EP1861379A1 - Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation - Google Patents

Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation

Info

Publication number
EP1861379A1
EP1861379A1 EP06723722A EP06723722A EP1861379A1 EP 1861379 A1 EP1861379 A1 EP 1861379A1 EP 06723722 A EP06723722 A EP 06723722A EP 06723722 A EP06723722 A EP 06723722A EP 1861379 A1 EP1861379 A1 EP 1861379A1
Authority
EP
European Patent Office
Prior art keywords
group
groups
alkyl
hydroxy
substituted
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Withdrawn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
EP06723722A
Other languages
German (de)
English (en)
Inventor
Hartmut Rehwinkel
Heike Schäcke
Stefan BÄURLE
Markus Berger
Anne Mengel
Konrad Krolikiewicz
Bernd Buchmann
Norbert Schmees
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.)
Bayer Pharma AG
Original Assignee
Bayer Schering Pharma AG
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 Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP1861379A1 publication Critical patent/EP1861379A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring

Definitions

  • Tetrahydronaphthalene derivatives process for their preparation and their use as anti-inflammatory agents
  • the invention relates to tetrahydronaphthalene derivatives, processes for their preparation and their use as anti-inflammatory agents.
  • the prior art WO 02/10143 discloses open-chain non-steroidal anti-inflammatory agents. These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.
  • the present invention relates to compounds of the general formula (I),
  • R 1 1, and R 2 independently of one another denote a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C 1 -C 10 ) -alkyl group, an optionally substituted (C 1 -C 10 ) -alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 6) perfluoroalkyl group, a cyano group, a nitro group or R 1 and R 2 together form a group selected from the groups -O-
  • R 3 and R 4 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C 1 -C 10) -alkyl group, an optionally substituted (C 1 -C 10) -alkoxy group, a (C 1 -C 10 ) alkylthio group, a (CrC-s) perfluoroalkyl group, R 5 a CRCI O alkyl group, by a plurality of groups or is selected from hydroxy, halogen, (CrC 5) alkoxy groups substituted C r Cio-alkyl group, an optionally substituted (C 3 -C 7) cycloalkyl group, an optionally substituted heterocyclyl, an optionally substituted aryl group, an optionally substituted independently by one or more groups selected from (C r C 5) alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1 -3 COOR 10 groups),
  • R 7 is a halogen atom, a (Ci-Cio) alkyl group which may optionally be substituted by OR 10 , SR 10 , N (R 10 R 11 ) or 1-3 halogen atoms
  • R 8 and R 9 are independently a hydrogen atom, a Halogen atom, a (C 1 -C 5 ) alkyl group which may be substituted by OR 10 , SR 10 , N (R 10 R 11 ), a cyano group or together with the carbon atom of the ring system a (C 3 -C 6 ) cycloalkyl ring or together an optionally substituted by hydroxy, halogen or cyano (-C-Cs) alkylidene group or R 7 and R 8 together a fused five to eight-membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1-2 keto groups, 1-2 (Ci -C 5 ) alkyl groups, 1-2 (CrC 5 ) alkoxy
  • R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10) - alkyl group, a (C -Cio) -Alkoxyados, a (Ci-C- ⁇ o) -Alkythiooire, a (Cr C 5 ) - perfluoroalkyl group, a cyano group, a nitro group or R 1 and R 2 together form a group selected from the groups
  • R 3 and R 4 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10 ) -alkyl group, a (C 1 -C 10 ) -alkoxy group, a (C 1 -C 10 ) -alkylthio group, a ( CrC 5 ) - perfluoroalkyl group, a cyano group
  • R 5 is a C 1 -C 6 -alkyl group, a C 1 -C 6 -alkyl group substituted by one or more groups selected from among 1 to 3 hydroxyl groups, halogen atoms, 1-3 (C 1 -C 5 ) -alkoxy groups, an optionally substituted phenyl group, optionally by 1-2 keto groups, 1-2 (Ci-C 5 ) -alkyl groups, 1-2 (Ci-C 5 ) -alkoxy groups, 1-3 hydroxy groups, 1-3 hal
  • R 7 is a halogen atom, a (Ci-Ci O ) alkyl group which may optionally be substituted by OR 10 , SR 10 , N (R 10 R 11 ) or 1-3 halogen atoms
  • R 8 and R 9 is independently a hydrogen atom, a Halogen atom, a methyl or ethyl group which may be substituted by OR 10 , SR 10 , NR 10 R 11 , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C 3 -C 6 ) -cycloalkyl ring or together a (CrC 5 ) Alkylidene group or R 7 and R 8 together form an annelated 5- to 8 -membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C 1 -C 5 ) -alkyl groups, 1-2 (C 1 -C 5 ) Alkoxy groups,
  • R5 is a Ci-C 10 alkyl group, by one or more groups selected from 1-3 hydroxy groups or halogen atoms substituted C 1 -C 10 - alkyl group, optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 - (C- ⁇ -C 5) alkyl groups, 1-2- (-C 5) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C 3) -Exoalkylidengue substituted phenyl, phthalidyl , Isoindolyl, dihydroindolyl, dihydroisoindolyl,
  • R 7 is a halogen atom, a methyl or ethyl group which may be substituted by OR 10 , SR 10 , N (R 10 R 11 ) or 1-3 halogen atoms
  • R 8 and R 9 are independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR 10 , SR 10 , N (R 10 ) 2 , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C 3 -C 6 ) -cycloalkyl ring or together a (CrC 5 ) alkylidene group or
  • R 7 and R 8 together form a fused 5- to 8 -membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C 5 ) -alkyl groups, 1-2 (Ct-C 5 ) - Alkoxy groups, 1-4 halogen atoms is substituted mean.
  • Another object of the present invention are stereoisomers of the general formula (I) wherein
  • R 3 is a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10 ) -alkyl group, a (C 1 -C 10 ) -alkoxy group
  • R 4 is a hydrogen atom
  • R 5 is optionally substituted by one or more groups selected from among 1-2 keto groups, 1-2- (C 1 -C 5 ) -alkyl groups, 1-2- (C 1 -C 5 ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CiC- 3 ) -exxalkyliden law substituted
  • R 7 and R 8 together form a fused five to eight-membered saturated or unsaturated carbo or heterocycle, b ⁇ command.
  • Another object of the present invention are stereoisomers of the general formula (I) wherein
  • R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-C 5 ) -
  • Alkyl group a (CrC 5 ) alkoxy group, a cyano group or
  • R 1 and R 2 together form a group selected from the groups -O- (CH 2 ) n -O-
  • R 3 and R 4 independently of one another represent a hydrogen atom, a hydroxyl
  • Alkyl group a (CrC 5 ) alkoxy group
  • R5 is a Ci-C 10 alkyl group, a substituted by one or more groups selected from 1-3 hydroxy groups or halogen atoms, C 1 -C- 10 -
  • Alkyl group one optionally by one or more groups selected from 1-2 keto groups, 1-2- (CrC 5 ) alkyl groups, 1-2- (CrC 5 ) alkoxy groups, 1-3
  • Tetrahydronaphthalinsystems may be linked and may optionally be hydrogenated at one or more sites
  • R 6 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group
  • R 7 is a halogen atom, a methyl or ethyl group which is linked to OR 10 , SR 10 ,
  • N (R 10 R 11 ) or 1-3 halogen atoms may be substituted R 8 and R 9 are independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR 10 , SR 10 , N (R 10 ) 2 , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C C 3 -C 6 -cycloalkyl ring or together form a (C 1 -C 5 ) -alkylidene group or
  • R 7 and R 8 together form a fused five- to eight-membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C 5 ) -alkyl groups, 1-2 (C 1 -C 5 ) -alkoxy groups, 1-4 halogen atoms is substituted mean.
  • Another object of the present invention are stereoisomers of the general formula (I) wherein
  • R 3 is a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 5 ) -alkyl group, a (C 1 -C 5 ) -alkoxy group, R 4 is a hydrogen atom
  • R 5 is optionally substituted by one or more groups selected from 1-2 keto groups, 1-2- (C 1 -C 5 ) -alkyl groups, 1-2- (C 1 -C 5 ) -alkoxy groups, 1-3 hydroxy groups, 1-3 Halogen atoms, 1-2 (CrC 3 ) -oxoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,
  • R 7 is a methyl or ethyl group
  • R 8 and R 9 are independently a hydrogen
  • R 1 and R 2 are independently hydrogen, hydroxy, halogen, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkoxy, R 3 is hydrogen, halogen, R 4 is hydrogen
  • R 5 is optionally substituted by 1-2 keto groups, 1-2 (Ci-C 5 ) alkyl groups, 1-2 (Ci-C 5 ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CrC 3 ) - Exoalkyliden recognition substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, which groups linked via any position with the amine of Tetrahydronaphthalinsystems and optionally hydrogenated at one or more sites R 6 fully fluorinated (Ci-Cs) alkyl group R 7 is a methyl or ethyl group,
  • R 8 and R 9 independently of one another represent a hydrogen atom, a methyl or ethyl group or together a methylene or ethylidene group, or R 7 and R 8 together denote a fused five- to six-membered saturated or unsaturated carbocycle.
  • a preferred subject of the present invention are stereoisomers of the general formula (I) wherein R 1 and R 2 independently of one another represent a hydrogen atom, a hydroxyl
  • R 3 is a hydrogen atom, a halogen atom
  • R 4 is a hydrogen atom
  • R 5 is optionally independently of one another by one or more
  • R 6 fully fluorinated (C- ⁇ -C 3 ) alkyl group
  • R 7 is a methyl or ethyl group
  • R 8 and R 9 are independently hydrogen, methyl or
  • R 7 is a (C 1 -C 5 ) -alkyl group or a halogen atom and in which R 7 is a (C 1 -C 3) Alkyl group and particularly preferably wherein R 7 represents a methyl or ethyl group.
  • halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom. As a substituent for R 5 is most preferably the fluorine atom.
  • the alkyl groups R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 and R 11 may be straight-chain or branched and are, for example, a methyl, ethyl, n-propyl n-butyl, iso-butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl.
  • a CrC 3 alkyl group is preferred. They may optionally be substituted by a group selected from 1-3 hydroxy, 1-3 halogen, 1-3 (CrC 3 ) alkoxy, and / or 1-3 COOR 11 groups. Preference is given to hydroxy groups.
  • the alkyl group R 5 has the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group hydroxy, halogen, (Ci-C 5 ) -alkyloxy.
  • the alkyl groups R 8 and R 9 have the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group OR 10 , SR 10 and N (R 10 R 11 ), wherein R 10 and R 11 are hydrogen, dC 5 alkyl or (CO) CrC 5 alkyl and alkyl is also as defined above.
  • the alkoxy groups can be straight-chain or branched and are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy , 2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group is preferred.
  • the alkylthio groups may be straight-chain or branched and may be a methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio , 2-methylbutylthio or 3-methylbutylthio group.
  • a methylthio or ethylthio group is preferred.
  • a partially or fully fluorinated alkyl group which may be straight-chain or branched
  • Trifluoromethyl fluoroethyl, 1, 1-difluoroethyl, 1, 2-difluoroethyl, 1, 1, 1-trifluoroethyl,
  • the reagents are commercially available or the published syntheses of the corresponding
  • the aromatic part of the tetrahydronaphthalene system may be substituted 1-4 times, preferably 1-2 times.
  • Suitable substituents are the definitions of the patent claims mentioned for R 1 , R 2 , R 3 and R 4 , for R 1 and R 2 independently of one another a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 4) -alkyl group , an optionally substituted (C 1 -C 10) -alkoxy group, a (C 1 -C 10) - Alkylthio group, a (CrC 5) perfluoroalkyl group, a cyano group, a nitro group, preferably each independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 5) - alkyl group, an optionally substituted (CrC 5) Alkoxy group, a (C 1 -C 5 ) al
  • a particular subject of the invention are compounds of general formula I according to one of the claims, wherein R 1 and R 2 independently of one another particularly preferably a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CrC 3 ) alkyl group, an optionally substituted (-C 3) alkoxy, (CrC 3) alkylthio group, a (-C 3) perfluoroalkyl group, most preferably a hydroxy group, a halogen atom, a (-C 3) alkyl group or a (C 1 -C 3) - Alkoxy group mean. If the text speaks of "basic structure", then the tetrahydronaphthalene system is meant.
  • the terminal atoms of the groups listed above are linked to directly adjacent aryl ring carbon atoms to form a fused ring.
  • the substituent NR 10 R 11 is , for example, NH 2 , NH (CH 3 ), N (CH 3 ) 2 , NH (C 2 H 5 ), N (C 2 Hs) 2 , NH (C 3 H 7 ), N ( C 3 Hy) 2 , NH (C 4 H 9 ), N (C 4 Hg) 2 , NH (C 5 H 11 ), N (C 5 Hn) 2 , NH (CO) CH 3 , NH (CO) C 2 H 5 , NH (CO) C 3 H 7 , NH (CO) C 4 H 9 , NH (CO) C 5 H 11 .
  • the cycloalkyl group means a saturated cyclic group having 3 to 7 ring carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (C 1 -C 5 ) -alkyl groups, (C 1 -C 5 ) -alkoxy groups , Methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.
  • the cycloalkylalkyl group means, for example, - (CH 2 ) -cycloalkyl, - (C 2 H 4 ) -cycloalkyl, - (C 3 H 6 ) -cycloalkyl, - (C 4 H 8 ) -cycloalkyl, - (C 5 H 10 ) - Cycloalkyl, wherein cycloalkyl is defined as described above.
  • (Ci-C 3 ) -Exoalkylidenoli is to be understood a group which is
  • the alkylidene group R 8 / R 9 may have 1 to 5 carbon atoms, may be symmetrical or asymmetric and may be optionally substituted by hydroxy, halo or cyano groups.
  • the heterocyclyl group is not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Suitable substituents are hydroxyl groups, halogen atoms, (C 1 -C 5 ) -alkyl groups, (C 1 -C 5 ) -alkoxy groups. Heterocyclylalkyl groups are to be understood as meaning heterocyclyl groups which are linked to the skeleton via a C 1 -C 5 -alkyl group, where the alkyl group may be straight-chain or branched.
  • Heterocyclylalkenyl groups are heterocyclyl groups which are bonded to the skeleton via an unsaturated C 2 -Cs-alkyl group, where the alkenylene groups may be straight-chain or branched.
  • Di ⁇ aryl group R 5 and R 6 may be phenyl or naphthyl. Suitable substituents for both groups come CrC 3 alkyl, hydroxy, -C 3 - alkoxy, Ci-C3 alkylthio, halo, cyano, COO (C r C 5) alkyl, COOH, N (R 10 R 11), nitro, into consideration. The degree of substitution may be one or more than one, may include several identical or different substituents. Mono- or disubstituted phenyl and naphthyl groups R 5 are preferred.
  • the aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also carry keto, (CrC 3 ) - Exoalkyliden.
  • partially hydrogenated phenyl is meant, for example, cyclohexadienyl, cyclohexenyl, cyclohexyl.
  • a partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.
  • the arylalkyl group is an aryl group which is linked to a skeleton via a C 1 -C 8 -alkyl group, where the alkyl group may be straight-chain or branched.
  • alkyl group may be straight-chain or branched.
  • benzyl or phenethylene may be mentioned.
  • An arylalkenyl group is an aryl group which is linked to a skeleton via a C 2 -C 8 -alkenyl group, where the alkenyl group may be straight-chain or branched.
  • the arylalkynyl group is an aryl group bonded to the skeleton via a C 2 -C 8 alkynyl group, where the alkynyl group may be straight-chain or branched.
  • a monocyclic or bicyclic heteroaryl group R 5 and R 6 which may be hydrogenated at one or more sites is understood as meaning all monocyclic or bicyclic aromatic ring systems which contain at least one heteroatom and at most seven heteroatoms. Preference is given to ring systems having 1-5 heteroatoms. Suitable heteroatoms are 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms, which can occur in all subcombinations in the ring system as long as they do not exceed the number specified for the respective heteroatom and, in total, the maximum number of seven heteroatoms. Besoners preferred are heterocyclic systems which have 1-3 heteroatoms in ring system and contain at least one nitrogen atom.
  • R 5 or R 6 is furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl , Pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolylonyl, dihydroisoindolonyl,
  • R 5 is optionally substituted by one or more groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 COOR 10 groups), C 5 ) alkoxy groups, hydroxy groups, halogen atoms, (C 1 -C 3 ) exoalkylidene-substituted mono- or bicyclic heteroaryl groups which optionally contain 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups , which group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more points means.
  • groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 COOR 10 groups), C 5 ) alkoxy groups, hydroxy groups, halogen atoms, (C 1 -C
  • R 5 is optionally substituted by one or more groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1 to 3 hydroxyl or 1 to 3 COOR 10 groups), (C 1 -C 4) -C 5 ) -alkoxy groups, hydroxy groups, halogen atoms, (CrC 3 ) exoalkylidene-substituted, optionally 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group where this group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites and contains at most 3 heteroatoms in the monocyclic ring system and at most 4 heteroatoms in the bicyclic ring system.
  • groups selected from (C 1 -C 5 ) -alkyl groups (which may optionally be substituted by 1
  • a preferred subject matter of the invention are compounds of the general formula I 1 in which R 5 is a phenyl, phthalidyl or isoindolyl radical which is optionally substituted by C 1 -C 5 -alkyl, halogen, hydroxyl, C 1 -C 5 -alkoxy, keto or (C 1 -C 3 ) -exoalkylidene , Dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroin
  • a preferred subject of the invention are compounds of general formula I, wherein R 5 is optionally substituted with C 1 -C 5 -alkyl, halogen, hydroxy, C 1 -C 5 -alkoxy, keto or (C 1 -C 3 ) -exoalkylidene-substituted phenyl, phthalidyl, isoindolyl , Dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, Cinnolinyl, phthalazinyl, 1, 7- or 1,8-naphthy
  • a preferred subject of the invention are compounds of general formula I, wherein R 5 is an optionally independently of one another with one or more Ci-C 5 alkyl, halogen, hydroxy, Ci-C 5 alkoxy, keto or (d C 3 ) Exoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl , Chromenyl, isochromenyl, chromenonyl, isochromenonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7 or 1, 8
  • a preferred subject of the invention are compounds of general formula I, wherein R 5 is an optionally independently of one another with one or more CrC 5 alkyl, halogen, hydroxy, Ci-C 5 alkoxy, keto or (C r C 3 ) Exoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, coumarinyl, isocoumarinyl, chromenyl, isochromenyl, chromenonyl, isochromenonyl, quinolinyl -, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolin
  • a preferred object are compounds of the general formula I in which R 5 is a phenyl or naphthyl radical which is optionally substituted by C 1 -C 5 -alkyl, halogen, hydroxyl, C 1 -C 5 -alkoxy, phthalidyl, thiophthalidyl, Benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl , Benzimidazole or indolyl group.
  • R 5 denotes a quinazolinyl, quinolonyl, isoquinolonyl, phthalazinonyl, optionally substituted by C 1 -C 3 -alkyl, halogen, hydroxyl, C 1 -C 3 -alkoxy Phthalazinyl, quinolinyl, isoquinolinyl, dihydroindolyl, dihydroisoindolyl, isochromenonyl group.
  • R 5 is a quinazolinyl, quinolonyl, isoquinolonyl, phthalazinonyl, quinolinyl, dihydroindolyl optionally substituted by C 1 -C 3 -alkyl, halogen, hydroxy, C 1 -C 3 -alkoxy , Dihydroisoindolyl-, Isochromenonyl distr, subject of the present invention.
  • heteroarylalkyl group it is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is bonded to the skeleton via a C 1 -C 8 -alkyl group which may be straight-chain or branched.
  • a heteroarylalkenyl group is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is bonded to the skeleton via a (C 2 -C 8) -alkenyl group which may be straight-chain or branched.
  • R 7 and R 8 form a five- to eight-membered carbocycle or heterocycle (also substituted), then there is a tricyclic system. Suitable heteroatoms are nitrogen, oxygen or sulfur. Suitable substituents are all radicals defined for R 1 . When R 7 and R 8 form a carbocycle, a five- to six-membered carbocycle is preferred.
  • the invention further provides compounds of the general formula I in which R 6 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group, a (C 3 -C 7 ) -cycloalkyl group, a (C 3 -C 7 ) -cycloalkyl (C 1 -C 8 ) -alkyl group, (C 3 -C 7 ) - Cycloalkyl (C 2 -C 8) alkenyl group, a heterocyclyl group, a heterocyclyl (CRC8) alkyl, heterocyclyl (C2-C8) alkenyl group, an aryl group, an aryl (-C 8) alkyl, aryl (C 2 -C 8) alkenyl means.
  • R 6 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -
  • An object of the invention are compounds of general formula I 1 wherein R 6 is a (C- ⁇ -C 5 ) alkyl group or an optionally partially or fully fluorinated (Ci-C 5 ) alkyl group, an aryl group, an aryl (Ci-C 8) alkyl, aryl (C 2 -C 8) alkenyl group, a (C 3 -C 7) - cycloalkyl, (C 3 -C 7) cycloalkyl (Ci-C alkyl group 8), (C 3 -C 7) - Cycloalkyl (C-2-C 8 ) alkenyl group means.
  • R 6 represents a (Ci-C 3 ) alkyl group or an optionally partially or fully fluorinated (Ci-C 3 ) alkyl group. Particularly preferred are the fully fluorinated alkyl groups. Most preferred is the CF 3 group.
  • R 6 is a C 1 -C 10 -alkyl group which may optionally be substituted by 1 to 3 hydroxyl groups, halogen atoms, an optionally substituted phenyl group, an optionally by 1 to 2 keto groups, 1 to 2 (CrC 5 ) alkyl groups, 1-2 (CrC 5 ) alkoxy groups, 1-3 halogen atoms, 1-2 (Cr C 3 ) exoalkylidene-substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 Mono- or bicyclic heteroaryl group containing sulfur atoms, which groups may be linked via any position with the nitrogen atom and may optionally be hydrogenated at one or more sites, means.
  • R 6 is a C 1 -C 10 -alkyl group which may optionally be substituted by 1 to 3 hydroxyl groups, halogen atoms, an optionally substituted phenyl group, an optionally by 1 to 2 keto groups, 1 to 2
  • the compounds of the general formula I according to the invention can exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers (eg: RRRR, RRRS, RRSR, RSRR, SRRR, RSRS, RRSS, RSSR, SRRS, SSRR, SRSR, RSSS, SRSS, SSRS, SSSR, SSSS), both as racemates, as well in enantiomerically pure form, both as pure diastereomers and as diastereomeric mixtures.
  • the compounds according to the invention may also be present in the form of salts with physiologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
  • Esters or ethers or amides of the compounds of the general formula I or other compounds which metabolize in the organism to compounds of the general formula I are likewise provided by the present invention.
  • the compounds according to the invention are prepared either a) by converting styrenes of the general formula (II) prepared by methods known in the prior art into the compounds of the general formula (III) by means of an optionally enantioselectively conducted ene reaction with chiral Lewis acids.
  • chiral Lewis acids it is possible to use: (R) - or (S) -SEGPHOS-PdCl 2 (Mikami et al., Tetrah. Asymm., 2004, 15, 3885-89), (R) - or (S) -BINOL- Ti (OiPr) 2 (Ding et al Tetrah. Lett.
  • (V) (VI) chlorinated hydrocarbons, such as methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids at temperatures ranging from -70 0 C to +80 0 C (preferably in the range from -30 0 C to +80 0 C) is cyclized to the compounds of general formula to compound (I).
  • chlorinated hydrocarbons such as methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids at temperatures ranging from -70 0 C to +80 0 C (preferably in the range from -30 0 C to +80 0 C) is cyclized to the compounds of general formula to compound (I).
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • the compounds of the general formula I according to the invention inhibit lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1.
  • LPS lipopolysaccharide
  • the concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits.
  • the anti-inflammatory activity of the compounds of the general formula I was tested in animal experiments by testing in the croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108).
  • the animals were topically applied croton oil in ethanolic solution to the ears.
  • the test substances were also applied topically or systemically simultaneously or two hours before the croton oil. After 16-24 hours ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration.
  • the compounds of the general formula I inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.
  • glucocorticoid therapy One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart, 1998].
  • the reason for this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and by free amino acids, which arise from the degradation of proteins (catabolic effect of glucocorticoids).
  • a key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT).
  • the activity of this enzyme can be photometric can be determined from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids.
  • TAT induction To measure the TAT induction, the animals are sacrificed 8 hours after administration of the test substances, the liver is removed and the TAT activity in the homogenate is measured.
  • the compounds of general formula I do not or only to a limited extent induce tyrosine aminotransferase in doses in which they are anti-inflammatory in this test.
  • the compounds of the general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:
  • the term "DISEASE” stands for the following indications:
  • rheumatic diseases in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica - reactive arthritis
  • Traumatic arthritis - Collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, StNI syndrome, Felty syndrome
  • kidney disease associated with inflammatory, allergic and / or proliferative processes (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes:
  • liver disease associated with inflammatory, allergic and / or proliferative processes (vii) liver disease associated with inflammatory, allergic and / or proliferative processes:
  • acute hepatitis of different origins e.g. viral, toxic, drug-induced
  • proctitis ocular diseases associated with inflammatory, allergic and / or proliferative processes:
  • xvi Organ and tissue transplants, graft-versus-host disease
  • Severe shock states eg, anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • xviii Substitution therapy for: congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome Acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.
  • congenital secondary adrenal insufficiency e.g. congenital hypopituitarism - acquired secondary adrenal insufficiency, e.g. postinfectious, tumors etc.
  • the compounds of the general formula I according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic glucocorticoids are used today (see Hatz, HJ, Glucocorticoids: Immunological Principles, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart , 1998).
  • the appropriate dose will vary and depends, for example, on the potency of the compound of general formula I, the host, the mode of administration and the nature and severity of the conditions to be treated, as well as the prophylactic use or therapeutic.
  • the invention further relates to combination therapies or combined compositions wherein a glucocorticoid receptor (GR) agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof, administered either simultaneously (optionally in the same composition) or sequentially together with one or more medicaments for the treatment of any of the above-mentioned conditions.
  • a GR agonist of the present invention may be combined with one or more drugs to treat such a condition.
  • the drug to be combined may be selected from the following list:
  • a PDE4 inhibitor including an isoform PDE4D inhibitor
  • Adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,
  • a muscarinic receptor antagonist for example an M1, M2 or M3 antagonist, such as a selective M3 antagonist
  • M1, M2 or M3 antagonist such as a selective M3 antagonist
  • ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
  • a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • such combination with a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is employed for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (e.g. for example, aminophylline or theophylline), which may also be administered by inhalation or orally.
  • xanthine e.g. for example, aminophylline or theophylline
  • the invention further relates to the use of the claimed compounds / stereoisomers for the manufacture of a medicament.
  • the invention further provides
  • the compounds of the general formula I according to the invention are particularly suitable for the preparation of a medicament for the therapy or prophylaxis of inflammatory diseases.
  • a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg of body weight.
  • this dose is conveniently administered several times a day.
  • an acute shock eg anaphylactic shock
  • single doses may be given that are well above the doses mentioned above.
  • the formulation of the pharmaceutical compositions based on the novel compounds is carried out in a conventional manner by the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinmannern, binders, humectants, lubricants, absorbents, diluents, previousskorrigentien, colorants, etc. processed and converted into the desired application form.
  • galenics carriers fillers, Zerfallbeeinmannern, binders, humectants, lubricants, absorbents, diluents, developed, etc.
  • crystal suspensions For intraarticular injection appropriately prepared crystal suspensions may be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy.
  • these can be used in the form of aerosols and inhalants.
  • the new compounds may be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.
  • formulations in gels, ointments, greases, creams, pastes, powders, milk and tinctures are possible.
  • the dosage of the compounds of general formula I should be in these preparations 0.01% - 20% in order to achieve a sufficient pharmacological effect.
  • the invention also encompasses the compounds of general formula I according to the invention as therapeutic active ingredient.
  • the invention further relates to the compounds of the general formula I according to the invention as a therapeutic active ingredient together with pharmaceutically acceptable and acceptable auxiliaries and excipients.
  • the invention also includes a pharmaceutical composition containing one of the pharmaceutically active compounds of the invention or their mixture or their pharmaceutically acceptable salt and pharmaceutically acceptable excipients and carriers.
  • the desired product can be prepared analogously to Example 1 from 5-amino-2-methyl-phthalazin-1 -one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal ,
  • the desired product can be prepared analogously to Example 1 from 5-amino-2-methylquinazoline and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal.
  • Example 7 2-Fluoro-5-r (2-methylquinoline-5-vinylamino-5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) naphthalene-1,6-diol
  • the desired product can be prepared analogously to Example 1 from 5-amino-2-methylquinoline and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) ⁇ entanal.
  • the desired product can be prepared analogously to Example 8 from 5-amino-7,8-difluoro-2-methylquinazoline and 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4- be made enal.
  • the following can be prepared analogously: a) 10-r (7,8-Difluoro-2-methylquinazoline-5-vinylamino1-6.7.8.8a.9,10-hexahydro-9- (trifluoromethyl) -phenanthren-9-ol
  • the desired product can be prepared analogously to Example 9 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) - propionaldehyde become.
  • the desired product can be prepared analogously to Example 9 from 5-aminoquinoline-2 (1 H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohex-2-enyl) propionaldehyde.
  • the desired product can be prepared analogously to Example 9 from 5-amino-2-methyl-quinoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohex-2-enyl) propionaldehyde.
  • the desired product can be prepared analogously to Example 9 from 5-amino-2-methyl-quinoline and 1-phenyl-1-cyclopentene.
  • the desired product can be prepared analogously to Example 9 from 5-amino-7,8-difluoro-2-methyl-quinazoline and 1-phenyl-1-cyclopentene.
  • the desired product can be prepared analogously to Example 10 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) - propionaldehyde.
  • the desired product can be prepared analogously to Example 10 from 5-aminoquinoline-2 (1 H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde. c) 4b.5.6.7, 8,8a, 9,10-octahydro-10-r (2-methylquinoline-5-vnamino-9- (trifluoromethoxy-phenanthrene-9-ol
  • the desired product can be prepared analogously to Example 10 from 5-amino-2-methyl-quinoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde.
  • the desired product can be prepared analogously to Example 10 from 5-amino-2-methyl-quinazoline and 1-phenyl-1-cyclopentene.
  • the desired product can be prepared analogously to Example 10 from 5-amino-7,8-difluoro-2-methyl-quinazoline and 1-phenyl-1-cyclopentene.
  • the suspension is shaken under a hydrogen atmosphere at normal pressure until complete reaction.
  • the mixture is filtered through Celite, rinsing thoroughly with ethyl acetate. After removal of the solvent, 108 mg of the saturated aldehyde are obtained as a mixture of 2 diastereomers.
  • the imine is produced by means of the aldehyde described in Example 1. After cyclization with boron tribromide, 38.3 mg of the nonpolar diastereomer of 5 - ⁇ [6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1 -yl] amino ⁇ isochromen-1-one and 9.1 mg of the polar diastereomer of 5 - ⁇ [6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino ⁇ isochromen-1-one.
  • Reaction mixture is heated to 190 0 C for 19 h. After cooling the reaction mixture and removing the solvent, the crude product is purified by column chromatography (silica gel, hexane, CH 2 Cl 2 / MeOH 0-5%). 1.03 g of 5-amino-8-fluoroquinoline-2 (7H) -one is obtained as a pale yellow solid.
  • the desired product can be prepared analogously to Example 15 from 5-amino-8-fluoroquinoline-2 (1 H) -one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal getting produced.
  • Ethyl 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoate 16.75 g (99.6 mmol) of 1- (4-fluoro 2-hydroxyphenyl) propan-1-one are added in 124 ml of acetone with 27.53 g (199.2 mmol) of potassium carbonate and 28.27 g (199.2 mmol) of iodomethane. After four hours of refluxing, the mixture is filtered through a glass fiber filter and the filtrate evaporated. The remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane).
  • the dichloromethane phase is separated off and the aqueous phase is extracted twice more with dichloromethane.
  • the combined organic extracts are washed with 10% sulfuric acid, saturated sodium bicarbonate solution and brine. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane).
  • Example 4 4- (3,4-Difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal: Analogously to Example 1 can from 2,3-difluorophenol 1, 2-difluoro-3-methoxy-4 - (1-methylpropenyl) benzene can be prepared as E / Z mixture.
  • Example 24A / 24B ( ⁇ ⁇ ö ⁇ Z ⁇ ⁇ ⁇ . S-Difluoro- ⁇ . ⁇ .T. ⁇ -tetrahydro-r. ⁇ -dimethyl- ⁇ -p-m ⁇ thylchinazolin- 5-yl) amino] -6- (trifluoromethyl) naphthalene -1, 6-diol (diastereomer 1) is cleaved by preparative chiral HPLC (Chiralpak AD-H 5 ⁇ ) into the enantiomerically pure compounds:
  • Example 25 Analogously to Example 25, 164 mg (0.43 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal and 72 mg (0.45 mmol) of 5-aminoquinoline -2 (1 H) -one condensed to the corresponding imine, which can then be cyclized analogously to Example 25 with boron tribromide to 2 diastereomers.
  • reaction mixture is mixed with 28 ml of water and the organic phase is separated off. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane).
  • reaction mixture After three and a half hours of stirring at ice bath temperature, the reaction mixture is poured onto a mixture of ice and saturated sodium bicarbonate solution. After dilution with ethyl acetate, the mixture is stirred vigorously for two hours and the organic phase is separated off. The aqueous phase is extracted again with ethyl acetate and the combined organic extracts are then washed with water and brine. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on flashmaster (amine phase, eluent methanol / dichloromethane).
  • Isolated are 10.1 mg (5.34%) of the nonpolar and 4.7 mg (2.48%) of the polar diastereomer of 5 - ⁇ [7-chloro-6-fluoro-2,5-dihydroxy-3,4 -dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-i -yl] amino ⁇ -1,3-dihydro-2H-indol-2-one.
  • Polar diastereomer 1 H-NMR (400 MHz, CD 3 OD), ⁇ 1, 28 (3H), 1, 40 (3H),
  • Example 28 5- (r7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethane-1.2.3.4-tetrahydronaphthalene-1-ylaminol iso-chromene-i -one 371.9 mg (0.76 mmol) of a A mixture of 5 - ⁇ [4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentylidene] amino ⁇ isochromen-1-one and 5 - ⁇ [ 4- (4-Chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino ⁇ -isochromen-1-one are cyclized with boron tribromide as described several times to isolate 1.5 mg (0.83%) of the desired compound.
  • Example 29 5 - ([7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1-ylaminoquinoline-2 (1H) - on 264.3 mg (0.54 mmol) of a mixture of 5 - ⁇ [4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino ⁇ - isoquinoline-1 (2H) -one and 5 - ⁇ [4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino ⁇ isoquinoline-2 (1H ) -on are cyclized using boron tribromide to isolate 7.4 mg (5.8%) of the desired compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Otolaryngology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Transplantation (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des dérivés de tétrahydronaphtaline de formule (I), des procédés de production associés et leur utilisation comme inhibiteurs d'inflammation.
EP06723722A 2005-03-22 2006-03-20 Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation Withdrawn EP1861379A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005014089A DE102005014089A1 (de) 2005-03-22 2005-03-22 Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
PCT/EP2006/002743 WO2006100100A1 (fr) 2005-03-22 2006-03-20 Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation

Publications (1)

Publication Number Publication Date
EP1861379A1 true EP1861379A1 (fr) 2007-12-05

Family

ID=36481394

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06723722A Withdrawn EP1861379A1 (fr) 2005-03-22 2006-03-20 Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation

Country Status (11)

Country Link
EP (1) EP1861379A1 (fr)
JP (1) JP2008534463A (fr)
CN (1) CN101146779A (fr)
AR (1) AR056949A1 (fr)
CA (1) CA2598205A1 (fr)
DE (1) DE102005014089A1 (fr)
GT (1) GT200600123A (fr)
PE (1) PE20061362A1 (fr)
TW (1) TW200716564A (fr)
UY (1) UY29434A1 (fr)
WO (1) WO2006100100A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1670458E (pt) 2003-10-08 2007-03-30 Schering Ag Derivados de tetra-hidronaftaleno, processo para a sua preparação e utilização como inibidor de inflamação
US7638515B2 (en) 2003-10-08 2009-12-29 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7662821B2 (en) 2003-10-08 2010-02-16 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US20080153859A1 (en) 2004-04-05 2008-06-26 Hartmut Rehwinkel Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
EP1834948A1 (fr) * 2006-03-15 2007-09-19 Bayer Schering Pharma Aktiengesellschaft Derives de tetrahydronaphtalene , procedes pour leur production et leur utilisation en tant qu'anti-inflammatoires
EP2072509A1 (fr) 2007-12-18 2009-06-24 Bayer Schering Pharma Aktiengesellschaft 1-aryl-1H-quinoline-2-ones : leur procédé de fabrication et leur utilisation en tant qu'agents anti-inflammatoires
CN101768086B (zh) * 2008-12-29 2014-03-26 北京富龙康泰生物技术有限公司 氨基甲醇衍生物及其盐类化合物及其合成方法和其药物用途
JP2013500962A (ja) 2009-07-31 2013-01-10 カディラ ヘルスケア リミティド グルココルチコイド受容体のモジュレーターとしての新規化合物
JP6115303B2 (ja) * 2012-05-18 2017-04-19 Jnc株式会社 隣接基としてカルボニル基を有するフェノール化合物およびその用途
EP3109237A1 (fr) 2015-06-22 2016-12-28 AnaMar AB Nouveaux antagonistes de 5-ht2
CN114450274A (zh) 2019-07-11 2022-05-06 伊斯凯普生物公司 作为lrrk2抑制剂的吲唑及氮杂吲唑

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0291327A3 (fr) * 1987-05-15 1989-01-25 Schering Corporation Dérivés aryl-substitués de naphtalène, benzoxépine, benzazépine et benzocycloheptène
FI900219A7 (fi) * 1987-07-16 1990-01-15 Byk Gulden Lomberg Chem Fab Uudet diatsolit
US5489584A (en) * 1994-12-29 1996-02-06 Allergan, Inc. Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
DE10038639A1 (de) * 2000-07-28 2002-02-21 Schering Ag Nichtsteroidale Entzündungshemmer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006100100A1 *

Also Published As

Publication number Publication date
PE20061362A1 (es) 2006-12-20
AR056949A1 (es) 2007-11-07
CN101146779A (zh) 2008-03-19
WO2006100100A1 (fr) 2006-09-28
DE102005014089A1 (de) 2006-09-28
GT200600123A (es) 2007-01-03
TW200716564A (en) 2007-05-01
CA2598205A1 (fr) 2006-09-28
JP2008534463A (ja) 2008-08-28
UY29434A1 (es) 2006-10-02

Similar Documents

Publication Publication Date Title
EP1492771B1 (fr) Derives de quinoleine et d'isoquinoleine, procede de production de ces derives et leur utilisation comme agents anti-inflammatoires
EP1670778B1 (fr) Pentanols rearranges, un procede pour leur production et leur utilisation en tant qu'anti-inflammatoires
EP1638945A1 (fr) Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
EP1994005A1 (fr) Dérivés de tétrahydronaphtalène, procédés de production desdits dérivés et leur utilisation comme anti-inflammatoires
DE102004063227A1 (de) Tricylische Aminoalkohole, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
WO2006100100A1 (fr) Derives de tetrahydronaphtaline, procedes de production associes et utilisation comme inhibiteurs d'inflammation
DE102004044680B3 (de) Alkyliden-Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer sowie diese enthaltende pharmazeutische Präparate
US20060229305A1 (en) Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
DE102005017286B3 (de) Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
US20060084652A1 (en) Alkylidene-tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
DE10346939A1 (de) Heterocyclisch substituierte Pentanole, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102004017662B3 (de) Mehrfach substituierte Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102005018026B4 (de) Substituierte Styrole, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE10347386B4 (de) Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
EP1863765A1 (fr) Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation
DE102005018025A1 (de) Mehrfach substituierte bizyklische Systeme, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102005017326A1 (de) Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE10330358A1 (de) Heterozyklisch substituierte Pentanol-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE10347383A1 (de) Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
WO2006108713A2 (fr) Derives de tetrahydronaphthaline, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation
EP1869013A1 (fr) Derives de chromane substitues, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation
HK1114095A (en) Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
DE102005020331A1 (de) 5-substituierte Chinolin- und Isochinolin-Derivate, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102005018024A1 (de) Benzazepine als neue Glucocorticoidmimetika, Verfahren zu ihrer Herstellung und ihre Verwendung

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: 20070905

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 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
RIN1 Information on inventor provided before grant (corrected)

Inventor name: MENGEL, ANNE

Inventor name: BERGER, MARKUS

Inventor name: BUCHMANN, BERND

Inventor name: KROLIKIEWICZ, KONRAD

Inventor name: SCHAECKE, HEIKE

Inventor name: REHWINKEL, HARTMUT

Inventor name: BAEURLE, STEFAN

Inventor name: SCHMEES, NORBERT

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SCHAECKE, HEIKE

Inventor name: SCHMEES, NORBERT

Inventor name: BUCHMANN, BERND

Inventor name: KROLIKIEWICZ, KONRAD

Inventor name: BERGER, MARKUS

Inventor name: MENGEL, ANNE

Inventor name: BAEURLE, STEFAN

Inventor name: REHWINKEL, HARTMUT

17Q First examination report despatched

Effective date: 20101013

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER PHARMA AKTIENGESELLSCHAFT

18D Application deemed to be withdrawn

Effective date: 20110224