EP2118075A1 - Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation - Google Patents

Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation

Info

Publication number
EP2118075A1
EP2118075A1 EP08708456A EP08708456A EP2118075A1 EP 2118075 A1 EP2118075 A1 EP 2118075A1 EP 08708456 A EP08708456 A EP 08708456A EP 08708456 A EP08708456 A EP 08708456A EP 2118075 A1 EP2118075 A1 EP 2118075A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
amino
fluoro
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.)
Ceased
Application number
EP08708456A
Other languages
German (de)
English (en)
Inventor
Frank Himmelsbach
Birgit Jung
Ralf Lotz
Markus Ostermeier
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 International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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
Priority claimed from EP07101785A external-priority patent/EP1956010A1/fr
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP08708456A priority Critical patent/EP2118075A1/fr
Publication of EP2118075A1 publication Critical patent/EP2118075A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Bicyclic heterocycles medicaments containing these compounds, their use and processes for their preparation
  • the present invention relates to bicyclic heterocycles of the general formula
  • R a represents a phenyl, 1-phenylethyl or indan-4-yl group in which the phenyl nucleus is in each case substituted by the radicals R 1 to R 3 , where
  • R 1 and R 2 which may be the same or different, each represents a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • Ci -4 alkyl hydroxy, Ci -4 alkoxy, C 2- 3-alkenyl or C 2- 3-alkynyl group
  • R 3 is a hydrogen, fluorine, chlorine or bromine atom or
  • R b is an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl , 4- (Ci -4 -alkyl-carbonyl) -piperazin-1-yl, 4- (Ci -4 -alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci -4 -Al kyl-carbonyl) - homopiperazin-1 -yl or 4- (Ci -4- alkylsulfonyl) homopiperazin-1-yl group, each mono-, di- or by R 4 mono- may be trisubstituted, where the substituents may be the same or different and
  • R 4 is a fluorine, chlorine, bromine or iodine atom
  • Ci -4 alkyl C 2-4 alkenyl or C 2-4 alkynyl group
  • Ci -4 alkylamino di- (Ci -4 alkyl) amino, Ci -4 -alkyl-carbonylamino,
  • Ci -4 alkylamino-Ci -4 alkyl an amino-Ci -4 alkyl, Ci -4 alkylamino-Ci -4 alkyl, di- (Ci -4 alkyl) amino- Ci- 4 alkyl, Ci -4 alkyl-carbonylamino-Ci -4 alkyl, N- (Ci -4 alkyl) -C -4 alkyl carbonylannino-Ci -4 alkyl, Ci -4 alkyl-sulfonylamino-Ci -4 alkyl or N- (Ci- 4 alkyl) -C -4 alkyl-sulfonylamino-Ci -4 alkyl group,
  • Ci -4 alkyl-carbonyl cyano, Ci -4 -alkyl-oxycarbonyl, carboxy, aminocarbonyl, Ci -4 -alkyl-aminocarbonyl, di- (Ci -4 alkyl) amino carbonyl,
  • Ci -4 alkylsulphanyl Ci -4 alkylsulfinyl, Ci -4 alkylsulfonyl, aminosulfonyl, Ci -4 -alkyl-aminosulphonyl or di- (Ci -4 alkyl) amino-sulfonyl group,
  • Ci -4 alkylsulfanyl-Ci -4 alkyl Ci -4 alkylsulfinyl-Ci -4 alkyl, Ci -4 alkyl Al kylsulfonyl- Ci -4 alkyl, aminosulfonyl-C -4, Ci -4 alkyl aminosulfonyl-Ci -4 alkyl or di- (Ci -4 alkyl) aminosulfonyl-Ci -4 alkyl group
  • R b heterocycles may additionally be substituted by an oxo group
  • R c is a hydrogen atom
  • Ci -4 -Al kyl which is substituted by a radical R 5 , wherein
  • R 5 is a hydroxy, Ci -3 alkyloxy, Cs-e-cycloalkyloxy, amino, Ci -3 alkylamino,
  • Ci -4 alkylcarbonylamino Ci-3-alkyloxy-Ci-3-alkyl- carbonylamino
  • Ci -4 -Alkyloxycarbonylamino- aminocarbonylamino
  • Ci-3-Alkylanninocarbonylannino- di- (Ci-3- alkyl) aminocarbonylannino
  • pyrrolidin-1 -ylcarbonylamino piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-Ci-3-alkyl-piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino- or a Ci Represents -4- alkylsulfonylamino group,
  • Ci koxy distrue-4 -alkyl which is substituted by a 1 in position by the radical R 6 is substituted pyrrolidinyl, piperidinyl or homopiperidinyl group wherein
  • R 6 represents a hydrogen atom or a C 1-3 -alkyl group
  • Ci -4 koxyolitic alkyl which is substituted by a substituted in the 4-position by the group R 6 morpholinyl, wherein R 6 is as hereinbefore defined, and wherein the above-mentioned in the definition of the radical R c pyrrolidinyl, Piperidinyl, piperazinyl and morpholinyl groups may each be substituted by one or two c 1-3 -alkyl groups, and
  • aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as meaning a phenyl group which is monosubstituted or disubstituted by R 7 , where the substituents may be identical or different and
  • R 7 denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C 1-3 -alkyl, hydroxy, C 1-3 -alkyloxy, difluoromethyl-trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano Group represents, and
  • a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group is understood, wherein the above-mentioned heteroaryl groups are each mono- or disubstituted by the radical R 7 , where the substituents may be identical or different and R 7 is defined as mentioned above, and
  • alkyl groups mentioned above may be straight-chain or branched.
  • R a represents a phenyl, 1-phenylethyl or indan-4-yl group in which the phenyl nucleus is in each case substituted by the radicals R 1 to R 3 , where
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom
  • phenyloxy or phenylmethoxy group wherein the phenyl portion of the aforementioned groups is optionally substituted by a fluorine or chlorine atom, or
  • a pyridyloxy or pyridinylmethoxy group wherein the pyridinyl moiety of the aforementioned groups is optionally substituted by a methyl or trifluoromethyl group,
  • R 2 is a hydrogen, fluorine or chlorine atom or a methyl group
  • R 3 represents a hydrogen atom
  • R b is an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, homopiperidin-1-yl, morpholin-4-yl, homonnorpholin-4-yl, piperazin-1-yl , 4- (Ci-C3 alkyl-carbonyl) -piperazin-1-yl, 4- (Ci -3 alkyl-sulfonyl) -piperazin-1 -yl, homopiperazin-1 -yl, 4- (Ci 3 -alkyl-carbonyl) - homopiperazine-1-yl or 4- (Ci- 3- alkylsulfonyl) -homopiperazin-1-yl-group, each of which may be mono- or disubstituted by R 4 , wherein the substituents may be the same or different and
  • R 4 is a fluorine atom
  • Ci -3 alkylamino di- (Ci -3 alkyl) amino, Ci -3 -alkyl-carbonylamino, N- (Ci -3 alkyl) -C -3 alkyl-carbonylamino -, Ci -3 -alkyl-sulfonylamino, or N- (Ci -3 -AI alkyl) -C -3 alkyl-sulfonylamino group,
  • Ci-s-alkylannino-Ci-s-alkyl di- (Ci -3 -alkyl) amino-C 3 -alkyl
  • Ci-s-alkyl-carbonylannino-Ci -S-alkyl N- (Ci -3 alkyl) -C -3 alkyl- carbonylamino-Ci -3 alkyl
  • Ci- 3- alkyloxy or Ci-s-alkyl-carbonyloxy group
  • Ci -4 alkylsulphanyl Ci -4 kylsulfinyl- Al, Ci -4 alkylsulphonyl, aminosulphonyl,
  • Ci-3-alkyl-anninosulfonyl or di (Ci-3-alkyl) anninosulfonyl group
  • Ci -4 alkylsulfanyl-Ci 3 alkyl Ci -4 alkyl alkylsulfinyl-Ci 3,
  • R c is a hydrogen atom
  • R 5 is a hydroxy, Ci-3-alkyloxy, amino, Ci-3-alkylamino, di (Ci-3-alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1 - yl, piperidine-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazine-1-yl or a 4-Ci- 3- alkyl-piperazin-1-yl-group, a propyloxy group which is substituted at the 3-position by the radical R 5 , wherein R 5 is defined as mentioned above, or
  • R 5 a butoxy group substituted in the 4-position by a radical R 5 , wherein R 5 is defined as mentioned above, and
  • alkyl groups may be straight-chain or branched
  • R a phenyl, a 1-phenylethyl, 3-Ethinylphenyl-, 3-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro, 3-chloro-2-fluoro-phenyl, 3-chloro- 4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-5-methylphenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl-phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan -4-yl group,
  • R b is an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazin-1-yl,
  • Ci -3 alkyl-carbonyl cyano, Ci -4 alkyl-oxycarbonyl, carboxy, aminocarbonyl, Ci-3 alkyl, aminocarbonyl or di- (Ci -3 alkyl) amino-carbonyl
  • Ci -4 alkylsulphanyl Ci kylsulfinyl- -4 -alkyl, Ci -4 alkylsulfonyl, aminosulfonyl, Ci -3 -alkyl-aminosulphonyl or di- (Ci -3 alkyl) amino-sulfonyl group .
  • Ci -4 alkylsulfanyl-Ci 3 alkyl Ci ⁇ alkylsulfinyl-Ci 3 alkyl
  • R c is a hydrogen atom
  • R 5 is a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4 yl,
  • R 5 a butoxy group substituted in the 4-position by the radical R 5 , wherein R 5 is defined as mentioned above, and
  • alkyl groups may be straight-chain or branched
  • R a phenyl, a 1-phenylethyl, 3-Ethinylphenyl-, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro, 5-chloro-2-fluoro-phenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2,4-difluoro-3-methyl phenyl, 2,5-difluoro-3-methyl-phenyl, 3-chloro-2-methyl-phenyl or an indan-4-yl group,
  • R b is an azetidine-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholin-4-yl, piperazine-1-yl, 4- (Ci- 3- alkyl-carbonyl) - piperazin-1-yl or 4- (Ci -3 -alkyl-sulfonyl) -piperazin-1 -yl group mono- by each of R 4, or may be disubstituted, wherein the substituents may be identical or different and
  • R 4 is a fluorine atom
  • Ci-2-alkylamino di (Ci-2-alkyl) amino, Ci-2-alkyl-carbonylamino, N- (Ci-2-alkyl) -Ci-2-alkyl-carbonylamino , Ci-2-alkyl-sulfonylamino or N- (Ci-2-alkyl) -Ci-2-alkyl-sulfonylamino group,
  • Ci -2 alkyloxy- or Ci ⁇ alkyl-carbonyloxy group
  • Ci-2 alkyloxy C 2-4 alkyl or C 2 alkyl-carbonyloxy Ci-2-alkyl group a Ci -2 alkyl-carbonyl, cyano, Ci-2 alkyl oxycarbonyl, carboxy, aminocarbonyl, Ci-2 alkyl anninocarbonyl- or di- (Ci- 2 alkyl) Annino-carbonyl Group,
  • Ci 2 alkyl group aminocarbonyl-Ci- 2 alkyl, Ci- 2 -alkylaminocarbonyl- Ci-2-alkyl- or di- ⁇ i ⁇ -alkylJaminocarbonyl-Ci ⁇ alkyl group,
  • Ci- 2 alkylsulfanyl-Ci- 2 alkyl Ci-2 alkylsulfinyl Ci- 2 alkyl or Ci -2 -Al kylsulfonyl-Ci-2-alkyl group,
  • R c is a hydrogen atom
  • R a is a 1-phenylethyl, 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl- , 2-fluoro-5-methyl-phenyl, 3-fluoro-5-methyl phenyl, 4-fluoro-3-methylphenyl, 2,4-difluoro-3-methylphenyl, 3-chloro-2-methylphenyl or an indan-4-yl group,
  • R b is an azetidin-1-yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl or 3-oxo-piperazin-1-yl group, each represented by R 4 mono- or may be disubstituted, wherein the substituents may be the same or different and
  • R 4 represents a methyl, hydroxy, cyano, aminocarbonyl, methylamino-carbonyl or dimethylamino-carbonyl group
  • R c is a methoxy group
  • R a is a 3-chloro-2-fluoro-phenyl group
  • R b is a 3-oxo-piperazine-1-yl group or represents a 4-methyl-3-oxo-piperazin-1-yl group, and
  • R c represents a methoxy group
  • R a is in particular the 3-chloro-2-fluorophenyl group
  • R b is the 3-oxopiperazine-1-yl or 4-methyl-3-oxopiperazine-1-yl group
  • R c is the methoxy group
  • the compounds of general formula I can be prepared, for example, by the following processes:
  • R a and R c are defined as mentioned above, with a compound of the general formula
  • Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group.
  • a halogen atom for example a chlorine or bromine atom
  • a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group.
  • the reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, preferably in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisopropylamine, at temperatures in the range of 20 0 C to 160 0 C, for example at temperatures in the range of 80 ° C to 140 0 C.
  • a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
  • a base such as potassium carbonate, potassium tert-butoxide, sodium hydride or N-ethyl-diisoprop
  • the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklarediethylester, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, Toluene or Ethylenglycoldiethylether at tempera temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C performed.
  • a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / Azodicarbonklathylester
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, Toluene or Ethylenglycoldiethylether at
  • R a and R c are defined as mentioned above, and Z 2 is a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulphonyloxy group such as a Methanesulfonyloxy- or p-toluenesulfonyloxy group, with a compound of the general formula
  • R b is defined as mentioned above.
  • the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate or N-ethyl-diisopropylamine, for example in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidinone at temperatures in the range of 0 0 C and 150 0 C performed.
  • an organic or inorganic base such as potassium carbonate or N-ethyl-diisopropylamine
  • R a and R c are defined as mentioned above, with a compound of the general formula
  • the reductive amination is, for example, in a solvent such as dichloromethane, 1, 2-dichloroethane, methanol, ethanol, tetrahydrofuran or dioxane in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid, optionally in the presence of acetic acid at temperatures between 0 0 C. and 80 0 C performed.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanborhydrid
  • acetic acid at temperatures between 0 0 C. and 80 0 C performed.
  • the reductive amination can also be carried out with hydrogen in the presence of a catalyst such as palladium on activated carbon or platinum oxide.
  • Another possibility is to form the enamine from the ketone of general formula VI and the amine of general formula VII with elimination of water, for example with titanium (IV) isopropoxide, and then to reduce this, for example with sodium borohydride or hydrogen / palladium activated carbon.
  • Halogenating agent for example an acid halide such as thionyl chloride,
  • R b and R c are defined as mentioned above and Z 3 represents a halogen atom, such as a chlorine or bromine atom,
  • reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N, N-diethylaniline, triethylamine or N-
  • Ethyl diisopropylamine at temperatures ranging from 20 0 C to 160 0 C, preferably carried out from 40 ° C to 120 0 C.
  • reaction of the compound of the general formula (IX) with the compound of the general formula (X) or salts thereof is expediently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, if appropriate in the presence of a base such as potassium carbonate, triethylamine or nitrogen.
  • a base such as potassium carbonate, triethylamine or nitrogen.
  • Ethyl diisopropylamine at temperatures in the range of 20 ° C and 160 ° C, preferably from 60 0 C to 120 ° C.
  • the reaction is carried out in isopropanol at the boiling temperature of the reaction mixture.
  • reaction of a compound of the general formula (VIII) to give a compound of the general formula (I) can also be carried out as a one-pot reaction, for example in acetonitrile in the presence of triethylamine.
  • R c represents one of the abovementioned, optionally substituted alkyloxy groups:
  • R c is a Ci -4 alkyl group, substituted by 1 to 3 fluorine atoms, methyl or ethyl group, a C 3- 7 cycloalkyl or C 3 -7-cycloalkyl-Ci -4 alkyl group, a tetrahydrofuran-3-yl alkyl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, a tetrahydrofuranyl-Ci -4 or tetrahydropyranyl-Ci -4 alkyl group, a substituted by R 7 C2 -4 alkyl group, wherein R 7 is as hereinbefore defined is a Ci -4 -Al kyl distr, which is substituted by a 1-position by the radical R 8 substituted pyrrolidinyl, piperidinyl or Homopiperidinylrios, or a Ci -4 -Al kyl distr, by a in 4-position the radical
  • Z 4 represents a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group.
  • the leaving group is a halogen atom such as a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group such as the methanesulfonyloxy or p-toluenesulfonyloxy group
  • the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, sodium hydride or N- Ethyl diisopropylamine performed.
  • the leaving group is a hydroxy group
  • the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative, such as
  • Triphenylphosphine / Azodicarbonklarediethylester performed.
  • R a and R b are defined as mentioned above and Z 5 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulphonyloxy group such as a Methansulfonyloxy- or p-toluenesulfonyloxy group, with
  • R a and R c are defined as mentioned above and R b contains one or more groups convertible into hydroxyl groups, for example an optionally substituted benzyloxy group, a silyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.
  • the cleavage of the protecting groups takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or Potassium hydroxide or aprotic, for example in the presence of iodothmethylsilane, at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
  • an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali metal base such as sodium hydroxide or
  • cleavage of a benzyl or Methoxybenzylrestes example, hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid
  • an acid such as hydrochloric acid
  • 2,4-dimethoxybenzyl radical preferably occurs in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or benzyl radical is carried out, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid
  • iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • cleavage of a silyloxy group is carried out, for example, by treatment with fluorides such as tetrabutylammonium fluoride, if appropriate using a solvent such as tetrahydrofuran or dioxane.
  • R a and R c are defined as mentioned above and R b with the proviso has the meanings mentioned above for R b that R b contains a protected nitrogen atom.
  • Typical protecting groups for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, wherein the phthalyl group is additionally suitable for the amino group.
  • the cleavage of the protecting group is carried out, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water,
  • Trifluoroacetic acid Trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of a
  • Alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in
  • Presence of iodothymethylsilane at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
  • cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrest for example hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
  • tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with Sodium hydroxide, if appropriate in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 0 C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid
  • Sodium hydroxide if appropriate in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 0 C.
  • the cleavage of a Phthalylrestes preferably takes place in the presence of hydrazine or a primary amine such as methylamine, ethylamine, n-butylamine or ethanolamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 0 C.
  • a primary amine such as methylamine, ethylamine, n-butylamine or ethanolamine
  • a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 0 C.
  • a compound of the general formula I which contains an amino, alkylamino or imino group can be obtained by acylation or
  • Formula I are converted, wherein as the acylating agent, for example
  • Carboxylic acid halides, carboxylic anhydrides and carboxylic acids with
  • Activating agents such as N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate and as
  • optionally present reactive groups such as hydroxyl, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction.
  • Suitable protective radicals for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.
  • the optional subsequent cleavage of a protective moiety used is carried out, for example hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 0 C, preferably at temperatures between 10 and 100 0 C.
  • an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali
  • cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrest for example hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 0 C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole.
  • tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • Trifluoracetylrestes The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 0 C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. ,
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be resolved into their enantiomers.
  • the resulting cis / trans mixtures can be purified by chromatography in their cis and trans isomers, the resulting compounds of general formula I, which occur in racemates, according to known methods (see Allinger NL and ENeI EL in “ Topics in Stereochemistry “, Vol. 6, Wiley Interscience, 1971)) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physicochemical differences according to methods known per se, eg by chromatography and / or fractional crystallization, in their diastereomers, which, if they are obtained in racemic form, then can be separated into the enantiomers as mentioned above.
  • the enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such.
  • Particularly common optically active acids are e.g.
  • optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.
  • the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids or bases.
  • suitable acids are hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, phosphoric, fumaric, succinic, benzoic, salicylic, mandelic, lactic, malonic, citric, L-malic, L-tartaric or maleic acids ,
  • Suitable bases for this example, sodium hydroxide, potassium hydroxide, calcium hydroxide, diethanolamine or N-methyl-D-glucamine into consideration.
  • Ci -4 alkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, / so-butyl, sec-butyl or te / t-butyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, f-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / t-butyl, etc.
  • C 2 - 3 alkenyl (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 3 carbon atoms, provided they have at least one double bond. For example: ethenyl or allyl.
  • C 2 - 3 -alkynyl (including those which are part of other radicals) mean alkynyl groups having 2 to 3 carbon atoms, provided they have at least one triple bond. For example: ethinyl or propargyl.
  • C 3-7 -cycloalkyl means cyclic alkyl groups having 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclopentyl or cyclohexyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6, 10 or 14 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • the deprotection of a compound of the general formula (XVII) to give a compound of the general formula (VIII) is carried out if PG is benzyl, for example with hydrogen in the presence of a catalyst such as palladium / carbon (for example analogously to Example IV).
  • a catalyst such as palladium / carbon
  • the cleavage of the protecting group, if PG is 4-methoxybenzyl or 2,4-dimethoxybenzyl may also be oxidative (eg with cerium (IV) ammonium nitrate or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or with acids (eg with trifluoroacetic acid in the presence of anisole).
  • a compound of the general formula (VIII) can then be converted into a compound of the general formula (IX) as described in the above process d).
  • the meanings for R b , R c , Z 1 and Z 3 in the compounds of Scheme 1 are defined as mentioned above.
  • the compounds according to the invention of the general formula I and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), which is inhibited, for example, by inhibition of the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected.
  • EGF-R epidermal growth factor receptor
  • the biological properties of the new compounds are tested, for example, as follows:
  • EGF-R mediated signal transduction may be e.g. with cells expressing human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha, respectively.
  • a murine hematopoietic cell line is genetically engineered to express functional human EGF-R. The proliferation of this cell line can therefore be stimulated by EGF.
  • the cells are cultured in RPMI / 1640 medium. Proliferation is stimulated with 20 ng / ml human EGF (Promega).
  • DMSO dimethyl sulfoxide
  • these compounds are dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures at various dilutions, the maximum DMSO concentration being 1%. The cultures are incubated for 48 hours at 37 ° C.
  • the relative cell count is measured with the Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation Assay (Promega) in OD units.
  • the relative cell count is calculated as a percentage of the control and the drug concentration, which inhibits the proliferation of the cells to 50% (IC50) derived.
  • the compounds of the general formula I according to the invention exhibit, for example, IC50 values of ⁇ 10 micromolar, preferably of ⁇ 1 micromolar. For example, the following results are obtained:
  • the compounds of the general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as shown by the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases e.g. benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds of the invention are also useful for the prevention and treatment of respiratory and pulmonary diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1 -anti-trypsin deficiency, or in cough, pulmonary emphysema, pulmonary fibrosis and hyper-reactive airways.
  • inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1 -anti-trypsin deficiency, or in cough, pulmonary emphysema, pulmonary fibro
  • the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder, which are associated with a disrupted activity of tyrosine kinases, such as in chronic inflammatory Changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting Adenomas and protein loss syndromes.
  • diseases of the gastrointestinal tract and the bile ducts and bladder which are associated with a disrupted activity of tyrosine kinases, such as in chronic inflammatory Changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as they occur in diseases of the gastrointestinal tract, which are associated with increased secretion, such as M. Menetrier, secreting Adenomas and protein loss syndromes.
  • the compounds of general formula I and their physiologically acceptable salts can be used to treat other diseases caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc ..
  • tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, the treatment of nasal polyps, etc ..
  • the compounds of the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (eg etoposide), mitotic inhibitors (eg, vinblastine), nucleic acid-interacting compounds (eg, cisplatin, cyclophosphamide, adhamycin), hormone antagonists (eg, tamoxifen), inhibitors of metabolic processes (eg, 5-FU, etc.), cytokines (eg, interferons), antibodies, etc.
  • topoisomerase inhibitors eg etoposide
  • mitotic inhibitors eg, vinblastine
  • nucleic acid-interacting compounds eg, cisplatin, cyclophosphamide, adhamycin
  • hormone antagonists eg, tamoxifen
  • inhibitors of metabolic processes eg, 5-FU, etc.
  • cytokines eg,
  • these compounds alone or in combination with other respiratory therapies, such as secretolytic (e.g., ambroxol, N-acetylcysteine), broncholytic (e.g., tiotropium or ipratropium or fenoterol, salmeterol, salbutamol), and / or anti-inflammatory (e.g., theophylline or
  • Glucocorticoids are used for the treatment of diseases in the region of the gastrointestinal tract. These compounds can also be given alone or in combination with motility or secretion-influencing substances. These combinations can be administered either simultaneously or sequentially.
  • the use of these compounds, either alone or in combination with other active substances, may be intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, by inhalation or transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in dosages of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
  • these are administered with one or more conventional inert carriers and / or diluents, e.g.
  • lactose cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycehn, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories incorporated.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in 1, 2-dichloroethane.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • the reaction is carried out in tetrahydrofuran.
  • 1 drag core contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
  • a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
  • coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax.
  • Composition 1 tablet contains:
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 0 C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
  • Diameter 10 mm, biplan with facet on both sides and one-sided part notch.
  • Composition 1 tablet contains: Active substance 150.0 mg
  • the granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
  • Composition 1 capsule contains:
  • Corn starch drink about 180.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
  • Capsule shell hard gelatin capsule size 1
  • Composition 1 suppository contains:
  • the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
  • composition 100 ml Suspension contain: active substance 1.00 g
  • Carboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
  • 5 ml of suspension contain 50 mg of active ingredient.
  • Active ingredient 10.0 mg 0.01 n hydrochloric acid s.q.
  • the active ingredient is dissolved in the required amount 0.01 N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.
  • 1 capsule contains:
  • Preparation The active substance is mixed with lactose for inhalation purposes.
  • the mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).
  • 1 hub contains:
  • the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
  • the pH of the solution is adjusted with 1 N hydrochloric acid.
  • the adjusted solution is filtered and filled into containers suitable for the hand nebulizer (cartridges).

Abstract

La présente invention concerne des hétérocycles bicycliques de formule générale (I) dans laquelle R<SUP>a</SUP>, R<SUP>b</SUP> et R<SUP>c</SUP> sont tels que définis dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, en particulier leurs sels physiologiquement tolérés avec des acides minéraux ou organiques ou des bases minérales ou organiques qui ont des propriétés pharmacologiquement intéressantes, en particulier un effet d'inhibition sur la transduction de signal médiée par des tyrosine kinases. L'invention a également pour objet l'utilisation de ces composés pour le traitement de maladies, en particulier de maladies tumorales et de l'hyperplasie prostatique bénine (BPH), d'affections des poumons et des voies respiratoires, ainsi que l'utilisation de ces composés.
EP08708456A 2007-02-06 2008-01-30 Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation Ceased EP2118075A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08708456A EP2118075A1 (fr) 2007-02-06 2008-01-30 Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07101785A EP1956010A1 (fr) 2007-02-06 2007-02-06 Hétérocycles bicycliques, médicament contenant cette composition, son utilisation et son procédé de fabrication
EP07118700 2007-10-17
PCT/EP2008/051141 WO2008095847A1 (fr) 2007-02-06 2008-01-30 Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation
EP08708456A EP2118075A1 (fr) 2007-02-06 2008-01-30 Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation

Publications (1)

Publication Number Publication Date
EP2118075A1 true EP2118075A1 (fr) 2009-11-18

Family

ID=39247377

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08708456A Ceased EP2118075A1 (fr) 2007-02-06 2008-01-30 Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation

Country Status (18)

Country Link
US (1) US7998949B2 (fr)
EP (1) EP2118075A1 (fr)
JP (1) JP5377332B2 (fr)
KR (1) KR20090116782A (fr)
AR (1) AR065195A1 (fr)
AU (1) AU2008212999A1 (fr)
BR (1) BRPI0807234A2 (fr)
CA (1) CA2677336A1 (fr)
CL (1) CL2008000356A1 (fr)
CO (1) CO6210816A2 (fr)
EA (1) EA200901041A1 (fr)
EC (1) ECSP099562A (fr)
IL (1) IL199923A0 (fr)
MA (1) MA31171B1 (fr)
MX (1) MX2009007610A (fr)
TN (1) TN2009000332A1 (fr)
TW (1) TW200846330A (fr)
WO (1) WO2008095847A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1921070A1 (fr) * 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation
CA2711582A1 (fr) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Heterocycles spirocycliques, formules comportant lesdits composes, leur utilisation et procedes de preparation associes
CA2731895C (fr) * 2008-08-08 2016-11-08 Boehringer Ingelheim International Gmbh Procede pour effectuer la synthese stereoselective d'heterocycles bicycliques
JP5539351B2 (ja) * 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング シクロヘキシルオキシ置換ヘテロ環、これらの化合物を含有する医薬、およびそれらを生成するための方法
EP2346507A1 (fr) * 2008-09-03 2011-07-27 Boehringer Ingelheim International GmbH Utilisation de dérivés de quinazoline pour le traitement de maladies virales
EP2289881A1 (fr) 2009-08-06 2011-03-02 Boehringer Ingelheim International GmbH Procédé de synthèse stéréo-sélective d'hétérocycles bi-cycliques
EA201201052A1 (ru) 2010-01-29 2013-02-28 Бёрингер Ингельхайм Интернациональ Гмбх Замещенные нафтиридины и их применение в качестве ингибиторов киназы syk
KR20140096571A (ko) * 2013-01-28 2014-08-06 한미약품 주식회사 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법

Family Cites Families (174)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985749A (en) 1975-12-22 1976-10-12 Eastman Kodak Company Process for preparation of 4-aminoquinazoline
JPS5538325A (en) 1978-09-11 1980-03-17 Sankyo Co Ltd 4-anilinoquinazoline derivative and its preparation
US4335127A (en) 1979-01-08 1982-06-15 Janssen Pharmaceutica, N.V. Piperidinylalkyl quinazoline compounds, composition and method of use
GB2160201B (en) 1984-06-14 1988-05-11 Wyeth John & Brother Ltd Quinazoline and cinnoline derivatives
US4845629A (en) 1985-07-18 1989-07-04 General De Investigacion Y Desarrollo S.A. Airport surveillance systems
KR910006138B1 (ko) 1986-09-30 1991-08-16 에자이 가부시끼가이샤 환상아민 유도체
US4921863A (en) 1988-02-17 1990-05-01 Eisai Co., Ltd. Cyclic amine derivatives
GB8910722D0 (en) 1989-05-10 1989-06-28 Smithkline Beckman Intercredit Compounds
US5252586A (en) 1990-09-28 1993-10-12 The Du Pont Merck Pharmaceutical Company Ether derivatives of alkyl piperidines and pyrrolidines as antipsychotic agents
DE4105503A1 (de) 1991-02-19 1992-08-20 Jenapharm Gmbh Ausgangsverbindungen zur herstellung von calcitriol sowie dessen abkoemmlingen, verfahren zur herstellung dieser ausgangsverbindungen sowie zwischenprodukte fuer dieses verfahren
US6645969B1 (en) 1991-05-10 2003-11-11 Aventis Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US5710158A (en) 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
CA2102780C (fr) 1991-05-10 2007-01-09 Alfred P. Spada Composes de type bis-monoaryle, aryle bicyclique et (ou) heteroaryle inhibant l'activite de tyrosine kinase des recepteurs de l'egf et (ou) du pdgf
US5721237A (en) 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
US5187168A (en) 1991-10-24 1993-02-16 American Home Products Corporation Substituted quinazolines as angiotensin II antagonists
GB9300059D0 (en) 1992-01-20 1993-03-03 Zeneca Ltd Quinazoline derivatives
WO1993017682A1 (fr) 1992-03-04 1993-09-16 Abbott Laboratories Antagonistes des recepteurs de l'angiotensine ii
UA35618C2 (uk) 1993-05-26 2001-04-16 Сінтекс (С.Ш.А.) Інк. 1-фенілалканони, як ліганди 5-нт4 рецептора, спосіб їх отримання, фармацевтична композиція та спосіб лікування
US5395846A (en) 1993-06-25 1995-03-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Amino Bi- and tri-carbocyclic aklane bis-aryl squalene synthase inhibitors
GB9314893D0 (en) 1993-07-19 1993-09-01 Zeneca Ltd Quinazoline derivatives
US5700823A (en) 1994-01-07 1997-12-23 Sugen, Inc. Treatment of platelet derived growth factor related disorders such as cancers
AU2096895A (en) 1994-03-07 1995-09-25 Sugen, Incorporated Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
TW321649B (fr) 1994-11-12 1997-12-01 Zeneca Ltd
GB2295387A (en) 1994-11-23 1996-05-29 Glaxo Inc Quinazoline antagonists of alpha 1c adrenergic receptors
GB9424233D0 (en) 1994-11-30 1995-01-18 Zeneca Ltd Quinazoline derivatives
US5642285A (en) 1995-01-31 1997-06-24 Trimble Navigation Limited Outdoor movie camera GPS-position and time code data-logging for special effects production
EP2163546B1 (fr) 1995-03-30 2016-06-01 Pfizer Products Inc. Derives de quinazoline
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
GB9508537D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
EP0824525B1 (fr) 1995-04-27 2001-06-13 AstraZeneca AB Derives de quinazoline
GB9508535D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivative
GB9508565D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quiazoline derivative
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US6046206A (en) 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
EP0850055B1 (fr) 1995-09-11 2005-06-29 Osteoarthritis Sciences, Inc. Inhibiteurs de proteine-tyrosine-kinase pour le traitement de l'osteo-arthrite
CA2238081A1 (fr) 1995-11-22 1997-05-29 S. Jane Desolms Inhibiteurs de la farnesyl-proteine transferase
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
WO1997027841A1 (fr) 1996-01-31 1997-08-07 Gist-Brocades B.V. Utilisation de compositions comprenant des composes stabilises et efficaces sur le plan biologique
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
US6184225B1 (en) 1996-02-13 2001-02-06 Zeneca Limited Quinazoline derivatives as VEGF inhibitors
GB9603097D0 (en) 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline compounds
GB9603095D0 (en) 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
DE69709319T2 (de) 1996-03-05 2002-08-14 Astrazeneca Ab 4-anilinochinazolin derivate
BR9708640B1 (pt) 1996-04-12 2013-06-11 inibidores irreversÍveis de tirosina-cinases e composiÇço farmacÊutica compreendendo os mesmo.
GB9607729D0 (en) 1996-04-13 1996-06-19 Zeneca Ltd Quinazoline derivatives
GB9707800D0 (en) 1996-05-06 1997-06-04 Zeneca Ltd Chemical compounds
US5938706A (en) 1996-07-08 1999-08-17 Feldman; Yasha I. Multi element security system
AU3766897A (en) 1996-07-13 1998-02-09 Glaxo Group Limited Fused heterocyclic compounds as protein tyrosine kinase inhibitors
US6004967A (en) 1996-09-13 1999-12-21 Sugen, Inc. Psoriasis treatment with quinazoline compounds
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
US6225318B1 (en) 1996-10-17 2001-05-01 Pfizer Inc 4-aminoquinazolone derivatives
EP1586322B1 (fr) 1996-11-05 2008-08-20 The Children's Medical Center Corporation Compositions contenant de thalidomide et de dexamethasone pour le traitement du cancer
ES2384551T3 (es) 1997-03-05 2012-07-06 Sugen, Inc. Formulaciones para agentes farmacéuticos hidrófobos
UA73073C2 (uk) 1997-04-03 2005-06-15 Уайт Холдінгз Корпорейшн Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція
AR012634A1 (es) 1997-05-02 2000-11-08 Sugen Inc Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion
US5929080A (en) 1997-05-06 1999-07-27 American Cyanamid Company Method of treating polycystic kidney disease
DE69815340T2 (de) 1997-05-06 2004-05-06 Wyeth Holdings Corp. Verwendung von chinazolin verbindungen zur behandlung von polyzystischer nierenkrankheit
ES2215310T3 (es) 1997-06-30 2004-10-01 Glaxo Group Limited Procedimiento para identificar compuestos que tienen una actividad sistemica reducida.
ZA986732B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
ZA986729B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitors of tyrosine kinases
TW436485B (en) 1997-08-01 2001-05-28 American Cyanamid Co Substituted quinazoline derivatives
AU8816298A (en) 1997-08-22 1999-03-16 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
CN1278176A (zh) 1997-11-06 2000-12-27 美国氰胺公司 喹唑啉衍生物作为用于治疗结肠息肉的酪氨酸激酶抑制剂的应用
GB9800575D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
MXPA00011773A (es) 1998-05-28 2002-06-04 Parker Hughes Inst Quinazolinas para tratar tumores en el cerebro.
AU4851599A (en) 1998-06-30 2000-01-17 Parker Hughes Institute Method for inhibiting c-jun expression using jak-3 inhibitors
US6384223B1 (en) 1998-07-30 2002-05-07 American Home Products Corporation Substituted quinazoline derivatives
AR020114A1 (es) 1998-07-30 2002-04-10 America Home Products Corp Proceso para la preparacion de derivados de quinazolina sustituida y compuestos para su exclusivo uso en dicho proceso
WO2000009481A1 (fr) 1998-08-11 2000-02-24 Takeda Chemical Industries, Ltd. Composes d'amide cyclique, procedes de production correspondants, intermediaires correspondants et herbicides
US7354894B2 (en) 1998-08-18 2008-04-08 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US6846799B1 (en) 1998-08-18 2005-01-25 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
CZ2001584A3 (cs) 1998-08-18 2002-06-12 The Regents Of The University Of California Prevence tvorby hlenu v dýchacích cestách podáváním antagonistů EGF-R
JP2002523403A (ja) 1998-08-21 2002-07-30 パーカー ヒューズ インスティテュート キナゾリン誘導体
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
BRPI9914164B8 (pt) 1998-09-29 2021-05-25 American Cyanamid Co compostos de 3-ciano quinolina
US6297258B1 (en) 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
WO2000020402A1 (fr) 1998-10-01 2000-04-13 Astrazeneca Ab Composes chimiques
TW575567B (en) 1998-10-23 2004-02-11 Akzo Nobel Nv Serine protease inhibitor
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
ES2351699T3 (es) 1999-02-10 2011-02-09 Astrazeneca Ab Derivados de quinazolina como inhibidores de la angiogénesis e intermedios de los mismos.
SK12112001A3 (sk) 1999-02-27 2001-12-03 Boehringer Ingelheim Pharma Kg 4-amino-chinazolínové a chinolínové deriváty, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie
US6080747A (en) 1999-03-05 2000-06-27 Hughes Institute JAK-3 inhibitors for treating allergic disorders
DE19911509A1 (de) 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19911510A1 (de) 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP1162974A1 (fr) 1999-03-19 2001-12-19 Parker Hughes Institute Formulations de quinazoline et leur utilisation therapeutique
US6258820B1 (en) 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
CA2373073A1 (fr) 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Composes cycliques et leurs utilisations
GB9910577D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6126917A (en) 1999-06-01 2000-10-03 Hadasit Medical Research Services And Development Ltd. Epidermal growth factor receptor binding compounds for positron emission tomography
MXPA01012899A (es) 1999-06-21 2002-07-30 Boehringer Ingelheim Pharma Heterociclos biciclicos, medicamentos que contienen estos compuestos, su empleo y procedimientos para su preparacion.
WO2001004102A1 (fr) 1999-07-07 2001-01-18 Astrazeneca Uk Limited Derives de quinazoline
GB9917408D0 (en) 1999-07-23 1999-09-22 Smithkline Beecham Plc Compounds
MXPA02001448A (es) 1999-08-12 2002-07-02 American Cyanamid Co Farmacos antiinflamatorios no esteroides e inhibidores de cinasa del receptor del factor de crecimiento epidermico que contiene composicion para el tratamiento o la inhibicion de polipos colonicos y cancer colorrectal.
GB9922173D0 (en) 1999-09-21 1999-11-17 Zeneca Ltd Chemical compounds
CA2384291A1 (fr) 1999-09-21 2001-03-29 Astrazeneca Ab Derives de quinazoline et leur utilisation comme produits pharmaceutiques
GB9922171D0 (en) 1999-09-21 1999-11-17 Zeneca Ltd Chemical compounds
CZ20021010A3 (cs) 1999-09-21 2002-06-12 Astrazeneca Ab Nové sloučeniny chinazolinu a farmaceutické kompozice, které je obsahují
EP1230225A2 (fr) 1999-11-01 2002-08-14 Eli Lilly And Company Derives de pyrimidine substitues en position 4 actifs pharmaceutiquement
KR100849151B1 (ko) 1999-11-05 2008-07-30 아스트라제네카 아베 Ｖｅｇｆ 억제제로서의 퀴나졸린 유도체
WO2001045641A2 (fr) 1999-11-30 2001-06-28 Parker Hughes Institute Inhibiteurs d'agregation de plaquettes induite par thrombine
DE60112268T2 (de) 2000-03-06 2006-05-24 Astrazeneca Ab Verwendung von quinazolinderivate als inhibitoren der angiogenese
US20060063752A1 (en) 2000-03-14 2006-03-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
GB0008368D0 (en) 2000-04-06 2000-05-24 Astrazeneca Ab Combination product
MXPA02009891A (es) 2000-04-07 2003-03-27 Astrazeneca Ab Compuestos de quinazolina.
AU6383101A (en) 2000-04-08 2001-10-23 Boehringer Ingelheim Pharma Kg Bicyclic heterocylces, medicaments containing said compounds, the use thereof and method for producing them
US6627634B2 (en) 2000-04-08 2003-09-30 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
AU2001258771A1 (en) 2000-05-19 2001-11-26 Takeda Chemical Industries Ltd. -secretase inhibitors
UA73993C2 (uk) 2000-06-06 2005-10-17 Астразенека Аб Хіназолінові похідні для лікування пухлин та фармацевтична композиція
EA005525B1 (ru) 2000-06-22 2005-04-28 Пфайзер Продактс Инк. Замещенные бициклические производные для лечения аномального роста клеток
PL202812B1 (pl) 2000-08-21 2009-07-31 Astrazeneca Ab Pochodna chinazoliny, jej kompozycja famaceutyczna oraz jej zastosowanie
DE10042060A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6740651B2 (en) 2000-08-26 2004-05-25 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6617329B2 (en) 2000-08-26 2003-09-09 Boehringer Ingelheim Pharma Kg Aminoquinazolines and their use as medicaments
DE10042062A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Hertellung
US6653305B2 (en) 2000-08-26 2003-11-25 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US20020082270A1 (en) 2000-08-26 2002-06-27 Frank Himmelsbach Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
DE10042058A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042061A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042059A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6656946B2 (en) 2000-08-26 2003-12-02 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6403580B1 (en) 2000-08-26 2002-06-11 Boehringer Ingelheim Pharma Kg Quinazolines, pharmaceutical compositions containing these compounds, their use and processes for preparing them
AU2002218192A1 (en) 2000-09-21 2002-04-02 Smithkline Beecham Plc Quinoline derivatives as antibacterials
JP2004511479A (ja) 2000-10-13 2004-04-15 アストラゼネカ　アクチボラグ キナゾリン誘導体
AU1339302A (en) 2000-10-20 2002-05-06 Biocryst Pharm Inc Biaryl compounds as serine protease inhibitors
EP1332141A1 (fr) 2000-10-25 2003-08-06 AstraZeneca AB Derives de quinazoline
US20030158196A1 (en) 2002-02-16 2003-08-21 Boehringer Ingelheim Pharma Gmbh Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
JP2004514718A (ja) 2000-11-02 2004-05-20 アストラゼネカ　アクチボラグ 抗癌剤としての置換キノリン類
ES2290199T3 (es) 2000-11-22 2008-02-16 Novartis Ag Mezcla que incluye un agente que reduce la actividad de fcve y un agente que reduce la actividad de fce.
AUPR201600A0 (en) 2000-12-11 2001-01-11 Fujisawa Pharmaceutical Co., Ltd. Quinazolinone derivative
DE10063435A1 (de) 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
GB0101577D0 (en) 2001-01-22 2001-03-07 Smithkline Beecham Plc Compounds
WO2002062767A1 (fr) 2001-02-07 2002-08-15 Sumitomo Pharmaceuticals Company, Limited Nouveaux derives de quinazoline
NZ516873A (en) 2001-02-12 2003-11-28 Warner Lambert Co Compositions containing retinoids and erb inhibitors and their use in inhibiting retinoid skin damage
WO2002066445A1 (fr) 2001-02-21 2002-08-29 Mitsubishi Pharma Corporation Derives de la quinazoline
WO2002068409A1 (fr) 2001-02-23 2002-09-06 Merck & Co., Inc. Antagonistes nmda/nr2b nonaryl-heterocycliques n-substitues
US6562319B2 (en) 2001-03-12 2003-05-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy
US20030125344A1 (en) 2001-03-23 2003-07-03 Bayer Corporation Rho-kinase inhibitors
JP4615755B2 (ja) 2001-04-04 2011-01-19 セイコーインスツル株式会社 半導体装置の製造方法
WO2002092579A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives de 4-anilinoquinazoline
WO2002092578A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives de quinazoline
WO2002092577A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives quinazoliniques
AR033765A1 (es) 2001-05-22 2004-01-07 Syngenta Participations Ag Procedimiento para la preparacion de derivados 3-alquil-3h-isobenzofuran-1-ona 7-sustituidos.
EP1396488A1 (fr) 2001-05-23 2004-03-10 Mitsubishi Pharma Corporation Compose heterocyclique condense et son utilisation medicale
EP1408980A4 (fr) 2001-06-21 2004-10-20 Ariad Pharma Inc Nouvelles quinazolines et leur utilisation
CN100343238C (zh) 2001-11-03 2007-10-17 阿斯特拉曾尼卡有限公司 用作抗肿瘤药物的喹唑啉衍生物
GB0128109D0 (en) 2001-11-23 2002-01-16 Astrazeneca Ab Therapeutic use
GB0128108D0 (en) 2001-11-23 2002-01-16 Astrazeneca Ab Therapeutic use
JP4181502B2 (ja) 2001-12-12 2008-11-19 ファイザー・プロダクツ・インク 異常な細胞増殖を治療するためのキナゾリン誘導体
DE10204462A1 (de) 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
TWI324597B (en) 2002-03-28 2010-05-11 Astrazeneca Ab Quinazoline derivatives
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
PL371188A1 (en) * 2002-03-30 2005-06-13 Boehringer Ingelheim Pharma Gmbh & Co.Kg 4-(n-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors
US20040044014A1 (en) 2002-04-19 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
JP2006515871A (ja) 2003-01-23 2006-06-08 ティー．ケイ． シグナル リミテッド 上皮増殖因子受容体チロシンキナーゼの不可逆阻害剤ならびにその使用
GB0309009D0 (en) 2003-04-22 2003-05-28 Astrazeneca Ab Quinazoline derivatives
DE10326186A1 (de) 2003-06-06 2004-12-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US20050059661A1 (en) 2003-07-28 2005-03-17 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
GB0317665D0 (en) 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
CA2533345A1 (fr) 2003-07-29 2005-02-10 Astrazeneca Ab Derivees de piperidyl-quinazoline utilises comme inhibiteurs de la tyrosine kinase
GB0321648D0 (en) 2003-09-16 2003-10-15 Astrazeneca Ab Quinazoline derivatives
WO2005026151A1 (fr) 2003-09-16 2005-03-24 Astrazeneca Ab Dérivés de quinozaline en tant qu'inhibiteurs de la tyrosine kinase
JP2007505878A (ja) 2003-09-19 2007-03-15 アストラゼネカ アクチボラグ キナゾリン誘導体
AU2004274227B2 (en) 2003-09-19 2008-04-24 Astrazeneca Ab Quinazoline derivatives
US20070043010A1 (en) 2003-09-25 2007-02-22 Astrazeneca Uk Limited Quinazoline derivatives
GB0322409D0 (en) 2003-09-25 2003-10-29 Astrazeneca Ab Quinazoline derivatives
US7456189B2 (en) 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10350717A1 (de) 2003-10-30 2005-06-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
AU2005287057A1 (en) 2004-09-17 2006-03-30 Osi Pharmaceuticals, Inc. (spirocyclylamido) aminothiophene compounds as c-Kit proto- oncogene inhibitors
KR20080077009A (ko) 2005-12-12 2008-08-20 베링거 인겔하임 인터내셔날 게엠베하 바이사이클릭 헤테로사이클, 당해 화합물을 함유하는 약제,이의 용도 및 이의 제조방법
EP1921070A1 (fr) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008095847A1 *

Also Published As

Publication number Publication date
TN2009000332A1 (fr) 2010-12-31
ECSP099562A (es) 2009-09-29
WO2008095847A1 (fr) 2008-08-14
JP5377332B2 (ja) 2013-12-25
US7998949B2 (en) 2011-08-16
CA2677336A1 (fr) 2008-08-14
AR065195A1 (es) 2009-05-20
EA200901041A1 (ru) 2010-02-26
JP2010518045A (ja) 2010-05-27
CL2008000356A1 (es) 2009-03-27
AU2008212999A1 (en) 2008-08-14
KR20090116782A (ko) 2009-11-11
IL199923A0 (en) 2010-04-15
MA31171B1 (fr) 2010-02-01
TW200846330A (en) 2008-12-01
CO6210816A2 (es) 2010-10-20
US20100022505A1 (en) 2010-01-28
MX2009007610A (es) 2009-07-24
BRPI0807234A2 (pt) 2014-06-03

Similar Documents

Publication Publication Date Title
EP1731511B1 (fr) Heterocycles bicycliques, medicaments contenant ces composés, leur utilisation et procédés permettant de les préparer
EP1492536B1 (fr) 4-(n-phenylamino)-quinazolines / quinolines en tant qu&#39;inhibiteurs de la tyrosine kinase
EP1315718B1 (fr) Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
EP1345910B9 (fr) Derives de la quinazoline, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
EP1280798B1 (fr) Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production
EP1315720B1 (fr) Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
EP1597240B1 (fr) Heterocycles bicycliques, medicaments les contenant, leur utilisation et leurs procedes de production
DE19911509A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042058A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP2118075A1 (fr) Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation
WO2007068552A1 (fr) Heterocycles bicycliques, medicaments contenant ces composes, utilisation et procede de fabrication de ceux-ci
DE10042061A1 (de) Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP1499619A1 (fr) Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production
EP1641767A2 (fr) Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et procede pour leur production
EP2298305A1 (fr) 4-(N-Phenylamino)-quinazolines/quinoline en tant qu&#39;inhibiteurs de tyrosine kinases
DE19911510A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042064A1 (de) Chinazoline, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19908567A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19911366A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
EP1670781A1 (fr) Derives de quinoleine et de quinazoline, medicaments contenant ces composes, utilisation et procede de production de ceux-ci
EP1956010A1 (fr) Hétérocycles bicycliques, médicament contenant cette composition, son utilisation et son procédé de fabrication
DE19928281A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10231711A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10023085A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE19954816A1 (de) Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090907

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: BA RS

RAX Requested extension states of the european patent have changed

Extension state: RS

Payment date: 20090907

Extension state: BA

Payment date: 20090907

17Q First examination report despatched

Effective date: 20120725

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20130720