindung der allgemeinen Formel (VII) oder deren Salzen erfolgt zweckmäßigerweise in einem Lösungsmittel wie Ethanol, Isopropanol, Acetonitril, Dioxan oder Dimethylformamid, gegebenfalls in Gegenwart einer Base wie Kaliumcarbonat, Triethylamin oder N-Ethyl-diisopropylamin, bei Temperaturen im Bereich von 20°C und 160°C, vorzugsweise von 600C bis 120°C. Vorzugsweise wird die Reaktion jedoch in Isopropanol bei der Siedetemperatur des Reaktionsgemisches durchgeführt. Die Umsetzung einer Verbindung der allgemeinen Formel (IV) zu einer Verbindung der allgemeinen Formel (I) kann auch als Eintopfreaktion, beispielsweise in Acetonitril in Gegenwart von Triethylamin, durchgeführt werden.The reaction of the compound of the general formula (VI) with the compound of the general formula (VII) or its salts is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, if appropriate in the presence of a base such as potassium carbonate, triethylamine or N- Ethyl diisopropylamine, at temperatures in the range of 20 ° C and 160 ° C, preferably from 60 0 C to 120 ° C. Preferably, however, the reaction is carried out in isopropanol at the boiling temperature of the reaction mixture. The reaction of a compound of the general formula (IV) to give a compound of the general formula (I) can also be carried out as a one-pot reaction, for example in acetonitrile in the presence of triethylamine.
c) Umsetzung einer Verbindung der allgemeinen Formelc) reaction of a compound of the general formula
mit einer Verbindung der allgemeinen Formelwith a compound of the general formula
H-Ra ,(VIII) in derHR a , (VIII) in the
Ra wie eingangs erwähnt definiert ist, in Gegenwart eines Reduktionsmittels.R a is as defined above, in the presence of a reducing agent.
Die reduktive Aminierung wird beispielsweise in einem Lösemittel wie Dichlormethan, 1 ,2- Dichlorethan, Methanol, Ethanol, Tetrahydrofuran oder Dioxan in Gegenwart eines Reduktionsmittels wie Natrium-triacetoxyborhydrid oder Natrium-cyanborhydrid, gegebenenfalls in Gegenwart von Essigsäure bei Temperaturen zwischen 00C und 800C durchgeführt. Die reduktive Aminierung kann auch mit Wasserstoff in Gegenwart eines Katalysators wie Palladium auf Aktivkohle oder Platinoxid erfolgen. Eine weitere Möglichkeit besteht darin, aus dem Keton der allgemeinen Formel VII und dem Amin der allgemeinen Formel VIII unter Wasserabspaltung, beispielsweise mit Titan(IV)-isopropylat, das Enamin zu bilden und dieses anschließend zu reduzieren, beispielsweise mit Natriumborhydrid oder Wasserstoff/Palladium auf Aktivkohle. 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.The reductive amination is, for example, in a solvent such as dichloromethane, 1, 2 dichloroethane, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid, optionally in the presence of acetic acid at temperatures between 0 0 C and 80 0 C performed. The reductive amination can also be carried out with hydrogen in the presence of a catalyst such as palladium on activated carbon or platinum oxide. Another possibility is to form the enamine from the ketone of general formula VII and the amine of general formula VIII with elimination of water, for example with titanium (IV) isopropoxide, and then to reduce this, for example with sodium borohydride or hydrogen / palladium activated carbon. 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- oder Tetrahydropyranylgruppe in Betracht.For example, come 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-, Benzyloxycarbonyl-, Benzyl-, Methoxybenzyl- oder 2,4-Dimethoxybenzylgruppe in Betracht.Protective radicals for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
Die gegebenenfalls anschließende Abspaltung eines verwendeten Schutzrestes erfolgt beispielsweise hydrolytisch in einem wässrigen Lösungsmittel, z.B. in Wasser, Iso- propanol/Wasser, Essigsäure/Wasser, Tetrahydrofuran/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 lodtrimethylsilan, bei Temperaturen zwischen 0 und 1200C, vorzugsweise bei Temperaturen zwischen 10 und 1000C. Die Abspaltung eines Benzyl-, Methoxybenzyl- oder Benzyloxycarbonyl restes 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 600C, und bei einem Wasserstoffdruck von 1 bis 7 bar, vorzugsweise jedoch von 3 bis 5 bar. Die Abspaltung eines 2,4-Dimethoxybenzylrestes erfolgt jedoch vorzugsweise in Trifluoressigsäure in Gegenwart von Anisol, Thioanisol, Pentamethylbenzol oder Triethylsilan.The optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C. However, the cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonyl restes takes place, for example hydrogenolytically, for example, 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 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, the cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole, thioanisole, pentamethylbenzene or triethylsilane.
Die Abspaltung eines tert.-Butyl- oder tert. -Butyloxycarbonylrest.es 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 elimination of a tert-butyl or tert. -Butyloxycarbonylrest.es is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
Die Abspaltung eines Trifluoracetyl restes erfolgt vorzugsweise durch Behandlung mit einer Säure wie Salzsäure gegebenenfalls in Gegenwart eines Lösungsmittels wie Essigsäure beiThe cleavage of a Trifluoracetyl rest is preferably carried out by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid
Temperaturen zwischen 50 und 120°C oder durch Behandlung mit Natronlauge gegebenenfalls in Gegenwart eines Lösungsmittels wie Tetrahydrofuran oder Methanol bei Temperaturen zwischen 0 und 500C.Temperatures between 50 and 120 ° C or by treatment with caustic soda optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
Weitere geeignete Schutzgruppen und Möglichkeiten zu ihrer Einführung und Abspaltung sind beispielsweise in „Protective Groups in Organic Synthesis" von Theodora W. Greene und Peter G. M. Wuts , Wiley-VCH, oder Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME beschrieben.Further suitable protecting groups and possibilities for their introduction and removal are described, for example, in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME.
Ferner 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, as already mentioned, the compounds of general formula I obtained can 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 inThus, for example, the resulting cis / trans mixtures can be purified by chromatography in their cis and trans isomers, the resulting compounds of general formula I, which in
Racematen auftreten, nach an sich bekannten Methoden (siehe Allinger N. L. und ENeI E. L. inRacemates occur, according to methods known per se (see Allinger N. L. and ENeI E. L. in
"Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 )) in ihre optischen Antipoden und"Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and
Verbindungen der allgemeinen Formel I mit mindestens 2 asymmetrischen Kohlenstoffatomen auf Grund ihrer physikalisch-chemischen 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.Compounds of general formula I having at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, e.g. 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 oderThe enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such. Ester or amide-forming optically active substance, in particular acids and their activated derivatives or
Alkohole, und Trennen des auf diese Weise erhaltenen diastereomeren Salzgemisches oderAlcohols, and separating the diastereomeric salt mixture thus obtained or
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 gebräuchliche, optisch aktive Säuren sind z.B. die D- und L-Formen von Weinsäure oder Dibenzoylweinsäure, Di-o-Tolylweinsäure, Äpfelsäure,Derivatives, e.g. due to different solubilities, wherein from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
Mandelsäure, Camphersulfonsäure, Glutaminsäure, Asparaginsäure oder Chinasäure. Als optisch aktiver Alkohol kommt beispielsweise (+)- oder (-)-Menthol und als optisch aktiver Acylrest in Amiden beispielsweise (+)-oder (-)-Menthyloxycarbonyl in Betracht. 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 oder Basen übergeführt werden. Als Säuren kommen hierfür beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Ethansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Benzoesäure, Salicylsäure, Mandelsäure, Milchsäure, Malonsäure, Zitronensäure, L-Äpfelsäure, L-Weinsäure oder Maleinsäure in Betracht. Als Basen kommen hierfür beispielsweise Natronlauge, Kalilauge, Calciumhydroxid, Diethanolamin oder N-Methyl- D-glucamine in Betracht.Mandelic acid, camphorsulfonic 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. 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 or bases. Examples of suitable acids are hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, phosphoric, fumaric, succinic, benzoic, salicylic, mandelic, lactic, malonic, citric, L-malic, L-tartaric or maleic acid , Suitable bases for this example, sodium hydroxide, potassium hydroxide, calcium hydroxide, diethanolamine or N-methyl-D-glucamine into consideration.
Die als Ausgangsstoffe verwendeten Verbindungen der allgemeinen Formeln Il bis VIII sind teilweise literaturbekannt oder können nach an sich literaturbekannten Verfahren (siehe Beispiele I bis IX) oder den vorstehend beschriebenen Verfahren, gegebenenfalls unter zusätzlicher Einführung von Schutzresten erhalten werden.Some of the compounds of the general formulas II to VIII used as starting materials are known from the literature or can be obtained by processes known from the literature (see Examples I to IX) or the processes described above, if appropriate with additional introduction of protective radicals.
Standardverfahren zur Herstellung der Ausgangsmaterialien sind beispielsweise in „March's Advanced Organic Chemistry" von Michael B. Smith and Jerry March, Wiley-VCH oder in „Science of Synthesis/Houben-Weyl", Thieme, beschrieben.Standard methods for preparing the starting materials are described, for example, in "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, Wiley-VCH or in "Science of Synthesis / Houben-Weyl", Thieme.
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 of the general formula (I) according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R) Inhibition of ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. In addition, it is possible that the signal transmission to further downstream components is blocked.
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 AusgangsverbindungenPreparation of the starting compounds
Beispiel I 4-[(3-Chlor-2-fluor-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-chinazolinExample I 4 - [(3-chloro-2-fluoro-phenyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline
Zu 9.0 g 4-[(3-Chlor-2-fluor-phenyl)amino]-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy- chinazolin in 110 ml Tetra hydrofu ran werden 25 ml 4M Schwefelsäure gegeben und das Gemisch 18 Stunden bei Raumtemperatur gerührt. Das Gemisch wird mit 4M Natronlauge alkalisch gestellt und mehrmals mit Essigester extrahiert. Die vereinigten organischen Phasen werden getrocknet, eingeengt und mit Diethylether verrührt. Der Feststoff wird abgesaugt und getrocknet.To 9.0 g of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 110 ml Tetra hydrofluoro ran 25 ml of 4M sulfuric acid and the mixture stirred for 18 hours at room temperature. The mixture is made alkaline with 4M sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried, concentrated and stirred with diethyl ether. The solid is filtered off with suction and dried.
Ausbeute: 7.4 g (90 % der Theorie) Massenspektrum (ESI+): m/z = 416, 418 [M+H]+ Yield: 7.4 g (90% of theory) Mass spectrum (ESI + ): m / z = 416, 418 [M + H] +
Beispiel IlExample Il
4-[(3-Chlor-2-fluor-phenyl)amino]-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline
Zu 18.1 g 4-[(3-Chlor-2-fluor-phenyl)amino]-6-hydroxy-7-methoxy-chinazolin (siehe beispielsweise Bioorganic & Medicinal Chemistry Letters (2006), 16(18), 4908-4912) in 125 ml Dimethylformamid werden bei 500C 12.5 g Kaliumcarbonat und 16 g 8- Methansulfonyloxy-1 ,4-dioxa-spiro[4.5]decan (siehe beispielsweise Journal of Medicinal Chemistry (1992), 35(12), 2243-7) gegeben und das Gemisch 18 Stunden bei 800C gerührt. Es werden nochmals 4.7 g Kaliumcarbonat und 4.0 g 8-Methansulfonyloxy-1 ,4-dioxa- spiro[4.5]decan zugegeben und weitere 7 Stunden bei 800C gerührt. Das Reaktionsgemisch wird abgekühlt, mit Wasser und Essigester verdünnt und der gebildete Niederschlag wird abgesaugt und getrocknet. Ausbeute: 12.2 g (47 % der Theorie) Massenspektrum (ESI+): m/z = 460, 462 [M+H]+ To 18.1 g of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6-hydroxy-7-methoxy-quinazoline (see, for example, Bioorganic & Medicinal Chemistry Letters (2006), 16 (18), 4908-4912) in 125 ml of dimethylformamide at 50 0 C 12.5 g of potassium carbonate and 16 g of 8- methanesulfonyloxy-1, 4-dioxa-spiro [4.5] decane (for example, see Journal of Medicinal Chemistry (1992), 35 (12), 2243-7) and the mixture stirred at 80 0 C for 18 hours. There are again 4.7 g of potassium carbonate and 4.0 g of 8-methanesulfonyloxy-1, 4-dioxa-spiro [4.5] decane was added and further 7 hours at 80 0 C stirred. The reaction mixture is cooled, diluted with water and ethyl acetate and the precipitate formed is filtered off with suction and dried. Yield: 12.2 g (47% of theory) Mass spectrum (ESI + ): m / z = 460, 462 [M + H] +
Beispielexample
4-[(3-Chlor-2-fluor-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy-chinazolin4 - [(3-chloro-2-fluoro-phenyl) amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline
Zu 17 g 3,4-Dihydro-4-oxo-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin in 120 ml Acetonitril werden 8.5 ml Phosphoroxychlorid zugetropft und das Gemisch auf 400CTo 17 g of 3,4-dihydro-4-oxo-6- (1, 4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in 120 ml of acetonitrile 8.5 ml of phosphorus oxychloride are added dropwise and the mixture at 40 0 C.
Innentemperatur erwärmt. Anschließend werden 13 ml Triethylamin zugetropft und dasHeated inside temperature. Then 13 ml of triethylamine are added dropwise and the
Reaktionsgemisch 2 Stunden refluxiert. Das Gemisch wird auf Raumtemperatur abgekühlt, mitReaction mixture refluxed for 2 hours. The mixture is cooled to room temperature, with
3.6 ml Triethylamin und dann tropfenweise mit 7.5 ml 3-Chlor-2-fluor-5-anilin in 10 ml Acetonitril versetzt. Das Reaktionsgemisch wird 5 Stunden auf 40°C erhitzt, danach abgekühlt und der Niederschlag abgesaugt. Der Feststoff wird mit einem Gemisch aus 1 M Salzsäure und 6M isopropanolischer Salzsäure versetzt und 24 Stunden gerührt. Der Niederschlag wird abgesaugt, nochmals mit einem Gemisch aus 1 M Salzsäure und 6M isopropanolischer3.6 ml of triethylamine and then treated dropwise with 7.5 ml of 3-chloro-2-fluoro-5-aniline in 10 ml of acetonitrile. The reaction mixture is heated for 5 hours at 40 ° C, then cooled and the precipitate is filtered off with suction. The solid is treated with a mixture of 1 M hydrochloric acid and 6M isopropanolic hydrochloric acid and stirred for 24 hours. The precipitate is filtered off, again with a mixture of 1 M hydrochloric acid and 6M isopropanolischer
Salzsäure versetzt und 6 Stunden gerührt. Der Niederschlag wird abgesaugt und zwischen 1 MHydrochloric acid and stirred for 6 hours. The precipitate is filtered off with suction and between 1 M
Natronlauge und Dichlormetan verteilt. Die organische Phase wird abgetrennt, getrocknet und eingeengt.Sodium hydroxide solution and dichlorometane distributed. The organic phase is separated, dried and concentrated.
Ausbeute: 17 g (80 % der Theorie) Massenspektrum (ESI+): m/z = 416, 418 [M+H]+ Yield: 17 g (80% of theory) Mass spectrum (ESI + ): m / z = 416, 418 [M + H] +
Beispiel IV 3,4-Dihydro-4-oxo-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolinExample IV 3,4-Dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline
16.0 g 3-Benzyl-3,4-dihydro-4-oxo-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin in 150 ml Eisessig werden in Gegenwart von 1.6 g Palladium auf Aktivkohle (10% Pd) bei 600C und einem Wasserstoffdruck von 50 psi hydriert. Der Katalysator wird abfiltriert und das Filtrat eingeengt, mit Toluol versetzt und erneut eingeengt. Der Rückstand wird mit Wasser versetzt und mit gesättigter Natriumhydrogencarbonat-Lösung leicht alkalisch gestellt. Der Niederschlag wird abgesaugt und getrocknet. Massenspektrum (ESI+): m/z = 333 [M+H]+ 16.0 g of 3-benzyl-3,4-dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxyquinazoline in 150 ml of glacial acetic acid are dissolved in the presence of 1.6 g of palladium on activated carbon (10% Pd) at 60 0 C and a hydrogen pressure of 50 psi hydrogenated. The catalyst is filtered off and the filtrate is concentrated, treated with toluene and concentrated again. The residue is mixed with water and made slightly alkaline with saturated sodium bicarbonate solution. The precipitate is filtered off with suction and dried. Mass spectrum (ESI + ): m / z = 333 [M + H] +
Beispiel VExample V
3-Benzyl-3,4-dihydro-4-oxo-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin3-Benzyl-3,4-dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline
Zu 20.0 g 3-Benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-chinazolin in 150 ml N, N- Dimethylformamid werden bei 500C 16.0 g Kaliumcarbonat und 20.0 g 8-Methansulfonyloxy- 1 ,4-dioxa-spiro[4.5]decan zugegeben und 18 Stunden bei 800C kräftig gerührt. Zur Vervollständigung der Reaktion wird noch dreimal jeweils Kaliumcarbonat und 8- Methansulfonyloxy-1 ,4-dioxa-spiro[4.5]decan zugegeben und jeweils mehrere Stunden bei 800C nachgerührt. Das Reaktionsgemisch wird abgekühlt und langsam mit insgesamt 500 ml Wasser versetzt. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet. Massenspektrum (ESI+): m/z = 423 [M+H]+ To 20.0 g of 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml of N, N-dimethylformamide at 50 0 C 16.0 g of potassium carbonate and 20.0 g of 8-Methansulfonyloxy- , 4-dioxa-spiro [4.5] decane added and stirred vigorously at 80 0 C for 18 hours. To complete the reaction is three times each of potassium carbonate and 8-methanesulfonyloxy-1, 4-dioxa-spiro [4.5] decane was added and stirred for several hours each time at 80 0 C. The reaction mixture is cooled and treated slowly with a total of 500 ml of water. The precipitate is filtered off with suction, washed with water and dried. Mass spectrum (ESI + ): m / z = 423 [M + H] +
Beispiel VIExample VI
3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-chinazolin 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline
169 g 3,4-Dihydro-4-oxo-6-acetyloxy-7-methoxy-chinazolin, 118.8 ml Benzylbromid und 138,2 g Kaliumcarbonat werden in 1600 ml Aceton für 8 Stunden auf 35-400C erwärmt. Die Mischung wird 15 Stunden bei Raumtemperatur gerührt und anschließend mit 2000 ml Wasser versetzt. Die Suspension wird auf 00C abgekühlt, der Niederschlag wird abgesaugt, mit 400 ml Wasser und 400 ml tert.-Butylmethylether gewaschen und bei 500C getrocknet. Der Feststoff wird in 4000 ml Methylenchlorid gelöst, filtriert und eingeengt. Der Rückstand wird in tert.- Butylmethylether suspendiert, abgesaugt und bei 50°C getrocknet. Ausbeute: 203 g (86% der Theorie) RrWert: 0.80 (Kieselgel, Methylenchlorid/Ethanol = 9:1 ) Massenspektrum (ESI+): m/z = 325 [M+H]+ 169 g of 3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline, 118.8 ml of benzyl bromide and 138.2 g of potassium carbonate are heated in 1600 ml of acetone for 8 hours at 35-40 0 C. The mixture is stirred for 15 hours at room temperature and then treated with 2000 ml of water. The suspension is cooled to 0 ° C., the precipitate is filtered off with suction, washed with 400 ml of water and 400 ml of tert-butyl methyl ether and dried at 50 ° C. The solid is dissolved in 4000 ml of methylene chloride, filtered and concentrated. The residue is suspended in tert-butyl methyl ether, filtered off with suction and dried at 50.degree. Yield: 203 g (86% of theory) Rr value: 0.80 (silica gel, methylene chloride / ethanol = 9: 1) mass spectrum (ESI + ): m / z = 325 [M + H] +
Beispiel VIIExample VII
3-Benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-chinazolin3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline
Verfahren A:Method A:
168.5 g 6-Hydroxy-7-methoxy-benzo[d][1 ,3]oxazin-4-on werden in 1200 ml Toluol gelöst und 74.7 ml Benzylamin werden zugegeben. Die Mischung wird 15 Stunden unter Rückfluss erhitzt und danach auf Raumtemperatur abgekühlt. Der Niederschlag wird abfiltriert und mit tert.- Butylmethylether gewaschen. Ausbeute 124 g (72% der Theorie)168.5 g of 6-hydroxy-7-methoxy-benzo [d] [1,3] oxazin-4-one are dissolved in 1200 ml of toluene and 74.7 ml of benzylamine are added. The mixture is refluxed for 15 hours and then cooled to room temperature. The precipitate is filtered off and washed with tert-butyl methyl ether. Yield 124 g (72% of theory)
Verfahren B:Method B:
200 g 3-Benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-chinazolin werden in 200 ml Wasser und 1000 ml Ethanol suspendiert. 300 ml 10N Natriumhydroxid Lösung werden bei Raumtemperatur zugegeben und die Mischung 1 Stunde auf 300C erwärmt. Nach Zugabe von 172 ml Essigsäure und 2000 ml Wasser wird die Mischung 20 Stunden bei Raumtemperatur gerührt. Der Niederschlag wird abgesaugt, mit Wasser und Aceton gewaschen und bei 600C getrocknet.200 g of 3-benzyl-3,4-dihydro-4-oxo-6-acetyloxy-7-methoxy-quinazoline are suspended in 200 ml of water and 1000 ml of ethanol. 300 ml of 10N sodium hydroxide solution are added at room temperature and the mixture is heated to 30 0 C for 1 hour. After addition of 172 ml of acetic acid and 2000 ml of water, the mixture is stirred for 20 hours at room temperature. The precipitate is filtered off, washed with water and acetone and at 60 0 C. dried.
Ausbeute: 172,2 g (98% der Theorie)Yield: 172.2 g (98% of theory)
RrWert: 0.25 (Kieselgel, Methylenchlorid/Ethanol = 19:1 )Rr value: 0.25 (silica gel, methylene chloride / ethanol = 19: 1)
Massenspektrum (ESI+): m/z = 283 [M+H]+ Mass Spectrum (ESI + ): m / z = 283 [M + H] +
Beispiel VIIIExample VIII
6-Hydroxy-7-methoxy-benzo[d][1 ,3]oxazin-4-on6-hydroxy-7-methoxybenzo [d] [1,3] oxazin-4-one
1 g 2-Amino-5-hydroxy-4-methoxy-benzoesäure (hergestellt durch Umsetzung von 2-Nitro-4,5- dimethoxy-benzoesäure-methylester mit Kalilauge zu 2-Nitro-5-hydroxy-4-methoxy- benzoesäure-Kaliumsalz und anschließender katalytischer Hydrierung in Gegenwart von Palladium auf Aktivkohle) und 20 ml Orthoameisensäure-triethylester werden für 2.5 Stunden auf 1000C erhitzt. Nach Abkühlen auf Raumtemperatur wird der Niederschlag abgesaugt und mit Diethylether gewaschen.1 g of 2-amino-5-hydroxy-4-methoxybenzoic acid (prepared by reacting methyl 2-nitro-4,5-dimethoxybenzoate with potassium hydroxide solution to give 2-nitro-5-hydroxy-4-methoxybenzoic acid Potassium salt and subsequent catalytic hydrogenation in the presence of palladium on activated carbon) and 20 ml of triethyl orthoformate are heated at 100 ° C. for 2.5 hours. After cooling to room temperature, the precipitate is filtered off with suction and washed with diethyl ether.
Ausbeute: 0.97 g (93% der Theorie)Yield: 0.97 g (93% of theory)
RrWert: 0.86 (Kieselgel, Methylenchlorid/Methanol/Essigsäure = 90:10:1 ) Massenspektrum (ESI+): m/z = 194 [M+H]+ Rr value: 0.86 (silica gel, methylene chloride / methanol / acetic acid = 90: 10: 1) mass spectrum (ESI + ): m / z = 194 [M + H] +
Beispiel IXExample IX
4-Chlor-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin4-Chloro-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline
Zu 12.1 g 3,4-Dihydro-4-oxo-6-(1 ,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-chinazolin inTo 12.1 g of 3,4-dihydro-4-oxo-6- (1,4-dioxa-spiro [4.5] decan-8-yl-oxy) -7-methoxy-quinazoline in
120 ml Acetonitril werden 6 ml Phosphoroxychlorid zugetropft und das Gemisch auf 400C Innentemperatur erwärmt. Anschließend werden 9.3 ml Triethylamin zugetropft und das Reaktionsgemisch 3 Stunden refluxiert. Das Gemisch wird auf Raumtemperatur abgekühlt und über Nacht stehengelassen. Die Lösung des Produkts wird ohne Reinigung weiter umgesetzt (s. Beispiel III).120 ml of acetonitrile are added dropwise 6 ml of phosphorus oxychloride and the mixture is heated to 40 0 C internal temperature. Then 9.3 ml of triethylamine are added dropwise and the Reaction mixture refluxed for 3 hours. The mixture is cooled to room temperature and allowed to stand overnight. The solution of the product is further reacted without purification (see Example III).
Herstellung der Endverbindungen:Preparation of the end compounds:
Beispiel 1example 1
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7- methoxy-chinazolin und 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4-ethyl-3-oxo-piperazin-1- yl)-cyclohexyloxy]-7-methoxy-chinazolin4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-ethyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-ethyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline
1500 mg 4-[(3-Chlor-2-fluor-phenyl)amino]-6-(4-oxo-cyclohexyloxy)-7-methoxy- chinazolin in 50 ml Dichlormethan werden mit 555 mg 4-Ethyl-3-oxo-piperazin und 250 μl Eisessig versetzt und 15 Minuten bei Raumtemperatur gerührt. Anschließend werden 1 100 mg Natrium-triacetoxyborhydrid zugesetzt und das Gemisch 18 Stunden bei Raumtemperatur gerührt. Es wird noch etwas Natrium-triacetoxyborhydrid nachgesetzt und weitere 3 Stunden gerührt. Das Reaktionsgemisch wird Dichlormethan und mit 1 M Natronlauge versetzt, kurz gerührt und mehrfach mit Dichlormethan extrahiert. Die vereinigten organischen Phasen werden über Magnesiumsulfat getrocknet und eingeengt. Durch Reinigung über eine Kieselgelsäule mit Essigester/Methanol/wässriger Ammoniak (95:5:0.1 bis 80:20:0.1 ) werden die beiden Titelverbindungen als Gemisch erhalten. Die Auftrennung des cis/trans- Gemisches erfolgt durch präparative HPLC (xBridge™ C18 der Fa. Waters; Acetonitril, Wasser, wässriges Ammoniak). Die Zuordnung der Isomeren erfolgt über 1 H-NMR Spektroskopie (400MHz, Dimethylsulfoxid-d6). 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-ethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7- methoxy-chinazolin:1500 mg of 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- (4-oxo-cyclohexyloxy) -7-methoxy-quinazoline in 50 ml of dichloromethane are mixed with 555 mg of 4-ethyl-3-oxo piperazine and 250 μl of glacial acetic acid and stirred for 15 minutes at room temperature. Subsequently, 1 100 mg of sodium triacetoxyborohydride are added and the mixture is stirred for 18 hours at room temperature. It is added a little more sodium triacetoxyborohydride and stirred for a further 3 hours. The reaction mixture is dichloromethane and 1M sodium hydroxide solution, stirred briefly and extracted several times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. Purification on a silica gel column with ethyl acetate / methanol / aqueous ammonia (95: 5: 0.1 to 80: 20: 0.1) gives the two title compounds as a mixture. The cis / trans mixture is separated by preparative HPLC (xBridge ™ C18 from Waters, acetonitrile, water, aqueous ammonia). The assignment of the isomers via 1 H-NMR spectroscopy (400MHz, dimethyl sulfoxide-d6). 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-ethyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline:
Ausbeute: 610 mg (32 % der Theorie)Yield: 610 mg (32% of theory)
Massenspektrum (ESI+): m/z = 528, 530 [M+H]+ charakteristisches Signal bei 4.71 (1 H, m)Mass spectrum (ESI + ): m / z = 528, 530 [M + H] + characteristic signal at 4.71 (1 H, m)
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4-ethyl-3-oxo-piperazin-1-yl)- cyclohexyloxy]-7-methoxy-chinazolin:4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-ethyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline:
Ausbeute: 520 mg (27 % der Theorie)Yield: 520 mg (27% of theory)
Massenspektrum (ESI+): m/z = 528, 530 [M+H]+ charakteristisches Signal bei 4.45 (1 H, m)Mass spectrum (ESI + ): m / z = 528, 530 [M + H] + characteristic signal at 4.45 (1 H, m)
Analog Beispiel 1 werden folgende Verbindungen erhalten:Analogously to Example 1, the following compounds are obtained:
(1 ) 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-cyclopropylmethyl-3-oxo-piperazin-1 -yl)- cyclohexyloxy]-7-methoxy-chinazolin und 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4- cyclopropylmethyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-chinazolin(1) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-cyclopropylmethyl-3-oxopiperazin-1-yl) cyclohexyloxy] -7-methoxy quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-cyclopropylmethyl-3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)- cyclohexyloxy]-7-methoxy-chinazolin4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-cyclopropylmethyl-3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline
Massenspektrum (ESI+): m/z = 554, 556 [M+H]+ Mass Spectrum (ESI + ): m / z = 554, 556 [M + H] +
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4-cyclopropylmethyl-3-oxo-piperazin-1-yl)- cyclohexyloxy]-7-methoxy-chinazolin Massenspektrum (ESI+): m/z = 554, 556 [M+H]+ 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-cyclopropylmethyl-3-oxopiperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline mass spectrum ( ESI + ): m / z = 554, 556 [M + H] +
(2) 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7- methoxy-chinazolin und 4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4-butyl-3-oxo-piperazin-1- yO-cyclohexyloxyJ-y-methoxy-chinazolin(2) 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-butyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7- methoxy-quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-butyl-3-oxopiperazine-1-y-cyclohexyloxy) -j-methoxy-quinazoline
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[cis-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7- methoxy-chinazolin4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- [cis-4- (4-butyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline
Massenspektrum (ESI+): m/z = 556, 558 [M+H]+ Mass spectrum (ESI + ): m / z = 556, 558 [M + H] +
4-[(3-Chlor-2-fluor-phenyl)amino]-6-[trans-4-(4-butyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7- methoxy-chinazolin Massenspektrum (ESI+): m/z = 556, 558 [M+H]+ 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- [trans-4- (4-butyl-3-oxo-piperazin-1-yl) -cyclohexyloxy] -7-methoxy-quinazoline mass spectrum ( ESI + ): m / z = 556, 558 [M + H] +
(3) 4-[(3-Chlor-2-fluor-phenyl)amino]-6-{cis-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]- cyclohexyloxy}-7-methoxy-chinazolin und 4-[(3-Chlor-2-fluor-phenyl)amino]-6-{trans-4-[4- (tetrahydropyran^-y^-S-oxo-piperazin-i-y^-cyclohexyloxy^y-methoxy-chinazolin(3) 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- {cis-4- [4- (tetrahydropyran-4-yl) -3-oxo-piperazin-1-yl] -cyclohexyloxy } -7-methoxy-quinazoline and 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- {trans-4- [4- (tetrahydropyran ^ -xy) -S-oxo-piperazine-iy ^ cyclohexyloxy ^ y-methoxy-quinazoline
4-[(3-Chlor-2-fluor-phenyl)amino]-6-{cis-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]- cyclohexyloxy}-7-methoxy-chinazolin4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- {cis-4- [4- (tetrahydropyran-4-yl) -3-oxo-piperazin-1-yl] -cyclohexyloxy} -7 methoxy-quinazoline
Massenspektrum (ESI+): m/z = 584, 586 [M+H]+ 4-[(3-Chlor-2-fluor-phenyl)amino]-6-{trans-4-[4-(tetrahydropyran-4-yl)-3-oxo-piperazin-1-yl]- cyclohexyloxyj-y-methoxy-chinazolinMass spectrum (ESI + ): m / z = 584, 586 [M + H] + 4 - [(3-chloro-2-fluoro-phenyl) -amino] -6- {trans-4- [4- (tetrahydropyran-4-yl) -3-oxo-piperazin-1-yl] -cyclohexyloxyj-y- methoxy-quinazoline
Massenspektrum (ESI+): m/z = 584, 586 [M+H]+ Mass spectrum (ESI + ): m / z = 584, 586 [M + H] +
Bei dieser Reaktion wurden folgende Nebenprodukte isoliert:In this reaction, the following by-products were isolated:
4-[(3-Chlor-2-fluor-phenyl)amino]-6-(cis-4-hydroxy-cyclohexyloxy)-7-methoxy-chinazolin Massenspektrum (ESI+): m/z = 418, 420 [M+H]+ 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- (cis-4-hydroxy-cyclohexyloxy) -7-methoxy-quinazoline Mass Spectrum (ESI + ): m / z = 418, 420 [M + H] +
4-[(3-Chlor-2-fluor-phenyl)amino]-6-(trans-4-hydroxy-cyclohexyloxy)-7-methoxy-chinazolin Massenspektrum (ESI+): m/z = 418, 420 [M+H]+ 4 - [(3-Chloro-2-fluoro-phenyl) -amino] -6- (trans-4-hydroxy-cyclohexyloxy) -7-methoxy-quinazoline Mass Spectrum (ESI + ): m / z = 418, 420 [M + H] +
Biologischer TestBiological test
Die biologischen Eigenschaften der neuen Verbindungen werden beispielsweise wie folgt geprüft:The biological properties of the new compounds are tested, for example, as follows:
Die Hemmung der EGF-R vermittelten Signalübertragung kann z.B. mit Zellen nachgewiesen werden, die humanen EGF-R exprimieren und deren Überleben und Proliferation von Stimulierung durch EGF bzw. TGF-alpha abhängt. Eine murine hämatopoetische Zelllinie wird derart genetisch verändert, dass sie funktionellen humanen EGF-R exprimiert. Die Proliferation dieser Zelllinie kann daher durch EGF stimuliert werden.Inhibition of EGF-R mediated signal transduction may be e.g. with cells expressing human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha, respectively. A murine hematopoietic cell line is genetically engineered to express functional human EGF-R. The proliferation of this cell line can therefore be stimulated by EGF.
Der Test wird wie folgt durchgeführt:The test is carried out as follows:
Die Zellen werden in RPMI/1640 Medium kultiviert. Die Proliferation wird mit 20 ng/ml humanem EGF (Promega) stimuliert. Zur Untersuchung der inhibitorischen Aktivität der erfindungsgemäßen Verbindungen werden diese Verbindungen in 100% Dimethylsulfoxid (DMSO) gelöst und in verschiedenen Verdünnungen den Kulturen zugefügt, wobei die maximale DMSO Konzentration 1 % beträgt. Die Kulturen werden für 48 Stunden bei 37°C inkubiert.The cells are cultured in RPMI / 1640 medium. Proliferation is stimulated with 20 ng / ml human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention, these compounds are dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration is 1%. The cultures are incubated for 48 hours at 37 ° C.
Zur Bestimmung der inhibitorischen Aktivität der erfindungsgemäßen Verbindungen wird die relative Zellzahl mit dem Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation AssayTo determine the inhibitory activity of the compounds according to the invention, the relative cell count is determined using the Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation Assay
(Promega) in O. D. Einheiten gemessen. Die relative Zellzahl wird in Prozent der Kontrolle berechnet und die Wirkstoffkonzentration, die die Proliferation der Zellen zu 50% hemmt (IC50), abgeleitet.(Promega) in O.D. units. The relative cell count is calculated as a percentage of the control and the drug concentration, which inhibits the proliferation of the cells to 50% (IC50) derived.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) zeigen beispielsweise IC50-The compounds of the general formula (I) according to the invention show, for example, IC50
Werte von < 10 micromolar, vorzugsweise von < 1 micromolar.Values of <10 micromolar, preferably <1 micromolar.
Indikationsgebieteindications
Wie gefunden wurde, zeichnen sich die Verbindungen der Formel (I) durch vielfältige Anwendungsmöglichkeiten auf therapeutischem Gebiet aus. Hervorzuheben sind solche Anwendungsmöglichkeiten, für welche die erfindungsgemäßen Verbindungen der Formel (I) aufgrund ihrer pharmazeutischen Wirksamkeit als Tyrosinkinase-Hemmer bevorzugt zur Anwendung gelangen können.As has been found, the compounds of formula (I) are characterized by a variety of therapeutic applications. To emphasize are those applications for which the compounds of the formula (I) according to the invention can preferably be used as a tyrosine kinase inhibitor due to their pharmaceutical activity.
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 general formula (I) according to the invention thus inhibit the signal transduction by tyrosine kinases, as exemplified by the human EGF receptor and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuro-epithelial 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 Fibrose, α1-Antitrypsin-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-antitrypsin deficiency, or in cough, emphysema, pulmonary fibrosis and hyperreactive 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 ulcerosa, 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.The compounds are also useful in the treatment of disorders of the gastrointestinal tract and bile ducts and bladder associated with impaired activity of the tyrosine kinases, e.g. in chronic inflammatory disorders, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in disorders of the gastrointestinal tract associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
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 Hyperproliferation (Psoriasis), benigner Prostatahyperplasie (BPH), inflammatorischer Prozesse, Erkrankungen des Immunsystems, Hyperproliferation hämatopoetischer Zellen, der Behandlung von Nasenpolypen, etc..In addition, the compounds of general formula (I) and their physiologically acceptable salts may be used for the treatment of other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc ..
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 Monotherapie 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, Cyclophosphamid, Adriamycin), Hormon-Antagonisten (z.B. Tamoxifen), Inhibitoren metabolischer 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.Due to their biological properties, the compounds of the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adriamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc. For the treatment of respiratory diseases, these compounds may be used alone or in combination with other respiratory therapies, such as secretolytic (eg Ambroxol, N- acetylcysteine), broncholytic (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (eg theophylline or glucocorticoids) active 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.
Formulierungenformulations
Die erfindungsgemäßen Verbindungen können oral, transdermal, inhalativ, parenteral oder sublingual verabreicht werden. Die erfindungsgemäßen Verbindungen liegen hierbei als aktive Bestandteile in üblichen Darreichungsformen vor, beispielsweise in Zusammensetzungen, die im wesentlichen aus einem inerten pharmazeutischen Träger und einer effektiven Dosis des Wirkstoffs bestehen, wie beispielsweise Tabletten, Dragees, Kapseln, Oblaten, Pulver, Lösungen, Suspensionen, Emulsionen, Sirupe, Suppositorien, transdermale Systeme etc.. Eine wirksame Dosis der erfindungsgemäßen Verbindungen liegt bei einer oralen Anwendung zwischen 0.1 und 5000, vorzugsweise zwischen 1 und 500, besonders bevorzugt zwischen 5- 300 mg/Dosis, bei intravenöser, subkutaner oder intramuskulärer Anwendung zwischen 0,001 und 50, vorzugsweise zwischen 0,1 und 10 mg/Dosis. Für die Inhalation sind erfindungsgemäß Lösungen geeignet, die 0,01 bis 1 ,0, vorzugsweise 0,1 bis 0,5 % Wirkstoff enthalten. Für die inhalative Applikation ist die Verwendung von Pulvern, ethanolischen oder wässrigen Lösungen bevorzugt. Gleichfalls ist es möglich, die erfindungsgemäßen Verbindungen als Infusionslösung, vorzugsweise in einer physiologischen Kochsalzlösung oder Nährsalzlösung einzusetzen.The compounds according to the invention can be administered orally, transdermally, by inhalation, parenterally or sublingually. The compounds of the invention are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc. An effective dose of the compounds according to the invention is between 0.1 and 5000, preferably between 1 and 500, more preferably between 5 and 300 mg / dose when administered orally during intravenous, subcutaneous or intramuscular administration 0.001 and 50, preferably between 0.1 and 10 mg / dose. For inhalation solutions are suitable according to the invention containing 0.01 to 1, 0, preferably 0.1 to 0.5% active ingredient. For inhalative administration, the use of powders, ethanolic or aqueous solutions is preferred. It is likewise possible to use the compounds according to the invention as infusion solution, preferably in a physiological saline solution or nutrient salt solution.
Die erfindungsgemäßen Verbindungen können allein oder in Kombination mit anderen erfindungsgemäßen Wirkstoffen, gegebenenfalls auch in Kombination mit weiteren pharmakologisch aktiven Wirkstoffen, zur Anwendung gelangen. Geeignete Anwendungsformen sind beispielsweise Tabletten, Kapseln, Zäpfchen, Lösungen, Säfte, Emulsionen oder dispersible Pulver. Entsprechende Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine, Schmiermitteln, wie Magnesiumstearat oder Talk, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxymethylcellulose, Celluloseacetatphthalat, oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen. Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Kollidon oder Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Zur Erzielung eines Depoteffektes oder zur Vermeidung von Inkompatibilitäten kann der Kern auch aus mehreren Schichten bestehen. Desgleichen kann auch die Drageehülle zur Erzielung eines Depoteffektes aus mehreren Schichten bestehen wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers. Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
Säfte der erfindungsgemäßen Wirkstoffe beziehungsweise Wirkstoffkombinationen können zusätzlich noch ein Süßungsmittel, wie Saccharin, Cyclamat, Glycerin oder Zucker sowie ein geschmacksverbesserndes Mittel, z.B. Aromastoffe, wie Vanillin oder Orangenextrakt, enthalten. Sie können außerdem Suspendierhilfsstoffe oder Dickungsmittel, wie Natriumcarboxymethylcellulose, Netzmittel, beispielsweise Kondensationsprodukte von Fettalkoholen mit Ethylenoxid, oder Schutzstoffe, wie p-Hydroxybenzoate, enthalten.Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
Injektionslösungen werden in üblicher Weise, z.B. unter Zusatz von Konservierungsmitteln, wie p-Hydroxybenzoaten, oder Stabilisatoren, wie Alkalisalzen der Ethylendiamintetraessigsäure hergestellt und in Injektionsflaschen oder Ampullen abgefüllt.Injection solutions are prepared in a conventional manner, e.g. prepared with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid and filled into injection bottles or ampoules.
Die eine oder mehrere Wirkstoffe beziehungsweise Wirkstoffkombinationen enthaltenden Kapseln können beispielsweise hergestellt werden, indem man die Wirkstoffe mit inerten Trägern, wie Milchzucker oder Sorbit, mischt und in Gelatinekapseln einkapselt.The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
Geeignete Zäpfchen lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln, wie Neutralfetten oder Polyäthylenglykol beziehungsweise dessen Derivaten, herstellen.Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
Bei der pharmazeutischen Anwendung werden die erfindungsgemäßen Verbindungen in der Regel bei warmblütigen Wirbeltieren, insbesondere beim Menschen, in Dosierungen von 0.01-In the pharmaceutical application, the compounds of the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.01-
100 mg/kg Körpergewicht, vorzugsweise bei 0.1-15 mg/kg verwendet. Zur Verabreichung können diese beispielsweise mit einem oder mehreren üblichen inerten Trägerstoffen und/oder100 mg / kg body weight, preferably at 0.1-15 mg / kg. For administration, these may be, for example, with one or more conventional inert carriers and / or
Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Zellulose,Diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose,
Magnesiumstearat, Polyvinylpyrrolidon, Zitronensäure, Weinsäure, Wasser, Wasser/Ethanol, Wasser/Glycerin, Wasser/Sorbit, Wasser/Polyethylenglykol, Propylenglykol, Stearylalkohol,Magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol,
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 werden.Carboxymethylcellulose or fatty substances such as hard fat or their suitable Mixtures are incorporated in conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
Die nachfolgenden Beispiele illustrieren die vorliegende Erfindung ohne sie jedoch in ihrem Umfang zu beschränken:The following examples illustrate the present invention without, however, limiting its scope:
Pharmazeutische FormulierungsbeispielePharmaceutical Formulation Examples
A) Dragees mit 75 mg WirksubstanzA) Dragees with 75 mg active substance
Zusammensetzung:Composition:
1 Drageekern enthält: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 mg Stempel: 9 mm, gewölbtCore weight: 230 mg. Stamp: 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. B) Tabletten mit 100 mg WirksubstanzDragee weight: 245 mg. B) tablets with 100 mg active substance
Zusammensetzung:Composition:
1 Tablette enthält:1 tablet contains:
Wirksubstanz 100.0 mgActive substance 100.0 mg
Milchzucker 80.0 mgLactose 80.0 mg
Maisstärke 34.0 mgCorn starch 34.0 mg
Polyvinylpyrrolidon 4.0 mgPolyvinylpyrrolidone 4.0 mg
Magnesiumstearat 2.0 mgMagnesium stearate 2.0 mg
220.0 mg220.0 mg
Herstellungverfahren: 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 500C wird erneut gesiebt (1.5 mm-Maschenweite) und das Schmiermittel zugemischt. Die preßfertige Mischung wird zu Tabletten verarbeitet.Production process: Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 0 C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
Tablettengewicht: 220 mgTablet weight: 220 mg
Durchmesser: 10 mm, biplan mit beidseitiger Facette und einseitiger Teilkerbe.Diameter: 10 mm, biplan with facet on both sides and one-sided part notch.
C) Tabletten mit 150 mg WirksubstanzC) tablets with 150 mg active substance
Zusammensetzung:Composition:
1 Tablette enthält:1 tablet contains:
Wirksubstanz 150.0 mgActive substance 150.0 mg
Milchzucker pulv. 89.0 mgMilk sugar powder 89.0 mg
Maisstärke 40.0 mgCornstarch 40.0 mg
Kolloide Kieselgelsäure 10.0 mgColloidal silicic acid 10.0 mg
Polyvinylpyrrolidon 10.0 mgPolyvinylpyrrolidone 10.0 mg
Magnesiumstearat 1.0 mgMagnesium stearate 1.0 mg
300.0 mg Herstellung:300.0 mg production:
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.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
D) Hartgelatine-Kapseln mit 150 mg WirksubstanzD) Hard 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 mg Milchzucker pulv. ca. 87.0 mgCorn starch drink. approx. 180.0 mg lactose powder approx. 87.0 mg
Magnesiumstearat 3.0 mg ca. 420.0 mgMagnesium stearate 3.0 mg approx. 420.0 mg
Herstellung: 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 mg Kapselhülle: Hartgelatine-Kapsel Größe 1.Preparation: The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device. The final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg capsule shell: hard gelatine capsule size 1.
E) Suppositorien mit 150 mg WirksubstanzE) Suppositories with 150 mg active substance
Zusammensetzung: 1 Zäpfchen enthält:Composition: 1 suppository contains:
Wirkstoff 150.0 mg Polyäthylenglykol 1500 550.0 mgActive ingredient 150.0 mg Polyethylene 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.
F) Suspension mit 50 mg WirksubstanzF) Suspension with 50 mg active substance
Zusammensetzung:Composition:
100 ml Suspension enthalten: Wirkstoff 1.00 g100 ml suspension contain: active substance 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 g Glycerin 5.00 gCane sugar 10.00 g glycerol 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 dist. ad 100.00 ml
Herstellung:production:
Destilliertes Wasser wird auf 700C erhitzt. Hierin wird unter Rühren p-Hydroxybenzoe- säuremethylester und -propylester sowie Glycerin und Carboxymethylcellulose-Natriumsalz gelöst. Es wird auf Raumtemperatur abgekühlt und unter Rühren der Wirkstoff zugegeben und homogen dispergiert. Nach Zugabe und Lösen des Zuckers, der Sorbitlösung und des Aromas wird die Suspension zur Entlüftung unter Rühren evakuiert.Distilled water is heated to 70 0 C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After 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.5 ml of suspension contain 50 mg of active ingredient.
G) Ampullen mit 10 mg Wirksubstanz Zusammensetzung:G) Ampoules with 10 mg active substance 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 HCl gelöst, mit Kochsalz isotonisch gestellt, sterilfiltriert und in 2 ml Ampullen abgefüllt.The active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.
H) Ampullen mit 50 mg WirksubstanzH) Ampoules with 50 mg active substance
Zusammensetzung: Wirkstoff 50.0 mg 0.01 n Salzsäure s.q.Composition: Active ingredient 50.0 mg 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 HCl 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.
I) Kapseln zur Pulverinhalation mit 5 mg WirksubstanzI) Capsules for powder inhalation with 5 mg active substance
1 Kapsel enthält:1 capsule contains:
Wirksubstanz 5.0 mgActive substance 5.0 mg
Lactose für Inhalationszwecke 15.0 mgLactose for inhalation 15.0 mg
20.0 mg20.0 mg
Herstellung:production:
Die Wirksubstanz wird mit Lactose für Inhalationszwecke gemischt. Die Mischung wird auf einerThe active substance is mixed with lactose for inhalation purposes. The mixture is on one
Kapselmaschine in Kapseln (Gewicht der Leerkapsel ca. 50 mg) abgefüllt.Capsule machine in capsules (weight of the empty capsule about 50 mg) bottled.
Kapselgewicht: 70.0 mg Kapselgröße: 3 J) Inhalationslösung für Handvernebler mit 2.5 mg WirksubstanzCapsule weight: 70.0 mg Capsule size: 3 J) Inhalation 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 1 N-Salzsäure q.s. Ethanol/Wasser (50/50) ad 15.000 mgBenzalkonium chloride 0.001 mg 1 N hydrochloric acid q.s. Ethanol / 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 1 N-Salzsäure eingestellt. Die eingestellte Lösung wird filtriert und in für den Handvernebler 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 1 N hydrochloric acid. The adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).
Füllmasse des Behälters: 4.5 g Fill weight of the container: 4.5 g

Claims

Patentansprüche claims
1. Verbindungen der allgemeinen Formel (I)1. Compounds of the general formula (I)
dadurch gekennzeichnet, dasscharacterized in that
Ra eine Ethyl-, Propyl-, Butyl-, Cyclopropyl-, Cyclopropylmethyl-, Cyclobutyl-, Cyclobutylmethyl-, 3-Tetrahydrofuranyl-, Tetrahydrofuranylmethyl-, 3-Tetrahydropyranyl-, 4- Tetrahydropyranyl- und Tetrahydropyranylmethyl-Gruppe, und wobei, soweit nichts anderes erwähnt wird, die vorstehend genannten Alkylgruppen geradkettig oder verzweigt sein können,R a represents an ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, 3-tetrahydrofuranyl, tetrahydrofuranylmethyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl and tetrahydropyranylmethyl group, and wherein, as far as nothing else is mentioned, the abovementioned alkyl groups may be straight-chain or branched,
gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze bedeutet.optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
2. Verbindungen nach Anspruch 1 , dadurch gekennzeichnet, dass2. Compounds according to claim 1, characterized in that
Ra einen Rest ausgewählt aus der Gruppe bestehend aus Ethyl-, Butyl-, Cyclopropylmethyl- und 4-Tetrahydropyranyl-Gruppe,R a is a radical selected from the group consisting of ethyl, butyl, cyclopropylmethyl and 4-tetrahydropyranyl group,
gegebenenfalls in Form ihrer Tautomeren, ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze bedeutet.optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
3. Verbindungen der Formel (I) nach einem der Ansprüche 1 bis 2 zur Verwendung als Arzneimittel.3. Compounds of formula (I) according to any one of claims 1 to 2 for use as Drug.
4. Verwendung nach Anspruch 3, dadurch gekennzeichnet, dass es sich um entzündliche oder allergische Erkrankungen der Atemwege handelt.4. Use according to claim 3, characterized in that it is inflammatory or allergic diseases of the respiratory tract.
5. Verwendung nach Anspruch 3 oder 4 dadurch gekennzeichnet, dass es sich um eine Erkrankung handelt, die ausgewählt ist aus der Gruppe bestehend aus Chronischer Bronchitis, akuter Bronchitis, Bronchitis aufgrund bakterieller oder viraler Infektion oder Pilzen oder Helminthen, allergischer Bronchitis, toxischer Bronchitis, chronisch obstruktiver Bronchitis (COPD), Asthma (intrinsisch oder allergisch), pediatrischem Asthma, Bronchiektasien, allergischer Alveolitis, allergischer oder nicht-allergischer Rhinitis, chronischer Sinusitis, zystischer Fibrose oder Mukoviszidose, alpha-1-Antitrypsin-Mangel, Husten, Lungenemphysem, interstitieller Lungenerkrankungen, Alveolitis, hyperreaktiver Atemwege, Nasenpolypen, Lungenödemen, Pneumonitis aufgrund unterschiedlicher Genese wie Strahlen-induziert oder durch Aspiration oder infektiöse, Kollagenosen wie Lupus eryth, systemische Sklerodermie, Sarkoidose und M. Boeck.5. Use according to claim 3 or 4, characterized in that it is a disease selected from the group consisting of chronic bronchitis, acute bronchitis, bronchitis due to bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or cystic fibrosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial Pulmonary diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary edema, pneumonitis due to different causes such as radiation-induced or by aspiration or infectious, collagenoses such as lupus eryth, systemic scleroderma, sarcoidosis and M. boeck.
6. Verwendung nach Anspruch 3, dadurch gekennzeichnet, dass es sich um entzündliche oder allergische Krankheitszustände handelt, bei denen Autoimmun-Reaktionen beteiligt sind.6. Use according to claim 3, characterized in that it is inflammatory or allergic disease states in which autoimmune reactions are involved.
7. Verwendung nach Anspruch 3 oder 6, dadurch gekennzeichnet, dass es sich um eine Erkrankung in Form von benignen oder malignen Tumoren handelt.7. Use according to claim 3 or 6, characterized in that it is a disease in the form of benign or malignant tumors.
8. Pharmazeutische Formulierung enthaltend eine Verbindung der Formel (I) gemäß einem der Ansprüche 1 oder 2.8. A pharmaceutical formulation comprising a compound of the formula (I) according to one of claims 1 or 2.
9. Oral applizierbare pharmazeutische Formulierung nach Anspruch 8 enthaltend eine Verbindung der Formel (I) gemäß Anspruch 1 oder 2.9. Orally administrable pharmaceutical formulation according to claim 8 comprising a compound of formula (I) according to claim 1 or 2.
10. Arzneimittelkombinationen, die neben einer oder mehrerer Verbindungen der Formel (I) gemäß einem der Ansprüche 1 oder 2 als weiteren Wirkstoff einen oder mehrere Verbindungen enthalten, die ausgewählt sind aus den Klassen der Betamimetika, Anticholinergika, Corticosteroiden, weitere PDE4-Inhibitoren, LTD4-Antagonisten, EGFR-Hemmern, Dopamin- Agonisten, H 1 -Antihistaminika, PAF-Antagonisten und PI3-Kinase Inhibitoren oder zwei- oder dreifach Kombinationen davon. 10. Medicament combinations which contain, in addition to one or more compounds of the formula (I) according to one of claims 1 or 2 as further active ingredient one or more compounds selected from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 Antagonists, EGFR inhibitors, dopamine agonists, H 1 antihistamines, PAF antagonists and PI3 kinase inhibitors or two or three combinations thereof.
EP09780994A 2008-08-08 2009-07-23 Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof Withdrawn EP2313398A1 (en)

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