WO2006100099A1 - Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation - Google Patents

Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation Download PDF

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WO2006100099A1
WO2006100099A1 PCT/EP2006/002742 EP2006002742W WO2006100099A1 WO 2006100099 A1 WO2006100099 A1 WO 2006100099A1 EP 2006002742 W EP2006002742 W EP 2006002742W WO 2006100099 A1 WO2006100099 A1 WO 2006100099A1
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group
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alkyl
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general formula
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Hartmut Rehwinkel
Duy Nguyen
Markus Berger
Heike Schäcke
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Bayer Schering Pharma Aktiengesellschaft
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Priority to EP06723721A priority Critical patent/EP1863765A1/fr
Priority to JP2008502339A priority patent/JP2008534462A/ja
Priority to CA002598969A priority patent/CA2598969A1/fr
Publication of WO2006100099A1 publication Critical patent/WO2006100099A1/fr

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Definitions

  • the invention relates to 5H-Benzocycloheptenderivate, processes for their preparation and their use as anti-inflammatory.
  • the prior art WO 00/32584 DE 100 38 639 and WO02 / 10143 disclose 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 therefore relates to compounds of the general formula
  • R 1 and R 2 independently of one another, are a hydrogen atom, a hydroxyl 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
  • R 11 is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 10) -alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 5 ) Perfluoroalkyl group,
  • R 12 is a hydrogen atom, a hydroxy group, a halogen atom, a
  • Cyano group an optionally substituted (C 1 -C 10) -alkyl group, a (Cr
  • R 3 is a Ci-Ci o alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Cr C5) -alkoxy groups, an optionally substituted (C 3 -C 7) - Cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally one or more groups selected from (C 1 -C 5 ) - alkyl groups (which may be optionally substituted by 1-3 hydroxy or 1-3 COOR 10 groups where R 10 is any hydroxy-protecting group, a benzyl group or a C 1 -C 10 -alkyl group, (C 1 -C 5 ) -alkoxy groups, halogen atoms, exomethylene-substituted, optionally 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1 -2 mono- or bicyclic heteroaryl group containing sulfur atoms and
  • C 5 alkoxy groups, 1 to 3 halogen atoms, 1 to 2 exomethylene-substituted mono- or bicyclic heteroaryl groups containing 1-3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms, a (C 1 -C 8 ) Alkylheteroaryl group or a (C 2 -C 8 ) alkenylheteroaryl group, where these groups may be linked via any position with the 5H-benzocycloheptene system and may optionally be hydrogenated at one or more sites,
  • R 6 and R 7 independently of one another represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the 5H-benzocycloheptene system a (Cs-C ⁇ J-cycloalkyl ring.
  • An object of the invention relates to 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 (C 1 -C 10) -alkyl group, a (C 1 -C 4) -alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 5 ) Perfluoralkyl distr, a cyano group, a nitro group or
  • Cyano group an optionally substituted (C 1 -C 10) -alkyl group, a (Cr
  • R 3 is a C 1 -C 10 -alkyl group which may optionally be substituted by a group selected from among 1-3 hydroxy groups, halogen atoms, or 1-3 (C 1 -C 5 ) -alkoxy groups, an optionally substituted (C 3 -C 7 ) - Cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally substituted by one or more groups selected from (C 1 -C 5 ) alkyl groups (which may be optionally substituted by 1-3 hydroxy or 1 -3 COOR 10 groups, where R 10 represents any hydroxy-protecting group, a benzyl group or a C 1 -C 10 -alkyl group,
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 - group, D a - CR 4 R ⁇ -CH 2 - or a -CH 2 -CR 4 R 5 group,
  • R 4 is a hydroxy group, a group OR 10 or an O (CO) R 10 group
  • R 5 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 8) alkylene (C 3 -C 7) cycloalkyl, (C 2 -C 8) alkenylene cycloalkyl (C3-C 7), a heterocyclyl group, a (d-C ⁇ JAlkylenheterocyclyl distr, (C 2 - C 8) Alkenylenheterocyclyl distr , an aryl group, a (CrC 8) alkylenearyl, (C 2 -C 8 C) group Alkinylenaryl- (C 2 -C 8) Alkenylenaryl distr, an optionally substituted by 1-2
  • Benzocycloheptensystem can be linked and may optionally be hydrogenated at one or more points,
  • R 6 and R 7 independently of one another represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the 5H-
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • Ring carbon atoms are linked, or NR 8 R 9 wherein R 8 and R 9 are independently hydrogen, Ci-C 5 -alkyl or (CO) -C 5 -C -Al may be alkyl,
  • R 3 is a CRCI O alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Cr
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (Ci-C 5) alkyl group or an optionally partially or completely fluorinated (Ci-C 5) alkyl group, an aryl group, a (Ci-C8) alkylenearyl, (C 2 -C 8) Alkenylenaryl distr, a ( C 3 - C 7 ) cycloalkyl group, a (Ci-C 8 ) alkylene (C 3 -C 7 ) cycloalkyl group, (C 2 -C 8 ) alkenylene (C 3 -C 7 ) cycloalkyl group
  • R 6 and R 7 independently of one another denote a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the benzocycloheptene system, denote a (C 3 -C 6 ) -cycloalkyl ring.
  • (CO) -C -C 5 alkyl may be,
  • R 3 is a Ci-Ci O -alkyl group which may be optionally substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Cr C 5 ) alkoxy groups, an optionally substituted phenyl group, optionally by 1-2 Keto groups, 1-2 (CrC 5 ) alkyl groups, 1-2- (Cr
  • Benzocycloheptensystems and may optionally be hydrogenated at one or more sites,
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group, an aryl group, a
  • R 6 and R 7 independently of one another represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the 5H-
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • R 3 is a C 1 -C 10 -alkyl group which may optionally be substituted by 1 to 3 hydroxyl groups, halogen atoms, an optionally C 1 -C 5 -alkyl, halogen, hydroxyl, C 1 -C 4 -alkoxy-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl , Dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7, or 1, 8-naphthyridinyl, dihydroindol
  • R 6 and R 7 independently of one another denote a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the benzocycloheptene system, a (C 3 -C 6 ) -cycloalkyl ring.
  • Another object of the invention are stereoisomers of the general formula I, wherein
  • Alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, and optionally hydrogenated at one or more sites A may be a -CR 6 R 7 OH 2 - or a -CH 2 -CR 6 R 7 group,
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (d-CsJ-alkyl group or an optionally partially or fully fluorinated (CrC 5 ) alkyl group
  • R 6 and R 7 are independently a hydrogen atom, a methyl or methyl
  • Benzocycloheptensystems a (C 3 -Ce) cycloalkyl ring mean.
  • Stereoisomers are particularly preferred of the general formula (I) wherein R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C 5) alkyl group, a (C 1 -C 5) - perfluoroalkyl , a cyano group, a (C 1 -C 5 ) -alkoxy group, or, together, a (C 1 -C 2 ) -alkylenedioxy group, in which case R 1 and R 2 must be directly adjacent, R 3 is optionally substituted by C 1 -C 4 -alkoxy.
  • R 5 is a (C 1 -C 5 ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 5 ) -alkyl group
  • R 6 and R 7 independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • An object of the invention are compounds of general formula I, wherein R 1 and R 2 are independently a hydrogen atom, a hydroxy
  • Ring carbon atoms are linked, or NR 8 R 9 wherein R 8 and R 9 are independently hydrogen, dC 5 -alkyl or (CO) -C -C 5 alkyl may be,
  • R 11 and R 12 represent a hydrogen atom
  • R 3 is a CRCI O alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Cr
  • Benzocycloheptensystems and may optionally be hydrogenated at one or more sites,
  • A is a -CR 6 R 7 OH 2 - or a -CH 2 -CR 6 R 7 - group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (Ci-C 5 ) -Alkyi Kunststoffe or an optionally partially or completely fluorinated (CiC 5 ) alkyl group, an aryl group, a (Ci-C 8 ) Alkylenarylrios, (C 2 -C 8 ) alkenylene, a (C 3 -
  • R 6 and R 7 are independently a hydrogen atom, a methyl or
  • R 1 and R 2 are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C- ⁇ o) alkyl group, a (Ci-Ci 0 ) -
  • Alkoxy group, a (Ci-Cio) -Alkythiooeuvre, a (CrC 5 ) - perfluoroalkyl group, a cyano group, a nitro group or R 1 and R 2 together form a group selected from the groups -O- (CH 2 ) n -O-, - O- (CH 2 ) n -CH 2 -, -O-CH CH-, -
  • Ring carbon atoms are linked, or NR 8 R 9 , wherein R 8 and R 9 are independently hydrogen, C 1 -C 5 -alkyl or
  • R 11 and R 12 is a hydrogen atom
  • R 3 is a CRCI O alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Cr
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group, R 4 is a hydroxy group
  • R 5 is a (C- ⁇ -C 5) alkyl group or an optionally partially or completely fluorinated (-C 5) alkyl group, an aryl group, a (Ci-C8) alkylenearyl, (C 2 -C 8) Alkenylenaryl distr, a ( C 3 - C 7 ) cycloalkyl group, a (Ci-C 8 ) alkylene (C 3 -C 7 ) cycloalkyl group, (C 2 -C 8 ) alkenylene (C 3 -C 7 ) cycloalkyl group
  • R 6 and R 7 independently of one another denote a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the 5H-benzocycloheptene system, a (C 3 -C 6 ) -cycloalkyl ring.
  • a particular subject of the invention are stereoisomers of general formula I, wherein
  • Alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, and optionally hydrogenated at one or more sites A may be a -CR 6 R 7 OH 2 - or a -CH 2 -CR 6 R 7 group,
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (Ci-C 5) alkyl group or an optionally partially or completely fluorinated (C-
  • R 6 and R 7 are independently a hydrogen atom, a methyl or
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • R 3 is phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, optionally substituted by C 1 -C 6 -alkyl, halogen, hydroxyl, C 1 -C 6 -alkoxy,
  • Quinolinyl isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7 or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, these groups being attached via any position with the amine of the
  • Benzocycloheptensystems can be linked and may optionally be mono- or polysubstituted with 1-2 keto groups, 1-2- (C 1 -Cs) - Alkyl groups, 1-2 exomethylene groups and may optionally be hydrogenated at one or more sites,
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 OH 2 - or a -CH 2 -CR 4 R 5 - group, R 4 is a hydroxy group
  • R 5 is a (d-CsJ-alkyl group or an optionally partially or completely fluorinated (CrC 5 ) -alkyl group
  • R 6 and R 7 are independently a hydrogen atom, a methyl or
  • stereoisomers of the general formula (I) 1 wherein R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C 5) alkyl group, a (-C 5) - perfluoroalkyl group, a cyano group , a (C 1 -C 5 ) -alkoxy group, or together a (C 1 -C 2 ) -alkylenedioxy group, in which case R 1 and R 2 must be directly adjacent, R 11 and R 12 are a hydrogen atom, R 3 phenyl, furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl,
  • R 5 is a (Ci-C 5) alkyl group or an optionally partially or completely fluorinated (-C 5) alkyl
  • R 6 and R 7 are independently a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring.
  • Stereoisomers are particularly preferred of the general formula (I) wherein R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C 5) alkyl group, a (C 1 -C 5) - perfluoroalkyl a cyano group, a (Ci-C 5 ) alkoxy group, or together a (CrC 2 ) alkylenedioxy group, in which case R 1 and R 2 must be directly adjacent, R 11 and R 12 represent a hydrogen atom,
  • R 3 is a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, optionally substituted by C 1 -C 8 -alkyl, halogen, hydroxyl, C 1 -C 6 -alkoxy,
  • Indolyl group which groups can be linked via any position with the amine of Benzocycloheptensystems and may optionally be mono- or polysubstituted with 1-2 keto groups, 1-2- (C- I -C 3 ) -
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group
  • R 4 is a hydroxy group
  • R 5 is a (CrC 5 ) -alkyl group or an optionally partially or completely fluorinated (d-CsJ-alkyl group
  • R 6 and R 7 independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • R 1 and R 2 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, a (C 1 -C 3 ) -alkyl group, a (C 1 -C 3 ) -perfluoroalkyl group, a cyano group , a (CrC 3 ) alkoxy group, R 11 and R 12 is a hydrogen atom,
  • R 3 is a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, optionally substituted by C 1 -C 3 -alkyl, halogen, hydroxyl, C 1 -C 3 -alkoxy , Isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1 J or 1, 8 Naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or
  • Indolyl group which groups via any position with the amine of the
  • Benzocycloheptensystems can be linked and may optionally be mono- or polysubstituted with 1-2 keto groups, 1-2- (CrC 3 ) -
  • A is a -CR 6 R 7 -CH 2 - or a -CH 2 -CR 6 R 7 group
  • D is a -CR 4 R 5 -CH 2 - or a -CH 2 -CR 4 R 5 group, R 4 is a hydroxy group
  • R 5 fully fluorinated (Ci-C 3 ) alkyl group
  • R 6 and R 7 are independently a hydrogen atom, a methyl or
  • Benzocycloheptensystems a (C 3 -C 6 ) cycloalkyl ring mean.
  • R 1 and R 2 are a hydrogen atom, a hydroxy group, a halogen atom, a (C 1 -C 3 ) -alkyl group, a CF 3 group, a Cyano group, a methoxy group, R 11 and R 12 is a hydrogen atom,
  • R 3 isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, quinolinyl, optionally substituted by C 1 -C 3 -alkyl, halogen, hydroxy, C 1 -C 3 -alkoxy or methylpyrrolidin-2-one-5-yl, Isoquinolinyl, quinazolinyl, quinolonyl, isoquinolonyl, indazolyl, dihydroindolonyl or dihydroisoindolonyl group, these groups being able to be linked via any position with the amine of the benzocycloheptene system and, if appropriate, being monosubstituted or polysubstituted with 1-2 keto groups, 1- 2- (C 1 -C 3 ) -alkyl groups, 1-2-exomethylene groups and optionally hydrogenated at one or more sites, A is a
  • R 6 and R 7 independently represent a hydrogen atom, a methyl or ethyl group.
  • R 1 and R 2 independently of one another represent a hydrogen atom, a halogen atom or a cyano group and R 11 and R 12 represent a hydrogen atom.
  • a very particularly preferred subject of the present invention are:
  • R 1 and R 2 independently of one another represent a hydrogen atom, a halogen atom or a cyano group
  • R 11 and R 12 represent a hydrogen atom
  • R 3 is an indazolyl, dihydroindolonyl, or quinolonyl group, which may optionally be substituted by a halogen atom or by methylpyrrolidin-2-one-5-yl,
  • A is -CH 2 -CR 6 R 7 or CR 6 R 7 -CH 2 -
  • R 4 is a hydroxy group
  • R 5 is a C 1 -C 3 perfluoroalkyl group
  • R 6 , R 7 is a methyl or ethyl group.
  • R 1 and R 2 independently of one another, are a hydrogen atom, a bromine or chlorine atom or a cyano group, R 11 and R 12 represent a hydrogen atom
  • R 3 is an indazolyl, dihydroindolonyl or quinolonyl group, which may optionally be substituted by a bromine atom or by methylpyrrolidin-2-one-5-yl, A is -CH 2 -C (CH 2 ) 2 , C (CH 2 ) 2 -CH 2 -
  • D is -CH 2 -C (CF 3 ) (OH)
  • R 4 is a hydroxy group
  • R 5 is a CF 3 group
  • R 6 , R 7 is a methyl group. Particularly preferred are the compounds
  • a further the subject of the invention are compounds of the general formula I according to claims 1-3, wherein R 3 a Ci-do-alkyl group, which can be optionally substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (CrC 5 ) -alkoxy groups, an optionally substituted (C 3 -C 7 ) -cycloalkyl group, an optionally substituted heterocyclyl group, optionally substituted by one or more groups selected from (C 1 -C 5 ) -alkyl groups, (C 1 -C 5 -alkoxy groups, halogen atoms, exomethylene groups, 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 which groups may be linked via any position with the amine of the 5H-Benzocycloheptensystems and may optionally be hydrogenated at one or more points means.
  • R 3 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, 2- (-C 5) - alkyl groups, 1-2- (Ci-C5) -alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene substituted 1-3 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.
  • a further subject is compounds of general formula I in which R 3 is an optionally substituted phenyl or naphthyl group, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl , Quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group.
  • a preferred subject of the invention are compounds of general formula I, wherein R 3 is a Ci-Cio-alkyl group which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1 J or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group.
  • a further preferred subject of the invention are stereoisomers of the general formula I according to one of the claims, in which R 3 is an indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, quinolonyl, isoquinolonyl , Dihydroquinolonyl, dihydroisoquinolonyl, indazolyl, indolonyl, isoindolonyl, dihydroindolonyl, or dihydroisoindolonyl group.
  • R 3 denotes an indazolyl, dihydroindolonyl, dihydroisoindolonyl, quinolonyl or isoquinolonyl group.
  • R 3 is indazolyl, Dihydroindolonyl-, and quinolonyl, which may optionally be substituted by a halogen atom or methylpyrrolidone.
  • the group A according to any one of the claims can be -CH 2 -CR 6 R 7 or - CR 6 R 7 -CH 2 -, -CH 2 -C (CH 3) 2 or -C (CH 3) 2 -CH 2 preferably -, more preferably -CR 6 R 7 OH 2 -, most preferably -C (CH 2 ) 2 -CH 2 -.
  • the group D may denote a -CR 4 R 5 OH 2 or a -CH 2 -CR 4 R 5 group, preferably a -CH 2 -CR 4 (R 5 ) group, in particular -CH 2 -C ( CF 3 ) (OH).
  • the group -AD- may preferably be -CH 2 -CR 6 R 7 -CH 2 -CR 4 (R 5 ) -, -CR 6 R 7 -CH 2 -CH 2 -CR 4 (R 5 ) -, and particularly preferred -CH 2 -C (CH 2 ) 2 -CH 2 -C (CF 3 ) (OH) - or -C (CH 2 ) 2 -CH 2 -CH 2 -C (CF 3 ) (OH) -.
  • the hydroxy group in R 4 may be protected, and preferably by one of the usual hydroxy protecting groups or as C- ⁇ -C 5 ether or ester (CO) R 10 are present.
  • the hydroxy group is preferred.
  • R 5 is a (Ci-C 5 ) alkyl group or an optionally partially or fully fluorinated (C- ⁇ -C 5 ) alkyl group, a (C 3 -C 7 ) cycloalkyl group , a (Ci-C 8) alkylene (C 3 -C 7) cycloalkyl, (C 2 -C 8) alkenylene (C 3 - C 7) cycloalkyl group, a heterocyclyl group, a (Cr C8) Alkylenheterocyclyl distr, (C 2 - C 8) Alkenylenheterocyclyl distr, an aryl group, a (Ci-C8) alkylenearyl group means a (C 2 -C 8) Alkenylenaryl distr.
  • R 5 is a (C r C 5 ) alkyl group or an optionally partially or fully fluorinated (Ci-C 5 ) alkyl group, an aryl group, a (C -C 8 ) Alkylenaryl distr, (C-2-C 8 ) Alkenylenaryl distr, a (C 3 -C 7 ) cycloalkyl group, a (Cr C 5 ) alkyl group or an optionally partially or fully fluorinated (Ci-C 5 ) alkyl group, an aryl group, a (C -C 8 ) Alkylenaryl distr, (C-2-C 8 ) Alkenylenaryl distr, a (C 3 -C 7 ) cycloalkyl group, a (Cr
  • C 8 alkylene (C 3 -C 7 ) cycloalkyl group, (C 2 -C 8 ) alkenylene (C 3 -C 7 ) cycloalkyl group means.
  • R 5 is a (CrC 3 ) alkyl group or an optionally partially or completely fluorinated
  • (CrC 3 ) alkyl group more preferably a fully fluorinated (CrC 3 ) alkyl group, most preferably a CF 3 group.
  • R 6 and R 7 independently of one another can denote a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the 5H-benzocycloheptene system, a (C 3 -C 6 ) -cycloalkyl ring. Preference is given to a hydrogen atom, a methyl or ethyl group, more preferably a methyl or ethyl group, very particularly preferably a methyl group.
  • the C 1 -C 10 or C 1 -C 5 -alkyl groups may be straight-chain or branched and may be a methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl - or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group.
  • a methyl or ethyl group is preferred.
  • They may optionally be substituted by 1-3 hydroxy and / or 1-3 COOR 10 groups. Preference is given to hydroxy groups.
  • C 1 -C 8 -alkyl group For a partially or fully fluorinated C 1 -C 8 -alkyl group, the following are suitable: partially or completely fluorinated fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1, 2-difluoroethyl, 1, 1, 1-trifluoroethyl, Tetrafluoroethyl, pentafluoroethyl. Of these, preferred are the trifluoromethyl or the pentafluoroethyl group.
  • a fully fluorinated alkyl group is, as known to those skilled in the perfluoroalkyl group.
  • the C 1 -C 1 0 - or C 5 alkoxy groups may be straight or branched and stand for a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy - or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group.
  • a methoxy or ethoxy group is preferred.
  • the C 1 -C 5 -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.
  • halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.
  • a (C 3 -C 7) -cycloalkyl group optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (CrC 5) - alkyl groups, (C r C 5) -alkoxy, NR 8 R 9 groups, COOR 10 - Groups, CHO, cyano, substituted saturated cyclic groups having 3 to 7 ring carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cylopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl to understand.
  • a (C r C 8) alkylene (C 3 -C 7) cycloalkyl group is, for example - (CH 2) cycloalkyl, - (C 2 H 4) -cycloalkyl, - (C 3 H 6) -cycloalkyl, - (C 4 H 8 ) -cycloalkyl, (CsHioJ-cycloalkyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, methylenecycloheptyl,.
  • the heterocyclyl group is a 5 to 7-membered non-aromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur as ring members, and at the same time, not more than one oxygen or sulfur atom is allowed as a ring member. It may, for example, be pyrrolidine, imidazolidine, pyrazolidine, piperidine.
  • Alkylene heterocyclyl groups are to be understood as meaning heterocyclyl groups which are bonded to the skeleton via a C 1 -C 8 -alkylene group, where the alkylene group may be straight-chain or branched.
  • Alkenylene heterocyclyl groups are heterocyclyl groups which are bonded to the skeleton via an unsaturated C 2 -C 6 -alkylene group, where the alkenylene groups may be straight-chain or branched.
  • Aryl groups in the meaning of the invention are the aromatic or partially aromatic carbocyclic groups having 6 to 14 carbon atoms which contain a ring, such as e.g. Phenyl or phenylene or more condensed rings such as e.g. Napthyl or anthranyl.
  • a ring such as e.g. Phenyl or phenylene or more condensed rings such as e.g. Napthyl or anthranyl.
  • Exemplary are phenyl, naphthyl, tetralinyl,
  • the aryl groups may be attached to any stable site
  • Compounds leads be substituted by one or more radicals from the group hydroxy, halogen, Ci-C 5 alkyl, Ci-C 5 alkoxy, cyano, CF 3 , nitro.
  • substituents for example, methoxy, ethoxy, propoxy, iso- Propoxy, hydroxy, fluoro, chloro, bromo, methyl, ethyl, propyl, iso-propyl or
  • the optionally substituted phenyl group and the naphthyl group are preferred.
  • An alkylenearyl group is an aryl group which is linked via a C-i-C ⁇ -alkylene group to the ring system, wherein the alkenylene group may be straight-chain or branched, and may optionally also carry a plurality of double bonds.
  • An alkenylenearily is an aryl group which is linked to a skeleton via a C 2 -C 8 -alkenylene group, wherein the alkenylene group may be straight-chain or branched.
  • the alkynylene-aryl group is an aryl group which is linked to the skeleton via a C- ⁇ -C ⁇ -alkynylene group, where the alkynylene group may be straight-chain or branched.
  • a mono- or bicyclic heteroaryl group 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. As heteroatoms 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms in question, which in all
  • Subcombinations may occur in the ring system, as long as they do not exceed the number specified for the respective heteroatom and in the sum of the maximum number of seven heteroatoms, particularly preferred are ring systems containing 1-3 nitrogen atoms and / or an oxygen or sulfur atom.
  • R 3 or R 5 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, indolonyi, dihydroindolonyl, isoindolonyl, , Dihydroisoindolonyl, benzofurany
  • R 3 or R 5 is tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl, 1H -Pyridin-4-ylidenaminyl, chromanyl, isochromanyl, chromenyl, isochromenyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-
  • 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.
  • physiologically acceptable anions for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
  • the compounds according to the invention are prepared by generating the open-chain precursors of the general formula II according to methods known in the art,
  • halogen compounds must first be prepared, in which case the halogen atom is replaced by a hydroxy group by substitution reaction on the aromatic compound according to methods known to those skilled in the art if appropriate, it can be converted into an alkoxy group by a method known to those skilled in the art.
  • Enol ether is cleaved under acidic conditions, for example, glacial acetic acid / HOAc / H 2 SO 4, and the resulting ⁇ -keto acid esterified under normal acidic conditions with an alcohol R y -OH, where R y is (CrC 5 ) alkyl, esterified to an ⁇ -ketoester of general formula VIII.
  • acidic conditions for example, glacial acetic acid / HOAc / H 2 SO 4
  • R y -OH where R y is (CrC 5 ) alkyl
  • CF 3 Si (CH 3 ) 3 introduces the CF 3 group.
  • DIBAH DIBAL
  • LAH LiAlH 4
  • the imine thus obtained is then IIa with the addition of Lewis acids at temperatures in the range of -7O 0 C to +80 0 C (preferably in the range from -30 0 C to +80 0 C) within cycled up to 14 days to give the compounds of general formula Ia.
  • a nitrile of the general formula XI is reacted with sodium hydride and the corresponding alkyl halides R 6 -Hal and / or R 7 -Hal or HaK (C 2 -C 5 ) -alkylene] -Hal, if appropriate, successively to give a compound of the general formula XII.
  • the resulting compound of general formula XII is reduced to the aldehyde under conventional conditions with braked hydrides such as diisobutylaluminum hydride (DIBAH, DIBAL)
  • the compound of the general formula XIII is converted into the acetylene and converted with CF 3 - (CO) COOR y into the ester XIV.
  • the ester is hydrogenated by the method known to those skilled in the art to the ester of the general formula XIII
  • the Lewis acids used are, for example, BBr 3, TiCl 4 , Ti (OR 3 ) 4 , TiCl 2 (OR 3 ) 2, TiBr 2 (OR 3 ) 2 , PdCl 4 , Pd (OR 3 ) 4l PdCl 2 (OR 3 ) 2) PdBr 2 (OR 3 ) 2 , ZnCl 2 , ZnBr 2 , AICI 3 , AlBr 3 , AIEtCl 2 , Al Me 2 Cl, Cu salts z.
  • Cu (OTf) 2 CuCl 2 , CuBr 2 , Yb (OTf) 3 , in question.
  • Lewis acids When using chiral Lewis acids, for example, the following Lewis acids are suitable: (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.
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays.
  • the substances show a high affinity for GR.
  • GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is mediated by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (for review see Cato AGB and Wade E, BioEssays 18, 371-378 1996).
  • 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.
  • 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 determined photometrically from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids.
  • the animals are sacrificed 8 hours after administration of the test substances, the liver is removed and the TAT activity in the Homogenate 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:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes - Chronic obstructive pulmonary diseases of any genesis, especially
  • - collagenoses of any genesis e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, still syndrome, Felty syndrome
  • Insect bites allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular disease
  • Erythematous diseases triggered by different noxae e.g. Blasting, chemicals, burns etc.
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes are associated with inflammatory, allergic and / or proliferative processes:
  • nephritides e.g. glomerulonephritis
  • 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:
  • tumor diseases associated with inflammatory, allergic and / or proliferative processes such as - acute lymphoblastic leukemia
  • Severe states of shock such as anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) Substitution therapy for: congenital primary adrenal insufficiency, e.g. Congenital adrenogenital syndrome
  • Acquired primary adrenal insufficiency e.g. Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.
  • congenital secondary adrenal insufficiency e.g. congenital hypopitotitarism
  • 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 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 is administered either simultaneously (optionally in the same composition) or sequentially together with one or more drugs for the treatment of any of the above-mentioned conditions.
  • a GR agonist of the present invention may be combined with one or more medicaments for the treatment of such Status.
  • 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, pirbuterol or indacaterol;
  • 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 ipratropium bromide
  • a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • 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 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 provides (i) the use of a compound of the invention of formula I or its mixture for the manufacture of a medicament for the treatment of a DISEASE; (H) a method for treating a DISEASE, which method comprises administering a compounding amount according to the invention, wherein the amount suppresses the disease, and wherein the
  • Connection amount is given to a patient who needs such a drug
  • a pharmaceutical composition for the treatment of a DISEASE which comprises treatment of one of the compounds of the invention or their mixture and at least one pharmaceutical excipient and / or carrier.
  • a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg of body weight.
  • a dose of 10 to 30,000 ⁇ g per kg body weight more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
  • this dose is conveniently administered several times a day.
  • an acute shock e.g., anaphylactic shock
  • single doses well above the above doses may be given.
  • the formulation of the pharmaceutical compositions based on the new compounds is carried out in a conventional manner by the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinpoundem, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc. processed and converted into the desired application form.
  • galenics carriers fillers, Zerfallbeeinpoundem, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, 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 which one of the pharmaceutically active compounds of the invention or their mixture or their pharmaceutically acceptable salt and a pharmaceutically acceptable salt or pharmaceutically acceptable excipients and carriers.
  • Enol ether cleavage used.
  • the crude product is mixed with 108 ml of a 1 M sulfuric acid and stirred at 90 0 C for 17 hours.
  • the reaction mixture is added under ice cooling with solid potassium carbonate to pH 9 (strong foaming) and extracted with diethyl ether.
  • the ether phase is discarded after DC control.
  • the aqueous phase is washed with conc. HCl acidified to pH 4.
  • reaction mixture is added to a mixture of saturated sodium bicarbonate solution and ice. After dilution with 50 ml of ethyl acetate, the mixture is stirred vigorously for 20 minutes. The organic phase is separated off and the aqueous phase is shaken once more with 50 ml of ethyl acetate. The combined organic extracts are washed with water and brine and dried over sodium sulfate. After filtering off the drying agent and the evaporation of the solvent, the remaining residue is chromatographed several times on silica gel (amine phase). 21, 5 mg (26.5%) of 4 - ⁇ [1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6-] are isolated
  • Reaction mixture was added to 500 ml_ saturated sodium bicarbonate solution and extracted three times with 200 ml of ethyl acetate. The combined organic extracts are washed with 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 phase ethyl acetate /
  • Ethyl 5- (3-chlorophenyl) -4A-dimethyl-2-hydroxy-2- (trifluoromethyl) pentanoate 5.26 g (18.59 mmol) of ethyl 5- (3-chlorophenyl) -4,4-dimethyl- Dissolve 2-oxopentanoate in 26.8 mL THF and add 3.17 g (22.3 mmol) (trifluoromethyl) trimethylsilane. After addition of 43 mg of tetrabutylammonium fluoride, the batch is stirred overnight at room temperature. 5.36 g of tetrabutylammonium fluoride are then added and the reaction mixture is stirred for a further two hours at room temperature.
  • reaction mixture is diluted with methyl tert-butyl ether and the phases are separated. After further shaking with methyl tert-butyl ether, the combined organic extracts are washed with water and brine and dried. After the solvent has been removed by evaporation, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / hexane). 4.34 g (66.2%) of the desired product are isolated.
  • ⁇ -dimethyl- ⁇ -rifluoromethyO- ⁇ H-benzocyclohepten-ol are added together with 8.09 mg (0.17 mmol) of sodium cyanide and 18.04 mg (0.083 mmol) of nickel bromide in 1 mL of 1-methyl-2-pyrrolidinone and in the Microwave (20 bar, 200 0 C, 20 minutes) reacted.
  • the reaction mixture is mixed with five ml of ethyl acetate. After addition of two ml of water, the mixture is stirred vigorously for 15 minutes at room temperature. It is shaken once more with ethyl acetate. The combined organic extracts are washed with water and brine.
  • Tetrabromomethane added. After stirring at room temperature for 16 hours, 10 g (54.75 mmol) of 2- (2-chlorophenyl) -2-methylpropanal, dissolved in 140 ml of dichloromethane, are added dropwise. After two hours of stirring, the reaction mixture is mixed with 350 mL of hexane, stirred vigorously and sucked through a frit filled with silica gel. After washing the residue with 600 mL of hexane / dichloromethane (1: 1), the filtrate is concentrated to dryness. The residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 6.31 g were isolated, but turned out to be the starting material and were therefore used again in the reaction to form the double bond.

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Abstract

L'invention concerne des dérivés de 5H-benzocycloheptène plusieurs fois substitués de formule (I), dans laquelle R3 désigne un groupe alkyle C1-C10, qui peut éventuellement être substitué par un groupe sélectionné parmi des groupes 1-3 hydroxy, des atomes d'halogène ou des groupes alcoxy 1-3 (C1-C5), un groupe cycloalkyle (C3-C7) éventuellement substitué, un groupe hétérocyclyle éventuellement substitué, un groupe aryle éventuellement substitué ou d'autres substituants, A signifie un groupe -CR6R7-CH2 ou -CH2-CR6R7, D représente un groupe -CR4R5-CH2 ou -CH2-CR4R5, R4 désigne un groupe hydroxy, un groupe OR10 ou un groupe O(CO)R10, R5 signifie un groupe alkyle (C1-C5) ou un groupe alkyle (C1-C5) éventuellement partiellement ou entièrement fluoré, un groupe cycloalkyle (C3-C7), un groupe cycloalkyle (C3-C7) alkylène (C1-C8), un groupe cycloalkyle (C3-C7) alkénylène (C2-C8), un groupe hétérocyclyle, un groupe hétérocyclyle alkylène (C1-C8), un groupe hétérocyclyle alkénylène (C2-C8), un groupe aryle, un groupe aryle alkylène (C1-C8), un groupe aryle alkénylène (C2-C8), un groupe aryle alkinylène (C2-C8) ou d'autres substituants, lesquels sont spécifiés dans les revendications. La présente invention porte également sur des procédés pour produire ces dérivés et sur leur utilisation comme inhibiteurs d'inflammation.
PCT/EP2006/002742 2005-03-22 2006-03-20 Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation WO2006100099A1 (fr)

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EP06723721A EP1863765A1 (fr) 2005-03-22 2006-03-20 Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation
JP2008502339A JP2008534462A (ja) 2005-03-22 2006-03-20 ６，７，８，９−テトラヒドロ−５−アミノ−５ｈ−ベンゾシクロヘプテン−６−オール誘導体類及び抗炎症剤として使用される関連する化合物類
CA002598969A CA2598969A1 (fr) 2005-03-22 2006-03-20 Derives de 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocycloheptene-6-ole et composes apparentes comme inhibiteurs d'inflammation

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DE102005014090A DE102005014090A1 (de) 2005-03-22 2005-03-22 5H-Benzocycloheptenderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
DE102005014090.4 2005-03-22

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MX2018009908A (es) * 2016-02-15 2018-09-07 Sanofi Sa Derivados de 6,7-dihidro-5h-benzo[7]anuleno como moduladores de receptores de estrogenos.
CN107118173B (zh) * 2017-07-12 2019-10-29 阿里生物新材料（常州）有限公司 一种环庚三烯并噁嗪类化合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2536509A1 (de) * 1974-08-26 1976-03-18 Takeda Chemical Industries Ltd Benzocycloheptenderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
WO1999005107A1 (fr) * 1997-07-25 1999-02-04 Smithkline Beecham Corporation Antagonistes du recepteur de vitronectine
WO2004069244A1 (fr) * 2003-02-07 2004-08-19 Warner-Lambert Company Llc Derives d'oxazolidinone n-substitues par un noyau bicyclique, utilises comme agents antibacteriens

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JPH02501737A (ja) * 1987-05-15 1990-06-14 シェリング・コーポレーション アリール置換ナフタリン，ベンゾオキセピン，ベンズアゼピン，ベンゾシクロヘプテン誘導体
PT87988B (pt) * 1987-07-16 1995-05-04 Byk Gulden Lomberg Chem Fab Processo para a preparacao de diazois e de composicoes farmaceuticas que os contem

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2536509A1 (de) * 1974-08-26 1976-03-18 Takeda Chemical Industries Ltd Benzocycloheptenderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
WO1999005107A1 (fr) * 1997-07-25 1999-02-04 Smithkline Beecham Corporation Antagonistes du recepteur de vitronectine
WO2004069244A1 (fr) * 2003-02-07 2004-08-19 Warner-Lambert Company Llc Derives d'oxazolidinone n-substitues par un noyau bicyclique, utilises comme agents antibacteriens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WONG, SHING CHUN ET AL: "Stereochemical considerations and the antiinflammatory activity of 6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols and related derivatives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 27, no. 1, 1984, pages 20 - 27, XP002387170 *

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CA2598969A1 (fr) 2006-09-28
PE20061350A1 (es) 2006-12-20
JP2008534462A (ja) 2008-08-28
TW200700389A (en) 2007-01-01
AR053189A1 (es) 2007-04-25
CN101146773A (zh) 2008-03-19
UY29435A1 (es) 2006-10-02
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