WO2006100099A1

WO2006100099A1 - 6, 7, 8, 9-tetrahydro-5-amino-5h-benzocyclohepten-6-ol derivatives and related compounds used as anti-inflammatory agents

Info

Publication number: WO2006100099A1
Application number: PCT/EP2006/002742
Authority: WO
Inventors: Hartmut Rehwinkel; Duy Nguyen; Markus Berger; Heike Schäcke
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2005-03-22
Filing date: 2006-03-20
Publication date: 2006-09-28
Also published as: AR053189A1; PE20061350A1; CA2598969A1; GT200600124A; PA8666801A1; CN101146773A; EP1863765A1; TW200700389A; DE102005014090A1; JP2008534462A; UY29435A1; DOP2006000065A

Abstract

The invention relates to polysubstituted 5H-benzocyclohepten derivatives of formula (I), in which R3 represents a C1-C10 alkyl group, which can be optionally substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5) alkoxy groups, an optionally substituted (C3-C7) cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, or other substituents, A represents a -CR6R7-CH2- or -CH2-CR6R7 group, D represents a -CR4R5-CH2- or -CH2-CR4R5 group, R4 represents a hydroxy group, an OR10 group or O(CO)R10 group, R5 represents a (C1-C5) alkyl group or an optionally partially or completely fluorinated (C1-C5) alkyl group, a (C3-C7) cycloalkyl group, a (C1-C8) alkene (C3-C7) cycloalkyl group, a (C2-C8) alkene (C3-C7) cycloalkyl group, a heterocyclyl group, a (C1-C8) alkene heterocyclyl group, a (C2-C8) alkene heterocyclyl group, an aryl group, a (C1-C8) alkene aryl group, a (C2-C8) alkenylene aryl group, a (C2-C8) alkynylene aryl group, or other substituents. Said other substituents are specified in the claims. The invention also relates to a method for producing said derivatives and to their use as anti-inflammatory agents.

Description

6, 7, 8, 9-TETRAHYDRO-S-AMINO-SH-BENZOCYCLOHEPTEN-O-OL DERIVATIVES AND RELATED COMPOUNDS AS AN INHIBITOR

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.

However, since the prior art compounds still have undesirable side effects or are not selective enough, the object remains to provide non-steroidal anti-inflammatory agents whose profile is improved over the prior art compounds.

This object is achieved by the compounds of the present invention set forth in the claims.

The present invention therefore relates to compounds of the general formula

^(l) EPO -DG

wherein

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

(C 1 -C 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- (CHz) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ W, -NH- (CH ₂ ) _{n +} r, -N (C _r C ₃ -alkyl) - (CH ₂ U-, -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 are} independently hydrogen, Ci-C _5- alkyl or (CO) -CrC ₅ -alkyl,

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

C ₁₀ ) alkoxy group,

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 / or 1-2 keto groups, which group can be linked via any position with the amine of the 5H-benzocycloheptene system, and optionally 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, 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 ₁ -C ₈ ) -alkylene (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₈₎ alkenylene cycloalkyl (C ₃ -C _7), a heterocyclyl group, a (Ci-C _δ) Alkylenheterocyclylgruppe, (C ₂ - C ₈₎ Alkenylenheterocyclylgruppe, an aryl group, a

_(Ci-C8) alkylenearyl, (C ₂ -C ₈₎ Alkenylenarylgruppe, (C ₂ -C ₈₎ Alkinylenaryl- group optionally substituted by 1-2 keto groups, 1-2- (C <ι-C ₅₎ alkyl groups, 1-2- (Cr

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-CβJ-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 ) Perfluoralkylgruppe, 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-, - (CHa) _{n +2} -, -NH- (CH ₂ J _{n +} I, -N (C _r C ₃ alkyl) -

where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms and / or nitrogen atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another are hydrogen, C 1 -C ₅ -alkyl or ( CO) -CrC ₅ -alkyl, 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 ₀ ) -alkoxy group, a (C 1 -C -o) -alkylthio group, a (C ₁ -C ₅ ) - Perfluoralkylgruppe, R ^{12 is} a hydrogen atom, a Hyroxygruppe, a halogen atom, a

Cyano group, an optionally substituted (C 1 -C 10) -alkyl group, a (Cr

Ci ₀ ) -alkoxy group,

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,

(CrC ₅ ) alkoxy, halogen, exomethylene 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, said group having a Any position may be linked to the amine of the 5H-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 a - CR ⁴ R ^δ -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-CβJAlkylenheterocyclylgruppe, (C ₂ - C ₈₎ Alkenylenheterocyclylgruppe , an aryl group, a (CrC ₈₎ alkylenearyl, (C ₂ -C ₈ C) group Alkinylenaryl- (C ₂ -C ₈₎ Alkenylenarylgruppe, an optionally substituted by 1-2 keto groups, 1-2- (C-ι-C ₅ ) alkyl groups, 1-2- (d-

C ₅ ) alkoxy groups, 1-3 halogen atoms, 1-2 substituted exomethylene groups,

Mono- or bicyclic heteroaryl group containing 1 to 3 nitrogen atoms and / or 1 to 2 oxygen atoms and / or _{1 to 2} sulfur atoms, a (C ₁ -C ₆ -alkyl heteroaryl group or a (C ₂ -C ₈ ) alkenylheteroaryl group, these groups being attached via any position to the 5H-

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.

A subgroup of the compounds according to the invention are compounds of the general formula I in which R ¹ and R ^2, independently of one another, are a hydrogen atom, a hydroxyl group, a halogen atom, a (C ₁ -C 10) -alkyl group, a (C ₁ -C 10) -alkoxy group, a (C 1 -C 10) -alkythio group, a (C 1 -C 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-, -

where n = 1 or 2 and the terminal atoms with directly adjacent ones

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

C ₅ ) alkoxy groups, an optionally substituted phenyl or a naphthyl group, an optionally substituted by 1-2 keto groups, 1-2- (CrC ₅ ) alkyl groups, 1-2- (Cr

C ₅ ) -alkoxy groups, 1-3 halogen atoms, 1-2 substituted exomethylene groups

1-3 mono- or bicyclic heteroaryl group containing nitrogen atoms and / or 1-2-oxygen atoms and / or 1-2 sulfur atoms, these groups may be linked via any position with the amine of the benzocycloheptene system 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 (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₎ Alkenylenarylgruppe, 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.

Preference is given to stereoisomers of the general formula (I) in which

R ¹ and R ² independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, a (C 1 -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) -alkythio group, a (C ₁ -C ₅ ) - Perfluoralkylgruppe, 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 -, -0-CH = CH-, -

(CH ₂ W-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 are} independently hydrogen, C 1 -C ₅ -alkyl or

(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

C ₅ ) -alkoxy groups, 1-3 halogen atoms, 1-2 substituted exomethylene groups 1-3 mono- or bi-cyclic heteroaryl group containing nitrogen atoms and / or 1-2-oxygen atoms and / or 1-2 sulfur atoms, these groups being attached via any position with the amine of the

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

(CrC ₈ ) alkylenaryl group, (C ₂ -C ₈ ) alkenylenaryl group, a (C ₃ -

C ₇ ) cycloalkyl group, a (C ₁ -C ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group,

(C ₂ -C ₈ ) alkenylene (C ₃ -C ₇ ) cycloalkyl group

Benzocycloheptensystems a (C ₃ -C ₆ ) cycloalkyl ring mean.

A particular subgroup are compounds of the general formula I in which

R ¹ and R ² independently represent a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C ₅ ) alkyl group, a (C _r C ₅ ) alkoxy group, a (CrC ₅ ) perfluoroalkyl group, a cyano 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-, - (CH ₂ ) _n + ₂ -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,

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, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, these groups can be linked via any position with the amine of the δH-Benzocycloheptensystems and optionally substituted one or more times with 1-2 keto groups, 1-2- (Ci-C ₃ ) alkyl groups, 1-2- (Ci-C ₃ ) Alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, and optionally hydrogenated at one or more sites A can be a -CR ⁶ R ⁷ -CH ₂ - or a -CH ₂ -CR ⁶ R ⁷ - group, D 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 fully fluorinated (Ci-C ₅ ) alkyl 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, a (C ₃ -C ₆ ) -cycloalkyl ring. Another object of the invention are stereoisomers of the general formula I, wherein

R ¹ and R ² independently of one another represent a hydrogen atom, a hydroxy group, a halogen atom, a (C 1 -C ₅ ) -alkyl group, a (C 1 -C ₅ ) -alkoxy group, a (C 1 -C ₅ ) -perfluoroalkyl group, a cyano group or R ₂ 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-, - (CH ₂ W-) wherein n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, R ^{3 is} a CiC-io-alkyl group which may be optionally substituted by 1-3 hydroxy groups, halogen atoms, optionally with C 1 -C 8 -alkyl, halogen, hydroxy, C 1 -C ₅ -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 , Dihydroindolonyl, Dihydroisoindolonyl-, benzimidazolyl or indolyl group, these groups via any position with the amine of the 5H-Benzocycloheptensystems may be linked and optionally substituted one or more times with 1-2 keto groups, 1-2- (Ci-C ₃ ) alkyl groups, 1-2- (CrC ₃ ) -

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

Ethyl group or together with the carbon atom of

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. C ₅ alkyl, halogen, hydroxy, CiC _δ alkoxy substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl-, Dihydroisochinolinyl-, thiophthalidyl, Benzoxazinonyl-, Phthalazinonyl-, quinolinyl, isoquinolinyl, quinolonyl, Isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl, which groups may be replaced by any of Position can be linked to the amine of Benzocycloheptensystems u may optionally be mono- or polysubstituted with 1-2 keto groups, 1-2- (CrC ₃ ) - 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 -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

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

Group, a halogen atom, a (CrC, o) alkyl group, a (Ci-Ci ₀₎ -

Alkoxy group, a (Ci-Ci ₀₎ -Alkythiogruppe, a (-C 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-, - (CH ₂ W-, where n = 1 or 2 and the terminal atoms with directly adjacent

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

C ₅ ) -alkoxy groups, 1-3 halogen atoms, 1-2 substituted exomethylene groups

1-3 mono- or bicyclic heteroaryl group containing nitrogen atoms and / or 1 -2-oxygen atoms and / or 1-2 sulfur atoms, these groups having at any position with the amine of the

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 ) -Alkyigruppe or an optionally partially or completely fluorinated (CiC ₅ ) alkyl group, an aryl group, a (Ci-C ₈ ) Alkylenarylgruppe, (C ₂ -C ₈ ) alkenylene, a (C ₃ -

(C ₂ -C ₈ ) alkenylene (C ₃ -C ₇ ) cycloalkyl group

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 mean.

Preference is given to stereoisomers of the general formula (I) in which

R ¹ and R ² are each independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C-ιo) alkyl group, a (Ci-Ci ₀ ) -

Alkoxy group, a (Ci-Cio) -Alkythiogruppe, 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-, -

(CH ₂ ) _n + ₂ -, where n = 1 or 2 and the terminal atoms with directly adjacent ones

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

(CO) -Ci-C ₅ -alkyl,

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

C ₅ ) alkoxy groups, an optionally substituted phenyl group, an optionally substituted by 1-2 keto groups, 1-2- (CrC ₅ ) alkyl groups, 1-2- (Cr C ₅ ) alkoxy groups, 1-3 halogen atoms, 1-2 Exomethylene groups substituted

1-3 mono- or bicyclic heteroaryl group containing nitrogen atoms and / or 1 -2-oxygen atoms and / or 1-2 sulfur atoms, these groups having at any position with the amine of the 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-ι-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₎ Alkenylenarylgruppe, 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

R ¹ and R ² independently represent a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-C ₅ ) alkyl group, a (CrCsJ alkoxy group, a (Ci-C ₅ ) - perfluoroalkyl group, a cyano 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-, - (CHz) _{n + 2} - where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, R ¹¹ and R ^{12 are} hydrogen, R ^{3 is} C -C -alkyl, which may optionally be substituted by 1-3 hydroxy groups , Halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl optionally substituted by C 1 -C ₅ -alkyl, halogen, hydroxy, C 1 -C ₅ -alkoxy -, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1 J- or 1, 8-Naphthyridiny L, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, these groups being in any position with the amine of the 5H-benzocycloheptene system may optionally be monosubstituted or polysubstituted with 1-2 keto groups, 1-2- (Ci-C-3) -alkyl groups, 1-2- (CrCa) -

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- | -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

Benzocycloheptensystems a (C ₃ -C ₆ ) cycloalkyl ring mean.

Stereoisomers are preferred of the general formula (I) wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, a (-C ₅₎ alkyl group, a _(Ci-C5) - perfluoroalkyl group, a cyano group, a (d-CsJ-alkoxy group, or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CHz) _n -CH ₂ -, -O-CH = CH-, - (CHz) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, R ¹¹ and R ^{12 is} a hydrogen atom,

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

Particularly preferred are 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, pyridazinyl , Pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, , Indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyr azinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, coumarinyl, isocumarinyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, , Isoquinolonyl, chiazazolinyl,

Quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl group, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridine-4 -onyl, 4-aminopyridyl, 1 H-pyridine 4-ylidenaminyl, chromanyl, isochromanyl, chromenyl, isochromenyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3, 4-Dihydro-2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazin-4-onyl, 3,4-dihydrobenz [1,4] oxazin-4-onyl, 3,4- Dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1 H-quinazolin-4-onyl, 3,4-dihydro-H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1, 5 ] naphthyridyl, 1 H- [1,5] naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl, 1,2-dihydropyrido [3,2-d] [1, 3] oxazin-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1, 3-dihydro-2H-isoindolyl, 1, 2-dihydroindazolyl, 1H Pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl, 2,2-dihydro-1H-pyrrolo [2,3-b] pyridine-3 -onylgr Uppe, where these 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- (CrC ₃ ) alkyl groups, 1-2 exomethylene groups and optionally on one or a plurality of sites may be hydrogenated, 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 (-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,

Dihydroisoquinolinyl, 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, 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 ) -

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 -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

Benzocycloheptensystems a (C ₃ -C ₆ ) cycloalkyl ring mean.

Particularly preferred are stereoisomers of the general formula (I) in which 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,

R ⁵ fully fluorinated (Ci-C ₃ ) alkyl group

R ⁶ and R ^{7 are} independently a hydrogen atom, a methyl or

Ethyl group or together with the carbon atom of

Benzocycloheptensystems a (C ₃ -C ₆ ) cycloalkyl ring mean.

Very particular preference is given to stereoisomers of the general formula (I) in which 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 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 -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 fully fluorinated (C ₁ -C ₃ ) -alkyl group

R ⁶ and R ⁷ independently represent a hydrogen atom, a methyl or ethyl group.

A particular subject of the invention are compounds which carry on the aromatic ring of the 5H-Benzocycloheptensystems one or two substituents selected from the group CrC ₅ alkyl, Ci-C ₅ alkoxy, Cr C ₅ perfluoroalkyl, halogen, hydroxy, nitro, -O- (CH ₂ ) _n -O- ₍ -O- (CH ₂ ) _H -CH ₂ -, -O- CH = CH-, - (CH ₂ W-, -NH- (CH ₂ ) _{n +} i, N (C ₁ -C ₃ -alkylHCH ₂ ) _{n +} i, -NH-N = CH-, where n = 1 or 2 and the terminal atoms of the divalent substituents are linked to directly adjacent ring carbon atoms.

Another preferred subject matter is compounds of the general formula I according to any one of the claims, wherein 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

Stereoisomers of the general formula I, in which

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 -

D -CH ₂ -CR ⁴ (R ⁵ )

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. Particular preference is given to compounds of the general formula I in which 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

1-Bromo-6,7,8,9-tetrahydro-5-r (1H-indazol-4-yl) -amino1,8,8-dimethyl-6

(Trifluoromethyl) -5-benzocvclohepten-6-ol.

4- (ri-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-vinyl) -1,3-dihydro-2H-indol-2-one and 4- (H -bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-vnaminoV7-bromo-1,3-dihydro-2H-indole-2 -one.

2-Chloro-6,7.8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6-

(Trifluoromethyl) -5-benzocvclohepten-6-ol.

4- (r 2 -chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -amino) -1,3-dihydro-2H-indole-2-one on,

6,7,8,9-tetrahydro-6-Hydroxy-8,8-dimethyl-5 - {[7- (1-methyl-5-oxopyrrolidin-2-yl) -

IH-indazole ^ ^ -vnaminoVδ- trifluormethvD-delta H-benzocvclohepten ^ carbonitrile,

(5f? * - c / s) -5- (r6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethvn-5H-benzocyclohepten-δ-aminol quinoline ^ d / - /) - In particular, (5R * -cis) -5- (r6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-ylamino> quinoline-2 (1 H) -one

A subgroup of these compounds are the compounds in which R ¹ and R ² together form the radicals -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) n -CH ₂ -, -O-CH = CH- , - (CH ₂ W-. -NH- (CH ₂ ) _{n + 1l} N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, another subgroup represent the compounds in which the alkyl radicals R ¹ and R ^{2 have} the meaning - (CH ₂ ) _{n + 2} - and thus together with the carbon atom of the chain form a 5- to 6-membered ring. 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.

The invention further provides compounds of the formula I in which 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.

Particular preference is given to stereoisomers of the general formula I according to one of the claims, in which R ³ denotes an indazolyl, dihydroindolonyl, dihydroisoindolonyl, quinolonyl or isoquinolonyl group. A very particularly preferred subject of the invention are compounds of general formula I according to one of the claims, wherein 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-ι-C ₅ ether or ester (CO) R ¹⁰ are present.

As the radical R ⁴ , the hydroxy group is preferred.

Another object of the invention are compounds of general formula I wherein R ^{5 is} a (Ci-C ₅ ) alkyl group or an optionally partially or fully fluorinated (C-ι-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) Alkylenheterocyclylgruppe, (C ₂ - C ₈₎ Alkenylenheterocyclylgruppe, an aryl group, a _(Ci-C8) alkylenearyl group means a (C ₂ -C ₈₎ Alkenylenarylgruppe.

A particular subject of the invention are stereoisomers of general formula I according to one of the claims, wherein 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 ) Alkylenarylgruppe, (C-2-C ₈ ) Alkenylenarylgruppe, 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.

Another object of the invention are stereoisomers of the general formula I according to one of the claims, in which 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.

A particular subject of the invention are all combinations of the radicals disclosed in the examples. definitions

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.

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.

The term halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.

Under 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,. (C ₂ -C ₈ ) -alkenylene (C ₃ -C ₇ ) -cycloalkyl group means, for example, - (CH = CH) -cycloalkyl, - [ C (CH ₃ ) = CH] -cycloalkyl, - [CH = C (CH ₃ )] -cycloalkyl, - (CH = CH-CH ₂ ) -cycloalkyl, - (CH ₂ -CH = CH) -cycloalkyl, - ( CH = CH-CH ₂ -CH ₂₎ -cycloalkyl, - (CH ₂ - CH = CH-CH ₂₎ -cycloalkyl, - (CH ₂ -CH ₂ -CH = CH) -cycloalkyl,

Cycloalkyl, - (CH = C (CH ₃ ) -CH ₂ ) -cycloalkyl. 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.

If a skeleton is mentioned, it means the bicyclic Bizyklohepten- ring system of general formula I.

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. Exemplary are phenyl, naphthyl, tetralinyl,

Anthranyl, indanyl, and indenyl.

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.

As substituents, for example, methoxy, ethoxy, propoxy, iso- Propoxy, hydroxy, fluoro, chloro, bromo, methyl, ethyl, propyl, iso-propyl or

Called trifluoromethyl groups.

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-Cβ-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 alkenylenearigruppe 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-α-Cβ-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. For example, they include compounds of formula I wherein 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, benzofuranyl, Benzimidazolyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, coumarinyl, isocumarinyl , Dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7 or 1, 8-naphthyridinyl, means to the present invention and represent a particular embodiment of the invention. When the heteroaryl groups are partially or fully hydrogenated so belong

Compounds of formula I wherein 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-

Tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazin-4-onyl, 3 , 4-Dihydrobenz [1,4] oxazin-4-onyl, 3,4-dihydro-2H-benzo [1, 4] thiazinyl, 4H-benzo [1, 4] thiazinyl, 1, 2,3,4-tetrahydroquinoxalinyl , 1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-quinazolin-4-onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1, 2, 3,4-Tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [1,5] naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H - naphthyridin-4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazin-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, qctahydroxy 2H-isoindolyl, 1, 3-dihydro-2H-isoindolyl, 1, 2-dihydroindazolyl, 1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl, 2,2-dihydro-1H-pyrrolo [2,3-b] pyridin-3-onyl, to the present invention.

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. Similar compounds which metabolize to compounds of the general formula I according to claim I in the organism belong to the subject of the present invention.

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,

optionally acid

or Lewis acid

(N) (D.

which are then cyclized by adding inorganic or organic acids or Lewis acids at temperatures in the range of -30 ⁰ C to +80 ⁰ C to the compounds of general formula I.

If compounds of the general formula I are to be prepared in which R ^{1 is} a (C _r C ₅ ) alkoxy group, the 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.

The compounds of general formula II are prepared according to the meaning of A by various methods:

I. Preparation of the compounds of general formula I. in which A is -CHy- (CR ⁶ R ⁷ V: (= compounds of general formula Ia): A compound of general formula III, wherein LG is any leaving group known to those skilled in the art ), such as ZBChlorid, bromide, iodide, sulfate, sulfonate, for example, tosylate, mesylate, under basic conditions, for example, aqueous NaOH or KOH in organic solvents such as benzene, toluene with an aldehyde of general formula IV Compounds of general formula V and phase transfer catalysis with conventional phase transfer catalysts such as quaternary ammonium salts such as tetrabutylammonium iodide, benzyltrimethylammonium chloride to compounds of general formula V

implemented. The aldehyde V is then reacted under Horner-Wittig conditions with the reagent VI, wherein R ^{x is} a (C-ι-C ₃ ) alkyl group or a benzyl group and the compound of general formula VII is obtained. After the ester has been saponified by a method known to a person skilled in the art, the

Vl

VN VIII

Enol ether is cleaved under acidic conditions, for example, glacial acetic acid / HOAc / H ₂ SO 4, and the resulting α-keto acid esterified under normal acidic conditions with an alcohol R ^y -OH, where R ^{y is} (CrC ₅ ) alkyl, esterified to an α-ketoester of general formula VIII. With Ruppert's reagent

VIII X

CF ₃ Si (CH ₃ ) ₃ introduces the CF ₃ group. Reducing agents such as diisobutylaluminum hydride (DIBAH = DIBAL) or lithium aluminum hydride (LAH = LiAlH ₄ ) reduce the ester to aldehyde X. The aldehyde is then as described in the prior art, reacted with an amine of the general formula R ³ -NH ₂ , wherein R ^{3 has} the meaning given in the claims.

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.

II. Preparation of the compounds of the general formula I in which A - (CR ⁶ R ⁷ VCH? - means (= compounds of the general formula Ib):

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)

L Dibah

2. CBr / triphenylphosphine

and then reacted with CBr ₄ / triphenylphosphine optionally with addition of zinc to give a compound of general formula XIII.

With butyllithium, 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

XIV VIIIb

Formula VIIIB, which then reduced analogously to the method I to the aldehyde, is reacted with the amine R ³ -NH ₂ to imine and then cyclized to

VIIIb

Compound of the general formula Ib.

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. As Cu (OTf) ₂ , CuCl ₂ , CuBr ₂ , Yb (OTf) ₃ , in question. 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. Leu., 2004, 45, 2009-12), (R) - or (S) -Cu ^f BuBOX,), (R) - or (S) -Cu 'PrBOX, (R) - or (S) -Cu PhBOX, (R) - or (S) -Cu AdaBOX (Evans et al., J. Am. Chem. Soc., 2000, 122, 7936-43), (R) - or (S) -Ph-pybox Sc (OTf) ₃ (Evans et al., J. Am. Chem. Soc., 2005, 127, 8006-7), (R) - or (S) - 'Pr Pybox Yb (OTf) ₃ , (R) - or (S) - ^f Bupybox Yb (OTf) ₃ , (R) - or (S) -Ph-pybox Yb (OTf) ₃ (Qian et al., Tetrah Asymm 2000, 11, 2347-57).

The novel intermediates of the syntheses listed are also the subject of the present invention.

The binding of the substances to the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is recombinant using verified receptors. Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays. In comparison to the reference substance [ ³ H] -dexamethasone, the substances show a high affinity for GR.

As a major molecular mechanism for the anti-inflammatory effect of glucocorticoids, the 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. 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). For this purpose, 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, Wissenschafliche 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. 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 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.

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative effect, 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:

(i) Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes: - Chronic obstructive pulmonary diseases of any genesis, especially

bronchial asthma

- Bronchitis of different origin

- Adult Respiratory Distress Syndrome (ARDS)

- Bronchiectasis - All forms of restrictive lung diseases, especially allergic

alveolitis,

- All forms of pulmonary edema, especially toxic pulmonary edema, eg radiation pneumonitis - Sarcoidoses and Granulomatoses, in particular Boeck's Disease (ii) Rheumatic Diseases / Autoimmune Diseases /

Joint diseases associated with inflammatory, allergic and / or proliferative processes: All forms of rheumatic diseases, especially rheumatoid

Arthritis, acute rheumatic fever, polymyalgia rheumatica, Behcet's disease

- Reactive arthritis

- Inflammatory soft tissue diseases of other genesis - Arthrotic symptoms in degenerative joint diseases (arthroses)

- Traumatic arthritis

- vitiligo

- collagenoses of any genesis, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, still syndrome, Felty syndrome

- Sarcoidoses and Granulomatoses

- - Rheumatic soft tissue diseases

(iii) allergies or pseudoallerg. Diseases associated with inflammatory and / or proliferative processes: All forms of allergic reactions, e.g. Quincke edema, hay fever,

Insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular disease

- allergic vasculitis (iv) vasculitis

- Panarteritis nodosa, temporal arteritis, erythema nodosum

- Polyarteritis nodosa

- Wegner granulomatosis

- Giant cell arteriitis (v) Dermatological disorders associated with inflammatory, allergic and / or proliferative processes:

- Atopic dermatitis (especially in children)

- All forms of eczema such as atopic dermatitis (especially in children) Exanthema of any genesis or dermatoses

- psoriasis and parapsoriasis form

- Pityriasis rubra pilaris

Erythematous diseases triggered by different noxae, e.g. Blasting, chemicals, burns etc.

- Bullous dermatoses, e.g. autoimune pemphigus vulgaris, bullous pemphigoid

- diseases of the lichenoid type,

- pruritus (eg allergic genesis) - Seborrheic dermatitis

- Rosacea-Formenkreis

- Pemphigus vulgaris

- Erythema exudative multiforme

- Balanitis - Vulvitis

- manifestation of vascular disease

- Hair loss like alopecia areata

- Cutaneous lymphomas

- Parapsoriasis (vi) Kidney diseases associated with inflammatory, allergic and / or proliferative processes:

- Nephrotic syndrome

All nephritides, e.g. glomerulonephritis

(vii) liver disease associated with inflammatory, allergic and / or proliferative processes:

- Acute liver cell decay

acute hepatitis of different origins, e.g. viral, toxic, drug-induced

- Chronic aggressive and / or chronic intermittent hepatitis (viii) Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes:

- regional enteritis (Crohn's disease)

- Ulcerative colitis - Gastritis

- Reflux esophagitis

- Gastroenteritides of other genesis, e.g. native sprue

(ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes:

- Anal eczema

- fissures

- Hemorrhoids

- idiopathic proctitis (x) ocular diseases associated with inflammatory, allergic and / or proliferative processes:

- allergic keratitis, uveitis, iritis,

- conjunctivitis

- Blepharitis - neuritis nervi optici

- Chorioditis

- Ophtalmia sympathica

(xi) diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes: - allergic rhinitis, hay fever

- otitis externa, e.g. due to contact problems, infection etc.

- Otitis media

(xii) Neurological disorders associated with inflammatory, allergic and / or proliferative processes: - brain edema, especially tumor-related cerebral edema

- Multiple sclerosis

- Acute encephalomyelitis

- Meningitis

various forms of seizures, e.g. BNS cramps - Acute spinal cord injury

- stroke

(xiii) blood disorders associated with inflammatory, allergic and / or proliferative processes such. B .: - Acquired hemolytic anemia

- ldopathic thrombocytopenia

(xiv) tumor diseases associated with inflammatory, allergic and / or proliferative processes such. For example: - acute lymphoblastic leukemia

- Malignant lymphomas

- Lymphogranulomatoses

- Lymphosarcomas

- Extensive metastases, especially in breast, bronchial and prostate cancers

(xv) endocrine disorders associated with inflammatory, allergic and / or proliferative processes, such as: B .:

- endocrine orbitopathy

- Thyrotoxic crisis - Thyreoiditis de Quervain

- Hashimoto's thyroiditis

- Graves' disease

- Endocrine Ophthalmopathy

- Granulomatous thyroiditis - Struma lymphomatosa

- Grave disease

(xvi) Organ and Tissue Transplantation, Graft-versus-host Disease (xvii)

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

Acquired secondary adrenal insufficiency, eg postinfectious, tumors etc. (xix) emesis associated with inflammatory, allergic and / or proliferative processes:

- e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting. (xx) Pain in inflammatory genesis, e.g. Lumbago (xxii) Various diseases.

Preferred is the local application of the compounds according to the invention for the treatment of diseases which are listed under (i), (ii), (iii), (v), (viii). (ix), (x), (xi), (xv), (xx), (xxi) are listed, in particular (i), (ii), (iii), (v), (x), (xi) , (xv).

In addition, 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, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart , 1998).

All of the aforementioned indications (i) to (xx) are described in detail in

Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche 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. For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, a GR agonist of the present invention may be combined with one or more medicaments for the treatment of such Status. Where such a combination is administered by inhalation, the drug to be combined may be selected from the following list:

A PDE4 inhibitor including an isoform PDE4D inhibitor;

• a selective ß.sub2. 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) such as ipratropium bromide, tiotropium bromide, oxitropium bromide,

Pirenzepine or telenzepin;

• a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); or,

• an inhibitor of p38 kinase function. For another object of the present invention, 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.

For the therapeutic effects in the above-mentioned disease states, 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;

(iii) 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.

In general, satisfactory results are expected in animals when the daily doses range from 1 μg to 100,000 μg of the compound of the invention per kg of body weight. For larger mammals, such as humans, a recommended daily dose is in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg body weight, more preferably a dose of 10 to 10,000 μg per kg body weight. For example, this dose is conveniently administered several times a day. For the treatment of 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, Zerfallbeeinflussem, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc. processed and converted into the desired application form. Reference may be made to Remington ^'s Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions in question. For parenteral administration, injection and infusion preparations are possible.

For intraarticular injection appropriately prepared crystal suspensions may be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

For rectal administration, 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.

For pulmonary administration of the new compounds, these can be used in the form of aerosols and inhalants.

For local application to the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses, the new compounds may be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.

For topical application, 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.

Experimental part

example 1

1-Bromo-6.7.8.9-tetrahydro-5-r (1H-indazol-4-vinylamino-8,8-dimethyl-6- (trifluoromethvn-5AV-benzocyclohepten-6-ol

3- (2-Bromophenyl) -2,2-dimethylpropanal 1, 63 g (40.81 mmol) of ground sodium hydroxide and 150.7 mg (0.41 mmol) of tetrabutylammonium iodide are charged in six milliliters of benzene. A mixture of 12.7 g (51 mmol) of 2-bromobenzyl bromide and 2.94 g (40.81 mmol) of isobutyraldehyde are added dropwise to this mixture at 6O ⁰ C and then the mixture was stirred for eight hours at this temperature. After stirring overnight at room temperature, the reaction mixture is mixed with 40 ml of water and shaken with 400 ml of diethyl ether. The organic phase is washed with water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 6.6 g (67.1%) of the desired compound are isolated. MS (El) m / e (relative intensity): 242 (M ⁺ , 3), 169/71 (100)

(E / Z) -Ethyl-5- (2-bromophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate To a solution of 7.34 g (23.371 mmol) of ethyl 2-diethylphosphono-2-ethoxyacetate in 21 ml of tetrahydrofuran are slowly added dropwise with ice cooling 14.75 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran / heptane / toluene and stirred at 0 ⁰ C for 30 minutes. To this yellow solution 6.6 g (27.37 mmol) of 3- (2-bromo-phenyl) -2,2-dimethyl-propanal dissolved in 31, 5 ml of anhydrous tetrahydrofuran was added dropwise at 0 ⁰ C. The cold bath is removed and the batch at 22 hours Room temperature stirred. The reaction mixture is mixed with 60 ml of water and shaken twice with 300 ml of diethyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution. After drying over sodium sulfate and evaporation of the solvent, the remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). Be isolated

6.63 g (68.2%) of the desired compound as an E / Z mixture. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 10-1, 40 (12H), 2.95-3.08 (2H), 3.68-3.80 (2H), 4.13 -4.32 (2H), 4.89 and 6.17 (collectively 1H), 7.00-7.10 (1H), 7.14-7.34 (2H), 7.55 (1H) ,

5- (2-bromophenyl) -4,4-dimethyl-2 ~ oxo-pentanoic acid

6.63 g (18.66 mmol) of (E / Z) -ethyl-5- (2-bromophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate are mixed with 186 ml of 1 M sodium hydroxide solution in a 2: 1 mixture of ethanol / water and stirred for 18 hours at room temperature. After stripping off the ethanol, the residue is extracted with diethyl ether. The organic phase is discarded. The aqueous phase is washed with conc. HCl acidified to pH 3. After extraction with diethyl ether, the combined organic extracts are washed neutral, dried, and the solvent is removed by rotary evaporation. The product obtained (5.83 g = 95.6%) is added directly to the

Enol ether cleavage used. For this purpose, 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. After extraction with diethyl ether, washing and drying of the organic phase, the solvent is spun off and the resulting residue (4.23 g = 79.8%) used crude in the next stage. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 10 (6H), 2.94 (2H), 3.00 (2H), 7.05-7.14 (1H), 7.18 -7.29 (2H), 7.58 (1H).

Methyl-5- (2-bromophenyl) -4,4-dimethyl-2-oxopentanoate 2 g (6.685 mmol) of 5- (2-bromophenyl) -4,4-dimethyl-2-oxopentanoic acid are dissolved in 11.6 ml of acetone and admixed at room temperature with 1.108 g (8.022 mmol) of potassium carbonate. After addition of 1, 23 g (8.691 mmol) of iodomethane, the mixture is refluxed for two hours. The potassium carbonate is filtered off with suction through a G4 frit, washed with acetone and the solvent is removed by rotary evaporation. Chromatography of the residue on silica gel (eluent ethyl acetate / hexane) gives 1, 1 g (52.6%) of the desired compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 10 (6H), 2.88 (2H), 2.93 (2H), 3.88 (3H), 7.03-7.11 ( 1H), 7.18-7.25 (2H), 7.58 (1H).

5- (2-Bromophenyl) -4,4-dimethyl-2- (trifluoromethyl) pentane-1,2-diol 1.1 g (3.512 mmol) of methyl 5- (2-bromophenyl) -4,4-dimethyl 2-oxopentanoate are dissolved in 5.7 ml of THF and treated at ⁰ ° C. with 599.2 mg (4.214 mmol) of (trifluoromethyl) trimethylsilane. After addition of 8.6 mg of tetrabutylammonium fluoride, the batch is stirred for one and a half hours at 0 to 5 ° C. The reaction mixture is added to ice-water and extracted twice with diethyl 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). 1.17 g (73.1%) of methyl 5- (2-bromophenyl) -4,4-dimethyl-2- (trimethylsilanyloxy) -2- (trifluoromethyl) -pentanoate are isolated. The ester is dissolved in 10.7 ml of toluene and treated at -10 ⁰ C with 5.35 ml of a 1, 2 M DIBAH solution. After one hour of stirring at -10 to 0 ⁰ C are carefully added dropwise at -10 ⁰ C initially 1, 77 ml of isopropanol and then 2.67 ml of water. After two hours of vigorous stirring, the precipitate is filtered off with suction through a frit, washed with ethyl acetate and the solvent is removed by rotary evaporation. There are obtained 1, 07 g of pentanediol as silyl ethers, which are used without further purification in the next stage. For this purpose, the crude product (1.07 g = 2.503 mmol) is dissolved in 14 ml of THF and admixed with 789.7 mg (2.503 mmol) of tetrabutylammonium fluoride. After stirring for 20 minutes

Room temperature, the batch is added to ice-water and extracted twice with diethyl ether. The combined organic extracts are washed with water and with brine. After drying with sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (eluent: ethyl acetate / hexane). 582.5 mg (65.5%) of the desired diol are isolated. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.93-1, 10 (6H), 1, 63 (1H), 1.79 (1H), 2.82-2.98 (2H), 3.52-3.72 (2H), 5.13 (1H), 5.59 (1H), 7.10-7.19 (1H), 7.25-7.40 (2H), 7.59 (1H).

5- (2-bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) -pentanal

To 580 mg (1.633 mmol) of 5- (2-bromophenyl) -4,4-dimethyl-2- (trifluoromethyl) -pentane-1,2-diol dissolved in 17 ml of dichloromethane are added 5.6 ml of dimethyl sulfoxide and 826 g of Added 2 mg (8.165 mmol) of triethylamine. After portionwise addition of 779.7 mg (4.899 mmol) SCVPyridinkomplex the mixture is stirred for 17 hours at room temperature. After the dropwise addition of 6.5 ml of saturated ammonium chloride solution, the batch is stirred for 15 minutes at room temperature and then extracted twice with diethyl ether. The combined organic extracts are washed with water and with brine. After drying and evaporation of the solvent, the residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 480.5 mg (83.3%) of the desired compound are isolated.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.95 (3H), 1, 02 (3H), 2.13-2.30 (2H), 2.80-2.93 (2H), 3.93 (1H), 7.02-7.13 (1H), 7.20-7.29 (2H), 7.58 (1H), 9.80 (1H).

5- (2-bromophenyl) -1,1,1-t-fluoro-2 - [(1H-indazol-4-ylmino) -methyl] -4,4-dimethylpentan-2-o /

100 mg (0.283 mmol) of the aldehyde described above and with 37.7 mg (0.283 mmol) of 4-aminoindazole are mixed with 0.4 ml of glacial acetic acid and stirred for four days at room temperature. The reaction mixture is stripped three times with toluene on a rotary evaporator and the residue is then chromatographed (silica gel, eluent ethyl acetate / hexane). 101, 8 mg (76.8%) of the desired compound are isolated.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 02 (3H), 1, 18 (3H), 2.09 (1H), 2.39 (1H), 2.98 (2H) , 5.10 (1H), 6.82 (1H), 7.00-7.10 (1H), 7.15-7.32 (2H), 7.35-7.49 (2H). , 7.56 (1H), 8.15 (1H), 8.23 (1H).

1-Bromo-6, 7, 8, 9-tetrahydro-5 - [(1H-indazol-4-yl) -amino] -8, 8-dimethyl-6- (trifluoromethyl) -5H-henzocyclohepten-6-ol

60 mg (0.128 mmol) of 5- (2-bromophenyl) -1,1,1-trifluoro-2 - [(1H-indazol-4-ylmino) -methyl] -4,4-dimethylpentan-2-ol are treated with 2 , 5 ml boron tribromide (1M in dichloromethane) and then stirred for seven days at room temperature. The reaction mixture is added dropwise at -3O ⁰ C dropwise with saturated sodium bicarbonate solution and stirred for 10 minutes after addition of ethyl acetate at room temperature. After extracting twice with ethyl acetate, the combined organic extracts are washed with water and with brine and dried. After the solvent has evaporated, the residue is chromatographed on the flash master. 43.3 mg (70.5%) of the desired compound are isolated.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 1, 00 (3H), 1, 30 (3H), 1, 40 (1H), 1, 96 (1H), 3.09 (1 H), 3.40 (1H), 5.30 (1H), 5.76 (1H), 6.79 (1H), 7.00-7.10 (2H), 7.41 ( 1H), 7.56 (1H), 8.13 (1H).

Example 2

4- (ri-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethvn-5H-benzocyclohepten-5-vinylaminoV-1,3-dihydro-2H-indol-2-one and 4-iπ- Bromo- 6J, 8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino) -7-bromo-1,3-dihydro-2H-indole-2 -one

7 - {[5- (2-Bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentylidene] amino} -1,3-dihydro-2H-indol-2-one

73 mg (0.21 mmol) of the 5- (2-bromophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentanal described in Example 1 are mixed with 30.62 mg (0.29 mmol). 4-amino-1, 3-dihydro-2H-indol-2-one and 0.29 mL glacial acetic acid stirred for five days at room temperature. The reaction mixture is stripped three times with toluene on a rotary evaporator and the remaining residue chromatographed on silica gel (eluent hexane / ethyl acetate). 82.9 mg of the desired imine are isolated. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 00 (3H), 1, 10 (3H), 2.02 (1H), 2.33 (1H) ₁ 2.95 (2H), 3 , 55 (2H), 4.90 (1H), 6.69 (1H), 6.83 (1H), 7.08 (1H), 7.18-7.32 (3H), 7 , 55 (1H), 8.09 (1H), 8.32 (1H).

4 - {[1-Bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} -1,3-dihydro 2H-indol-2-one (I) and 4 - {[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocycloheptene 5-yl] amino} - 7-bromo-1,3-dihydro-2H-indol-2-one (II) 81 mg (0.17 mmol) of the imine described above are mixed at room temperature with 3.4 ml of a 1M Bortribromidlösung added in dichloromethane and stirred for 13 days at this temperature. For workup, the 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

(trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} -1, 3-dihydro-2H-indol-2-one (I) and

7.9 mg (8.4%) of 4 - {[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6-

(trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} -7-bromo-1,3-dihydro-2H-indol-2-one (II).

(I): ¹ H NMR (400 MHz, CD ₃ OD): δ = 0.92 (3H), 1, 20 (3H), 1, 30 (1H), 1.88 (1H), 2 , 98 (1H), 3.30 (2H, signal is below the methanol signal), 3.48 (1H), 5.15 (1H), 5.87 (1H), 6.23 (1H), 6 , 89 (1H), 7.05 (1H), 7.31 (1H), 7.50 (1H). (II): ¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.90 (3H), 1, 20 (3H), 1, 30 (1H), 1, 87 (1H), 2 , 98 (1H), 3.30 (2H, signal is below the methanol signal), 3.59 (1H), 5.10 (1H), 5.82 (1H), 6.99 (1H ), 7.09 (1H), 7.30 (1H), 7.50 (1H). Example 3

2-Chloro-6,7,8,9-tetrahydro-5- (1H-indazol-4-ylamino) -8.8-dimethyl-6- (trifluoromethvO-5 / - / - benzocyclohepten-6-ol

3- (3-chlorophenyl) -2,2-dimethylpropanal

7.95 g (198.7 mmol) of ground sodium hydroxide and 734 mg (1.98 mmol) of tetrabutylammonium iodide are initially charged in 38.2 ml of benzene. At 60 ^° C., a mixture of 40 g (248.4 mmol) of 3-chlorobenzyl bromide and 14.33 g (198.7 mmol) of isobutyraldehyde are added dropwise to this mixture

(Heating of the reaction mixture to 72 ⁰ C). The batch is then stirred at 60 ^° C. for 60 hours. After stirring for 24 hours at room temperature, the reaction mixture is mixed with 200 ml of ice water and shaken three times with 200 ml of methyl tert-butyl ether. The combined organic phases are washed with water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). Are 31, 74 g (81, 2%) of the desired compound (purity about 50%). MS (Cl) m / e (relative intensity): 214 (100%)

(E / Z) -Ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate To a solution of 21, 36 g (79.62 mmol) of ethyl 2-diethylphosphono-2-ethoxyacetate In 100 ml of tetrahydrofuran, while cooling with ice, 85.2 ml of a 2 M solution of lithium diisopropylamide are slowly added

Dropped tetrahydrofuran / heptane / toluene and stirred at 0 ⁰ C for 30 minutes. 28.46 g (based on the purity 15.66 g = 79.62 mmol) of 3- (3-chlorophenyl) -2,2-dimethyl-propanal, dissolved in 100 ml of anhydrous tetrahydrofuran, at ⁰ ° are added to this yellow solution C added dropwise. The cold bath is removed and the approach stirred overnight at room temperature. The reaction mixture is added to 400 ml of water and shaken three times with 200 ml of methyl tert-butyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution. After drying over sodium sulfate and evaporation of the solvent, the remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). Be isolated 25.76 g (> 100%) of the desired compound as an E / Z mixture. MS (Cl) m / e (relative intensity): 330 (35%), 328 (100%), 185 (53%).

5- (3-Chloφhenyl) -4,4-dimethyl-2-oxo-pentanoic acid

28.47 g (91.58 mmol) of (E / Z) -ethyl-5- (3-chlorophenyl) -4,4-dimethyl-2-ethoxypent-2-enoate are mixed with 751 ml of 1 M sodium hydroxide solution in a 2: 1 mixture of ethanol / water and stirred overnight at room temperature. After stripping off the ethanol on a rotary evaporator, the residue is diluted with 200 ml of water and extracted three times with 200 ml each of methyl tert-butyl ether. The organic phase is discarded. The aqueous phase is washed with conc. HCl acidified to pH 3. After extraction with methyl tert-butyl ether (three times), the combined organic extracts are washed neutral, dried and the solvent is removed by rotary evaporation. The product obtained (15.82 g = 61.1%) is used directly in the enol ether cleavage. For this purpose, the crude product with 330 mL of 1 M sulfuric acid and 87 mL glacial acetic acid and stirred for two days at 90 ⁰ C. Since the reaction was not complete after two days, an additional 44 mL of glacial acetic acid were added. After stirring for a total of six days, the reaction mixture is basified with solid potassium carbonate while cooling with ice-bath (pH 9, vigorous foaming) and extracted three times with methyl tert-butyl ether. The ether phase is discarded after DC control. The aqueous phase is washed with conc. HCl acidified to pH 4. After extraction with methyl tert-butyl ether, washing and drying of the organic phase, the solvent is spun off and the residue obtained (11, 9 g = 83.8%) used crude in the next stage.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 09 (6H), 2.69 (2H), 2.84 (2H), 7.00 (1H), 7.13 (1H) , 7,22 (2H). Ethyl 5- (3-chlorophenyl) -4,4-dimethyl-2-oxopentanoate

10.61 g (41.65 mmol) of 5- (3-chlorophenyl) -4,4-dimethyl-2-oxopentanoic acid are dissolved in

259 ml_ ethanol, with 4.7 ml_ conc. Sulfuric acid added and boiled for six and a half hours at reflux. After cooling, the

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 /

Hexane) chromatographed. Be isolated 5.26 g (44.6%) of the desired

Ester.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.05 (6H), 1.38 (3H), 2.68 (2H), 2.73 (2H), 4.30

(2H) ₁ 7.00 (1H), 7.12 (1H), 7.20 (2H).

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. The 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. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.89 (3H), 1, 00 (3H), 1, 35 (3H), 1, 90-2.06 (2H), 2.50 ( 1H), 2.80 (1H), 3.92 (1H), 4.27-4.45 (2H), 7.09 (1H), 7.20 (3H).

5- (3-chlorophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentanal 2 g (5.67 mmol) of ethyl 5- (3-chlorophenyl) -4,4-dimethyl-2-hydroxy-2- (trifluoromethyl) pentanoate are dissolved in 74.1 ml of diethyl ether. At 0 ^° C., 161.4 mg (4.25 mmol) of lithium aluminum hydride are added in portions. After stirring for one hour at 0 ^° C., 12 ml of saturated sodium bicarbonate solution are added dropwise, and the mixture is stirred vigorously at room temperature for a further two hours. After addition of a little silica gel, the mixture is stirred for a further 10 minutes and the reaction mixture is subsequently filtered off with suction through a glass fiber filter. The ether phase is washed with brine, dried over sodium sulfate and the solvent is removed by rotary evaporation. The crude product is chromatographed on the Flashmaster. Obtained are 1, 43 g (81, 6%) of a 9: 7 mixture of the desired aldehyde and the starting material. This mixture is used without further purification in the next stage.

5- (3-chlorophenyl) -1,1, 1-trifluoro-2 - [(1H-indazol-4-ylmino) -methyl] -4,4-dimethylpentan-2-ol

300 mg (0.97 mmol) of the above-described mixture of aldehyde and ester and 129.39 mg (0.97 mmol) of 4-aminoindazole are admixed with 1.4 mL of glacial acetic acid and stirred at room temperature for four days. The reaction mixture is stripped three times with toluene on a rotary evaporator and the residue is then chromatographed on silica gel (eluent ethyl acetate / hexane). 117.4 mg (28.5%) of the desired compound are isolated. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.95 (3H), 1, 09 (3H), 1.90 (1H), 2.24 (1H), 2.59 (1H 2.85 (1H), 6.82 (1H), 7.09 (1H), 7.15-7.32 (3H), 7.38-7.52 (2H), 8, 13 (1H), 8.20 (1H).

2-Chloro-6, 7, 8, 9-tetrahydro-5- (1H-indazol-4-ylamino) -8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-6-ol

116mg (0.27mmol) of 5- (3-chlorophenyl) -1, 1, 1-trifluoro-2 - [(1H-indazol-4-ylmino) -methyl] -4,4-dimethylpentan-2-ol with 5.47 mL boron tribromide (1 M in dichloromethane) and then stirred for seven days at room temperature. The reaction mixture is then added to a mixture of saturated sodium bicarbonate solution and ice and stirred vigorously at room temperature for 20 minutes after addition of ethyl acetate. The Ethyl acetate phase is separated and the aqueous phase extracted once more with ethyl acetate. The combined organic extracts are washed with water and with brine and dried. After the solvent has been removed by evaporation, the residue is chromatographed on silica gel (mobile phase (dichloromethane / methanol)) to isolate 67.9 mg (58.5%) of the desired compound.

¹ H-NMR (300 MHz ₁ CD ₃ OD): δ = 0.88 (3H), 1, 19 (3H), 1.42 (1H), 1.90 (1H), 2.60 (1H 3.11 (1H), 5.23 (1H) ₁ 5.73 (1H), 6.73 (1H), 7.00 (1H), 7.10 (1H), 7.18 (1H), 7.30 (1H), 8.09 (1H).

Example 4

4- (r 2 -chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] -aminol-1,3-dihydro-2H-indol-2-one

7 - {[5- (3-Chloro-phenyl) -2-hydroxy-4A-dimethyl-2- (trifluoromethyl) -pentylidene] -amino} -1,3-dihydro-2H-indol-2-one

450 mg (1.46 mmol) of the mixture of 5- (3-chlorophenyl) -2-hydroxy-4,4-dimethyl-2- (trifluoromethyl) pentanal described in Example 3 and the corresponding ester are mixed with 216 mg (1 , 46 mmol) of 4-amino-1,3-dihydro-2H-indol-2-one and 2.1 ml of glacial acetic acid are stirred for four days at room temperature. The reaction mixture is stripped three times with toluene on a rotary evaporator and the remaining residue chromatographed on silica gel (eluent hexane / ethyl acetate). 307.1 mg (48%) of the desired imine are isolated. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.90 (3H), 1, 02 (3H), 1.85 (1H), 2.20 (1H), 2.52 (1H ), 2.81 (1H), 3.54 (2H), 4.90 (1H), 6.69 (1H), 6.86 (1H), 7.08 (1H), 7 , 15-7.32 (4H), 8.04 (1H), 8.50 (1H). 4 ~ {[2-Chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6 ~ (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} -1,3-dihydro -2H-Indol-2-one 305 mg (0.69 mmol) of the imine described above are added at room temperature with 13.9 mi_ of a 1M Bortribromidlösung in dichloromethane and stirred for five days at this temperature. For workup, the reaction mixture is poured onto a mixture of saturated

Sodium bicarbonate solution and ice added. 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 desiccant and the evaporation of the solvent, the remaining residue is chromatographed several times on silica gel (eluent dichloromethane / methanol). 175.5 mg (57.5%) of the desired compound 4 - {[2-chloro-6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-6-] are isolated

(trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} -1, 3-dihydro-2H-indol-2-one. ¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.84 (3H), 1, 15 (3H), 1.40 (1H), 1.85 (1H), 2.58 (1 H), 3.06 (1H), 3.25 (1H, signal is below the methanol signal), 3.45 (1H), 5.10 (1H), 5.90 (1H), 6 , 23 (1H), 6.89 (1H), 7.15 (2H), 7.28 (1H).

Example 5

6,7,8,9-Tetrahydro-6-hydroxy-8,8-dimethyl-5 - [[7- (1-methyl-5-oxopyrrolidin-2-yl) -1 / - / - indazol-4-ylamino} - 6- (trifluoromethyl) -5H-benzocycloheptene-2-carbonitrile 35 mg (0.083 mmol) of the 2-chloro-6,7,8,9-tetrahydro-δ-iH-indazole-1-ylamino ^ δ described in Example 3. δ-dimethyl-δ-rifluoromethyO-δH-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. For working up, 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. After drying the organic phase, the solvent is removed by rotary evaporation and the residue is chromatographed on flashmaster (amine phase, eluent methanol / dichloromethane). Obtained are 16.4 mg (38.8%) of 6,7,8,9-tetrahydro-6-hydroxy-8,8-dimethyl-5 - {[7- (1-methyl-5-oxopyrrolidin-2-yl ) -1H-indazol-4-yl] amino} -6- (trifluoromethyl) -5 / - / - benzocycloheptene-2-carbonitrile (80%).

¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.85 (3H), 1, 20 (3H), 1.45 (1H), 1.90-2.08 (2H), 2.35 -2.60 (6H), 2.69 (1H), 3.22 (1H), 5.34 (1H), 5.75 (1H), 6.83 (1H), 7.45-7.59 (3H), 8.20 (1H).

Example 6

(5R * -c / sV5- {f6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl-V5H-benzocyclohepten-δ-phenol-quinoline) d H) -one

2- (2-chlorophenyl) -2-methylpropanenitrile

25 g (164.92 mmol) of 2-chlorobenzyl cyanide are dissolved in 250 ml of dimethylformamide and the solution is mixed with 68 g (346.33 mmol) of iodomethane. At ⁰ ° C., 13.9 g (346.33 mmol) of a sodium hydride suspension (w = 55-60%) are now added in portions. After stirring overnight at room temperature, the reaction mixture is added to ice-water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and then brine. After drying over sodium sulfate, the solvent is spun off and the residue on silica gel (Mobile phase methyl tert-butyl ether / hexane) chromatographed. Be isolated

27.25 g (91.8%) of the desired compound.

¹ H-NMR (300 MHz ₁ CDCl ₃ ): δ = 1.99 (6H), 7.24-7.33 (2H), 7.40-7.50 (2H).

2- (2-chlorophenyl) -2-methylpropanal

27.25 g (151, 69 mmol) of the above-described nitrile are dissolved in 510 ml of toluene. At -70 ⁰ C 186.9 mL of a 1, 2 molar solution of DIBAH in toluene are added dropwise. After stirring for two and a half hours at this temperature, 26.1 mL of isopropanol and then 1.72 L of a 10% L - (+) - tartaric acid solution are added dropwise. The temperature rises. Overall, the batch is stirred vigorously for one hour at room temperature. After three extractions with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried and the solvent is removed by rotary evaporation. The residue obtained (27.5 g = 100%) is further used crude. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.50 (6H), 7.21-7.46 (4H), 9.72 (1H).

1-chloro-2- (3,3-dibromo-1,1-dimethylprop-2-enyl) benzene

29.5 g (112.31 mmol) of triphenylphosphine are dissolved in 350 ml of dichloromethane. After addition of 7.34 g (112.31 mmol) of zinc dust, the batch is cooled to ⁰ ° C. and then 37.2 g (112.31 mmol) are added in portions.

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.

In a modified variant, 34.3 g (103.46 mmol) of tetrabromomethane are dissolved in 414 ml of dichloromethane and, at ⁰ ° C., 54.4 g (207.41 mmol) of triphenylphosphine are added in portions. After one hour Stirring at 0 ^° C., the recovered 6.31 g (34.55 mmol) of 2- (2-chlorophenyl) -2-methylpropanal, dissolved in 80 ml of dichloromethane, are added dropwise. The mixture is stirred overnight at room temperature. The reaction mixture is added to 1.3 liters of hexane. After one hour vigorous stirring is filtered off with suction through Celite and the solvent is removed by rotary evaporation. The residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 4.67 g (41.4%) of the desired product (still containing some starting material) are isolated. ¹ H-NMR (300 MHz ₁ CDCl ₃ ): δ = 1.60 (6H), 6.93 (1H), 7.16-7.25 (2H), 7.38 (1H), 7, 43 (1H).

1-Chloro-2- (1, 1-dimethylprop-2-ynyl) benzene

4.46 g (13.66 mmol) of the dibromoalkene described above are dissolved in 180 mL

Dissolved tetrahydrofuran and at -70 ⁰ C dropwise with 16.1 mL (26.8 mmol) of a Butyllithiumlösung (15% in hexane). After stirring for two hours at this temperature, carefully 2.7 ml of water are added dropwise and the mixture is then vigorously stirred for two hours at room temperature. After the reaction mixture has been treated with methyl tert-butyl ether, the organic phase is washed with water and then with brine. After drying the organic phase, the solvent is removed by rotary evaporation and the residue (2.83 g> 100%) is used crude in the next stage. ¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.71 (6H), 2.30 (1H), 7.16-7.20 (2H), 7.30 (1H), 7.63 (1H).

Ethyl 5- (2-chlorophenyl) -2-hydroxy-5-methyl-2- (trifluoromethyl) hex-3-inoate

2.83 g (15.84 mmol) of 1-chloro-2- (1, 1-dimethylprop-2-ynyl) benzene are dissolved in 150 ml of tetrahydrofuran and the mixture is cooled to -60 ⁰ C. At this temperature, 9.8 ml (15.84 mmol) of n-butyllithium solution (15% strength in hexane) are then added dropwise and the mixture is subsequently stirred at 0 ^° C. for two hours. After again cooling to -60 ⁰ C are now 1, 9 mL (15.84 mmol)

Ethyltrifluorpyruvat added dropwise. After stirring for 24 hours at room temperature, the reaction mixture is added to saturated ammonium chloride solution. After extracting three times with methyl tert. Butyl ether becomes the united one organic extracts washed with brine. After drying with sodium sulfate and evaporation of the solvent, the residue is chromatographed on the Flashmaster. 2.4 g (43.6%) of the desired compound are isolated. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.49 (3H), 1.79 (6H), 4.12 (1H), 4.41 (2H), 7.17-7.25 (2H), 7.39 (1H), 7.58 (1H).

Ethyl 2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanoate

2.3 g (6.59 mmol) are mixed with 231 mg Pd / C (10%) and 16 mL of ethanol and stirred under a hydrogen atmosphere overnight at room temperature. The catalyst is filtered off with suction through a glass filter and the filtrate is evaporated. 2.14 g of a mixture consisting of the desired saturated product and the corresponding alkene compound are isolated. This mixture is hydrogenated one more time (15 mL ethanol, 214 mg Pd / C, hydrogen atmosphere, stirring at room temperature for 24 h). After the catalyst has been filtered off with suction through a glass fiber filter, the filtrate is evaporated in a rotary evaporator and the residue is chromatographed on the flash master. Be isolated 995.2 mg (46.2%) of a product containing predominantly the Deschlorverbindung. MS (Cl) m / e (relative intensity): 336 (100%)

2-Hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanal 995.2 mg (2.82 mmol) of ethyl 2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexanoate are added in 11 Dissolved 5 mL of diethyl ether and treated at 0 ⁰ C in portions with 82.79 mg of lithium aluminum hydride. After stirring for 1 hour at this temperature, 10 mL of saturated sodium bicarbonate solution are carefully added dropwise and the mixture is then vigorously stirred for one hour. After extracting three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, with

Dried sodium sulfate and the solvent was removed by rotary evaporation. The remaining residue is chromatographed on the Flashmaster. 211.3 mg of the desired aldehyde are obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1, 25-1, 38 (1H), 1, 32 (6H), 1, 60-1, 85 (3H) ₁ 3.71 (1H ), 7.15-7.40 (5H), 9.49 (1H).

5 ~ {[4 - (- 2-hydroxy-5-methyl-5-phenyl-2- (trifluoromethyl) hexylidene] amino} quinoline-2 (1H) -one

211 mg (0.684 mmol) of the aldehyde described above and 109.8 mg (0.684 mmol) of 5-amino-quinolin-2 (1 H) -one are stirred in 2.6 ml of glacial acetic acid for three days at room temperature. The batch is evaporated to dryness and the residue is chromatographed on the Flashmaster. 177.9 mg (57.7%) of the desired imine are isolated.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1, 30-1, 40 (6H) ₁ 1.41-2.00 (4H), 4.70 (1H), 6.68-6.80 (2H), 7.13-7.25 (1H), 7.25-7.35 (4H), 7.40 (1H), 7.52 (1H), 7.82 (1H), 8.11 (1H).

(5R * -cis) -5 - {[6J ^ 9-tetrahydro-6-hydroxy-9,9-dimethyl-6 '(trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline-2 (1H) -one

83.85 mg (0.19 mmol) of the imine just described are dissolved in one milliliter of dichloromethane. After cooling to ⁰ ° C., 1, 9 ml of a one molar solution of boron tribromide in dichloromethane are added dropwise. The batch is then stirred for a fortnight at room temperature. The reaction mixture is added to a mixture of saturated sodium bicarbonate solution and ice and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate and the solvent is removed by rotary evaporation. The remaining residue is chromatographed on the Flashmaster. 10.8 mg (13%) of the desired compound are isolated.

¹ H-NMR (400 MHz, DMSO [d6]): δ = 1.28-1.50 (7H), 1, 73-1, 87 (1H), 1.89-2.01 (1H), 2 , 10-2.23 (1H), 5.14 (1H), 5.72 (1H), 6.20-6.55 (3H), 7.00-7.12 (2H), 7.20 ( 1 H), 7.30 (1H), 7.40 (1H), 8.19 (1H), 11, 5 (1H).

Using the corresponding imines could be synthesized analogously: δ -tθJ-δ-θ-tetrahydro-e-hydroxy-θ-θ-trimethyl-θ-trifluoromethyl-δ H -benzocyclohepten-5-yl] amino} isoquinoline-1 (2H) -one;

5 - {[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} 1, 3-dihydro-2H-indole 2-one; 5 - {[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} 2,3-dihydro-isoindol-1 one;

5 - {[6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} isochromen-1-one;

9,9-dimethyl-5 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] - 6- (trifluoromethyl) -67, δ, 9-tetrahydro-5H-benzocyclohepten-6-ol;

9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol;

9,9-dimethyl-5 - [(2-methylquinolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5 / - / - benzocyclohepten-6-ol; δ-ili-chloro-ΘJ.δ.g-tetrahydro---hydroxy-g.θ-dimethyl-e-ctrifluoromethyl-δH-benzocyclohepten-5-yl] -amino} quinoline-2 (1H) -one;

1-chloro-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol; δ1-p-chloro-γJ.S.Θ-tetrahydro-θ-hydroxy-θ.θ-dimethyl-θ-cetrifluoromethyl-δH-benzocyclohepten-δ-yl] -amino} quinoline-2 (1H) -one;

2-chloro-9,9-dimethyl-δ - [(2-methylquinazolin-δ-yl) amino] -θ-trifluoromethyl-ej.δ.θ-tetrahydro-δH-benzocycloheptene-e-ol; δ-lti-chloro-fluoro-ej → .θ-tetrahydro-δ-hydroxy-θ.θ-dimethyl-e-cetrifluoromethyl) -δH-benzocyclohepten-δ-yl] amino} quinoline-2 (1H) -one ; 1-chloro-2-fluoro-9,9-dimθthyl-δ - [(2-methylquinazolin-δ-yl) amino] -

6- (trifluoromethyl) -6,7, δ, 9-tetrahydro-5H-benzocyclohepten-6-ol; δ - {[2-chloro-1-fluoro-6,7, δ, 9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -δH-benzocyclohepten-δ-yl] amino} quinoline 2 (1H) -one;

2-chloro-1-fluoro-9,9-dimethyl-δ - [(2-ethyl-quinazolin-6-yl) -amino] -θ-trifluoromethyl-γ-γ-δ-tetrahydro-δH-benzocyclohepten-δ-ol; δ - {[1-bromo-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -δH-benzocyclohepten-δ-yl] amino} quinoline-2 (1H ) -one; 1-bromo-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol;

5 - {[2-Bromo-6,7,8,9-Trifluoro-6-hydroxy-9,9-dimethyl-6- (trifluoromethyl) -5H-benzocyclohepten-5-yl] amino} quinoline-2 (1H ) -one; 2-bromo-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol;

5 - {[1-bromo-2-chloro-6,7,8,9-tetrahydro-6-hydroxy-9,9-dimethyl-6- (trifluorinethyl) -

5H-benzocyclohepten-5-yl] amino} quinoline-2 (1H) -one;

1-Bromo-2-chloro-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -6- (trifluoromethyl) -6,7,8,9-tetrahydro-5 / - / - benzocyclohepten-6-ol;

S - ^ - Bromo-i-chloro-βJ ^ .Θ-tetrahydro-θ-hydroxy-θ.θ-dimethyl-β-Ctrifluormethyl) -

5H-benzocyclohepten-5-yl] amino} quinoline-2 (1H) -one;

2-bromo-1-chloro-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol; δ- ^ i-dichloro-ej.δ.θ-tetrahydro-θ-hydroxy-θ.g-dimethyl-e-ctrifluoromethylVδH-benzocyclohepten-5-yl] amino} quinoline-2 (1H) -one;

1, 2-dichloro-9,9-dimethyl-5 - [(2-methylquinazolin-5-yl) amino] -

6- (trifluoromethyl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol.

Claims

claims

1. Compounds of the general formula (I)

wherein

R ¹ and R ² , independently of one another, represent a hydrogen atom, a hydroxyl

Group, a halogen atom, an optionally substituted (C1-C-10) -

Alkyl group, a (C _r Cio) alkoxy, a (C-ι-C-ιo) alkylthio group, a (Ci-C 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-, - (CH ₂ W-, -NH- (CH ₂ W,

-N (Ci-C ₃ -alkylMCH ₂ W-. -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ independently of one another may be hydrogen, C 1 -C ₅ -alkyl or (CO) -CrC ₅ -alkyl,

R ¹¹ is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (CRCI _O) -alkyl group, a (C-rcio) alkoxy, (CRCI ₀₎ 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 (CRCI _O) -alkyl group, a (Ci-C-ιo) alkoxy group,

R ^{3 is} a C 1 -C ₁₀ alkyl group which may optionally be substituted by a group selected from 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, one optionally by one or more groups selected from (CiC ₅ ) alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups, wherein R ^{10 is} any hydroxy protecting group, a benzyl group or a C 1 -C 10 -alkyl group,

(CrC ₅ ) -alkoxy, halogen, exomethylene, 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, these groups on a Any position may be linked to the amine of the 5H-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 a - CR ⁴ R ⁵ -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 (CrC 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 ₁ -C ₈ ) -alkylene (C ₃ -C ₇ ) -cycloalkyl group,

(C ₂ -C ₈₎ alkenylene (C ₃ -C ₇₎ cycloalkyl group, a heterocyclyl group, a (CrC ₈₎ Alkylenheterocyclylgruppe, (C ₂ -C ₈₎ Alkenylenheterocyclylgruppe, an aryl group, a (CrC ₈₎ alkylenearyl group, _(C2 - C ₈ ) alkenylenaryl group, (C ₂ -C ₈ ) alkynylaryl group, an optionally substituted by 1-2 keto groups, 1-2- (CrC ₅ ) -alkyl groups,

2- (C 1 -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, C ₁ -C ₅ ) -alkylene heteroaryl group or a (C ₂ -C ₈ ) alkenylene heteroaryl 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 denote a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the 5H-benzocycloheptene system, denote a (C ₃ -C ₆ ) -cycloalkyl ring.

2. stereoisomers of the general formula (I) according to claim 1,

wherein

R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, a (CrCio) -alkyl group, a (Ci-Ci ₀₎ -

Alkoxy group, a (CrCio) -Alkythiogruppe, a (-C 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-, -0 - (CH ₂ VCH ₂ -, -O-CH = CH-, - (CH ₂ W, where n = 1 or 2 and the terminal atoms with directly adjacent

Ring carbon atoms are linked, or NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 can be} independently hydrogen, CrC ₅ alkyl or (CO) -Ci-C ₅ alkyl, R ¹¹ and R ^{12 is} a hydrogen atom

R ³ is a CrCio-alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1- 3 (CrC _δ J-alkoxy, an optionally substituted phenyl or naphthyl group, optionally substituted by 1-2 Keto groups, 1-2- (Ci-C ₅ ) -alkyl groups, 1-

2- (C ₁ -C ₅ ) alkoxy, 1-3 halogen, 1-2 exomethylene substituted 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1- 2 sulfur atoms containing mono- or bicyclic heteroaryl group, said Groups over any position with the amine of 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,

R ^{5 is} a (Ci-C ₅ ) alkyl group or an optionally partially or completely fluorinated (CrC ₅ ) alkyl group, an aryl group, a (d-CsJAlkylenarylgruppe, (C ₂ -C ₈ ) alkenylene, one (C ₃ -C ₇ ) Cycloalkyl group, a (CrC ₈ ) alkylene (C ₃ -C ₇ ) cycloalkyl group, (C ₂ -C ₈ ) alkenylene (C ₃ -C ₇ ) cycloalkyl group

3. stereoisomers of the general formula (I) according to claim 1,

wherein

R ¹ and R ² independently of one another are a hydrogen atom, a hydroxyl group, a halogen atom, a (C 1 -C 10) -alkyl group, a (C ₁ -C 10) -

Alkoxy group, a (C ₁ -C 10) -alkythio group, a (C ₁ -C 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 VCH ₂ -, -O-CH = CH-, - (CH ₂ W-, where n = 1 or 2 and the terminal atoms with directly adjacent

Ring carbon atoms are linked, or NR ⁸ R ⁹ , where R ⁸ and R ^{9 can} independently of one another be hydrogen, C 1 -C ₅ -alkyl or (CO) -CrC ₅ -alkyl, R ¹¹ and R ^{12 represent} a hydrogen atom,

R ^{3 is} a Ci-C-io-alkyl group which may optionally be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C-ι-C ₅ ) alkoxy, an optionally substituted phenyl group, an optionally by 1-2 keto groups, 1-2- (Ci-C ₅ ) alkyl groups, 1- 2- (CrC ₅ ) alkoxy groups, 1-3 halogen atoms, 1-2 Exomethylengruppen substituted 1-3 nitrogen atoms and / or 1 -2 Mono- or bicyclic heteroaryl group containing oxygen atoms and / or 1 to 2 sulfur atoms, these groups being attached via any position with the amine of the

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 (CrC ₅₎ alkyl group or an optionally partially or completely fluorinated (C-ι-C ₅₎ alkyl group, an aryl group, a (CrC ₈₎ AIkylenarylgruppe, (C ₂ -C ₈₎ Alkenylenarylgruppe, 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, denote a (C ₃ -C ₆ ) -cycloalkyl ring.

4. stereoisomers of the general formula (I) according to claim 1,

wherein

R ¹ and R ² independently of one another are a hydrogen atom, a hydroxyl group, a halogen atom, a (C 1 -C ₅ ) -alkyl group, a (C 1 -C ₅ ) - Alkoxy group, a (CrC ₅ ) - perfluoroalkyl group, a cyano group or R ¹ and R ² together form a group selected from the groups -O- (CHz) _n -O-, -O- (CHa) _n -CH ₂ -, -0 -CH = CH-, - (CHz) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,

R ¹¹ and R ^{12 represent} a hydrogen atom,

R ^{3 is} a C _r Cio-alkyl group which may optionally be substituted by 1 to 3 hydroxy groups, halogen atoms, a phenyl optionally substituted by C 1 -C ₅ -alkyl, halogen, hydroxy, C 1 -C 6 -alkoxy, phthalidyl, isoindolyl, dihydroindolyl , Dihydroisoindolyl, dihydroisoquinolinyl,

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, these groups may be linked via any position with the amine of the 5H-Benzocycloheptensystems and may optionally be mono- or polysubstituted with 1-2 keto groups, 1-2- (Ci-C ₃ ) alkyl groups, 1-2 (CrC ₃ ) alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups, and optionally 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

5. stereoisomers of the general formula (I) according to claim 1,

in which R ¹ and R ² independently of one another represent a hydrogen atom, a hydroxyl

Group, a halogen atom, a (Ci-C ₅ ) alkyl group, a (C ₁ -Os) - perfluoroalkyl group, a cyano group, a (Ci-C ₅ ) alkoxy group, or together a (C-ι-C ₂ ) - Alkylenedioxy group, in which case R ¹ and R ² must be directly adjacent, R ^{3 is} a phenyl optionally substituted by C 1 -C ₅ -alkyl, halogen, hydroxyl, C 1 -C 6 -alkoxy, phthalidyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl, dihydroisoquinolinyl, 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, these groups over any position with the amine of

Benzocycloheptensystems can be linked and optionally substituted one or more times can be hydrogenated with 1-2 keto groups, 1-2- (Ci-Ca) - alkyl groups, 1-2 exomethylene groups and optionally at one or more sites, A is a -CR ⁶ R ^{7 is} 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 ( -C ₅₎ alkyl group or an optionally partially or completely fluorinated (C-ι-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.

6. stereoisomers of the general formula (I) according to claim 1, wherein R ¹ and R ² independently represent a hydrogen atom, a

Hydroxy group, a halogen atom, a (Ci-C ₃ ) alkyl group, a CF ₃ group, a cyano group, a methoxy group,

R ¹¹ and R ^{12 are} a hydrogen atom, R ^{3 is} an isoindolyl, dihydroindolyl, optionally substituted by C ₁ -C ₃ -alkyl, halogen, hydroxy, C ₁ -C ₃ -alkoxy or methylpyrrolidin-2-one-5-yl,

Dihydroisoindolyl, dihydroisoquinolinyl, quinolinyl, isoquinolinyl, quinazolinyl

, Quinolonyl, isoquinolonyl, indazolyl, dihydroindolonyl or

Dihydroisoindolonylgruppe, wherein these groups over an arbitrary position with the amine of the

Alkyl groups, 1-2 exomethylene groups and optionally 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 fully fluorinated (CrC ₃ ) alkyl group

7. Use of the stereoisomers according to one of the preceding claims for the preparation of a medicament.

8. Use of the stereoisomers of claims 1-5 for the manufacture of a medicament for the treatment of inflammatory diseases

9. Use according to claim 8, for the preparation of a medicament for the treatment of

Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes,

- Rheumatic diseases, autoimmune diseases, joint diseases with inflammatory, allergic and / or associated with proliferative processes,

- allergies or pseudoallerg. Diseases associated with inflammatory and / or proliferative processes,

Dermatological disorders associated with inflammatory, allergic and / or proliferative processes,

O eye diseases associated with inflammatory, allergic and / or proliferative processes,

- diseases of the ear, nose and throat, which are associated with inflammatory, allergic and / or proliferative processes, or endocrine diseases, which are associated with inflammatory, allergic and / or proliferative processes.

10. Pharmaceutical preparations containing at least one stereoisomer according to claim 1-5 or mixtures thereof and pharmaceutically acceptable carriers.

11. A process for preparing the stereoisomers of the general formula I, characterized in that stereoisomers of the general formula II

wherein the radicals have the meanings given above are cyclized with the addition of inorganic or organic acids or Lewis acids.

12. A process for the preparation of the compounds of general formula II according to claim 11, wherein AD is -CH ₂ - (CR ⁶ R ⁷ ) - (CH ₂ ) -C (OH) (CF ₃ ) - (compound of general formula IIa) , characterized in that a compound of general formula IM, wherein LG means chloride, bromide, iodide, sulfate, sulfonate, under basic conditions in organic solvents with an aldehyde of general formula IV

Compounds of general formula V under phase transfer catalysis with conventional phase transfer catalysts to compounds of general formula V

is reacted, the aldehyde V is then reacted under Horner-Wittig conditions with the reagent VI, wherein R ^{x is} a (Ci-C- ₃ ) alkyl group or a benzyl group and the compound of general formula VII is obtained. After saponification of the ester by a method known to those skilled in the art, the enol ether is subjected to acidic conditions

Vl

VN VIII cleaved and the α-keto acid obtained under normal acidic conditions with an alcohol R ^y -OH, wherein R ^{y is} (C-ι-C ₅ ) -alkyl, is esterified to an α-keto ester of the general formula VIII, which Ruppert's reagent

VIII X

CF ₃ Si (CH ₃ ) _{3 is} reacted and reduced to the aldehyde X under conditions known to those skilled in the art, which is then reacted as described in the prior art, with an amine of the general formula R ³ -NH ₂ to the imine of general formula IIa wherein R ^{3 has} the meaning given in the preceding claims and AD represents -CH ₂ - (CR ⁶ R ⁷ ) - (CH ₂ ) -C (OH) (CFa) - which may be further reacted according to claim 11.

13. A process for preparing the compounds of general formula II according to claim 11, AD - (CR ⁶ R ⁷ ) - (CH ₂ ) 2-C (OH) (CF ₃ ) - means (compound of the general formula IIb), characterized 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 Hal - [(C ₂ -C ₅ ) -alkylene] -Hal, where appropriate, successively to give a compound of the general formula Formula XII,

which is reduced under conventional conditions to aldehyde

CBr / triphenylphosphine

and then reacted with CBr ₄ / triphenylphosphine optionally with zinc addition to give a compound of general formula XIII. becomes,

which is converted into acetylene with butyllithium and is converted with CF ₃ - (CO) COOR ^y into the ester XIV, which is hydrogenated by the method known to the person skilled in the art to give the ester of the formula VIIIb and analogously to the process according to claim 12,

XIV VIIIb reduced to the aldehyde and with the amine R -NH ₂ to imine

VIIIb IIb of general formula IIb wherein R ³ in the preceding Claims and wherein AD - (CR ⁶ R ⁷ ) - (CH ₂ ) 2-C (OH) (CF ₃ ) - means is reacted according to

Claim 11 can be further implemented.

14. stereoisomers of the general formula I, according to any one of claims 1-5 in the form of salts with physiologically acceptable anions.

15. Stereoisomers according to claim 14, in the form of their hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.