EP1474149A2 - Use of tyrosine kinase inhibitors for the treatment of inflammatory processes - Google Patents

Use of tyrosine kinase inhibitors for the treatment of inflammatory processes

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Publication number
EP1474149A2
EP1474149A2 EP03704477A EP03704477A EP1474149A2 EP 1474149 A2 EP1474149 A2 EP 1474149A2 EP 03704477 A EP03704477 A EP 03704477A EP 03704477 A EP03704477 A EP 03704477A EP 1474149 A2 EP1474149 A2 EP 1474149A2
Authority
EP
European Patent Office
Prior art keywords
amino
group
oxo
alkyl
quinazoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03704477A
Other languages
German (de)
French (fr)
Inventor
Birgit Jung
Hubert PÜSCHNER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1474149A2 publication Critical patent/EP1474149A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention is the use of quinazolines of the general formula
  • the compounds are also useful in the treatment of inflammatory diseases of the gastrointestinal tract or bile duct or gall bladder associated with impaired activity of the tyrosine kinases, e.g. in acute or chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, ulcers or polyposis in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion such as M. Menetrier, secreting adenomas or protein loss syndromes,
  • inflammatory diseases of the joints such as rheumatoid arthritis
  • inflammatory diseases of the skin, eyes in inflammatory pseudopolyps, in colitis cystica profunda or in pneumatosis cystoides intestinales.
  • Preferred areas of application include inflammatory diseases of the respiratory organs or of the intestine, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestine.
  • COPD chronic bronchitis
  • chronic sinusitis asthma, Crohn's disease, ulcerative colitis or polyposis of the intestine.
  • Particularly preferred indications are inflammatory diseases of the respiratory tract or the lungs, such as chronic bronchitis (COPD) or asthma.
  • COPD chronic bronchitis
  • X is a nitrogen atom or a carbon atom substituted by a cyano group
  • R a represents a hydrogen atom or a C 1-4 -alkyl group
  • R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
  • R 1 and R 2 which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • A is an oxygen atom or a substituted optionally by a C- ⁇ - 4 alkyl imino group
  • B is a bond, a carbonyl or sulfonyl group
  • C is a methylene, ethylene or ethenylene group, n one of the numbers 0 or 1,
  • D is an amino, C alkylamino, C 3-5 cycloalkylamino or di- (C ⁇ - 4 alkyl) amino or di (C 3-5 cycloalkyl) amino group in which the alkyl and cycloalkyl moieties may be the same or different,
  • R 3 is a hydroxy, C ⁇ . 4 alkoxy, C ⁇ - alkoxycarbonyl, amino, C M alkylamino or di- (C ⁇ - 4 alkyl) amino group,
  • N- (C ⁇ - 4- alkyl) -N- (C2- 4 -alkyl) -amino group in which the alkyl moieties in the ß, ⁇ or ⁇ position to the nitrogen atom of the amino group may optionally be substituted by the radical R 3 where R 3 is defined as mentioned above,
  • a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 C 2 -alkyl groups, which may be substituted on either a ring carbon atom or on one of the alkyl groups by the group R 3 , R 3 being as defined above,
  • each group a methylene group in the 4 position by an oxygen or sulfur atom, by a substituted by the radical R 4 imino within, by a sulphinyl - or sulfonyl group is replaced, wherein
  • R 4 is a hydrogen atom, a C ⁇ - 4 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 _ 7 cycloalkyl, C3-7 cycloalkyl-C ⁇ ⁇ alkyl, tetra hydrofuran 3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl, C ⁇ -alkylcarbonyl, C ⁇ -alkylsulfonyl, aminocarbonyl, C ⁇ -4 -alkylamino- carbonyl represents - or di- (C ⁇ - 4 alkyl) -aminocarbonyl distr,
  • a morpholino or 2-oxo-morpholin-4-yl group the C- ⁇ - by a methyl, ethyl or 3 alkoxymethyl group may be substituted,
  • R c is a hydrogen atom, a C ⁇ ⁇ alkoxy C ⁇ _ 4 alkoxy, C alkoxy, C 4-7 cycloalkoxy, or C. 3 7 cycloalkyl-C ⁇ - alkoxy group 6, in which the cycloalkyl moiety in each case by a C ⁇ -3 -AlkyI-, hydroxy, C ⁇ - 4 alkoxy, amino, C ⁇ - 4 alkylamino, di- (C ⁇ - 4 -alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino, N- (C ⁇ _ 2 ⁇ - alkyl) -piperazino-, hydroxy-C 2 -alkyl-, C ⁇ - 4- alkoxy-C ⁇ 2 - alkyl, amino-2 C ⁇ - alkyl, C alkylamino C- ⁇ - 2 alkyl, Pyrrolidino-C ⁇ - 2- alkyl, Piperidino- C ⁇ -2-al
  • N- (C 1. 2, alkyl) piperazino-C. 1 2- alkyl group may be substituted, wherein the above-mentioned monosubstituted cycloalkyl moieties may be additionally substituted by a C- ⁇ - 3 alkyl group, or
  • R 6 -C 1-4 -alkyl in the 4-position by an R 6 -C 1-4 -alkyl, R 6 -CO-, R 6 -C ⁇ -4 -alkylene-CO, (R 5 NR 7 ) -C ⁇ alkylene-CO-
  • R 7 is OC 1-4 -alkylene-CO-, R ⁇ -d ⁇ -alkylene-CO-
  • R 7 is SO-C 1-4 -alkylene-CO- or R 7 SO 2 -CC-4-alkylene-CO Group substituted piperazino or homopiperazino group, in which
  • R 5 represents a hydrogen atom or a C- M- alkyl group
  • R ⁇ an optionally by one or two C.
  • a morpholino-C ⁇ _ 4 -alkoxy or 2-oxo-morpholin-4-yl-C ⁇ - 6 -alkoxy distr which may be substituted by 1 or 2 methyl or ethyl groups, or
  • each mono-substituted by R 8, R 9 by mono-, di- or tri-substituted or mono-substituted by R 8 and additionally mono- or disubstituted by R 9 may wherein the substituents may be the same or different, wherein
  • R 8 is a cyano, carboxy, C ⁇ -4 alkoxycarbonyl, aminocarbonyl, C ⁇ -4 alkyl aminocarbonyl, di (C 1-4 alkyl) aminocarbonyl, C ⁇ - 4 alkylsulfenyl, -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, hydroxy, C 1 -C 4 -alkylsulfonyloxy, trifluoromethyloxy,
  • 6- to 7-membered Alkylenimino judgment each one methylene group in the 4-position by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (-C.-alkyl) -imino group may be replaced, and
  • R 9 is a fluorine, chlorine, bromine or iodine atom, a C ⁇ - 4 alkyl, trifluoromethyl or
  • a preferred object is the use according to the invention of the compounds of general formula (I) in which X is a nitrogen atom or a carbon atom substituted by a cyano group,
  • R a is a hydrogen atom or a C ⁇ - 4 alkyl group
  • R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
  • R and R 2 which may be the same or different, each represents a hydrogen
  • A is an oxygen atom or an imino group optionally substituted by a C 1-4 -alkyl group
  • B is a bond or a carbonyl group
  • C is a methylene, ethylene or ethenylene group
  • n one of the numbers 0 or 1
  • an N- (C 1 4 alkyl.) -N- (C 2-4 alkyl) amino group in which the alkyl moieties in SS, ⁇ - or ⁇ -position to the nitrogen atom of the amino group is optionally substituted by the radical R 3 is substituted can be R 3 is a hydroxy, C 1-3 alkoxy, C ⁇ -3 alkoxycarbonyl, amino, Cw alkylamino or di- (C ⁇ - 4 alkyl) amino group,
  • a 5- to 7-membered alkyleneimino group optionally substituted by 1 to 2 methyl groups, which may be substituted on either a ring carbon atom or on one of the methyl groups by the group R 3 , wherein R 3 is defined as mentioned above,
  • R 4 is a hydrogen atom, a -C. 3 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3- 6 cycloalkyl, C. 3 6 -cycloalkyl-C ⁇ . 3- alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl-, -C. 3- alkyl carbonyl, C ⁇ - 3 represents alkylsulfonyl, aminocarbonyl, C ⁇ -3 alkylaminocarbonyl or di (Ci.s-AlkylJ-aminocarbonyl,
  • a morpholino or 2-oxo-morpholin-4-yl group which may be substituted by a methyl, ethyl or C ⁇ -3 alkoxymethyl group,
  • R G is a hydrogen atom, a C- alkoxy, C 4-7 cycloalkoxy or C 3-7 cycloalkyl-C ⁇ . 4 -alkoxy, in which the cycloalkyl part in each case by a -C. 3- alkyl or C 1-3 alkoxy group may be substituted,
  • R 6 is an optionally substituted by one or two C ⁇ - 2 alkyl-substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl- or
  • a morpholino-C ⁇ - 4 -alkoxy- or 2-oxo-morpholin-4-yl -C. 6 -alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or
  • a particularly preferred object is the use according to the invention of the compounds of the general formula (I) in which
  • X is a nitrogen atom or a carbon atom substituted by a cyano group
  • R a is a hydrogen atom
  • R b is a phenyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 and R 2 is substituted, wherein
  • R 1 and R 2 which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom,
  • a -C. 4 alkyl, C 2 - 5 alkenyl or C 2 - 5 alkynyl group represents,
  • A is an oxygen atom or an imino group
  • B is a bond or a carbonyl group
  • C is a methylene, ethylene or ethenylene group
  • n one of the numbers 0 or 1
  • D is a di (C 1 -C 4) alkylamino group in which the alkyl moieties may be identical or different,
  • N- (C ⁇ -4- alkyl) -N- (C 2-4 -alkyl) -amino group in which the alkyl moieties in the ⁇ -, ⁇ - or ⁇ -position to the nitrogen atom of the amino group may optionally be substituted by the radical R 3 can, being
  • R 3 is a -C 3 -alkoxy or -C. 3- alkoxycarbonyl group
  • R c is a hydrogen atom, a C ⁇ - 4 -alkoxy-C ⁇ -4-alkoxy, C- alkoxy, C4 7 cycloalkoxy, or Cs ⁇ cycloalkyl-Ci ⁇ alkoxy group in which the cycloalkyl moiety in each case by a C ⁇ _ 3- alkyl or C 3-alkoxy group may be substituted, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C ⁇ -3 -alkyloxy, 3-pyrrolidinyl -C. 3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl C ⁇ .
  • R ⁇ is optionally substituted by one or two C ⁇ _ 2 alkyl groups substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4- (C ⁇ - 4- alkyl ) -morpholinyl group,
  • Another object of the present invention is a method for the treatment of
  • Respiratory and pulmonary diseases associated with increased or altered mucus production e.g. in respiratory diseases of the respiratory tract such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, 1-antitrypsin deficiency, or cough, emphysema, pulmonary fibrosis and hyperreactive airways,
  • respiratory diseases of the respiratory tract such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, 1-antitrypsin deficiency, or cough, emphysema, pulmonary fibrosis and hyperreactive airways,
  • inflammatory diseases of the gastrointestinal tract and the bile ducts and gall bladder associated with impaired activity of the tyrosine kinases e.g. in acute or chronic inflammatory conditions, such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers and polyposis in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion such as M. Menetrier, secreting adenomas and protein loss syndromes,
  • inflammatory diseases of the joints such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, in inflammatory pseudopolyps, as well as in colitis cystica profunda and in pneumatosis cystoides intestinales,
  • Preferred and particularly preferred embodiments of the method according to the invention correspond in terms of the compounds and the indications to the embodiments mentioned above for the use according to the invention.
  • the compounds mentioned in dosages of 0.001-10 mg / kg body weight, preferably at 0.01-1, 5 mg / kg are used, wherein the administration is expediently 1 to 3 times a day.
  • the active ingredients may be administered orally, buccally, parenterally, by inhalation nebulization, rectally or topically.
  • Parenteral administration may include subcutaneous, intravenous, and intramuscular injections and infusion techniques.
  • customary administration forms can be used, for example those mentioned in the abovementioned administration forms cited above for the active substances.
  • the active ingredients optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, e.g.
  • lactose cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or its suitable mixtures, in common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
  • the active ingredients may be administered orally in a wide variety of different dosage forms, for example, together with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, troches, cookies, hard candies, powders, vaporizers, aqueous suspensions, elixirs, syrups and the like be formulated.
  • Such carriers include, for example, solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents.
  • such oral formulations are suitably sweetened and / or flavored by means of various agents commonly used for this purpose.
  • the active ingredients are present in such oral dosage forms with concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts sufficient to provide the desired dosage units.
  • Other suitable dosage forms for the active agents include controlled release formulations and devices well known to those skilled in the art.
  • solutions of the active ingredients in sesame or peanut oil or in aqueous propylene glycol are useful as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent made isotonic with sufficient salt or glucose.
  • these particular aqueous solutions are particularly suitable for the purpose of intravenous, intramuscular and subcutaneous injections.
  • the sterile aqueous media used are readily available by conventional techniques well known to those skilled in the art.
  • the dosage form of the particular compound or compounds may include, for example, solutions, lotions, ointments, creams, gels, suppositories, sustained rate release formulations, and devices thereto.
  • dosage forms include the particular compound (s) and may include ethanol, water, penetrant, and inert carriers such as gel generators, mineral oil, emulsifiers, benzyl alcohol and the like.
  • Inhaled administration takes place in the form of powder formulations with lactose and other excipients or in the form of aqueous solutions as aerosol.
  • the inhalable powders which can be used in the context of the use according to the invention may contain the active ingredient or the active ingredient combination either alone or in admixture with suitable physiologically acceptable auxiliaries.
  • physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and Polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • oligo- and Polysaccharides eg dextrans
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • lactose preferably lactose monohydrate
  • lactose monohydrate is used as excipient.
  • the propellant-containing inhalable inhalation aerosols which can be used in the context of the inventive use can dissolve the active ingredient or the active ingredient combination in the propellant gas or contain it in dispersed form.
  • the propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusting agents. All of these ingredients are known in the art.
  • the inhalative administration of the active compound according to the invention or the active ingredient combination in the form of propellant-free solutions or suspensions come as a solvent aqueous or alcoholic, preferably ethanolic solutions into consideration.
  • the solvent may be water only or it may be a mixture of water and ethanol.
  • the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume. The remaining volume percentages are filled up with water.
  • the solutions or suspensions containing the active ingredient or combination of active ingredients are optionally adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids.
  • acids selected from inorganic or organic acids can be used;
  • inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid.
  • ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • the compounds of the general formula (I) and their salts have valuable properties, in particular an antiinflammatory effect.
  • E 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ( ⁇ 4- [bis (2-methoxyethyl) -amino] -1-oxo-2-buten-1-yl ⁇ -amino ) -7-cyclopropylmethoxy-quinazoline,
  • G 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy -quinazoline,
  • H 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ⁇ [4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2 buten-1-yl] amino ⁇ -7-cyclopropylmethoxy-quinazoline,
  • K 4 - [(R) - (1-phenylethyl) amino] -6 - ⁇ [4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1 -ylamino ⁇ -7-cyclopropylmethoxyquinazoline,
  • Test 1 Inhibition of the smoke-induced accumulation of granulocytes in the lung tissue
  • Pulmonary indications Inhibition of the cigarette smoke-induced influx of neutrophilic granulocytes into the lung tissue by the EGF receptor kinase inhibitor 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((S) -6- methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline.
  • mice Male rats (strain: Sprague-Dawley) weighing 250-300 g were exposed to the smoke of 8 cigarettes per day for 5 days.
  • the animals in which with 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] - 7-methoxy-quinazoline (Compound A) -treated group received intratracheal administration of 0.03 or 0.1 mg / kg of Compound A in a volume of 0.05 ml daily 30 min before the onset of smoking exposure under anesthesia with isoflurane.
  • Test 2 Demonstration of a general anti-inflammatory mode of action
  • Inhibitor 4 [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine (Compound N).
  • MPO myeloperoxidase
  • the homogenates were centrifuged off at 15700 g in an Eppendorf bench centrifuge for 5 min at room temperature. From the supernatant, 50 ml was taken and mixed with 250 ml of phosphate buffer (50 mmol / l) containing 0.197 mg / ml of O-dianisidine dihydrochloride. After a 10 minute incubation at room temperature, absorption was measured with a spectrophotometer at a wavelength of 450 nm.
  • Intradermal injection of zymosan resulted in a marked increase in tissue MPO activity.
  • Treatment of the animals with the EGFR kinase inhibitor 4- [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-diphyridine] significantly inhibited this increase ( p ⁇ 0.005) to 60%.
  • the reaction is mixed with water and methylene chloride and made alkaline with sodium hydroxide solution.
  • the separated aqueous phase is extracted again with methylene chloride and a little methanol.
  • the combined organic extracts are washed with water, dried and concentrated. There remains a yellow resin, which is chromatographed on a silica gel column with methylene chloride / methanol (98: 2) as the eluent.
  • the desired product is stirred with a little te / iButylmethyether, the finely crystalline precipitate is filtered off, washed with feft butyl methyl ether and dried at 50 ° C in a vacuum.
  • Example 3 Analogously to Example 3, the following compounds are obtained: (1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino ⁇ - 7-cyclopropylmethoxy-quinazoline
  • the crude product is then taken up in 10 ml of methylene chloride and, with ice bath cooling, within five minutes to a mixture of 1.0 g of 6-amino-4- [(3-methylphenyl) amino] -7-methoxy-quinazoline and 2.0 ml of Hünig base in the 50th ml of tetrahydrofuran was added dropwise.
  • the reaction mixture is stirred for two hours under ice-bath cooling and for a further two hours at room temperature.
  • 6.7 ml of Hünig base 5.48 g of sarcosine ethyl ester hydrochloride and 3 ml of dimethylformamide are added and the whole is stirred overnight at room temperature.
  • reaction mixture is in a Cooled ice water bath, mixed with 75 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution and stirred vigorously for 10 minutes.
  • the organic phase is separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate.
  • the solvent is distilled off in vacuo, leaving a brownish foam.
  • reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution.
  • the organic phase is dried over magnesium sulfate and concentrated in vacuo.
  • the flask residue is stirred with diethyl ether and filtered with suction.
  • the title compound is obtained as a white solid. Yield: 280 mg (85% of theory), m.p .: 190 ° C
  • the crude bromocrotonic acid chloride is taken up in 30 ml of methylene chloride and, with ice-bath cooling, to a solution of 7.00 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-amino-7-cyclopropylmethoxy-quinazoline and 10.20 ml Hünigbase added dropwise in 150 ml of tetrahydrofuran.
  • the reaction mixture is stirred for about 1.5 hours under ice-bath cooling and for a further two hours at room temperature.
  • 5.20 g of N- (2-methoxy-ethyl) -N-methyl-amine are added and the reaction mixture is stirred overnight at room temperature.
  • FIG. 1 describes the inhibition of the smoke-induced accumulation of neutrophilic granulocytes.
  • Figure 2 describes the inhibition of zymosan-induced neutrophil influx at the mouse ear.

Abstract

The invention relates to the use of quinazolines of general formula (1) wherein A, B, C, D, X, Ra, Rb, Rc and n have the designations defined in claim 1, or the compounds (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]-pyrimido[5,4-d]pyrimidine, (2) 4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, (3) 4-{[3-chloro-4-(3-fluoro-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}-furan-2-yl)quinazoline, or the antibodies Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 and EGFR-antisense, and the tautomers, stereoisomers and salts thereof, especially the physiologically compatible salts thereof comprising inorganic or organic acids or bases, for producing a medicament for the prevention or treatment of respiratory tract diseases or pulmonary diseases.

Description

(54) Bezeichnung: VERWENDUNG VON TYROSINKINASE-INHIBITOREN ZUR BEHANDLUNG INFLAMMATORI- SCHER PROZESSE(54) Title: USE OF TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF INFLAMMATORY PROCESSES
Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer ProzesseUse of tyrosine kinase inhibitors for the treatment of inflammatory processes
Gegenstand der vorliegenden Erfindung ist die Verwendung von Chinazolinen der allgemeinen FormelThe present invention is the use of quinazolines of the general formula
0 in der A, B, C, D, X, Ra, Rb, Rc und n wie in Anspruch 1 definiert sind, oder0 in which A, B, C, D, X, R a , R b , R c and n are as defined in claim 1, or
der Verbindungenthe connections
(1) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- 5 pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) amino] -5-pyrimido [5,4-d] pyrimidine,
(2) 4-[(R)-(1-Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin,(2) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyI- 0 ethyl)amino]methyl}-furan-2-yl)chinazolin oder(3) 4 - {[3-chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyloxy) amino] methyl} -furan 2-yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
5 deren Tautomere, deren Stereoisomere und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, zur Herstellung eines Arzneimittels zur Vorbeugung und Behandlung von Erkrankungen der Atemwege oder der Lunge, die mit einer vermehrten oder veränderten Schleimproduktion einhergehen, wie z.B. bei entzündlichen Erkrankungen der Atemwege wie akute Bronchitis, chronische Bronchitis, chronisch obstruktive Bronchitis (COPD), Asthma, Bronchiektasien, allergische oder nicht- allergische Rhinitis oder Sinusitis, zystische Fibröse, α1-Antitrypsin-Mangel, bei Husten, Lungenemphysem, Lungenfibrose oder hyperreaktiven Atemwegen.5 their tautomers, their stereoisomers and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, for the preparation of a medicament for the prevention and treatment of Respiratory or pulmonary disorders associated with increased or altered mucus production, such as respiratory tract inflammatory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, Cystic fibrosis, α1-antitrypsin deficiency, cough, emphysema, pulmonary fibrosis or hyperresponsive airways.
Ferner sind die Verbindungen auch geeignet zur Behandlung entzündlicher Erkrankungen des Magen-Darm-Traktes oder der Gallengänge oder Gallenblase, die mit einer gestörten Aktivität der Tyrosinkinasen einhergehen, wie sie z.B. bei akuten oder chronisch entzündlichen Veränderungen zu finden sind, wie Cholezystitis, M. Crohn, Colitis ulcerosa, Geschwüren oder bei Polyposis 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 oder Proteinverlustsyndrome,Further, the compounds are also useful in the treatment of inflammatory diseases of the gastrointestinal tract or bile duct or gall bladder associated with impaired activity of the tyrosine kinases, e.g. in acute or chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, ulcers or polyposis in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion such as M. Menetrier, secreting adenomas or protein loss syndromes,
desweiteren zur Behandlung von entzündlichen Erkrankungen der Gelenke, wie rheumatoider Arthritis, von entzündlichen Erkrankungen der Haut, der Augen, bei entzündlichen Pseudopolypen, bei Colitis cystica profunda oder bei Pneumatosis cystoides intestinales.in addition, for the treatment of inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, in inflammatory pseudopolyps, in colitis cystica profunda or in pneumatosis cystoides intestinales.
Als bevorzugte Anwendungsgebiete seien entzündliche Erkrankungen der Atemwegsorgane oder des Darmes genannt, wie chronische Bronchitis (COPD), chronische Sinusitis, Asthma, M. Crohn, Colitis ulcerosa oder Polyposis des Darmes.Preferred areas of application include inflammatory diseases of the respiratory organs or of the intestine, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestine.
Besonders bevorzugte Anwendungsgebiete sind entzündliche Erkrankungen der Atemwege oder der Lunge wie chronische Bronchitis (COPD) oder Asthma.Particularly preferred indications are inflammatory diseases of the respiratory tract or the lungs, such as chronic bronchitis (COPD) or asthma.
In der obigen allgemeinen Formel (I) bedeutetIn the above general formula (I)
X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoffatom,X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom oder eine C^-Alkylgruppe, Rb eine Phenyl-, Benzyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert sein kann, wobeiR a represents a hydrogen atom or a C 1-4 -alkyl group, R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor-, Brom- oder Jodatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
eine C- -Alkyl-, Hydroxy-, C3-6-Cycloalkyl-, C4-6-Cycloalkoxy-, C2-5-Alkenyl- oder C2-5-Alkinylgruppe,a C 1-4 alkyl, hydroxy, C 3 - 6 cycloalkyl, C 4 - 6 cycloalkoxy, C 2-5 alkenyl, or C 2 - 5 alkynyl group,
eine Aryl-, Aryloxy-, Arylmethyl- oder Arylmethoxygruppe,an aryl, aryloxy, arylmethyl or arylmethoxy group,
eine C3-5-Alkenyloxy- oder C3-5-Alkinyloxygruppe, wobei die Mehrfachbindung vom Sauerstoffatom isoliert ist,a C 3-5 alkenyloxy or C 3-5 alkynyloxy group wherein the multiple bond is isolated from the oxygen atom,
eine C -Alkylsulfenyl-, Cι-4-Alkylsulfonyl-, C- -Alkylsulfonyl- oxy-, Trifluormethylsulfenyl-, Trifluormethylsulfinyl- oder Trifluormethylsuifonyl- gruppe,a C-alkyl sulfenyl, Cι- 4 alkylsulfonyl, C alkylsulfonyl oxy, Trifluormethylsulfenyl-, trifluoromethylsulphinyl or Trifluormethylsuifonyl- group,
eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe,a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
eine durch 1 bis 5 Fluoratome substituierte Ethyl- oder Ethoxygruppe,an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
eine Cyano- oder Nitrogruppe oder eine gegebenenfalls durch eine oder zwei Cι-4-Alkylgruppen substituierte Aminogruppe, wobei die Substituenten gleich oder verschieden sein können,a cyano or nitro group or an optionally substituted by one or two Cι- 4 alkyl amino group, wherein the substituents may be identical or different,
A ein Sauerstoffatom oder eine gegebenenfalls durch eine C-ι-4-Alkylgruppe substituierte Iminogruppe,A is an oxygen atom or a substituted optionally by a C-ι- 4 alkyl imino group,
B eine Bindung, eine Carbonyl- oder Sulfonylgruppe,B is a bond, a carbonyl or sulfonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe, n eine der Zahlen 0 oder 1 ,C is a methylene, ethylene or ethenylene group, n one of the numbers 0 or 1,
D eine Amino-, C- -Alkylamino-, C3-5-Cycloalkylamino- oder Di-(Cι-4-Alkyl)-amino- oder Di-(C3-5-Cycloalkyl)-aminogruppe, in der die Alkyl- und Cycloalkylteile gleich oder verschieden sein können,D is an amino, C alkylamino, C 3-5 cycloalkylamino or di- (Cι- 4 alkyl) amino or di (C 3-5 cycloalkyl) amino group in which the alkyl and cycloalkyl moieties may be the same or different,
eine C2-4-Alkylaminogruppe, in der der Alkylteil in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert ist, wobeia C 2-4 alkylamino group in which the alkyl moiety in .beta. γ-, or δ-position is substituted to the nitrogen atom of the amino group by the group R 3, wherein
R3 eine Hydroxy-, Cι.4-Alkoxy-, Cι- -Alkoxycarbonyl-, Amino-, CM-Alkylamino- oder Di-(Cι-4-Alkyl)-aminogruppe,R 3 is a hydroxy, Cι. 4 alkoxy, Cι- alkoxycarbonyl, amino, C M alkylamino or di- (Cι- 4 alkyl) amino group,
eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte 4- bis 7- gliedrige Alkyleniminogruppe oderan optionally substituted by one or two methyl groups 4- to 7-membered alkyleneimino group or
eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte 6- bis 7- gliedrige Alkyleniminogruppe, in der jeweils eine Methylengruppe in Position 4 durch ein Sauerstoff- oder Schwefelatom, durch eine Sulfinyl-, Sulfonyl-, Imino- oder N-(Cι-4-Alkyl)-iminogruppe ersetzt ist, darstellt,an optionally substituted by one or two methyl groups 6- to 7-membered Alkyleniminogruppe, in each of which a methylene group in position 4 by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (Cι- 4 alkyl ) imino group is replaced,
eine N-(Cι-4-Alkyl)-N-(C2-4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobei R3 wie vorstehend erwähnt definiert ist,an N- (Cι- 4- alkyl) -N- (C2- 4 -alkyl) -amino group, in which the alkyl moieties in the ß, γ or δ position to the nitrogen atom of the amino group may optionally be substituted by the radical R 3 where R 3 is defined as mentioned above,
eine Di-(C2-4-Alkyl)-aminogruppe, in der beide C-2-4-Alkylteile jeweils in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert sind, wobei die Substituenten gleich oder verschieden sein können und R3 wie vorstehend erwähnt definiert ist,a di- (C 2 -4 alkyl) amino group in which both C-2 4 -Alkylteile in each SS, γ- or δ-position to the nitrogen atom of the amino group by the group R 3 are substituted, wherein the substituents may be the same or different and R 3 is as defined above,
eine C3-7-Cycloalkylamino- oder C3-7-Cycloalkyl-Cι.3-alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine weitere Cι_4-Alkylgruppe substituiert sein kann,a C 3-7 cycloalkylamino or C 3-7 cycloalkyl-Cι. 3 alkylamino, in each of which the nitrogen atom may be substituted by a further Cι_-C4 alkyl group,
eine Amino- oder Cι-4-Alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine gegebenenfalls durch 1 bis 3 Cι-4-Alkylgruppen substituierte Tetrahydrofuran- 3-yl-, Tetrahydropyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, 1 -(Tetrahydrofuran-3-yl)-piperidin-4-yl-, 1 -(Tetrahydropyran-3-yl)-piperidin-4-yI-,an amino or alkylamino group Cι- 4, in each of which the nitrogen atom by an optionally substituted by 1 to 3 alkyl groups Cι -4 tetrahydrofuran 3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1- (tetrahydrofuran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran-3-yl) -piperidine -4-Yi,
1-(Tetrahydropyran-4-yl)-piperidin-4-yl-, 3-Pyrrolidinyl-, 3-Piperidinyl-, 4-Piperidinyl-, 3-Hexahydro-azepinyl- oder 4-Hexahydro-azepinylgruppe substituiert ist,1- (tetrahydropyran-4-yl) -piperidin-4-yl, 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or 4-hexahydro-azepinyl group is substituted,
eine gegebenenfalls durch 1 bis 4 Cι-2-Alkylgruppen substituierte 4- bis 7-gliedrige Alkyleniminogruppe, die entweder an einem Ringkohlenstoffatom oder an einer der Alkylgruppen durch die Gruppe R3 substituiert sein kann, wobei R3 wie vorstehend erwähnt definiert ist,a 4- to 7-membered alkyleneimino group, optionally substituted by 1 to 4 C 2 -alkyl groups, which may be substituted on either a ring carbon atom or on one of the alkyl groups by the group R 3 , R 3 being as defined above,
eine durch eine Tetrahydrofuranyl-, Tetrahydropyranyl- oder Tetrahydrofuranyl- methylgruppe substituierte Piperidinogruppe,a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranyl methyl group,
eine gegebenenfalls durch 1 oder 2 Cι_2-Alkylgruppen substituierte 6- bis 7-gliedrige Alkyleniminogruppe, in der jeweils eine Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Imino- gruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobeioptionally substituted by 1 or 2 Cι_ 2 alkyl substituted 6- to 7-membered alkyleneimino, each group a methylene group in the 4 position by an oxygen or sulfur atom, by a substituted by the radical R 4 imino within, by a sulphinyl - or sulfonyl group is replaced, wherein
R4 ein Wasserstoffatom, eine Cι-4-Alkyl-, 2-Methoxy-ethyl-, 3-Methoxy-propyl-, C3_7-Cycloalkyl-, C3-7-Cycloalkyl-Cι^-alkyl-, Tetra hydrofuran-3-yl-, Tetrahydro- pyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, Formyl-, C^-Alkylcarbonyl-, C^-Alkylsulfonyl-, Aminocarbonyl-, Cι-4-Alkylamino- carbonyl- oder Di-(Cι-4-Alkyl)-aminocarbonylgruppe darstellt,R 4 is a hydrogen atom, a Cι- 4 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 _ 7 cycloalkyl, C3-7 cycloalkyl-Cι ^ alkyl, tetra hydrofuran 3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl, C ^ -alkylcarbonyl, C ^ -alkylsulfonyl, aminocarbonyl, Cι -4 -alkylamino- carbonyl represents - or di- (Cι- 4 alkyl) -aminocarbonylgruppe,
eine Morpholino- oder 2-Oxo-morpholin-4-yl-Gruppe, die durch eine Methyl-, Ethyl- oder C-ι-3-Alkoxymethylgruppe substituiert sein kann,a morpholino or 2-oxo-morpholin-4-yl group, the C-ι- by a methyl, ethyl or 3 alkoxymethyl group may be substituted,
eine gegebenenfalls durch 1 bis 3 Methylgruppen substituierte Imidazolylgruppe,an imidazolyl group optionally substituted by 1 to 3 methyl groups,
eine Cs^-Cycloalkylgruppe, in der eine Methylengruppe durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Iminogruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobei R4 wie vorstehend erwähnt definiert ist, eine Hydroxy- oder oder aucha Cs ^ cycloalkyl group in which a methylene group is replaced by an oxygen or sulfur atom, by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, R 4 being as defined above, a hydroxy or or
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
Rc ein Wasserstoffatom, eine Cι^-Alkoxy-Cι_4-alkoxy-, C- -Alkoxy-, C4-7-Cycloalkoxy- oder C3.7-Cycloalkyl-Cι-6-alkoxygruppe, in denen der Cycloalkylteil jeweils durch eine Cι-3-AlkyI-, Hydroxy-, Cι-4-Alkoxy-, Amino-, Cι-4-Alkylamino-, Di-(Cι-4-alkyl)-amino-, Pyrrolidino-, Piperidino-, Morpholino-, Piperazino-, N-(Cι_2ι-Alkyl)-piperazino-, Hydroxy-Cι-2-alkyl-, Cι-4-Alkoxy-Cι-2-alkyl-, Amino-Cι-2-alkyl-, C -Alkylamino- C-ι-2-alkyl-, Pyrrolidino-Cι-2-alkyl-, Piperidino- Cι-2-alkyl-, Morpholino-Cι.2-alkyl-, Piperazino-Cι-2-alkyl- oderR c is a hydrogen atom, a Cι ^ alkoxy Cι_ 4 alkoxy, C alkoxy, C 4-7 cycloalkoxy, or C. 3 7 cycloalkyl-Cι- alkoxy group 6, in which the cycloalkyl moiety in each case by a Cι -3 -AlkyI-, hydroxy, Cι- 4 alkoxy, amino, Cι- 4 alkylamino, di- (Cι- 4 -alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino, N- (Cι_ 2ι- alkyl) -piperazino-, hydroxy-C 2 -alkyl-, Cι- 4- alkoxy-Cι 2 - alkyl, amino-2 Cι- alkyl, C alkylamino C-ι- 2 alkyl, Pyrrolidino-Cι- 2- alkyl, Piperidino- Cι-2-alkyl, Morpholino-Cι. 2- alkyl, Piperazino-Cι -2 alkyl or
N-(C1.2-Alkyl)-piperazino-C1.2-alkylgruppe substituiert sein kann, wobei die vorstehend erwähnten monosubstituierten Cycloalkylteile zusätzlich durch eine C-ι-3-Alkylgruppe substituiert sein können, oderN- (C 1. 2, alkyl) piperazino-C. 1 2- alkyl group may be substituted, wherein the above-mentioned monosubstituted cycloalkyl moieties may be additionally substituted by a C-ι- 3 alkyl group, or
eine ,3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-4-alkyloxy-, 3-PyrrolidinyS-Cι_4-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-Cι-4-alkyloxy-, 3-Piperidinyl- Cι-4-alkyloxy-, 4-Piperidinyl-Cι-4-alkyloxy-, 3-Hexahydro-azepinyloxy-, 4-Hexahydro- azepinyloxy-, 2-Hexahydro-azepinyl-Cι-4-alkyloxy-, 3-Hexahydro-azepinyl- C-ι-4-alkyloxy- oder 4-Hexahydro-azepinyl-Cι-4-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,a, 3-pyrrolidinyloxy, 2-pyrrolidinyl-Cι -4 alkyloxy, 3-PyrrolidinyS Cι_-4 alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl Cι- 4 alkyloxy, 3 -Piperidinyl- Cι- 4 alkyloxy, 4-piperidinyl-Cι- 4 alkyloxy, 3-hexahydro-azepinyloxy-, azepinyloxy- hexahydro-4, 2-hexahydro-azepinyl-Cι- 4 alkyloxy, 3- hexahydro-azepinyl C-ι-4-alkyloxy or 4-hexahydro-azepinyl-Cι- 4 alkyloxy group, in which the ring nitrogen atom is substituted by the radical R 4 respectively, wherein R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-C1-4-alkyl-, R6-CO-, R6-Cι-4-alkylen-CO-, (R5NR7)-C^-alkylen-CO-, R7O-C1-4-alkylen-CO-, R^-d^-alkylen-CO-, R7SO-C1-4- alkylen-CO- oder R7SO2-Cι-4-alkylen-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denenin the 4-position by an R 6 -C 1-4 -alkyl, R 6 -CO-, R 6 -Cι -4 -alkylene-CO, (R 5 NR 7 ) -C ^ alkylene-CO- , R 7 is OC 1-4 -alkylene-CO-, R ^ -d ^ -alkylene-CO-, R 7 is SO-C 1-4 -alkylene-CO- or R 7 SO 2 -CC-4-alkylene-CO Group substituted piperazino or homopiperazino group, in which
R5 ein Wasserstoffatom oder eine C-M-Alkylgruppe bedeutet,R 5 represents a hydrogen atom or a C- M- alkyl group,
Rδ eine gegebenenfalls durch eine oder zwei Cι.2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oder 2-Oxo-4-(Cι-4-alkyl)-morpholinylgruppe und R7 eine gegebenenfalls durch eine oder zwei Cι_2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuran-3-yl-, 2-Oxo-tetrahydrofuran-4-yl-, 2-Oxo-tetrahydro- pyran-3-yl-, 2-Oxo-tetrahydropyran-4-yl- oder 2-Oxo-tetrahydropyran-5-yl-Grup- pe bedeuten,R δ an optionally by one or two C. 2- alkyl-substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4- (Cι -4 -alkyl) -morpholinylgruppe and R 7 is a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, optionally substituted by one or two Cι_ 2 alkyl groups, 2- Oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group,
eine Morpholino-Cι_4-alkoxy- oder 2-Oxo-morpholin-4-yl-Cι-6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, odera morpholino-Cι_ 4 -alkoxy or 2-oxo-morpholin-4-yl-Cι- 6 -alkoxygruppe, which may be substituted by 1 or 2 methyl or ethyl groups, or
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe.a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group.
Unter den bei der Definition der vorstehend erwähnten Reste erwähnten Arylteilen ist eine Phenylgruppe zu verstehen, die jeweils durch R8 monosubstituiert, durch R9 mono-, di- oder trisubstituiert oder durch R8 monosubstituiert und zusätzlich durch R9 mono- oder disubstituiert sein kann, wobei die Substituenten gleich oder verschieden sein können, wobeiAmong the mentioned in the definition of the above-mentioned groups is a phenyl group aryl portions to be understood that each mono-substituted by R 8, R 9 by mono-, di- or tri-substituted or mono-substituted by R 8 and additionally mono- or disubstituted by R 9 may wherein the substituents may be the same or different, wherein
R8 eine Cyano-, Carboxy-, Cι-4-Alkoxycarbonyl-, Aminocarbonyl-, Cι-4-Alkyl- aminocarbonyl-, Di-(C1-4-alkyl)-aminocarbonyl-, Cι-4-Alkylsulfenyl-, Cι-4-Alkyl- sulfinyl-, C^-Alkylsulfonyl-, Hydroxy-, Cι- -Alkylsulfonyloxy-, Trifluormethyloxy-,R 8 is a cyano, carboxy, Cι -4 alkoxycarbonyl, aminocarbonyl, Cι -4 alkyl aminocarbonyl, di (C 1-4 alkyl) aminocarbonyl, Cι- 4 alkylsulfenyl, -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, hydroxy, C 1 -C 4 -alkylsulfonyloxy, trifluoromethyloxy,
Nitro-, Amino-, Cι-4-Alkylamino-, Di-(Cι-4-alkyl)-amino-, Cι-4-Alkylcarbonylamino-, N-(C1-4-Alkyl)-Cι-4-alkylcarbonylamino-, Cι-4-Alkylsulfonylamino-, N-(Cι-4-Alkyl)- Cι-4-alkylsulfonylamino-, Aminosulfonyl-, Cι-4-Alkylaminosulfonyl- oder Di- (Cι-4-Alkyl)-aminosulfonylgruppe oder eine Carbonylgruppe, die durch eine 5- bis 7-gliedrige Alkyleniminogruppe substituiert ist, wobei in den vorstehend erwähntenNitro, amino, Cι- 4 alkylamino, di- (Cι-4-alkyl) -amino, Cι- 4 alkylcarbonylamino, N- (C 1-4 alkyl) 4 -Cι- -alkylcarbonylamino- , Cι -4 alkylsulfonylamino, N- (Cι-4-alkyl) - Cι- 4 alkylsulfonylamino, aminosulfonyl, Cι- 4 alkylaminosulfonyl or di- (Cι- 4 alkyl) -aminosulfonylgruppe or a carbonyl group, which is substituted by a 5- to 7-membered Alkyleniminogruppe, wherein in the aforementioned
6- bis 7-gliedrigen Alkyleniminogruppen jeweils eine Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine Sulfinyl-, Sulfonyl-, Imino- oder N-(Cι. -Alkyl)-imino-Gruppe ersetzt sein kann, und6- to 7-membered Alkyleniminogruppen each one methylene group in the 4-position by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (-C.-alkyl) -imino group may be replaced, and
R9 ein Fluor-, Chlor-, Brom- oder Jodatom, eine Cι-4-Alkyl-, Trifluormethyl- oderR 9 is a fluorine, chlorine, bromine or iodine atom, a Cι- 4 alkyl, trifluoromethyl or
C-ι-4-Alkoxygruppe darstellen.Represent C-ι-4-alkoxy group.
Ein bevorzugter Gegenstand ist die erfindungsgemäße Verwendung der Verbindungen der allgemeinen Formel (I), in der X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoffatom,A preferred object is the use according to the invention of the compounds of general formula (I) in which X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom oder eine Cι-4-Alkylgruppe,R a is a hydrogen atom or a Cι- 4 alkyl group,
Rb eine Phenyl-, Benzyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert sein kann, wobeiR b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
R und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-,R and R 2 , which may be the same or different, each represents a hydrogen,
Fluor-, Chlor- oder Bromatom,Fluorine, chlorine or bromine atom,
eine C^-Alkyl-, Hydroxy-, C-u-Alkoxy-, C3-6-Cycloalkyl-, C^-δ-Cycloalkoxy-, C2-5-Alkenyl- oder C2-5-Alkinylgruppe,a C ^ alkyl, hydroxy, Cu-alkoxy, C 3 - 6 cycloalkyl, C ^ - δ cycloalkoxy, C 2 - 5 alkenyl or C 2 - 5 alkynyl group,
eine Methyl-, Trifluormethyl- oder Methoxygruppe darstellen,represent a methyl, trifluoromethyl or methoxy group,
A ein Sauerstoffatom oder eine gegebenenfalls durch eine C^-Alkylgruppe substituierte Iminogruppe,A is an oxygen atom or an imino group optionally substituted by a C 1-4 -alkyl group,
B eine Bindung oder eine Carbonylgruppe,B is a bond or a carbonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe,C is a methylene, ethylene or ethenylene group,
n eine der Zahlen 0 oder 1 ,n one of the numbers 0 or 1,
D eine Di-(Cι-4-Alkyl)-aminogruppe, in der die Alkylteile gleich oder verschieden sein können,D, amino group, a di- (Cι- 4 alkyl) in which the alkyl portions can be the same or different,
eine N-(C1.4-Alkyl)-N-(C2-4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobei R3 eine Hydroxy-, C1-3-Alkoxy-, Cι-3-Alkoxycarbonyl-, Amino-, C-w-Alkylamino- oder Di-(Cι-4-Alkyl)-aminogruppe,an N- (C 1 4 alkyl.) -N- (C 2-4 alkyl) amino group in which the alkyl moieties in SS, γ- or δ-position to the nitrogen atom of the amino group is optionally substituted by the radical R 3 is substituted can be R 3 is a hydroxy, C 1-3 alkoxy, Cι -3 alkoxycarbonyl, amino, Cw alkylamino or di- (Cι- 4 alkyl) amino group,
eine Pyrrolidino-, Piperidino- oder Morpholinogruppe darstellt,represents a pyrrolidino, piperidino or morpholino group,
eine Di-(C2-4-Alkyl)-aminogruppe, in der beide C2-4-Alkylteile jeweils in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert sind, wobei die Substituenten gleich oder verschieden sein können und R3 wie vorstehend erwähnt definiert ist,a di- (C 2-4 alkyl) amino group in which both C 2-4 -Alkylteile in each SS, γ- or δ-position are substituted to the nitrogen atom of the amino group by the group R 3, wherein the substituents are identical or may be different and R 3 is defined as mentioned above,
eine C3_5-Cycloalkylamino- oder C3-5-Cycloalkyl-C -3-alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine weitere Cι-4-Alkylgruppe substituiert ist,a C 3 _ 5 cycloalkylamino or C 3-5 -cycloalkyl-C alkylamino -3, in which the nitrogen atom is substituted by a further Cι- 4 alkyl group each,
eine C- -Alkylaminogruppe, in der das Stickstoffatom durch eine Tetrahydrofuran- 3-yl-, Tetrahydropyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, 1 -(Tetrahydrofuran-3-yl)-piperidin-4-yi-, 1 -(Tetrahydropyran-3-yl)-piperidin-4-yl- oder 1-(Tetrahydropyran-4-yl)-piperidin-4-yIgruppe substituiert ist,a C 1-6 -alkylamino group in which the nitrogen atom is replaced by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1- (tetrahydrofuran-3-yl) -piperidine-4- yl, 1 - (tetrahydropyran-3-yl) -piperidin-4-yl or 1- (tetrahydropyran-4-yl) -piperidin-4-yl group,
eine gegebenenfalls durch 1 bis 2 Methylgruppen substituierte 5- bis 7-gliedrige Alkyleniminogruppe, die entweder an einem Ringkohlenstoffatom oder an einer der Methylgruppen durch die Gruppe R3 substituiert sein kann, wobei R3 wie vorstehend erwähnt definiert ist,a 5- to 7-membered alkyleneimino group optionally substituted by 1 to 2 methyl groups, which may be substituted on either a ring carbon atom or on one of the methyl groups by the group R 3 , wherein R 3 is defined as mentioned above,
eine durch eine Tetrahydrofuranyl-, Tetrahydropyranyl- oder Tetrahydrofuranyl- methylgruppe substituierte Piperidinogruppe,a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranyl methyl group,
eine gegebenenfalls durch 1 oder 2 Methylgruppen substituierte Piperidinogruppe, in der die Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Imino-gruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobeian optionally substituted by 1 or 2 methyl groups piperidino group in which the methylene group is replaced in the 4-position by an oxygen or sulfur atom, by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, wherein
R4 ein Wasserstoffatom, eine Cι.3-Alkyl-, 2-Methoxy-ethyl-, 3-Methoxy-propyl-, C3-6-Cycloalkyl-, C3.6-Cycloalkyl-Cι.3-alkyl-, Tetrahydrofuran-3-yl-, Tetrahydro- pyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, Cι.3-Alkyl- carbonyl-, Cι-3-Alkylsulfonyl-, Aminocarbonyl-, Cι-3-Alkylaminocarbonyl- oder Di- (Ci.s-AlkylJ-aminocarbonylgruppe darstellt,R 4 is a hydrogen atom, a -C. 3 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3- 6 cycloalkyl, C. 3 6 -cycloalkyl-Cι. 3- alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl-, -C. 3- alkyl carbonyl, Cι- 3 represents alkylsulfonyl, aminocarbonyl, Cι -3 alkylaminocarbonyl or di (Ci.s-AlkylJ-aminocarbonyl,
eine Morpholino- oder 2-Oxo-morpholin-4-yl-Gruppe, die durch eine Methyl-, Ethyl- oder Cι-3-Alkoxymethylgruppe substituiert sein kann,a morpholino or 2-oxo-morpholin-4-yl group which may be substituted by a methyl, ethyl or Cι -3 alkoxymethyl group,
eine C5-6-Cycloalkylgruppe, in der eine Methylengruppe durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Iminogruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobei R4 wie vorstehend erwähnt definiert ist,a C 5-6 cycloalkyl group in which a methylene group is replaced by an oxygen or sulfur atom, by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, R 4 being as defined above,
eine Hydroxy- oder Cι-4-Alkoxygruppe, oder aucha hydroxy or Cι- 4 alkoxy group, or
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
RG ein Wasserstoffatom, eine C- -Alkoxy-, C4-7-Cycloalkoxy- oder C3-7-Cycloalkyl-Cι.4-alkoxygruppe, in denen der Cycloalkylteil jeweils durch eine Cι.3-Alkyl- oder Cι-3-Alkoxygruppe substituiert sein kann,R G is a hydrogen atom, a C- alkoxy, C 4-7 cycloalkoxy or C 3-7 cycloalkyl-Cι. 4 -alkoxy, in which the cycloalkyl part in each case by a -C. 3- alkyl or C 1-3 alkoxy group may be substituted,
eine 3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-Cι-3-alkyloxy-, 3-Piperidinyl- Cι_3-alkyloxy- oder 4-Piperidinyl-Cι-3-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,a 3-pyrrolidinyloxy, 2-pyrrolidinyl-Cι -3 -alkyloxy, 3-pyrrolidinyl-Cι -3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl-Cι- 3 -alkyloxy-, 3 -Piperidinyl- Cι_ 3 -alkyloxy or 4-piperidinyl-Cι- 3 -alkyloxygruppe in which each of the ring nitrogen atom is substituted by the radical R 4 , wherein R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-C1-4-alkyl-, R6-CO- oder R6-Cι-4-alkyien-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denena piperazino or homopiperazino group substituted in the 4-position by an R 6- C 1-4 -alkyl, R 6 -CO or R 6- Cι- 4- alkyl-CO-group, in which
R6 eine gegebenenfalls durch eine oder zwei Cι-2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oderR 6 is an optionally substituted by one or two Cι- 2 alkyl-substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl- or
2-Oxo-4-(Cι-4-alkyl)-morpholinylgruppe bedeutet,2-oxo-4- (Cι- 4 alkyl) -morpholinylgruppe means
eine Morpholino-Cι-4-alkoxy- oder 2-Oxo-morpholin-4-yl-Cι.6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, oder eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe bedeutet, odera morpholino-Cι- 4 -alkoxy- or 2-oxo-morpholin-4-yl -C. 6 -alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or
der Verbindungenthe connections
(1) 4-[(3-ChIor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine,
(2) 4-[( ?)-(1 -Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrroIo[2,3-d]pyrimidin,(2) 4 - [(?) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin oder(3) 4 - {[3-Chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2 -yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
deren Tautomere, deren Stereoisomere oder deren Salze.their tautomers, their stereoisomers or their salts.
Ein besonders bevorzugter Gegenstand ist die erfindungsgemäße Verwendung der Verbindungen der allgemeinen Formel (I), in derA particularly preferred object is the use according to the invention of the compounds of the general formula (I) in which
X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoffatom,X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom,R a is a hydrogen atom,
Rb eine Phenyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert ist, wobeiR b is a phenyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 and R 2 is substituted, wherein
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom,
eine Cι.4-Alkyl-, C2-5-Alkenyl- oder C2-5-Alkinylgruppe darstellen, A ein Sauerstoffatom oder eine Iminogruppe,a -C. 4 alkyl, C 2 - 5 alkenyl or C 2 - 5 alkynyl group represents, A is an oxygen atom or an imino group,
B eine Bindung oder eine Carbonylgruppe,B is a bond or a carbonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe,C is a methylene, ethylene or ethenylene group,
n eine der Zahlen 0 oder 1 ,n one of the numbers 0 or 1,
D eine Di-(Cι^-Alkyl)-aminogruppe, in der die Alkylteile gleich oder verschieden sein können,D is a di (C 1 -C 4) alkylamino group in which the alkyl moieties may be identical or different,
eine Methylamino- oder Ethylaminogruppe, in denen jeweils das Stickstoffatom durch eine 2-Methoxyethyl-, Tetrahydrofuran-3-yl, Tetrahydropyran-4-yl, Tetrahydrofuran-2- ylmethyl, Cyclopropyl- oder Cyclopropylmethylgruppe substituiert ist,a methylamino or ethylamino group in each of which the nitrogen atom is substituted by a 2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, cyclopropyl or cyclopropylmethyl group,
eine N-(Cι-4-Alkyl)-N-(C2-4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobeian N- (Cι -4- alkyl) -N- (C 2-4 -alkyl) -amino group, in which the alkyl moieties in the β-, γ- or δ-position to the nitrogen atom of the amino group may optionally be substituted by the radical R 3 can, being
R3 eine Cι-3-Alkoxy- oder Cι.3-Alkoxycarbonylgruppe,R 3 is a -C 3 -alkoxy or -C. 3- alkoxycarbonyl group,
eine Bis-(2-methoxyethyl)-aminogruppe,a bis (2-methoxyethyl) amino group,
eine gegebenenfalls durch eine Methyl- oder Methoxymethylgruppe substituierte Morpholino- oder 2-Oxo-morpholin-4-yl~Gruppe,an optionally substituted by a methyl or methoxymethyl group morpholino or 2-oxo-morpholin-4-yl ~ group,
eine Hydroxy- oder Cι^.-Alkoxygruppe, oder aucha hydroxy or -C ^ .- alkoxy group, or also
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
Rc ein Wasserstoffatom, eine Cι-4-Alkoxy-Cι-4-alkoxy-, C- -Alkoxy-, C4-7-Cycloalkoxy- oder Cs^-Cycloalkyl-C-i^-alkoxygruppe, in denen der Cycloalkylteil jeweils durch eine Cι_3-Alkyl- oder Cι-3-Alkoxygruppe substituiert sein kann, eine 3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Pyrrolidinyl-Cι.3-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-Cι.3-alkyloxy-, 3-Piperidinyl- Cι-3-alkyloxy- oder 4-Piperidinyl-Cι-3-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,R c is a hydrogen atom, a Cι- 4 -alkoxy-Cι-4-alkoxy, C- alkoxy, C4 7 cycloalkoxy, or Cs ^ cycloalkyl-Ci ^ alkoxy group in which the cycloalkyl moiety in each case by a Cι_ 3- alkyl or C 3-alkoxy group may be substituted, a 3-pyrrolidinyloxy, 2-pyrrolidinyl-Cι -3 -alkyloxy, 3-pyrrolidinyl -C. 3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl Cι. 3 alkyloxy, 3-piperidinyl Cι -3 alkyloxy or 4-piperidinyl Cι -3 alkyloxy group, in each of which the ring nitrogen atom is substituted by the radical R 4, wherein R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-Cι-4-alkyl-, R6-CO- oder R6-Cι_4-alkylen-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denena in position 4 by a R 6 -Cι -4 -alkyl, R 6 -CO- or R 6 -Cι_ 4 alkylene-CO group substituted piperazino or homopiperazino group in which
Rδ eine gegebenenfalls durch eine oder zwei Cι_2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oder 2-Oxo-4-(Cι-4-alkyl)-morpholinylgruppe bedeutet,R δ is optionally substituted by one or two Cι_ 2 alkyl groups substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4- (Cι- 4- alkyl ) -morpholinyl group,
eine Morpho!ino-C-ι_4-a!koxy- oder 2-Oxo-morpholin-4-yl-Cι-6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, odera morpho! ino-C-ι_ 4 -a! koxy or 2-oxo-morpholin-4-yl-Cι- 6 alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe bedeuten, odera tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or
der Verbindungenthe connections
(1) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) amino] pyrimido [5,4-d] pyrimidine,
(2) 4-[(R)-(1-Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin,(2) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin oder(3) 4 - {[3-Chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2 -yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
deren Tautomere, deren Stereoisomere oder deren Salze. Zur erfindungsgemäßen Verwendung kommen beispielsweise die folgenden Verbindungen der allgemeinen Formel (I) zum Einsatz:their tautomers, their stereoisomers or their salts. For the use according to the invention, for example, the following compounds of the general formula (I) are used:
(1 ) 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,(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine 1-yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [( vinylcarbonyl) amino] -quinazoline
(6) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(8) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopropylmethoxy-chinazolin,(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1 -oxo-2-buten-1 -yl)amino]-7-cyclopropyl- methoxy-chinazolin,(9) 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,
(10) 4-[(f?)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopropylmethoxy-chinazolin, (11 ) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}- 7-cyclopentyloxy-chinazolin,(10) 4 - [(f?) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-ylamino} - 7 cyclopropylmethoxy-quinazoline, (11) 4 - [(R) - (1-Phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7 -cyclopentyloxy-quinazoline,
(12) 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,(12) 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-cyclopropylmethoxy-quinazoline,
(13) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin(13) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
(14) 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,(14) 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,
(15) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1 -oxo-2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin,(15) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline,
(16) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methy!-2-oxo-morpholin-4-y!)- ethoxy]-7-methoxy-chinazolin,(16) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] - 7-methoxy-quinazoline,
(17) 4-[(3-Chlor-4-fluorphenyl)aminoj-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(17) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene-1 yl} amino) -7-cyclopropylmethoxy-quinazoline,
(18) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopentyloxy-chinazolin,(18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline,
(19) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoIin(19) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazolin
(20) 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,(20) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2- butene-1-yl] amino} -7-cyclopropylmethoxy quinazoline,
(21) 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, (22) 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,(21) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2- buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(23) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(23) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2 buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline,
(24) 4-[(3-Chlor-4-fluorphenyI)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin,(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (R) -tetrahydrofuran-3-yloxy) -quinazoline,
(25) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin,(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (S) -tetrahydrofuran-3-yloxy) -quinazoline,
(26) 4-[(3-Chlor-4-fluorphenyI)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopentyloxy-chinazolin,(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopentyloxy-quinazoline,
(27) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo- 2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin,(27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(28) 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,(28) 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,
(29) 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,(29) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(30) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin(30) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine
(31 ) 4-[(3-Chlor-4-f luorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolin,(31) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
(32) 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin,(32) 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline,
(33) 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazolin, (34) 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,(33) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, (34) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(35) 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2- buten-1 -yl]amino}-7-ethoxy-chinolin,(35) 3-Cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-1-yl] amino} -7-ethoxy-quinoline,
(36) 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin,(36) 4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl ) quinazoline,
(37) Cetuximab,(37) cetuximab,
(38) Trastuzumab,(38) trastuzumab,
(39) ABX-EGF,(39) ABX-EGF,
(40) Mab ICR-62,(40) Mab ICR-62,
(41 ) EGFR-antisense(41) EGFR antisense
oder deren Salze, wobeior their salts, where
die Verbindungenthe connections
(1 ) 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,(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine 1-yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin, (5) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline, (5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [( vinylcarbonyl) amino] -quinazoline
(6) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(8) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-cyclopropylmethoxy-chinazolin,(8) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropyl- methoxy-chinazolin,(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N- [(ethoxycarbonyl) methyl] amino} -1- oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline,
(10) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopropylmethoxy-chinazolin,(10) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino] -7-cyclopropylmethoxy -quinazoline,
(11 ) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopentyloxy-chinazolin,(11) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-ylamino] -7-cyclopentyloxy -quinazoline,
(12) 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,(12) 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-cyclopropylmethoxy-quinazoline,
(13) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin(13) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
(14) 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,(14) 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,
(15) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin, (16) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,( 15 ) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, (16) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
(17) 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,(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy quinazoline,
(18) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopentyloxy-chinazolin,(18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline,
(19) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin(19) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
(20) 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,(20) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2- butene-1-yl] amino} -7-cyclopropylmethoxy quinazoline,
(21 ) 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,(21) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2 buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(22) 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,(22) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(23) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin,(23) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(24) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin,(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (R) -tetrahydrofuran-3-yloxy) -quinazoline,
(25) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin,(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (S) -tetrahydrofuran-3-yloxy) -quinazoline,
(26) 4-[(3-Chior-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopentyloxy-chinazolin, (27) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo- 2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin,(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopentyloxy-quinazoline, (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(28) 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,(28) 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,
(29) 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,(29) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(30) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin(30) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine
(31 ) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolin,(31) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
oderderen Salze als bevorzugt undor their salts as preferred and
die Verbindungenthe connections
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(3) 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,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine- 1-yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin,(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(5) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropyl- methoxy-chinazolin, (6) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}- 7-cyclopropylmethoxy-chinazolin und(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N- [(ethoxycarbonyl) methyl] amino} -1- oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline, (6) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7 cyclopropylmethoxyquinazoline and
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolin(7) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
oder deren Salze als besonders bevorzugt zu betrachten sind.or their salts are considered to be particularly preferred.
Ein weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Behandlung vonAnother object of the present invention is a method for the treatment of
Erkrankungen der Atemwege und der Lunge, die mit einer vermehrten oder veränderten Schleimproduktion einhergehen, wie z.B. bei entzündlichen Erkrankungen der Atemwege wie akute Bronchitis, chronische Bronchitis, chronisch obstruktive Bronchitis (COPD), Asthma, Bronchiektasien, allergische oder nichtallergische Rhinitis oder Sinusitis, zystische Fibröse, 1-Antitrypsin-Mangel, oder bei Husten, Lungenemphysem, Lungenfibrose und hyperreaktiven Atemwegen,Respiratory and pulmonary diseases associated with increased or altered mucus production, e.g. in respiratory diseases of the respiratory tract such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, 1-antitrypsin deficiency, or cough, emphysema, pulmonary fibrosis and hyperreactive airways,
zur Behandlung entzündlicher Erkrankungen des Magen-Darm-Traktes und der Gallengänge und Gallenblase, die mit einer gestörten Aktivität der Tyrosinkinasen einhergehen, wie sie z.B. bei akuten oder chronisch entzündlichen Veränderungen zu finden sind, wie Cholezystitis, M. Crohn, Colitis ulcerosa sowie Geschwüren und bei Polyposis im Magen-Darm-Trakt oder wie sie bei Erkrankungen des Magen- Darm-Traktes, die mit einer vermehrten Sekretion einhergehen, vorkommen, wie M. Menetrier, sezemierende Adenome und Proteinverlustsyndrome,for the treatment of inflammatory diseases of the gastrointestinal tract and the bile ducts and gall bladder associated with impaired activity of the tyrosine kinases, e.g. in acute or chronic inflammatory conditions, such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers and polyposis in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion such as M. Menetrier, secreting adenomas and protein loss syndromes,
desweiteren zur Behandlung von entzündlichen Erkrankungen der Gelenke, wie rheumatoider Arthritis, von entzündlichen Erkrankungen der Haut, der Augen, bei entzündlichen Pseudopolypen sowie bei Colitis cystica profunda und bei Pneumatosis cystoides intestinales,furthermore, for the treatment of inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, in inflammatory pseudopolyps, as well as in colitis cystica profunda and in pneumatosis cystoides intestinales,
umfassend die Verabreichung einer wirksamen Menge eines oder mehrerer der vorstehend genannten erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder gegebenenfalls eines deren physiologisch verträglichen Salze an einen Patienten, der einer solchen Behandlung bedarf.comprising the administration of an effective amount of one or more of the abovementioned compounds of the general formula (I) according to the invention or optionally a physiologically acceptable salt thereof to a patient in need of such treatment.
Bevorzugte und besonders bevorzugte Ausführungsformen des erfindungsgemäßen Verfahrens entsprechen bezüglich der Verbindungen und den Indikationen den vorstehend für die erfindungsgemäße Verwendung genannten Ausführungsformen.Preferred and particularly preferred embodiments of the method according to the invention correspond in terms of the compounds and the indications to the embodiments mentioned above for the use according to the invention.
Bei dem erfindungsgemäßen Verfahren werden die genannten Verbindungen in Dosierungen von 0.001-10 mg/kg Körpergewicht , vorzugsweise bei 0.01-1 ,5 mg/kg eingesetzt, wobei die Gabe zweckmäßigerweise 1 bis 3 mal täglich erfolgt.In the method according to the invention, the compounds mentioned in dosages of 0.001-10 mg / kg body weight, preferably at 0.01-1, 5 mg / kg are used, wherein the administration is expediently 1 to 3 times a day.
Die Wirkstoffe können oral, bukkal, parenteral, durch Inhalations-Zerstäubung, rektal oder topisch verabreicht werden. Eine parenterale Verabreichung kann subkutane, intravenöse, und intramuskuläre Injektionen und Infusionstechniken umfassen.The active ingredients may be administered orally, buccally, parenterally, by inhalation nebulization, rectally or topically. Parenteral administration may include subcutaneous, intravenous, and intramuscular injections and infusion techniques.
Zur Verabreichung können übliche Darreichungsformen verwendet werden, beispielsweise die in den vorstehend zu den Wirkstoffen zitierten genannten Darreichungsformen. Beispielsweise lassen sich die Wirkstoffe, gegebenenfalls in Kombination mit anderen Wirksubstanzen, zusammen mit einem oder mehreren inerten üblichen Trägerstoffen und/oder Verdünnungsmitteln, z.B. mit Maisstärke, Milchzucker, Rohrzucker, mikrokristalliner Zellulose, Magnesiumstearat, Polyvinyl- pyrrolidon, Zitronensäure, Weinsäure, Wasser, Wasser/Ethanol, Wasser/Glycerin, Wasser/Sorbit, Wasser/Polyethylenglykol, Propylenglykol, Cetylstearylalkohol, Carboxymethylcellulose oder fetthaltigen Substanzen wie Hartfett oder deren geeigneten Gemischen, in übliche galenische Zubereitungen wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen oder Zäpfchen einarbeiten.For administration, customary administration forms can be used, for example those mentioned in the abovementioned administration forms cited above for the active substances. For example, the active ingredients, optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or its suitable mixtures, in common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
Die Wirkstoffe können oral in einer breiten Vielfalt von verschiedenen Dosierungsformen verabreicht werden, beispielsweise können sie zusammen mit verschiedenen pharmazeutisch annehmbaren inerten Trägern in Form von Tabletten, Kapseln, Pastillen, Plätzchen, harten Bonbons, Pulvern, Zerstäubungen, wässrigen Suspensionen, Elixiren, Sirupen und dergleichen formuliert werden. Derartige Träger umfassen beispielsweise feste Verdünner oder Füllstoffe, sterile wässrige Medien und verschiedene nichttoxische organische Lösungsmittel. Zudem können derartige orale Formulierungen auf geeignete Weise mit Hilfe von verschiedenen, üblicherweise für diesen Zweck eingesetzten Agenzien gesüsst und/oder aromatisiert sein. Im allgemeinen sind die Wirkstoffe in solchen oralen Dosierungsformen mit Konzentrationsspiegeln vorhanden, deren Bereich, bezogen auf die Gesamtzusammensetzung, von etwa 0.5 Gew.-% bis etwa Gew.-90 % reicht, in Mengen, die ausreichen, um die gewünschten Dosierungseinheiten zu ergeben. Andere geeignete Dosierungsformen für die Wirkstoffe umfassen Formulierungen zur kontrollierten Freisetzung und Vorrichtungen, die den Fachpersonen auf dem betreffenden Gebiet wohlbekannt sind.The active ingredients may be administered orally in a wide variety of different dosage forms, for example, together with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, troches, cookies, hard candies, powders, vaporizers, aqueous suspensions, elixirs, syrups and the like be formulated. Such carriers include, for example, solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. In addition, such oral formulations are suitably sweetened and / or flavored by means of various agents commonly used for this purpose. In general, the active ingredients are present in such oral dosage forms with concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts sufficient to provide the desired dosage units. Other suitable dosage forms for the active agents include controlled release formulations and devices well known to those skilled in the art.
Zu Zwecken der parenteralen Verabreichung sind Lösungen der Wirkstoffe in Sesam- oder Erdnussöl oder in wässrigem Propylenglykol verwendbar, sowie sterile wässrige Lösungen der entsprechenden pharmazeutisch annehmbaren Salze. Derartige wässrige Lösungen sollten nötigenfalls auf geeignete Weise gepuffert und der flüssige Verdünner mit genügend Salz oder Glucose isotonisch gemacht werden. Besonders eignen sich diese bestimmten wässrigen Lösungen zum Zwecke von intravenösen, intramuskulären und subkutanen Injektionen. In diesem Zusammenhang sind die verwendeten sterilen wässrigen Medien nach gängigen, den Fachpersonen wohlbekannten Techniken leicht zu erhalten. Beispielsweise wird gewöhnlich destilliertes Wasser als flüssiger Verdünner verwendet, und das Endpräparat wird durch einen geeigneten Bakterienfilter wie ein Filter aus gesintertem Glas oder aus Kieselgur oder aus unglasiertem Porzellan geführt. Bevorzugte Filter dieses Typus umfassen die Berkefeld-, Chamberland- und Asbestscheiben-Metall-Seitzfilter, bei denen das Fluid mit Hilfe einer Saugpumpe in einen sterilen Behälter hinein gesaugt wird. Während der Herstellung dieser injizierbaren Lösungen sollten durchgehend die nötigen Verfahrensschritte vorgenommen werden, um zu sichern, dass die Endprodukte in sterilem Zustand erhalten werden. Zu Zwecken der transdermalen Verabreichung kann die Dosierungsform der bestimmten Verbindung oder Verbindungen beispielsweise Lösungen, Lotionen, Salben, Cremes, Gele, Zäpfchen, Formulierungen zur dauerhaften geschwindigkeitsbegrenzten Freisetzung und Vorrichtungen dazu umfassen. Derartige Dosierungsformen umfassen die bestimmte Verbindung bzw. die bestimmten Verbindungen und können Ethanol, Wasser, Eindringfördermittel und inerte Träger wie Gel-Erzeuger, Mineralöl, Emulgatoren, Benzylalkohol und dergleichen umfassen.For purposes of parenteral administration, solutions of the active ingredients in sesame or peanut oil or in aqueous propylene glycol are useful as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent made isotonic with sufficient salt or glucose. These particular aqueous solutions are particularly suitable for the purpose of intravenous, intramuscular and subcutaneous injections. In this regard, the sterile aqueous media used are readily available by conventional techniques well known to those skilled in the art. For example, distilled water is usually used as the liquid diluent, and the final preparation is passed through a suitable bacterial filter such as a sintered glass or diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, Chamberland and asbestos disc metal Seitz filters in which the fluid is sucked into a sterile container by means of a suction pump. During the preparation of these injectable solutions, the necessary procedural steps should be taken throughout to ensure that the final products are maintained in a sterile condition. For purposes of transdermal administration, the dosage form of the particular compound or compounds may include, for example, solutions, lotions, ointments, creams, gels, suppositories, sustained rate release formulations, and devices thereto. Such dosage forms include the particular compound (s) and may include ethanol, water, penetrant, and inert carriers such as gel generators, mineral oil, emulsifiers, benzyl alcohol and the like.
Eine inhalative Verabreichung erfolgt in Form von Pulverformulierungen mit Lactose und anderen Hilfsstoffen oder in Form wässriger Lösungen als Aerosol. Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren Inhalationspulver können den Wirkstoff oder die Wirkstoffkombination entweder allein oder im Gemisch mit geeigneten physiologisch unbedenklichen Hilfsstoffen enthalten. Ist der Wirkstoff oder die Wirkstoffkombination im Gemisch mit physiologisch unbedenklichen Hilfsstoffen enthalten, können zur Darstellung dieser erfindungsgemäßen Inhalationspulver die folgenden physiologisch unbedenklichen Hilfsstoffe zur Anwendung gelangen: Monosaccharide (z.B. Glucose oder Arabinose), Disaccharide (z.B. Lactose, Saccharose, Maltose), Oligo- und Polysaccharide (z.B. Dextrane), Polyalkohole (z.B. Sorbit, Mannit, Xylit), Salze (z.B. Natriumchlorid, Calciumcarbonat) oder Mischungen dieser Hilfsstoffe miteinander. Bevorzugt gelangen Mono- oder Disaccharide zur Anwendung, wobei die Verwendung von Lactose oder Glucose, insbesondere, aber nicht ausschließlich in Form ihrer Hydrate, bevorzugt ist. A!s besonders bevorzugt im Sinne der Erfindung gelangt Lactose, höchst bevorzugt Lactosemonohydrat als Hilfsstoff zur Anwendung.Inhaled administration takes place in the form of powder formulations with lactose and other excipients or in the form of aqueous solutions as aerosol. The inhalable powders which can be used in the context of the use according to the invention may contain the active ingredient or the active ingredient combination either alone or in admixture with suitable physiologically acceptable auxiliaries. If the active substance or the combination of active ingredients contained in a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and Polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. For the purposes of the invention, lactose, most preferably lactose monohydrate, is used as excipient.
Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Inhaltionsaerosole können den Wirkstoff oder die Wirkstoffkombination im Treibgas gelöst oder in dispergierter Form enthalten. Die zur Herstellung der Inhalationsaerosole einsetzbaren Treibgase sind aus dem Stand der Technik bekannt. Geeignete Treibgase sind ausgewählt aus der Gruppe bestehend aus Kohlenwasser- Stoffen wie n-Propan, n-Butan oder Isobutan und Halogenkohlenwasserstoffen wie bevorzugt fluorierten Derivaten des Methans, Ethans, Propans, Butans, Cyclo- propans oder Cyclobutans. Die vorstehend genannten Treibgase können dabei allein oder in Mischungen derselben zur Verwendung kommen. Besonders bevorzugte Treibgase sind fluorierte Alkanderivate ausgewählt aus TG134a (1,1,1,2-Tetrafluor- ethan), TG227 (1,1,1 ,2,3,3,3-Heptafluorpropan) und Mischungen derselben.The propellant-containing inhalable inhalation aerosols which can be used in the context of the inventive use can dissolve the active ingredient or the active ingredient combination in the propellant gas or contain it in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Inhalationsaerosole können ferner weitere Bestandteile wie Kosolventien, Stabilisatoren, oberflächenaktive Mittel (Surfactants), Antioxidantien, Schmiermittel sowie Mittel zur Einstellung des pH-Werts enthalten. All diese Bestandteile sind im Stand der Technik bekannt.The propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusting agents. All of these ingredients are known in the art.
Erfolgt die inhalative Applikation des erfindungsgemäßen Wirkstoffs oder der Wirkstoffkombination in Form von treibgasfreien Lösungen oder Suspensionen kommen als Lösungsmittel wässrige oder alkoholische, bevorzugt ethanolische Lösungen in Betracht. Das Lösungsmittel kann ausschließlich Wasser sein oder es ist ein Gemisch aus Wasser und Ethanol. Der relative Anteil an Ethanol gegenüber Wasser ist nicht begrenzt, bevorzugt liegt die maximale Grenze jedoch bei bis zu 70 Volumenprozent, insbesondere bei bis zu 60 Volumenprozent und besonders bevorzugt bei bis zu 30 Volumenprozent. Die restlichen Volumenprozente werden von Wasser aufgefüllt. Die den Wirkstoff oder die Wirkstoffkombination enthaltenden Lösungen oder Suspensionen werden gegebenenfalls mit geeigneten Säuren auf einen pH-Wert von 2 bis 7, bevorzugt von 2 bis 5 eingestellt. Zur Einstellung dieses pH-Werts können Säuren ausgewählt aus anorganischen oder organischen Säuren Verwendung finden; Beispiele für besonders geeignete anorganische Säuren sind Salzsäure, Bromwasserstoffsäure, Salpetersäure, Schwefelsäure und/oder Phosphorsäure. Beispiele für besonders geeignete organische Säuren sind: Ascorbinsäure, Zitronensäure, Äpfelsäure, Weinsäure, Maleinsäure, Bernsteinsäure, Fumarsäure, Essigsäure, Ameisensäure und/oder Propionsäure und andere. Bevorzugte anorganische Säuren sind Salzsäure, Schwefelsäure. Unter den organischen Säuren sind Ascorbinsäure, Fumarsäure und Zitronensäure bevorzugt. Gegebenenfalls können auch Gemische der genannten Säuren eingesetzt werden, insbesondere in Fällen von Säuren, die neben ihren Säuerungseigenschaften auch andere Eigenschaften, z.B. als Geschmackstoffe, Antioxidantien oder Komplexbildner besitzen, wie beispielsweise Zitronensäure oder Ascorbinsäure. Erfindungsgemäß besonders bevorzugt wird Salzsäure zur Einstellung des pH-Werts verwendet.If the inhalative administration of the active compound according to the invention or the active ingredient combination in the form of propellant-free solutions or suspensions come as a solvent aqueous or alcoholic, preferably ethanolic solutions into consideration. The solvent may be water only or it may be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume. The remaining volume percentages are filled up with water. The solutions or suspensions containing the active ingredient or combination of active ingredients are optionally adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used; Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Optionally, mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid. Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
Wie bereits eingangs erwähnt, weisen die Verbindungen der allgemeinen Formel (I) und deren Salze wertvolle Eigenschaften auf, insbesondere eine antiinflamma- torische Wirkung.As already mentioned, the compounds of the general formula (I) and their salts have valuable properties, in particular an antiinflammatory effect.
Beispielsweise wurden die Verbindungen A = 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,For example, the compounds were A = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy -quinazoline,
B = 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,B = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [ (vinylcarbonyl) amino] -quinazoline,
C = 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,C = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [(vinylcarbonyl ) amino] -quinazoline,
D = 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,D = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [ (vinylcarbonyl) amino] -quinazoline,
E = 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,E = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) -amino] -1-oxo-2-buten-1-yl} -amino ) -7-cyclopropylmethoxy-quinazoline,
F = 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,F = 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-cyclopropylmethoxy-quinazoline,
G = 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,G = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy -quinazoline,
H = 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin,H = 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2 buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline,
I = 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,I = 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,
K = 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo- 2-buten-1 -yljamino}-7-cyclopropylmethoxy-chinazolin,K = 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1 -ylamino} -7-cyclopropylmethoxyquinazoline,
L = 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin und M = 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolinL = 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline and M = 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
zur Untersuchung der antiinflammatorischen Wirkung den folgenden Tests unterworfen:for testing the anti-inflammatory effect, subjected to the following tests:
Test 1 : Hemmung der Rauch-induzierten Akkumulation von Granulozyten im LungengewebeTest 1: Inhibition of the smoke-induced accumulation of granulocytes in the lung tissue
Lungenindikationen: Hemmung des Zigarettenrauch-induzierten Einstroms von neutrophilen Granulozyten in das Lungengewebe durch den EGF-Rezeptor Kinase Hemmer 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin.Pulmonary indications: Inhibition of the cigarette smoke-induced influx of neutrophilic granulocytes into the lung tissue by the EGF receptor kinase inhibitor 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((S) -6- methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline.
Methode:Method:
Männliche Ratten (Stamm: Sprague-Dawley) mit einem Gewicht von 250-300 g wurden 5 Tage lang dem Rauch von 8 Zigaretten pro Tag ausgesetzt. Die Tiere in der mit 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin (Verbindung A) behandelten Gruppe erhielten täglich 30 min vor Beginn der Rauchexposition unter einer Narkose mit Isofluran eine intratracheale Gabe von 0.03 oder 0.1 mg/kg der Verbindung A in einem Volumen von 0.05 ml verabreicht. Am letzten Versuchstag wurden die Tiere 4 Stunden nach der letzten Rauchexposition getötet und das Lungengewebe entnommen. Aus jeder Lunge wurde eine Probe von 70 - 200 mg entnommen und und in ein mit 1ml 0,5% Hexadecyltrimethylammoniumbromid vorbereitetes Reaktionsgefäß gegeben. Die Proben wurden 15 sec mit einem Ultraturrax homogenisiert. Die Homogenate wurden bei 15700 g in einer Eppendorf Tischzentrifuge 5 min bei Raumtemperatur abzentrifugiert. Von dem Überstand wurden 50 ml entnommen und mit 250 ml Phosphatpuffer (50mmol/l), der 0.197 mg/ml O-Dianisidin Dihydrochlorid enthielt, vermischt. Nach einer 10 minütigen Inkubation bei Raumtemperatur wurde mit einem Spektralphotometer bei einer Wellenlänge von 450 nm die Absorption gemessen. Durch lineare Regression wurde die Dosis ermittelt, die zu einer Hemmung der MPO- Aktivität um 50% (= ID50) führte. Ergebnis:Male rats (strain: Sprague-Dawley) weighing 250-300 g were exposed to the smoke of 8 cigarettes per day for 5 days. The animals in which with 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] - 7-methoxy-quinazoline (Compound A) -treated group received intratracheal administration of 0.03 or 0.1 mg / kg of Compound A in a volume of 0.05 ml daily 30 min before the onset of smoking exposure under anesthesia with isoflurane. On the last day of the experiment, the animals were sacrificed 4 hours after the last smoke exposure and the lung tissue removed. From each lung, a 70-200 mg sample was taken and placed in a reaction vessel prepared with 1 ml of 0.5% hexadecyltrimethylammonium bromide. The samples were homogenized for 15 sec with an Ultraturrax. The homogenates were centrifuged off at 15700 g in an Eppendorf bench centrifuge for 5 min at room temperature. From the supernatant, 50 ml was taken and mixed with 250 ml of phosphate buffer (50 mmol / l) containing 0.197 mg / ml of O-dianisidine dihydrochloride. After a 10 minute incubation at room temperature, absorption was measured with a spectrophotometer at a wavelength of 450 nm. Linear regression was used to determine the dose that resulted in a 50% inhibition of MPO activity (= ID50). Result:
Exposition von Zigarettenrauch führte bei Ratten zu einem Einstrom von neutrophilen Granulozyten in das Lungengewebe, gemessen durch den Gewebsgehalt an Myeloperoxidase, die spezifisch ist für neutrophile Granulozyten. Intratracheale Behandlung der Tiere mit dem EGFR Kinase Hemmer A bewirkte eine signifikante (p<0,005) Hemmung der Rauch:bedingten Akkumulation von Granulozyten und erzeugte damit eine antiinflammatorische Wirkung.Exposure to cigarette smoke in rats resulted in an influx of neutrophil granulocytes into the lung tissue, as measured by the tissue content of myeloperoxidase specific for neutrophil granulocytes. Intratracheal treatment of the animals with the EGFR kinase inhibitor A caused a significant (p <0.005) inhibition of smoke: induced accumulation of granulocytes and thus generated an anti-inflammatory effect.
Weitere Ergebnisse sind in der folgenden Tabelle zusammengefaßt:Further results are summarized in the following table:
Test 2: Nachweis eines generellen anti-entzündlichen Wirkprinzips durchTest 2: Demonstration of a general anti-inflammatory mode of action
Hemmung des Zymosan-induzierten Einstroms von neutrophilen Granulozyten am Mäuseohr durch den EGF-Rezeptor KinaseInhibition of zymosan-induced influx of neutrophilic granulocytes at the mouse ear by the EGF receptor kinase
Hemmer 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino- cyclohexyl)amino]-pyrimido[5,4-d]pyrimidin (Verbindung N). Methode:Inhibitor 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine (Compound N). Method:
Bestimmung des Influx von neutrophilen Granulozyten durch Messung der Myeloperoxidase (MPO) - Aktivität im Gewebe. MPO ist spezifisch für neutrophile Granulozyten.Determination of neutrophil granulocyte influx by measuring myeloperoxidase (MPO) activity in tissue. MPO is specific for neutrophil granulocytes.
Weibliche Mäuse (Stamm: NMRI) mit einem Gewicht von 20-25 g wurden mit Pentobarbital 60 mg/kg i.p. narkosisiert. In das rechte Ohr wurde 10 μg Zymosan, gelöst in physiologischer Kochsalzlösung in einem Volumen von 10 μl intradermal appliziert. 24 h nach der intradermalen Applikation von Zymosan wurden die Tiere durch eine Überdosis Pentobarbital getötet. Eine Ohrbiopsie (0 = 8 mm) wurde am linken (unbehandelten) und rechten (behandelten) Ohr durchgeführt und in ein mit 1 ml 0,5% HTAB vorbereitetes Reaktionsgefäß gegeben. Die Proben wurden 15 sec mit einem Ultraturrax homogenisiert. Die Homogenate wurden bei 15700 g in einer Eppendorf Tischzentrifuge 5 min bei Raumtemperatur abzentrifugiert. Von dem Überstand wurden 50 ml entnommen und mit 250 ml Phosphatpuffer (50 mmol/l), der 0.197 mg/ml O-Dianisidin Dihydrochlorid enthielt, vermischt. Nach einer 10 minütigen Inkubation bei Raumtemperatur wurde mit einem Spektralphotometer bei einer Wellenlänge von 450 nm die Absorption gemessen.Female mice (strain: NMRI) weighing 20-25 g were treated with pentobarbital 60 mg / kg i.p. narkosisiert. 10 μg of zymosan dissolved in physiological saline solution in a volume of 10 μl was administered intradermally to the right ear. 24 hours after the intradermal administration of zymosan, the animals were killed by an overdose of pentobarbital. An ear biopsy (0 = 8 mm) was performed on the left (untreated) and right (treated) ear and placed in a reaction vessel prepared with 1 ml of 0.5% HTAB. The samples were homogenized for 15 sec with an Ultraturrax. The homogenates were centrifuged off at 15700 g in an Eppendorf bench centrifuge for 5 min at room temperature. From the supernatant, 50 ml was taken and mixed with 250 ml of phosphate buffer (50 mmol / l) containing 0.197 mg / ml of O-dianisidine dihydrochloride. After a 10 minute incubation at room temperature, absorption was measured with a spectrophotometer at a wavelength of 450 nm.
Ergebnis:Result:
Die intradermale Injektion von Zymosan führte zu einer deutlichen Eröhung der MPO-Aktivität im Gewebe. Behandlung der Tiere mit dem EGFR Kinase Hemmer 4- [(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]-pyrimido[5,4- djpyrimidin hemmte diesen Anstieg signifikant (p < 0.005) zu 60%.Intradermal injection of zymosan resulted in a marked increase in tissue MPO activity. Treatment of the animals with the EGFR kinase inhibitor 4- [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-diphyridine] significantly inhibited this increase ( p <0.005) to 60%.
Die vorstehend genannten Verbindungen, deren Herstellung nicht bereits zum Stand der Technik gehört, werden nach folgenden Verfahren erhalten:The abovementioned compounds whose preparation is not already known in the art are obtained by the following processes:
Beispiel 1example 1
4-[(3-Chlor-4-fluor-phenyl)amino]-7-{3-[4-(2-oxo-tetrahydrofuran-4-yl)-piperazin-1-yl]- propyloxy}-6-[(vinylcarbonyl)aminoj-chinazolin Eine Mischung aus 166 mg Acrylsäure und 0.77 ml Triethylamin in 10 ml Tetrahydrofuran wird im Trockeneis/Aceton-Kühlbad auf -50°C abgekühlt und mit einer Lösung aus 175 μl Acrylsäurechlorid in 4 ml Tetrahydrofuran versetzt. Das Reaktionsgemisch wird 45 Minuten bei dieser Temperatur gerührt. Anschließend wird eine Lösung aus 427 mg 6-Amino-4-[(3-chlor~4-fluor-phenyl)amino]-7-{3-[4-(2-oxo- tetrahydrofuran-4-yl)-piperazin-1-yl]-propyloxy}-chinazolin in 10 ml Tetrahydrofuran innerhalb von 20 Minuten zugetropft. Nun läßt man das Reaktionsgemisch langsam auf 0°C erwärmen und rührt bei dieser Temperatur, bis die Umsetzung vollständig ist. Anschließend wird mit Eiswasser versetzt, wobei sich ein zäher Niederschlag bildet. Dieser wird mehrmals gründlich mit Essigester/Methanol extrahiert. Die vereinigten organischen Phasen werden mit gesättigter Natriumchlorid-Lösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Das gelbliche, harzartige Rohprodukt wird chromatographisch über eine Kieselgelsäule mit Methylenchlorid/Methanol (95:5) als Laufmittel gereinigt. Ausbeute: 148 mg (31 % der Theorie),4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- {3- [4- (2-oxo-tetrahydrofuran-4-yl) -piperazin-1-yl] -propyloxy} -6- [ (vinylcarbonyl) aminoj-quinazoline A mixture of 166 mg of acrylic acid and 0.77 ml of triethylamine in 10 ml of tetrahydrofuran is cooled in a dry ice / acetone cooling bath to -50 ° C and treated with a solution of 175 .mu.l of acrylic acid chloride in 4 ml of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at this temperature. A solution of 427 mg of 6-amino-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- {3- [4- (2-oxo-tetrahydrofuran-4-yl) -piperazine] is then added. 1-yl] -propyloxy} quinazoline in 10 ml of tetrahydrofuran was added dropwise within 20 minutes. Now let the reaction mixture slowly warm to 0 ° C and stirred at this temperature until the reaction is complete. Then it is mixed with ice water, forming a tough precipitate. This is extracted several times thoroughly with ethyl acetate / methanol. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The yellowish, resinous crude product is purified by chromatography on a silica gel column with methylene chloride / methanol (95: 5) as the eluent. Yield: 148 mg (31% of theory),
Rf-Wert: . 0.45 (Kieselgel, Methylenchlorid/Methanol/konzentrierte, wäßrige Ammoniaklösung = 90:10:0.1) Massenspektrum (ESI-): m/z = 567, 569 [M-H]~ R f value:. 0.45 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI): m / z = 567, 569 [MH] ~
Analog Beispiel 1 wird folgende Verbindung erhalten:Analogously to Example 1, the following compound is obtained:
4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]- piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazin-1-yl} ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline
Rf-Wert: 0.46 (Kieselgel, Methylenchlorid/Methanol/konzentrierte, wäßrige Ammoniaklösung = 90:10:0.1)R f value: 0.46 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)
Massenspektrum (ESI-): m/z = 581 , 583 [M-H]~ Mass spectrum (ESI): m / z = 581, 583 [MH] ~
Beispiel 2Example 2
4-[(3-Chlor-4-fluor-phenyl)amino]-7-[3-(2,2-dimethyl-6-oxo-morpholin-4-yl)-propyloxy]- 6-[(vinylcarbonyl)amino]-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) -amino ] -quinazoline
Zu 101 mg Acrylsäure in 5 ml Tetrahydrofuran unter Stickstoffatmosphäre werden 0.47 ml Triethylamin gegeben. Diese Mischung wird in einem Trockeneis/Aceton- Kühlbad auf etwa -50°C abgekühlt und mit 119 mg Acrylsäurechlorid in 3 ml Tetrahydrofuran versetzt, wobei ein farbloser Niederschlag entsteht. Die Suspension wird noch etwa eine Stunde bei dieser Temperatur gerührt. Anschließend werden 240 mg 6-Amino-4-[(3-chlor-4-fluor-phenyl)amino]-7-[3-(2,2-dimethyl-6-oxo-morpho- lin-4-yl)-propyloxy]-chinazolin in 7 ml Tetrahydrofuran bei -55°C zugetropft. Man läßt das Reaktionsgemisch im Kühlbad langsam auf- -30°C erwärmen. Nach etwa einer Stunde wird das Trockeneis/Aceton-Kühlbad gegen ein Eis/Natriumchlorid-Kühlbad ausgetauscht. Man läßt das Reaktionsgemisch darin auf 0°C erwärmen. Sobald die Umsetzung vollständig ist, wird die Reaktion mit Wasser und Methylenchlorid versetzt und mit Natronlauge alkalisch gestellt. Die abgetrennte wäßrige Phase wird nochmals mit Methylenchlorid und wenig Methanol extrahiert. Die vereinigten organischen Extrakte werden mit Wasser gewaschen, getrocknet und eingeengt. Es bleibt ein gelbes Harz zurück, welches über eine Kieselgelsäule mit Methylenchlorid/Methanol (98:2) als Laufmittel chromatographiert wird. Das gewünschte Produkt wird mit wenig te/iButylmethyether verrührt, der feinkristalline Niederschlag wird abgesaugt, mit feft Butylmethyether nachgewaschen und bei 50°C im Vakuum getrocknet.0.47 ml of triethylamine are added to 101 mg of acrylic acid in 5 ml of tetrahydrofuran under a nitrogen atmosphere. This mixture is dried in a dry ice / acetone Cooled cooling bath to about -50 ° C and treated with 119 mg of acrylic acid chloride in 3 ml of tetrahydrofuran, producing a colorless precipitate. The suspension is stirred for a further hour at this temperature. Subsequently, 240 mg of 6-amino-4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) - propyloxy] quinazoline in 7 ml of tetrahydrofuran was added dropwise at -55 ° C. The reaction mixture is allowed to warm slowly to -30 ° C. in a cooling bath. After about one hour, the dry ice / acetone cooling bath is replaced with an ice / sodium chloride cooling bath. The reaction mixture is allowed to warm to 0 ° C therein. Once the reaction is complete, the reaction is mixed with water and methylene chloride and made alkaline with sodium hydroxide solution. The separated aqueous phase is extracted again with methylene chloride and a little methanol. The combined organic extracts are washed with water, dried and concentrated. There remains a yellow resin, which is chromatographed on a silica gel column with methylene chloride / methanol (98: 2) as the eluent. The desired product is stirred with a little te / iButylmethyether, the finely crystalline precipitate is filtered off, washed with feft butyl methyl ether and dried at 50 ° C in a vacuum.
Ausbeute: 160 mg (60 % der Theorie), Rf-Wert: 0.42 (Kieselgel, Methylenchlorid/Methanol = 95:5) Massenspektrum (ESP): m/z = 526, 528 [M-H]~ Yield: 160 mg (60% of theory), Rf value: 0:42 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESP): m / z = 526, 528 [MH] ~
Analog Beispiel 2 werden folgende Verbindungen erhalten:Analogously to Example 2, the following compounds are obtained:
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbony!)amino]-chinazolin(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbony) amino] -quinazoline
RrWert: 0.32 (Kieselgel, Methylenchlorid/Methanol = 95:5) Massenspektrum (ESP): m/z = 498, 500 [M-H]~ Rr value: 0.32 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESP): m / z = 498, 500 [MH] ~
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyl- oxy]-6-[(vinylcarbonyl)amino]-chinazolin(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -butyl-oxy] - 6 - [(vinylcarbonyl) amino] -quinazoline
Rf-Wert: 0.30 (Kieselgel, Methylenchlorid/Methanol = 95:5) Massenspektrum (ESI+): m/z = 550, 552 [M+Na]+ (3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyl- oxy]-6-[(vinylcarbonyl)amino]-chinazolinR f value: 0.30 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI + ): m / z = 550, 552 [M + Na] + (3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyl-oxy] - 6 - [(vinylcarbonyl) amino] -quinazoline
Massenspektrum (ESP): m/z = 526, 528 [M-HfMass Spectrum (ESP): m / z = 526, 528 [M-Hf
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)-butyl- oxy]-6-[(vinylcarbonyl)amino]-chinazolin Schmelzpunkt: 110-1 2°C Massenspektrum (ESI"): m/z = 540, 542 [M-H]" (4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butoxy-oxy] -6- [(vinylcarbonyl) amino] quinazoline Melting point: 110-1 2 ° C Mass spectrum (ESI " ): m / z = 540, 542 [MH] "
Beispiel 3Example 3
4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}- 7-cyclopropylmethoxy-chinazolin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopropyl-methoxy-quinazoline
Zu einer Lösung aus 640 mg 4-Brom-2-butensäure in 10 ml Methylenchlorid werden bei Raumtemperatur 0.67 ml Oxalylchlorid und ein Tropfen Dimethylformamid gegeben Das Reaktionsgemisch wird noch ca. eine halbe Stunde bei Raumtemperatur gerührt, bis die Gasentwicklung beendet ist. Das entstandene Säurechlorid wird am Rotationsverdampfer im Vakuum weitgehend vom Lösungsmittel befreit. Anschließend wird das Rohprodukt in 10 ml Methylenchlorid gelöst und unter Eisbad-Kühlung zu einer Mischung aus 1.00 g 6-Amino-4-[(3-chlor-4-fluorphenyl)- amino]-7-cyclopropylmethoxy-chinazolin und 1.60 ml Hünigbase in 50 ml Tetrahydrofuran getropft. Das Reaktionsgemisch wird 1.5 Stunden im Eisbad und weitere 2 Stunden bei Raumtemperatur gerührt. Dann werden 2.90 ml Diethylamin zugesetzt und das Gemisch wird 2.5 Tage bei Raumtemperatur gerührt. Zur Aufarbeitung wird das Reaktionsgemisch filtriert und das Filtrat eingeengt. Der Kolbenrückstand wird chromatographisch über eine Kieselgelsäule mit Essigester/Methanol (19:1) gereinigt. Ausbeute: 550 mg (40 % der Theorie) Schmelzpunkt: 114°C0.67 ml of oxalyl chloride and one drop of dimethylformamide are added to a solution of 640 mg of 4-bromo-2-butenoic acid in 10 ml of methylene chloride at room temperature. The reaction mixture is stirred for a further half hour at room temperature until the evolution of gas has ended. The resulting acid chloride is largely freed from the solvent on a rotary evaporator in vacuo. The crude product is then dissolved in 10 ml of methylene chloride and cooled with ice bath to a mixture of 1.00 g of 6-amino-4 - [(3-chloro-4-fluorophenyl) -amino] -7-cyclopropylmethoxy-quinazoline and 1.60 ml Hünigbase in 50 ml of tetrahydrofuran was added dropwise. The reaction mixture is stirred for 1.5 hours in an ice bath and for a further 2 hours at room temperature. Then 2.90 ml of diethylamine are added and the mixture is stirred for 2.5 days at room temperature. For workup, the reaction mixture is filtered and the filtrate is concentrated. The flask residue is purified by chromatography on a silica gel column with ethyl acetate / methanol (19: 1). Yield: 550 mg (40% of theory) Melting point: 114 ° C
Massenspektrum (ESI+): m/z = 498, 500 [M+H]+ Mass spectrum (ESI + ): m / z = 498, 500 [M + H] +
Analog Beispiel 3 werden die folgenden Verbindungen erhalten: (1) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]- amino}-7-cyclopropylmethoxy-chinazolinAnalogously to Example 3, the following compounds are obtained: (1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} - 7-cyclopropylmethoxy-quinazoline
Rf-Wert: 0.53 (Kieselgel, Essigester/Methanol = 9:1)R f value: 0.53 (silica gel, ethyl acetate / methanol = 9: 1)
Massenspektrum (ESP): m/z = 510, 512 [M-H]" Mass Spectrum (ESP): m / z = 510, 512 [MH] "
(2) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]- amino}-7-cyclopropylmethoxy-chinazolin(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline
Schmelzpunkt: 137°CMelting point: 137 ° C
Massenspektrum (ESP): m/z = 470, 472 [M+H]+ Mass Spectrum (ESP): m / z = 470, 472 [M + H] +
(3) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]amino}-7- cyclopropylmethoxy-chinazolin(3) 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7 - cyclopropylmethoxy-quinazoline
RrWert: 0.37 (Kieselgel, Essigester/Methanol = 9:1 ) Massenspektrum (ESP): m/z = 488 [M+H]+ Rr value: 0.37 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESP): m / z = 488 [M + H] +
(4) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-y!)-1 -oxo-2-buten-1 -yl]amino}-7- cyclopentyloxy-chinazölin(4) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7- cyclopentyloxy-quinazol
RrWert: 0.35 (Kieselgel, Essigester/Methanol = 9:1) Massenspektrum (ESP): m/z = 502 [M+H]+ Rr value: 0.35 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESP): m / z = 502 [M + H] +
(5) 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1-oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
RrWert: 0.51 (Kieselgel, Essigester/Methanol = 9:1) Massenspektrum (ESI+): m/z = 558, 560 [M+H]+ Rr value: 0.51 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI + ): m / z = 558, 560 [M + H] +
Beispiel 4Example 4
4-[(3-Methylphenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-methyIamino}-1-oxo- 2-buten-1-yl)amino]-7-methoxy-chinazolin4 - [(3-Methylphenyl) amino] -6 - [(4- {N - [(ethoxycarbonyl) methyl] -N-methylamino} -1-oxo-2-buten-1-yl) amino] -7-methoxy -quinazoline
Zu einer Lösung aus 842 mg 4-Brom-2-butensäure in 15 ml Methylenchlorid werden bei Raumtemperatur 0.86 ml Oxalylchlorid und ein Tropfen Dimethylformamid gegeben. Das Reaktionsgemisch wird noch ca. eine Stunde bei Raumtemperatur gerührt, bis die Gasentwicklung beendet ist. Das entstandene Säurechlorid wird am Rotationsverdampfer im Vakuum weitgehend vom Lösungsmittel befreit. Anschließend wird das Rohprodukt in 10 ml Methylenchlorid aufgenommen und unter Eisbad-Kühlung innerhalb von fünf Minuten zu einer Mischung aus 1.0 g 6-Amino-4- [(3-methylphenyl)amino]-7-methoxy-chinazolin und 2.0 ml Hünigbase in 50 ml Tetra- hydrofuran getropft. Das Reaktionsgemisch wird zwei Stunden unter Eisbad-Kühlung und noch zwei weitere Stunden bei Raumtemperatur gerührt. Anschließend werden 6.7 ml Hünigbase, 5.48 g Sarcosinethylesterhydrochlorid und 3 ml Dimethylformamid zugegeben und das Ganze über Nacht bei Raumtemperatur gerührt. Zur Aufarbeitung wird das Reaktionsgemisch am Rotationsverdampfer im Vakuum einge- engt und der Kolbenrückstand zwischen 75 ml Essigester und 75 ml Wasser verteilt. Die organische Phase wird mit Wasser und gesättigter Natriumchlorid-Lösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wird chromatographisch über eine Kieselgelsäule mit Methylenchlorid/Methanol (20 : 1) gereinigt. Aubeute: 326 mg (20 % der Theorie) Schmelzpunkt: 122-124°C Massenspektrum (ESP): m/z = 464 [M+HTo a solution of 842 mg of 4-bromo-2-butenoic acid in 15 ml of methylene chloride, 0.86 ml of oxalyl chloride and one drop of dimethylformamide are added at room temperature. The reaction mixture is stirred for a further hour at room temperature until the evolution of gas has ended. The resulting acid chloride is on Rotary evaporator largely freed from solvent in vacuo. The crude product is then taken up in 10 ml of methylene chloride and, with ice bath cooling, within five minutes to a mixture of 1.0 g of 6-amino-4- [(3-methylphenyl) amino] -7-methoxy-quinazoline and 2.0 ml of Hünig base in the 50th ml of tetrahydrofuran was added dropwise. The reaction mixture is stirred for two hours under ice-bath cooling and for a further two hours at room temperature. Then 6.7 ml of Hünig base, 5.48 g of sarcosine ethyl ester hydrochloride and 3 ml of dimethylformamide are added and the whole is stirred overnight at room temperature. For workup, the reaction mixture is concentrated on a rotary evaporator under reduced pressure and the flask residue is partitioned between 75 ml of ethyl acetate and 75 ml of water. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on a silica gel column with methylene chloride / methanol (20: 1). Yield: 326 mg (20% of theory) Melting point: 122-124 ° C Mass spectrum (ESP): m / z = 464 [M + H
Analog Beispiel 4 wird folgende Verbindung erhalten:Analogously to Example 4, the following compound is obtained:
4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbo- nyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-chinazolin RrWert: 0.62 (Aluminiumoxid, Cyclohexan/Essigester = 1:1) Massenspektrum (El): m/z = 627, 629 [M]+ 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 Rr Value: 0.62 (alumina, cyclohexane / ethyl acetate = 1: 1) Mass Spectrum (El): m / z = 627, 629 [M] +
Beispiel 5Example 5
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)- 1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclopropylmethoxy-quinazoline
950 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-((R)-2- hydroxy-3-methoxy-propyl)-amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy- chinazolin und 195 μl Methansulfonsäure in 10 ml Acetonitril werden etwa vier Stunden unter Rückfluß erhitzt. Zur Aufarbeitung wird das Reaktionsgemisch in einem Eiswasserbad abgekühlt, mit 75 ml Essigester und 25 ml gesättigter Natriumhydro- gencarbonat-Lösung versetzt und 10 Minuten kräftig durchgerührt. Die organische Phase wird abgetrennt, mit gesättigter Natriumhydrogencarbonat-Lösung und gesättigter Natriumchlorid-Lösung gewaschen und über Magnesiumsulfat getrocknet. Das Lösungsmittel wird im Vakuum abdestilliert, wobei ein bräunlicher Schaum zurückbleibt.950 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N - [(ethoxycarbonyl) methyl] -N - ((R) -2-hydroxy-3-methoxy- propyl) amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline and 195 μl of methanesulfonic acid in 10 ml of acetonitrile are refluxed for about four hours. For workup, the reaction mixture is in a Cooled ice water bath, mixed with 75 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. The organic phase is separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off in vacuo, leaving a brownish foam.
Ausbeute: 610 mg (69 % der Theorie), RrWert: 0.55 (Kieselgel, Methylenchlorid/Methanol = 9:1 ) Massenspektrum (ESP): m/z = 570, 572 [M+H]+ Yield: 610 mg (69% of theory), Rr value: 0.55 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESP): m / z = 570, 572 [M + H] +
Analog Beispiel 5 wird die folgende Verbindung enthalten:Analogously to Example 5, the following compound is included:
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin-4-yl)- 1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclopropylmethoxy-quinazoline
Beispiel 6Example 6
4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-1 -oxo-2- buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoIin4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-butene -1-yl] amino} -7-cyclopropylmethoxy-quinazolin
Eine Gemisch aus 700 mg 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-{N-[(fe/f.butyl- oxycarbonyl)methyl]-N-((S)-2-hydroxy-prop-1 -yl)-amino}-1 -oxo-2-buten-1 -yl)amino]-7- cyclopropylmethoxy-chinazolin und 228 mg p-Toluolsulfonsäure-hydrat in 20 ml Acetonitril wird fünf Stunden unter Rückfluß erhitzt. Dann werden weitere 200 mg p-Toluolsulfonsäure-hydrat zugegeben und es wird nochmals fünf Stunden unter Rückfluß erhitzt. Zur Aufarbeitung wird das Reaktionsgemisch zur Trockne eingeengt. Der Kolbenrückstand wird zwischen Essigester und gesättigter Natrium- carbonat-Lösung verteilt. Die organische Phase wird abgetrennt, mit gesättigter Natriumcarbonat-Lösung, Wasser und gesättigter Natriumchlorid-Lösung gewa- sehen, über Magnesiumsulfat getrocknet und eingeengt. Der ölige Rückstand wird durch Verrühren mit 15 ml Diethylether zur Kristallisation gebracht. Schmelzpunkt: 173-175°C Massenspektrum (ESP): m/z = 540, 542 [M+H]+ Analog Beispiel 6 werden die folgenden Verbindungen erhalten:A mixture of 700 mg of 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4- {N - [(fe / f-butyl-oxycarbonyl) -methyl] -N - ((S) -2-hydroxy-prop-1-yl) -amino} -1-oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxy-quinazoline and 228 mg of p-toluenesulfonic acid hydrate in 20 ml of acetonitrile becomes five hours heated to reflux. Then a further 200 mg of p-toluenesulfonic acid hydrate are added and the mixture is heated under reflux for a further five hours. For workup, the reaction mixture is concentrated to dryness. The flask residue is partitioned between ethyl acetate and saturated sodium carbonate solution. The organic phase is separated off, washed with saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The oily residue is crystallized by stirring with 15 ml of diethyl ether. Melting point: 173-175 ° C Mass Spectrum (ESP): m / z = 540, 542 [M + H] + Analogously to Example 6, the following compounds are obtained:
(1 ) 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 RrWert: 0.54 (Kieselgel, Methylenchlorid/Methanol = 9:1) Massenspektrum (ESP): m/z = 540, 542 [M+H]+ (1) 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-cyclopropylmethoxy-quinazoline Rr Value: 0.54 (silica gel, methylene chloride / methanol = 9: 1) Mass Spectrum (ESP): m / z = 540, 542 [M + H] +
(2) 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 (Die Reaktion wird mit Methansulfonsäure in Acetonitril durchgeführt) RrWert: 0.38 (Kieselgel, Methylenchlorid/Methanol = 9:1) Massenspektrum (ESP): m/z = 556, 558 [M+H(2) 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 (The reaction is carried out with methanesulfonic acid in acetonitrile) Rr value: 0.38 (silica gel, methylene chloride / methanol = 9 : 1) Mass spectrum (ESP): m / z = 556, 558 [M + H
Beispiel 7Example 7
4-[(3-Brom-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yi)-ethoxy]-7- methoxy-chinazolin4 - [(3-Bromo-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
Zu 380 mg 4-[(3-Brom-ρhenyl)amino]-6-(2-{N-[(tert.butyloxycarbonyl)methyl]-N-((S)- 2-hydroxy-propyl)-amino}-ethoxy)-7-methoxy-chinazolin in 8 ml Acetonitril werden 90 μl Methansulfonsäure gegeben. Das Reaktionsgemisch wird ca. drei Stunden unter Rückfluß erhitzt, dann wird nochmals ein Äquivalent Methansulfonsäure zugegeben und weiter unter Rückfluß erhitzt, bis die Umsetzung vollständig ist. Zur Aufarbeitung wird das Reaktionsgemisch mit Essigester verdünnt und mit gesättigter Natriumhydrogencarbonat-Lösung und gesättigter Natriumchlorid-Lösung gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet und im Vakuum eingeengt. Der Kolbenrückstand wird mit Diethylether verrührt und abgesaugt. Man erhält die Titelverbindung als weißen Feststoff. Ausbeute: 280 mg (85 % der Theorie), Schmelzpunkt: 190°CTo 380 mg of 4 - [(3-bromo-phenyl) -amino] -6- (2- {N - [(tert -butyloxycarbonyl) -methyl] -N - ((S) -2-hydroxy-propyl) -amino} - ethoxy) -7-methoxy-quinazoline in 8 ml of acetonitrile are added 90 ul of methanesulfonic acid. The reaction mixture is heated under reflux for about three hours, then another one equivalent of methanesulfonic acid is added and further heated to reflux until the reaction is complete. For workup, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The flask residue is stirred with diethyl ether and filtered with suction. The title compound is obtained as a white solid. Yield: 280 mg (85% of theory), m.p .: 190 ° C
Massenspektrum (ESP): m/z = 485, 487 [M-H]~ Mass spectrum (ESP): m / z = 485, 487 [MH] ~
Analog Beispiel 7 wird folgende Verbindung erhalten: 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yI)-ethoxy]-7- methoxy-chinazolinAnalogously to Example 7, the following compound is obtained: 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
(Die Reaktion wird mit Trifluoressigsäure in Acetonitril durchgeführt) Schmelzpunkt: 212-213°C Massenspektrum (ESP): m/z = 461 , 463 [M+Hf(The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 212-213 ° C Mass spectrum (ESP): m / z = 461, 463 [M + Hf
Beispiel 8Example 8
4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline
Zu einer Lösung aus 4.50 g Bromerotonsäure in 60 ml Methylenchlorid werden 4.70 ml Oxalylchlorid getropft. Anschließend wird ein Tropfen N,N^Dimethylformamid zugegeben. Nach ca. 30 Minuten ist die Gasentwicklung beendet und das Reaktionsgemisch wird am Rotationsverdampfer eingeengt. Das rohe Bromcroton- säurechlorid wird in 30 ml Methylenchlorid aufgenommen und unter Eisbad-Kühlung zu einer Lösung aus 7.00 g 4-[(3-Chlor-4-fluorphenyl)aminoJ-6-amino-7-cyclopropyl- methoxy-chinazolin und 10.20 ml Hünigbase in 150 ml Tetrahydrofuran getropft. Das Reaktionsgemisch wird etwa 1.5 Stunden unter Eisbadkühlung und weitere zwei Stunden bei Raumtemperatur gerührt. Nun werden 5.20 g N-(2-Methoxy-ethyl)-N- methyl-amin zugegeben und das Reaktionsgemisch wird über Nacht bei Raumtemperatur gerührt. Zur Aufarbeitung es wird mit Methylenchlorid verdünnt und gründlich mit Wasser gewaschen. Die organische Phase wird über Magnesiumsulfat getrocknet und eingeengt. Das Rohprodukt wird chromatographisch über eine Kieselgelsäule mit Essigester gefolgt von Essigester/Methanol (19:1) als Laufmittel gereinigt.4.70 ml of oxalyl chloride are added dropwise to a solution of 4.50 g of bromoteronic acid in 60 ml of methylene chloride. Subsequently, a drop of N, N ^ dimethylformamide is added. After about 30 minutes, the evolution of gas is complete and the reaction mixture is concentrated on a rotary evaporator. The crude bromocrotonic acid chloride is taken up in 30 ml of methylene chloride and, with ice-bath cooling, to a solution of 7.00 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-amino-7-cyclopropylmethoxy-quinazoline and 10.20 ml Hünigbase added dropwise in 150 ml of tetrahydrofuran. The reaction mixture is stirred for about 1.5 hours under ice-bath cooling and for a further two hours at room temperature. Now 5.20 g of N- (2-methoxy-ethyl) -N-methyl-amine are added and the reaction mixture is stirred overnight at room temperature. For workup, it is diluted with methylene chloride and washed thoroughly with water. The organic phase is dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on a silica gel column with ethyl acetate followed by ethyl acetate / methanol (19: 1) as eluent.
Ausbeute: 5.07 g (51 % der Theorie) Massenspektrum (ESP): m/z = 512, 514 [M-Hj" RrWert: 0.25 (Kieselgel, Essigester/Methanol = 9:1 )Yield: 5.07 g (51% of theory) Mass spectrum (ESP): m / z = 512, 514 [M-Hj " Rr value: 0.25 (silica gel, ethyl acetate / methanol = 9: 1)
Analog Beispiel 8 werden folgende Verbindungen erhalten:The following compounds are obtained analogously to Example 8:
(1 ) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1 -ylj- amino}-7-cyclopentyloxy-chinazolin Massenspektrum (ESP): m/z = 482, 484 [M-H]~ RrWert: 0.11 (Kieselgel, Essigester/Methanol = 9:1)(1) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl-amino} -7-cyclopentyloxy -quinazoline Mass spectrum (ESP): m / z = 482, 484 [MH] ~ Rr value: 0.11 (silica gel, ethyl acetate / methanol = 9: 1)
(2) 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 Massenspektrum (ESP): m/z = 532 [M-H]~ RrWert: 0.40 (Kieselgel, Essigester/Methanol = 9:1)(2) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino) -1-oxo-2] buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline Mass Spectrum (ESP): m / z = 532 [MH] ~ Rr Value: 0.40 (silica gel, ethyl acetate / methanol = 9: 1)
(3) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyI)-N-ethyl-amino]-1 -oxo-2- buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin(3) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -1-oxo-2-one butene-1-yl-amino) -7-cyclopropylmethoxy-quinazoline
Massenspektrum (ESP): m/z = 502 [M-H]~ RrWert: 0.20 (Kieselgel, Essigester/Methanol = 9:1)Mass spectrum (ESP): m / z = 502 [MH] ~ Rr value: 0.20 (silica gel, ethyl acetate / methanol = 9: 1)
(4) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo- 2-buten-1-yI}amino)-7-cyclopropylmethoxy-chinazolin(4) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2- buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
Massenspektrum (ESP): m/z = 488 [M-H]~ RrWert: 0.25 (Kieselgel, Essigester/Methanol = 9:1)Mass spectrum (ESP): m / z = 488 [MH] ~ Rr value: 0.25 (silica gel, ethyl acetate / methanol = 9: 1)
(5) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1- oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin Massenspektrum (ESP): m/z = 514 [M-H]~ RrWert: 0.15 (Kieselgel, Essigester/Methanol = 9:1)(5) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline Mass Spectrum (ESP): m / z = 514 [MH] ~ Rr Value: 0.15 (silica gel, ethyl acetate / methanol = 9: 1)
(6) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]- amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin Massenspektrum (ESP): m/z = 486, 488 [M+H]+ (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline mass spectrum (ESP): m / z = 486, 488 [M + H] +
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]- amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin Massenspektrum (ESP): m/z = 486, 488 [M+H]+ (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline mass spectrum (ESP): m / z = 486, 488 [M + H] +
RrWert: 0.45 (Kieselgel, Methylenchlorid/Methanol = 5:1)Rr value: 0.45 (silica gel, methylene chloride / methanol = 5: 1)
(8) 4-[(3-ChIor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1- oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazolin Massenspektrum (ESP): m/z = 528, 530 [M+Hj+ RrWert: 0.25 (Kieselgel, Essigester/Methanol = 9:1)(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopentyloxy-quinazoline Mass spectrum (ESP): m / z = 528, 530 [M + Hj + Rr value: 0.25 (silica gel, ethyl acetate / methanol = 9: 1)
(9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2- buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin Massenspektrum (ESP): m/z = 508, 510 [M-H Schmelzpunkt: 140°C(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-butene-1-yl] amino} -7-cyclopentyloxy-quinazoline mass spectrum (ESP): m / z = 508, 510 [MH Melting point: 140 ° C
(10) 4-[(3-Chlor-4-fluorρhenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]- amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin Massenspektrum (ESP): m/z = 500, 502 [M+H]+ Schmelzpunkt: 110-112°C(10) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline Mass Spectrum (ESP): m / z = 500, 502 [M + H] + Melting point: 110-112 ° C
(11) 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 Massenspektrum (ESP): m/z = 500, 502 [M+H]+ (11) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -amino} -7- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline Mass Spectrum (ESP): m / z = 500, 502 [M + H] +
RrWert: 0.23 (Kieselgel, Essigester/Methanol/konz. wässriges Ammoniak 90:10:0.1)Rr value: 0.23 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia 90: 10: 0.1)
Legende zu den Abbildungen:Legend to the pictures:
Figur 1 beschreibt die Hemmung der Rauch-induzierten Akkumulation von neutrophilen Granulozyten.FIG. 1 describes the inhibition of the smoke-induced accumulation of neutrophilic granulocytes.
Figur 2 beschreibt die Hemmung des Zymosan-induzierten Neutrophileneinstroms am Mäuseohr. Figure 2 describes the inhibition of zymosan-induced neutrophil influx at the mouse ear.

Claims

Patentansprüche claims
1. Verwendung von Chinazolinen der allgemeinen Formel1. Use of quinazolines of the general formula
in derin the
X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoffatom,X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom oder eine C-u-Alkylgruppe,R a is a hydrogen atom or a Cu-alkyl group,
Rb eine Phenyl-, Benzyl- oder 1-Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert sein kann, wobeiR b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-,R 1 and R 2 , which may be the same or different, each represents a hydrogen,
Fluor-, Chlor-, Brom- oder Jodatom,Fluorine, chlorine, bromine or iodine atom,
eine C- -Alkyl-, Hydroxy-, C-M-Alkoxy-, C3-6-Cycloalkyl-, C4-6-Cycloalkoxy-, C2-5-Alkenyl- oder C -5-Alkinylgruppe,a C alkyl, hydroxy, C M alkoxy, C 3 - 6 cycloalkyl, C 4-6 cycloalkoxy, C 2-5 alkenyl or C - 5 alkynyl group,
eine Aryl-, Aryloxy-, Arylmethyl- oder Arylmethoxygruppe,an aryl, aryloxy, arylmethyl or arylmethoxy group,
eine C3-5-Alkenyloxy- oder C3,5-Alkinyloxygruppe, wobei die Mehrfachbindung vom Sauerstoffatom isoliert ist, eine C-M-Alkylsulfenyl-, C- -Alkylsulfinyl-, Cι-4-Alkylsulfonyl-, Cι-4-Alkylsulfonyl- oxy-, Trifluormethylsulfenyl-, Trifluormethylsulfinyl- oder Trifluormethylsulfonyl- gruppe,a C3 5 alkenyloxy or C 3, 5 alkynyloxy group, wherein the multiple bond is isolated from the oxygen atom, a C -Alkylsulfenyl- M, C, alkylsulfinyl, Cι-4-alkylsulfonyl, Cι-4-alkylsulfonyl oxy, Trifluormethylsulfenyl- group, trifluoromethylsulphinyl or trifluoromethylsulphonyl,
eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe,a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
eine durch 1 bis 5 Fluoratome substituierte Ethyl- oder Ethoxygruppe,an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
eine Cyano- oder Nitrogruppe oder eine gegebenenfalls durch eine oder zwei C-ι-4-Alkylgruppen substituierte Aminogruppe, wobei die Substituenten gleich oder verschieden sein können,a cyano or nitro group or an optionally substituted by one or two C-ι- 4 alkyl amino group, wherein the substituents may be identical or different,
A ein Sauerstoffatom oder eine . gegebenenfalls durch eine Cι-4-Alkylgruppe substituierte Iminogruppe,A is an oxygen atom or a. optionally substituted by a Cι -4 alkyl group substituted imino group,
B eine indung, eine Carbonyl- oder Sulfonylgruppe,B is an indung, a carbonyl or sulfonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe,C is a methylene, ethylene or ethenylene group,
n eine der Zahlen 0 oder 1 ,n one of the numbers 0 or 1,
D eine Amino-, C^-Alkylamino-, C3-5-Cycloalkylamino- oder Di-(Cι-4-Alkyl)-amino- oder Di-(C3-5-Cycloalkyl)-aminogruppe, in der die Alkyl- und Cycloalkylteile gleich oder verschieden sein können,D is an amino, C ^ alkylamino, C 3-5 cycloalkylamino or di- (Cι- 4 alkyl) amino or di (C 3-5 cycloalkyl) amino group in which the alkyl and cycloalkyl moieties may be the same or different,
eine C^-Alkylaminogruppe, in der der Alkylteil in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert ist, wobeia C 1-6 alkylamino group in which the alkyl moiety in the β-, γ- or δ-position to the nitrogen atom of the amino group is substituted by the radical R 3 , where
R3 eine Hydroxy-, C^-Alkoxy-, Cι_3-Alkoxycarbonyl-, Amino-, Cι_4-Alkylamino- oder Di-(C1-4-Alkyl)-aminogruppe,R 3 is hydroxy, C ^ alkoxy, Cι_ 3 alkoxycarbonyl, amino, Cι_ 4 alkylamino or di (C 1-4 alkyl) amino group,
eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte 4- bis 7- gliedrige Alkyleniminogruppe oder eine gegebenenfalls durch eine oder zwei Methylgruppen substituierte 6- bis 7- gliedrige Alkyleniminogruppe, in der jeweils eine Methylengruppe in Position 4 durch ein Sauerstoff- oder Schwefelatom, durch eine Sulfinyl-, Sulfonyl-, Imino- oder N-(Cι-4-Alkyl)-iminogruppe ersetzt ist, darstellt,an optionally substituted by one or two methyl groups 4- to 7-membered alkyleneimino group or an optionally substituted by one or two methyl groups 6- to 7-membered Alkyleniminogruppe, in each of which a methylene group in position 4 by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (Cι- 4 alkyl ) imino group is replaced,
eine N-(Cι.4-Alkyl)-N-(C2-4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobei R3 wie vorstehend erwähnt definiert ist,be amino group in which the alkyl moieties in .beta. γ-, or δ-position to the nitrogen atom optionally substituted amino group by the radical R 3 - N- (Cι 4 alkyl.) -N- (4 alkyl C 2) where R 3 is defined as mentioned above,
eine Di-(C2-4-Alkyl)-aminogruppe, in der beide C2-4-Alkylteile jeweils in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert sind, wobei die Substituenten gleich oder verschieden sein können und R3 wie vorstehend erwähnt definiert ist,a di- (C 2-4 alkyl) amino group in which both C 2-4 -Alkylteile in each SS, γ- or δ-position are substituted to the nitrogen atom of the amino group by the group R 3, wherein the substituents are identical or may be different and R 3 is defined as mentioned above,
eine Cs^-Cycloalkylamino- pder C3-7-Cycloalkyl-Cι-3-alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine weitere Cι.4-Alkylgruppe substituiert sein kann,a Cs ^ -Cycloalkylamino- C 3 - 7 -cycloalkyl-Cι- 3 -alkylamino group, in which in each case the nitrogen atom by a further -C. 4- alkyl group may be substituted,
eine Amino- oder C1- -Alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine gegebenenfalls durch 1 bis 3 Cι_4-Alkylgruppen substituierte Tetrahydrofuran- 3-yl-, Tetrahydropyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, 1 -(Tetrahydrofuran-3-yl)-piperidin-4-yl-, 1 -(Tetrahydropyran-3-yl)-piperidin-4-yl-,an amino or C 1 -alkylamino group in which in each case the nitrogen atom is replaced by an optionally substituted by 1 to 3 Cι_ 4 alkyl groups tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl- , 1- (tetrahydrofuran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran-3-yl) -piperidin-4-yl,
1-(Tetrahydropyran-4-yl)-piperidin-4-yl-, 3-Pyrrolidinyl-, 3-Piperidinyl-, 4-Piperidinyl-, 3-Hexahydro-azepinyl- oder 4-Hexahydro-azepinylgruppe substituiert ist,1- (tetrahydropyran-4-yl) -piperidin-4-yl, 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydro-azepinyl or 4-hexahydro-azepinyl group is substituted,
eine gegebenenfalls durch 1 bis 4 Cι-2-Alkylgruppen substituierte 4- bis 7-gliedrige Alkyleniminogruppe, die entweder an einem Ringkohlenstoffatom oder an einer der Alkylgruppen durch die Gruppe R3 substituiert sein kann, wobei R3 wie vorstehend erwähnt definiert ist,a 4- to 7-membered alkyleneimino group which is optionally substituted by 1 to 4 C 1 -C 2 -alkyl groups and which may be substituted by the group R 3 either on a ring carbon atom or on one of the alkyl groups, R 3 being defined as mentioned above,
eine durch eine Tetrahydrofuranyl-, Tetrahydropyranyl- oder Tetrahydrofuranyl- methylgruppe substituierte Piperidinogruppe,a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranyl methyl group,
eine gegebenenfalls durch 1 oder 2 C -2-Alkylgruppen substituierte 6- bis 7-gliedrige Alkyleniminogruppe, in der jeweils eine Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Imino- gruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobeia 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 C 2 -alkyl groups, in each of which a methylene group is in the 4-position by a Oxygen or sulfur atom is replaced by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, wherein
R4 ein Wasserstoffatom, eine Cι-4-Alkyl-, 2-Methoxy-ethyl-, 3-Methoxy-propyl-, C3.7-Cycloalkyl-, C3-7-Cycloalkyl-Cι-4-alkyl-, Tetrahydrofuran-3-yl-, Tetrahydro- pyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, Formyl-, C^-Alkylcarbonyl-, Cι.4-Alkylsulfonyl-, Aminocarbonyl-, Cι-4-Alkylamino- carbonyl- oder Di-(C1-4-Alkyl)-aminocarbonylgruppe darstellt,R 4 is a hydrogen atom, a Cι- 4- alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 . 7 cycloalkyl, C 3 - 7 cycloalkyl-alkyl Cι- 4, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl-, formyl, C ^ Alkylcarbonyl, Cι. 4 alkylsulfonyl, aminocarbonyl, Cι -4 alkylamino carbonyl or di- represents (C 1-4 alkyl) aminocarbonyl group,
eine Morpholino- oder 2-Oxo-morpholin-4-yl-Gruppe, die durch eine Methyl-, Ethyl- oder Cι.3-Alkoxymethylgruppe substituiert sein kann,a morpholino or 2-oxo-morpholin-4-yl group represented by a methyl, ethyl or C. 3- alkoxymethyl group may be substituted,
eine gegebenenfalls durch 1 bis 3 Methylgruppen substituierte Imidazoiylgruppe,an optionally substituted by 1 to 3 methyl groups imidazoiyl group,
eine C5-7-Cycloalkylgruppe, in der eine Methylengruppe durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Iminogruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobei R4 wie vorstehend erwähnt definiert ist,a C 5 - is replaced 7 cycloalkyl group wherein a methylene group by an oxygen or sulfur atom, by a substituted by the radical R 4 imino group, by a sulphinyl or sulphonyl group, wherein R 4 is defined as mentioned above,
eine Hydroxy- oder Cι-4-Alkoxygruppe, oder aucha hydroxy or Cι -4 alkoxy, or
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
Rc ein Wasserstoffatom, eine C-u-Alkoxy-C-M-alkoxy-, Cι_4-Alkoxy-, C4-7-Cycloalkoxy- oder C3.7-Cycloalkyl-Cι-6-a!koxygruppe, in denen der Cycloalkylteil jeweils durch eine Cι-3-Alkyl-, Hydroxy-, C-ι-4-Alkoxy-, Amino-, Cι.4-Alkylamino-, Di-(Cι.4-alkyl)-amino-, Pyrrolidino-, Piperidino-, Morpholino-, Piperazino-, N-(Cι. -Alkyl)-piperazino-, Hydroxy-C1-2-alkyl-, Cι.4-Alkoxy-Cι-2-alkyl-, Amino-Cι.2-alkyl-, Cι-4-Alkylamino- Cι-2-alkyl-, Di-(Cι.4-alkyl)-amino-Cι-2-alkyl-, Pyrrolidino-Cι.2-alkyl-, Piperidino- Cι.2-alkyl-, Morpholino-C1-2-alkyl-, Piperazino-C-ι-2-alkyl- oderR c is a hydrogen atom, a Cu-alkoxy-C-M alkoxy, Cι_ 4 alkoxy, C 4 - 7 cycloalkoxy or C. 3 7 -cycloalkyl-Cι- 6 -a! Koxygruppe, in which the cycloalkyl moiety in each case by a -C -3 alkyl, hydroxy, C-ι- 4 alkoxy, amino, -C. 4- Alkylamino-, di- (-C. 4 -alkyl) amino, pyrrolidino, piperidino, morpholino, piperazino, N- (-C.-alkyl) piperazino, hydroxy-C 1-2 alkyl -, Cι. 4- alkoxy-Cι- 2 -alkyl-, amino-Cι. 2- alkyl, Cι- 4- alkylamino-Cι -2 -alkyl-, di- (Cι. 4 -alkyl) -amino-Cι- 2 -alkyl-, pyrrolidino-Cι. 2- alkyl-, piperidino -Cι. 2- alkyl-, morpholino-C 1-2 -alkyl-, piperazino-C-ι- 2 -alkyl- or
N-(C1.2-Alkyl)-piperazino-Cι-2-alkylgruppe substituiert sein kann, wobei die vorstehend erwähnten monosubstituierten Cycloalkylteile zusätzlich durch eine Cι-3-Alkylgruppe substituiert sein können, oder eine 3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-4-alkyloxy-, 3-Pyrrolidinyl-Cι^-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-Cι-4-alkyloxy-, 3-PiperidinyI- Cι-4-alkyloxy-, 4-Piperidinyl-Cι-4-alkyloxy-, 3-Hexahydro-azepinyloxy-, 4-Hexahydro- azepinyloxy-, 2-Hexahydro-azepinyl-Cι^.-alkyloxy-, 3-Hexahydro-azepinyl- Cι-4-alkyloxy- oder 4-Hexahydro-azepinyl-C^-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,N- (C 1. 2, alkyl) piperazino-2 Cι- alkyl group may be substituted, wherein the mono-substituted cycloalkyl moieties mentioned above may additionally be substituted by a Cι -3 alkyl group, or a 3-pyrrolidinyloxy, 2-pyrrolidinyl-Cι- 4 alkyloxy, alkyloxy 3-pyrrolidinyl-Cι ^ alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl Cι- 4, 3- PiperidinyI- Cι- 4 alkyloxy, 4-piperidinyl-Cι- 4 alkyloxy, 3-hexahydro-azepinyloxy-, azepinyloxy- hexahydro-4, 2-hexahydro-azepinyl-Cι ^ .- alkyloxy, 3-hexahydro -azepinyl- Cι- 4 -alkyloxy or 4-hexahydro-azepinyl-C ^ alkyloxy group, in each of which the ring nitrogen atom is substituted by the radical R 4 , wherein R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-Cι_4-alkyl-, R6-CO-, R6-Cι-4-alkylen-CO-, (R5NR7)-Cι-4-alkylen-CO-, R7O-C1_4-alkylen-CO-, R7S-C1.4-alkylen-CO-, R7SO-C1-4- alkylen-CO- oder R7SO2-Cι-4-alkylen-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denena in 4-position by an R 6 -Cι_ 4 -alkyl, R 6 -CO-, R 6 -Cι- 4 -alkylene-CO-, (R 5 NR 7 ) -Cι- 4 -alkylene-CO-, R 7 OC 1 _ 4 alkylene-CO-, R 7 SC. 1 4 -alkylene-CO-, R 7 SO-C 1-4 - alkylene-CO- or R 7 SO 2 -Cι- 4 -alkylene-CO group substituted piperazino or homopiperazino group, in which
R5 ein Wasserstoffatom oder eine C- -Alkylgruppe bedeutet,R 5 represents a hydrogen atom or a C 1-4 alkyl group,
R6 eine gegebenenfalls durch eine oder zwei Cι_2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oder 2-Oxo-4-(Cι.4-alkyl)-morpholinylgruppe undR 6 is an optionally substituted by one or two Cι_ 2 alkyl groups substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4- (Cι. 4- alkyl ) -morpholinyl group and
R7 eine gegebenenfalls durch eine oder zwei Cι-2-Alkylgruppen substituierteR 7 is optionally substituted by one or two -CC 2 alkyl groups
2-Oxo-tetrahydrofuran-3-yl-, 2-Oxo-tetrahydrofuran-4-yl-, 2-Oxo-tetrahydro- pyran-3-yl-, 2-Oxo-tetrahydropyran-4-yl- oder 2-Oxo-tetrahydropyran-5-yl-Grup- pe bedeuten,2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo tetrahydropyran-5-yl group,
eine oder 2-Oxo-morpholin-4-yl-Cι-6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, odera or 2-oxo-morpholin-4-yl-Cι -6 alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe bedeuten, wobeia tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, wherein
unter den bei der Definition der vorstehend erwähnten Reste erwähnten Arylteilen eine Phenylgruppe zu verstehen ist, die jeweils durch R8 monosubstituiert, durch R9 mono-, di- oder trisubstituiert oder durch R8 monosubstituiert und zusätzlich durch R9 mono- oder disubstituiert sein kann, wobei die Substituenten gleich oder verschieden sein können, worinamong the aryl moieties mentioned in the definition of the abovementioned radicals is a phenyl group which is monosubstituted by R 8 in each case, mono-, di- or tri-substituted by R 9 or monosubstituted by R 8 and additionally by R 9 mono- or disubstituted, where the substituents may be the same or different, wherein
R8 eine Cyano-, Carboxy-, C-u-Alkoxycarbonyl-, Aminocarbonyl-, C-M-Alkyl- aminocarbonyl-, Di-(Cι-4-alkyl)-aminocarbonyl-, Cι-4-Alkylsulfenyl-, Cι_ -Alkyl- sulfinyl-, C-ι-4-Alkylsulfonyl-, Hydroxy-, Cι.4-Alkylsulfonyloxy-, Trifluormethyloxy-, Nitro-, Amino-, Cι. -Alkylamino-, Di-(Cι-4-alkyl)-amino-, Cι-4-Alkylcarbonylamino-, N-(Cι-4-Alkyl)-Cι-4-alkylcarbonylamino-, C- -Alkylsulfonylamino-, N-(Cι-4-Alkyl)- Cι-4-alkylsulfonylamino-, Aminosulfonyl-, Cι-4-Alkylaminosulfonyl- oder Di- (Cι.4-Alkyl)-aminosulfonylgruppe oder eine Carbonylgruppe, die durch eine 5- bisR 8 aminocarbonyl, a cyano, carboxy, Cu-alkoxycarbonyl, aminocarbonyl, C M alkyl, di- (Cι- 4 alkyl) aminocarbonyl, Cι- 4 -Alkylsulfenyl-, Cι_ alkyl sulfinyl, C-ι- 4 alkylsulfonyl, hydroxy, -C. 4- Alkylsulfonyloxy-, Trifluormethyloxy-, nitro, amino, -C. Alkylamino, di- (Cι- 4 alkyl) amino, Cι -4 alkylcarbonylamino, N- (Cι -4 alkyl) -4 -Cι -alkylcarbonylamino-, C, alkylsulfonylamino, N- ( Cι- 4 alkyl) - Cι -4 alkylsulfonylamino, aminosulfonyl or Cι -aminosulfonylgruppe -4 alkylaminosulfonyl or di- (Cι 4 alkyl) carbonyl group, by a 5- to.
7-gliedrige Alkyleniminogruppe substituiert ist, wobei in den vorstehend erwähnten 6- bis 7-gliedrigen Alkyleniminogruppen jeweils eine Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine Sulfinyl-, Sulfonyl-, Imino- oder N-(C1.4-Alkyl)-imino-Gruppe ersetzt sein kann, und7-membered alkyleneimino group is substituted, wherein, in the above-mentioned 6- to 7-membered Alkyleniminogruppen each a methyl group in the 4 position by an oxygen or sulfur atom, by a sulphinyl, sulphonyl, imino or N- (C 1 4- alkyl) -imino group may be replaced, and
R9 ein Fluor-, Chlor-, Brom- oder Jodatom, eine G- -Alkyl-, Trifiuormethyl- oder Cι-4-Alkoxygruppe darstellen,R 9 is a fluorine, chlorine, bromine or iodine atom, a GSM alkyl, Trifiuormethyl- or Cι- 4 alkoxy group represent,
der Verbindungenthe connections
(1) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) amino] pyrimido [5,4-d] pyrimidine,
(2) 4-[(R)-(1-Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin,(2) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin oder(3) 4 - {[3-Chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2 -yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
deren Tautomere, deren Stereoisomere oder deren Salze zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von mit Entzündungen einhergehenden Erkrankungen der Atemwege oder der Lunge. their tautomers, their stereoisomers or their salts for the manufacture of a medicament for the prevention or treatment of inflammatory diseases of the respiratory tract or the lungs.
2. Verwendung der Chinazoline der allgemeinen Formel (I) gemäß Anspruch 1, in denen2. Use of the quinazolines of the general formula (I) according to claim 1, in which
X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoffatom,X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom oder eine C- -Alkylgruppe,R a represents a hydrogen atom or a C 1-4 -alkyl group,
Rb eine Phenyl-, Benzyl- oder 1 -Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert sein kann, wobeiR b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus can be substituted by the radicals R 1 and R 2 , in each case
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom,
eine C- -Alkyl-, Hydroxy-, Cι-4-Alkoxy-, C3.6-Cycloalkyl-, C2-5-Alkenyl- oder C2-5-Alkinylgruppe,a C-alkyl, hydroxy, Cι- 4- alkoxy, C 3 . 6 -cycloalkyl-, C 2 -5-alkenyl or C 2-5 -alkynyl group,
eine Methyl-, Trifluormethyl- oder Methoxygruppe darstellen,represent a methyl, trifluoromethyl or methoxy group,
A ein Sauerstoffatom oder eine gegebenenfalls durch eine C-u-Alkylgruppe substituierte Iminogruppe,A denotes an oxygen atom or an imino group which is optionally substituted by a C 1-8 -alkyl group,
B eine Bindung oder eine Carbonylgruppe,B is a bond or a carbonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe,C is a methylene, ethylene or ethenylene group,
n eine der Zahlen 0 oder 1 ,n one of the numbers 0 or 1,
D eine Di-(C-ι^-Alkyl)-aminogruppe, in der die Alkylteile gleich oder verschieden sein können, eine N-(Cι^-Alkyl)-N-(C -4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobeiD is a di- (C 1-4 -alkyl) -amino group in which the alkyl moieties may be identical or different, an N- (Cι ^ alkyl) -N- (C - C4 alkyl) amino group in which the alkyl moieties in .beta. γ-, or δ-position may be substituted to the nitrogen atom of the amino group is optionally substituted by the radical R 3, in which
R3 eine Hydroxy-, Cι-3-Alkoxy-, Cι-3-Alkoxycarbonyl-, Amino-, C-M-Alkylamino- oder Di-(Cι. -Alkyl)-arhinogruppe,R 3 is a hydroxy, Cι -3 alkoxy, Cι -arhinogruppe -3 alkoxycarbonyl, amino, C, M alkylamino or di- (Cι. Alkyl),
eine Pyrrolidino-, Piperidino- oder Morpholinogruppe darstellt,represents a pyrrolidino, piperidino or morpholino group,
eine Di-(C2-4-Alkyl)-aminogruppe, in der beide C2-4-Alkylteile jeweils in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe durch den Rest R3 substituiert sind, wobei die Substituenten gleich oder verschieden sein können und R3 wie vorstehend erwähnt definiert ist,a di- (C 2-4 alkyl) amino group in which both C 2-4 -Alkylteile in each SS, γ- or δ-position are substituted to the nitrogen atom of the amino group by the group R 3, wherein the substituents are identical or may be different and R 3 is defined as mentioned above,
eine C3-5-CycloaIkylamino- oder C3-5-Cycloalkyl-Cι.3-alkylaminogruppe, in denen jeweils das Stickstoffatom durch eine weitere Cι- -Alkylgruppe substituiert ist,a C 3-5 -cycloalkylamino or C 3-5 -cycloalkyl-Cι. 3 -alkylamino group, in each of which the nitrogen atom is substituted by another C 1 -alkyl group,
eine Cι-4-Alkylaminogruppe, in der das Stickstoffatom durch eine Tetrahydrofuran- 3-yl-, Tetrahydropyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, 1-(Tetrahydrofuran-3-yl)-piperidin-4-yl-, 1-(Tetrahydropyran-3-yl)-piperidin-4-yl- oder 1-(Tetrahydropyran-4-yl)-piperidin-4-ylgruppe substituiert ist,a Cι- 4 alkylamino, in which the nitrogen atom by a 3-yl- tetrahydrofuran, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl-, 1- (tetrahydrofuran-3-yl) -piperidin-4 -yl, 1- (tetrahydropyran-3-yl) -piperidin-4-yl or 1- (tetrahydropyran-4-yl) -piperidin-4-yl group,
eine gegebenenfalls durch 1 bis 2 Methylgruppen substituierte 5- bis 7-gliedrige Alkyleniminogruppe, die entweder an einem Ringkohlenstoffatom oder an einer der Methylgruppen durch die Gruppe R3 substituiert sein kann, wobei R3 wie vorstehend erwähnt definiert ist,a 5- to 7-membered alkyleneimino group optionally substituted by 1 to 2 methyl groups, which may be substituted on either a ring carbon atom or on one of the methyl groups by the group R 3 , wherein R 3 is defined as mentioned above,
eine durch eine Tetrahydrofuranyl-, Tetrahydropyranyl- oder Tetrahydrofuranyl- methylgruppe substituierte Piperidinogruppe,a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranyl methyl group,
eine gegebenenfalls durch 1 oder 2 Methylgruppen substituierte Piperidinogruppe, in der die Methylengruppe in 4-Stellung durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Iminogruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobei R4 ein Wasserstoffatom, eine Cι.3-Alkyl-, 2-Methoxy-ethyl-, 3-Methoxy-propyl-, C3-6-Cycloalkyl-, C3.6-Cycloalkyl-Cι.3-alkyl-, Tetrahydrofuran-3-yl-, Tetrahydro- pyran-3-yl-, Tetrahydropyran-4-yl-, Tetrahydrofuranylmethyl-, Cι-3-Alkyl- carbonyl-, Cι-3-Alkylsulfonyl-, Aminocarbonyl-, Cι_3-Alkylaminocarbonyl- oder Di- (Cι-3-Alkyl)-aminocarbonylgruppe darstellt,an optionally substituted by 1 or 2 methyl groups piperidino group in which the methylene group is replaced in the 4-position by an oxygen or sulfur atom, by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, wherein R 4 is a hydrogen atom, a -C. 3- alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 -6-cycloalkyl, C 3 . 6 -cycloalkyl-Cι. 3 alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, Tetrahydrofuranylmethyl-, Cι -3 alkyl carbonyl, Cι -3 alkylsulfonyl, aminocarbonyl, C 1-3 represents alkylaminocarbonyl or di (C 1-3 -alkyl) aminocarbonyl group,
eine Morpholino- oder 2-Oxo-morpholin-4-yl-Gruppe, die durch eine Methyl-, Ethyl- oder Cι-3-Alkoxymethylgruppe substituiert sein kann,a morpholino or 2-oxo-morpholin-4-yl group which may be substituted by a methyl, ethyl or C 1-3 alkoxymethyl group,
eine Cs-β-Cycloalkylgruppe, in der eine Methylengruppe durch ein Sauerstoff- oder Schwefelatom, durch eine durch den Rest R4 substituierte Iminogruppe, durch eine Sulfinyl- oder Sulfonylgruppe ersetzt ist, wobei R4 wie vorstehend erwähnt definiert ist,a Cs-β-cycloalkyl group in which a methylene group is replaced by an oxygen or sulfur atom, by an imino group substituted by the radical R 4 , by a sulfinyl or sulfonyl group, wherein R 4 is defined as mentioned above,
eine Hydroxy- oder Cι_4-Alkoxygruppe, oder aucha hydroxy or Cι_ 4 alkoxy group, or also
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
Rc ein Wasserstoffatom, eine C-M-Alkoxy-C-M-alkoxy-, C-ι-4-Alkoxy-, C -7-Cycloalkoxy- oder C3-7-Cycloalkyl-Cι-4-alkoxygruppe, in denen der Cycloalkylteil jeweils durch eine Cι-3-Alkyl- oder Cι.3-Alkoxygruppe substituiert sein kann,R c is a hydrogen atom, a C- M alkoxy-C- M alkoxy, C-ι- 4 alkoxy, C 7 -cycloalkoxy or C 3 -7-cycloalkyl-Cι- 4- alkoxy, in which the cycloalkyl part in each case by a -C 3 alkyl or -C. 3 alkoxy group may be substituted,
eine 3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-Cf..3-alkyloxy-, 3-Piperidinyl- Cι.3-alkyloxy- oder 4-Piperidinyl-Cι_3-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C 3 -alkyloxy, 3-pyrrolidinyl-C 1-3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl Cf. 3 -alkyloxy-, 3-piperidinyl Cι. 3 -alkyloxy- or 4-piperidinyl-C 1-3 -alkyloxy groups, in each of which the ring nitrogen atom is substituted by the radical R 4 , where R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-C-ι^-alkyl-, R6-CO- oder R6-Cι-4-alkylen-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denen R6 eine gegebenenfalls durch eine oder zwei Cι-2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oder 2-Oxo-4-(Cι-4-alkyl)-morpholinylgruppe bedeutet,a in position 4 by a R 6 -C-^ -alkyl, R 6 -CO- or R 6 -Cι -4 alkylene-CO group substituted piperazino or homopiperazino group in which R 6 is a 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4 which is optionally substituted by one or two C 1 -C 2 -alkyl groups (C 1 -C 4 ) alkyl) -morpholinyl group,
eine Morpholino-C-u-alkoxy- oder 2-Oxo-morpholin-4-yl-C-ι-6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, odera morpholino-Cu-alkoxy or 2-oxo-morpholin-4-yl-C-ι -6- alkoxy group which may be substituted by 1 or 2 methyl or ethyl groups, or
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe bedeutet, odera tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or
der Verbindungenthe connections
(1) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) amino] pyrimido [5,4-d] pyrimidine,
(2) 4-[(R)-(1-Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin,(2) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin oder(3) 4 - {[3-Chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2 -yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
deren Tautomere, deren Stereoisomere oder deren Salze.their tautomers, their stereoisomers or their salts.
3. Verwendung der Chinazoline der allgemeinen Formel (I) gemäß Anspruch 1 , in denen3. Use of the quinazolines of the general formula (I) according to claim 1, in which
X ein Stickstoffatom oder ein durch eine Cyanogruppe substituiertes Kohlenstoff- atom,X is a nitrogen atom or a carbon atom substituted by a cyano group,
Ra ein Wasserstoffatom, Rb eine Phenyl- oder 1 -Phenylethylgruppe, in denen der Phenylkern jeweils durch die Reste R1 und R2 substituiert ist, wobeiR a is a hydrogen atom, R b is a phenyl or 1-phenylethyl group in which the phenyl nucleus in each case by the radicals R 1 and R 2 is substituted, wherein
R1 und R2, die gleich oder verschieden sein können, jeweils ein Wasserstoff-, Fluor-, Chlor- oder Bromatom,R 1 and R 2 , which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom,
eine C1- -Alkyl-, C2-5-Alkenyl- oder C2-5-Alkinylgruppe darstellen,a C 1- alkyl, C 2 - 5 alkenyl or C 2 - 5 alkynyl group represents,
A ein Sauerstoffatom oder eine Iminogruppe,A is an oxygen atom or an imino group,
B eine Bindung oder eine Carbonylgruppe,B is a bond or a carbonyl group,
C eine Methylen-, Ethylen- oder Ethenylengruppe,C is a methylene, ethylene or ethenylene group,
n eine der Zahlen 0 oder 1 ,n one of the numbers 0 or 1,
D eine Di-(Cι-4-Alkyl)-aminogruppe, in der die Alkylteile gleich oder verschieden sein können,D is a di- (Cι -4 alkyl) amino group in which the alkyl portions can be the same or different,
eine Methylamino- oder Ethylaminogruppe, in denen jeweils das Stickstoffatom durch eine 2-Methoxyethyl-, Tetrahydrofuran-3-yl, Tetrahydropyran-4-yl, Tetrahydrofuran-2- ylmethyl, Cyclopropyl- oder Cyclopropylmethylgruppe substituiert ist,a methylamino or ethylamino group in each of which the nitrogen atom is substituted by a 2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, cyclopropyl or cyclopropylmethyl group,
eine N-(Cι-4-Alkyl)-N-(C2-4-alkyl)-aminogruppe, in der die Alkylteile in ß-, γ- oder δ-Stellung zum Stickstoffatom der Aminogruppe gegebenenfalls durch den Rest R3 substituiert sein können, wobeian N- (Cι -4 alkyl) -N- (C 2-4 alkyl) amino group in which the alkyl moieties in .beta. γ-, or may be substituted to the nitrogen atom of the amino group is optionally substituted by the radical R 3 δ-position can, being
R3 eine Cι.3-Alkoxy- oder Ci-3-Alkoxycarbonylgruppe,R 3 is a -C. 3- alkoxy or C 1-3 -alkoxycarbonyl group,
eine Bis-(2-methoxyethyl)-aminogruppe,a bis (2-methoxyethyl) amino group,
eine gegebenenfalls durch eine Methyl- oder Methoxymethylgruppe substituierte Morpholino- oder 2-Oxo-morpholin-4-yl-Gruppe, eine Hydroxy- oder C- -Alkoxygruppe, oder auchan optionally substituted by a methyl or methoxymethyl group morpholino or 2-oxo-morpholin-4-yl group, a hydroxy or C 1-4 alkoxy group, or also
ein Wasserstoffatom, wenn n die Zahl 0 ist, unda hydrogen atom when n is the number 0, and
Rc ein Wasserstoffatom, eine C- -Alkoxy-, C -7-Cycloalkoxy- oder C3-7-Cycloalkyl-Cι-4-alkoxygruppe, in denen der Cycloalkylteil jeweils durch eine C-ι-3-Alkyl- oder Cι.3-Alkoxygruppe substituiert sein kann,R c is a hydrogen atom, a C- alkoxy, C -7- cycloalkoxy or C 3-7 -cycloalkyl-Cι- 4- alkoxy, in which the cycloalkyl each by a C-ι- 3 alkyl or -C. 3 alkoxy group may be substituted,
eine 3-Pyrrolidinyloxy-, 2-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Pyrrolidinyl-Cι-3-alkyloxy-, 3-Piperidinyloxy-, 4-Piperidinyloxy-, 2-Piperidinyl-C-|.3-alkyloxy-, 3-Piperidinyl- Cι-3-alkyloxy- oder 4-Piperidinyl-Cι.3-alkyloxygruppe, in denen jeweils das Ringstickstoffatom durch den Rest R4 substituiert ist, wobei R4 wie vorstehend erwähnt definiert ist,a 3-pyrrolidinyloxy, 2-pyrrolidinyl-Cι -3 -alkyloxy, 3-pyrrolidinyl-Cι -3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-piperidinyl-C |. 3 -alkyloxy-, 3-piperidinyl- Cι- 3 -alkyloxy- or 4-piperidinyl -C. 3 -alkyloxy group in which the ring nitrogen atom is substituted by the radical R 4 , where R 4 is defined as mentioned above,
eine in 4-Stellung durch eine R6-Cι^-alkyl-, R6-CO- oder R6-C1-4-alkylen-CO-Gruppe substituierte Piperazino- oder Homopiperazinogruppe, in denena substituted in the 4-position by an R 6 -Cι ^ -alkyl, R 6 -CO- or R 6 -C 1-4 alkylene-CO group substituted piperazino or Homopiperazinogruppe, in which
R6 eine gegebenenfalls durch eine oder zwei Cι_2-Alkylgruppen substituierte 2-Oxo-tetrahydrofuranyl-, 2-Oxo-tetrahydropyranyl-, 2-Oxo-1 ,4-dioxanyl- oder 2-Oxo-4-(Cι-4-alkyl)-morpholinylgruppe bedeutet,R 6 is optionally substituted by one or two Cι_ 2 alkyl groups substituted 2-oxo-tetrahydrofuranyl, 2-oxo-tetrahydropyranyl, 2-oxo-1, 4-dioxanyl or 2-oxo-4- (Cι- 4- alkyl ) -morpholinyl group,
eine Morpholino-C1.4-alkoxy- oder 2-Oxo-morpholin-4-yl-Cι-6-alkoxygruppe, die durch 1 oder 2 Methyl- oder Ethylgruppen substituiert sein kann, odera morpholino-C 1 . 4 -alkoxy- or 2-oxo-morpholin-4-yl-Cι- 6 -alkoxygruppe, which may be substituted by 1 or 2 methyl or ethyl groups, or
eine Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy, Tetrahydrofuranylmethoxy- oder Tetrahydropyranylmethoxygruppe bedeutet, odera tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, or
der Verbindungenthe connections
(1 ) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin,(1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4-dimethylamino-cyclohexyl) amino] pyrimido [5,4-d] pyrimidine,
(2) 4-[(R)-(1-Phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin, (3) 4-{[3-Chlor-4-(3-fluor-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-niethansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin oder(2) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine, (3) 4 - {[3-Chloro-4- (3-fluoro-4-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-niethansulfonyl-ethyl) -amino] -methyl} -furan-2 -yl) quinazoline or
der Antikörper Cetuximab C225, Trastuzumab, ABX-EGF, Mab ICR-62 oder EGFR- antisense,the antibody cetuximab C225, trastuzumab, ABX-EGF, Mab ICR-62 or EGFR antisense,
deren Tautomere, deren Stereoisomere oder deren Salze.their tautomers, their stereoisomers or their salts.
4. Verwendung der Chinazoline der allgemeinen Formel (I) gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass die Chinazoline ausgewählt sind aus der Gruppe bestehend aus4. Use of the quinazolines of the general formula (I) according to one of claims 1 to 3, characterized in that the quinazolines are selected from the group consisting of
(1) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)- carbonyll-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin,(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl-piperazine-1 yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)~6-methyl~2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]"Chinäzo!in,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] "Chinäzo! in,
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morphoIin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(5) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-(2,2-dimethyl-6-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2,2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6 - [( vinylcarbonyl) amino] -quinazoline
(6) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]- amino}-7-cyclopropylmethoxy-chinazolin, (8) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopropylmethoxy-chinazolin,(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline, (8) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1 -oxo-2-buten-1 -yl)amino]-7-cyclopropyl- methoxy-chinazolin,(9) 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,
(10) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopropylmethoxy-chinazolin,(10) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino] -7-cyclopropylmethoxy -quinazoline,
(11 ) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopentyloxy-chinazolin,(11) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-ylamino] -7-cyclopentyloxy -quinazoline,
(12) 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,(12) 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-cyclopropylmethoxy-quinazoline,
(13) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin(13) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
(14) 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,(14) 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,
(15) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin,(15) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline,
(16) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,(16) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
(17) 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,(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy quinazoline,
(18) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopentyloxy-chinazolin, (19) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin(18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline, (19) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
(20) 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,(20) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxyethyl) amino] -1-oxo-2- buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline,
(21) 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,(21) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2- buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(22) 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,(22) 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(23) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(23) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2 buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline,
(24) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -• yl]ämino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin,(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] -imino} -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline,
(25) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin,(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (S) -tetrahydrofuran-3-yloxy) -quinazoline,
(26) 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,(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopentyloxy-quinazoline,
(27) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo- 2-buten-1-yl]amino}-7-cyclopentyloxy-chinazolin,(27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(28) 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,(28) 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,
(29) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 - yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoIin, (30) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolin,(29) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] -chinazoIin, (30) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
(31) 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin,(31) 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline,
(32) 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl- carbonyl)amino]-chinazolin,(32) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline,
(33) 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)chinazolin,(33) 4 - {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl ) quinazoline,
den Verbindungenthe connections
(34) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin(34) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine
(35) 4-[(R)-(1-Phenyl-ethyI)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,(35) 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine,
(36) 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2- buten-1-yl]amino}-7-ethoxy-chinolin und den Antikörpern(36) 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} 7-ethoxy-quinoline and the antibodies
(37) Cetuximab,(37) cetuximab,
(38) Trastuzumab,(38) trastuzumab,
(39) ABX-EGF,(39) ABX-EGF,
(40) Mab ICR-62,(40) Mab ICR-62,
(41 ) EGFR-antisense(41) EGFR antisense
sowie deren Salze. and their salts.
5. Verwendung der Chinazoline der allgemeinen Formel (I) gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass die Chinazoline ausgewählt sind aus der Gruppe bestehend aus5. Use of the quinazolines of the general formula (I) according to one of claims 1 to 3, characterized in that the quinazolines are selected from the group consisting of
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)- carbonyl3-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-chinazolin,(1) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl-3-piperazine-1 yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(3) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxyj-6-[(vinylcarbonyl)amino]-chinazolin,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxyj-6- [ (vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(5) 4-[(3-Ch!or-4-fluor-phenyl)amino]-7-[4-(252-dimethyl-6-oxo-morpholin-4-yi)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin(5) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4- (2 5 2-dimethyl-6-oxomorpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline
(6) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-buten-1 -yl]- amino}-7-cyclopropylmethoxy-chinazolin,(7) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-buten-1-yl] -amino} -7- cyclopropylmethoxy-quinazoline,
(8) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopropylmethoxy-chinazolin,(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy -quinazoline,
(9) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1 -oxo-2-buten-1 -yl)amino]-7-cyclopropyl- methoxy-chinazolin,(9) 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,
(10) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopropylmethoxy-chinazolin, (11 ) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yi)-1-oxo-2-buten-1-yl]amino}- 7-cyclopentyloxy-chinazolin,(10) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino] -7-cyclopropylmethoxy -quinazoline, (11) 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7 -cyclopentyloxy-quinazoline,
(12) 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,(12) 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-cyclopropylmethoxy-quinazoline,
(13) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-({4-[bis-(2-methoxyethyl)-amino]-1 -oxo-2- buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin(13) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ({4- [bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline
(14) 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)oxy3-chinazolin,(14) 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) Oxy3-quinazoline,
(15) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1 -oxo-2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin,(15) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline,
(16) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin,(16) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- methoxy-quinazoline,
(17) 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,(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy quinazoline,
(18) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-cyclopentyloxy-chinazolin,(18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline,
(19) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((S)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin(19) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((S) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo] 2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline
(20) 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(NlN-bis-(2-methoxy-ethyl)-amino)-1-oxo- 2-buten-1 -yl]amino}-7-cyclopropylmethoxy-chinazolin,(20) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - {[4- (N l N-bis- (2-methoxy-ethyl) -amino) -1-oxo-2- butene-1-yl] amino} -7-cyclopropylmethoxy quinazoline,
(21 ) 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, (22) 4-[(R)-(1 -Phenyl-ethyI)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 - oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin,(21) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl-amino] -1-oxo-2- buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, (22) 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-one buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline,
(23) 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]- 1 -oxo-2-buten-1 -yl}amino)-7-cyclopropylmethoxy-chinazolin,(23) 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2 buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline,
(24) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin,(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (R) -tetrahydrofuran-3-yloxy) -quinazoline,
(25) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazolin,(25) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ( (S) -tetrahydrofuran-3-yloxy) -quinazoline,
(26) 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,(26) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-butene 1 -yl} amino) -7-cyclopentyloxy-quinazoline,
(27) 4-[(3-Chlor-4-f!uorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo- 2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin ,(27) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline,
(28) 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl3amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin,(28) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl-3-amino} -7 - [(R ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(29) 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,(29) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- [ (S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,
(30) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxyj-7-methoxy- chinazolin und der Verbindung(30) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxyj-7-methoxy-quinazoline and the compound
(30) 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]- pyrimido[5,4-d]pyrimidin(30) 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6 - [(4-dimethylamino-cyclohexyl) -amino] -pyrimido [5,4-d] pyrimidine
sowie deren Salze. and their salts.
6. Verwendung der Chinazoline der allgemeinen Formel (I) gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass die Chinazoline ausgewählt sind aus der Gruppe bestehend aus6. Use of the quinazolines of the general formula (I) according to one of claims 1 to 3, characterized in that the quinazolines are selected from the group consisting of
(1 ) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(1) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(2) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)- butyloxy]-6-[(vinylcarbonyl)amino]-chinazolin,(2) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [4 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(3) 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,(3) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl] -piperazine- 1-yl} -ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline,
(4) 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-6-[(vinylcarbonyl)amino]-chinazolin,(4) 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- [(vinylcarbonyl) amino] -quinazoline,
(5) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N- [(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropyl- methoxy-chinazolin,(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- [2- (ethoxycarbonyl) -ethyl] -N- [(ethoxycarbonyl) methyl] amino} -1- oxo-2-buten-1-yl) amino] -7-cyclopropylmethoxyquinazoline,
(6) 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}- 7-cyclopropylmethoxy-chinazolin und(6) 4 - [(R) - (1-Phenyl-ethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-butene-1-ylamino] -7-cyclopropylmethoxy -quinazoline and
(7) 4-[(3-Chlor-4-fluorphenyl)amino]-6-[3-(morpholin-4-yl)-propyloxy]-7-methoxy- chinazolin(7) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
sowie deren Salze.and their salts.
7. Verwendung nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass es sich um eine Behandlung der oberen und unteren Atmungsorgane oder des Darmes handelt. 7. Use according to one of claims 1 to 6, characterized in that it is a treatment of the upper and lower respiratory organs or the intestine.
8. Verwendung nach Anspruch 7, dadurch gekennzeichnet, dass es sich bei den Erkrankungen um COPD, chronische Sinusitis, Asthma, zystische Fibröse, M. Crohn, Colitis ulcerosa oder Polyposis des Darmes handelt.8. Use according to claim 7, characterized in that the diseases are COPD, chronic sinusitis, asthma, cystic fibrosis, Crohn's disease, ulcerative colitis or polyposis of the intestine.
9. Verwendung nach Anspruch 8, dadurch gekennzeichnet, dass es sich bei den Erkrankungen um COPD, Asthma oder zystische Fibröse handelt. 9. Use according to claim 8, characterized in that the diseases are COPD, asthma or cystic fibrosis.
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