DE102005014089A1 - Tetrahydronaphthalene derivatives, process for their preparation and their use as anti-inflammatory agents - Google Patents

Abstract

The invention relates to tetrahydronaphthalene derivatives of general formula (I), DOLLAR F1 process for their preparation and their use as anti-inflammatory agents.

Description

The The invention relates to tetrahydronaphthalene derivatives, processes for their Production and its use as an anti-inflammatory.

Out In the prior art WO 02/10143 are open-chain non-steroidal inflammatories known. These compounds show effect dissociation in the experiment between anti-inflammatory and undesirable metabolic effects and are superior to the nonsteroidal glucocorticoids described so far or at least have an equally good effect.

The Prior art compounds still have disadvantages so that the expert is motivated to continue looking for new connections, to bind to the glucocorticoid receptor.

It Now compounds have been found that are at least comparable Effect as the compounds described in the prior art exhibit.

worin
R¹ und R² unabhängig voneinander ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, eine (C₁-C₅)-Pertluoralkylgruppe, eine Cyanogruppe, eine Nitrogruppe oder R¹ und R² zusammen eine Gruppe ausgewählt aus den Gruppen -O-(CH₂)_n-O-, -O-(CH₂)_n-CH₂-, -O-CH=CH-, -(CH₂)_n+2-, -NH-(CH₂)_n+1, N(C₁-C₃-alkyl)-(CH₂)_n+1, -NH-N=CH-, wobei n = 1 oder 2 ist und die endständigen Atome mit direkt benachbarten Ring-Kohlenstoffatomen verknüpft sind,
oder NR¹⁰R¹¹, wobei R¹⁰ und R¹¹ unabhängig voneinander Wasserstoff, C₁-C₅-Alkyl oder (CO)-C₁-C₅-Alkyl sein können,
R³ und R⁴ unabhängig voneinander ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine Cyanogruppe, eine gegebenenfalls substituierte (C₁-C₁₀)- Alkylgruppe, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, eine (C₁-C₅)-Perfluoralkylgruppe,
R⁵ eine C₁-C₁₀-Alkylgruppe, eine durch eine oder mehrere Gruppen ausgewählt aus Hydroxygruppen, Halogenatome, (C₁-C₅)-Alkoxygruppen substituierte C₁-C₁₀-Alkylgruppe,
eine gegebenenfalls substituierte (C₃-C₇)-Cycloalkylgruppe,
eine gegebenenfalls substituierte Heterocyclylgruppe,
eine gegebenenfalls substituierte Arylgruppe,
eine gegebenenfalls unabhängig voneinander durch eine oder mehrere Gruppen ausgewählt aus (C₁-C₅)-Alkylgruppen (welche gegebenenfalls substituiert sein können durch 1–3 Hydroxy oder 1–3 COOR¹⁰-Gruppen), (C₁-C₅)-Alkoxygruppen, Hydroxygruppen, Halogenatomen, 1–2 (C₁-C₃)-Exoalkylidengruppen substituierte, gegebenenfalls 1–4 Stickstoffatome und/oder 1–2 Sauerstoffatome und/oder 1–2 Schwefelatome und/oder 1–2 Ketogruppen enthaltende mono- oder bizyklische Heteroarylgruppe, wobei diese Gruppe über eine beliebige Position mit dem Amin des Tetrahydronaphthalinsystems verknüpft sein kann und gegebenenfalls an einer oder mehreren Stellen hydriert sein kann,
R⁶ eine (C₁-C₅)-Alkylgruppe oder eine gegebenenfalls teilweise oder vollständig fluorierte (C₁-C₅)-Alkylgruppe, eine (C₃-C₇)-Cycloalkylgruppe, eine (C₃-C₇)-Cycloalkyl(C₁-C₈)alkylgruppe, (C₃-C₇)-Cycloalkyl(C₂-C₈)alkenylgruppe, eine Heterocyclylgruppe, eine Heterocyclyl(C₁-C₈)alkylgruppe, Heterocyclyl(C₂-C₈)alkenylgruppe, eine Arylgruppe, eine Aryl(C₁-C₈)alkylgruppe,
Aryl(C₂-C₈)alkenylgruppe, Aryl(C₂-C₈)alkinylgruppe, eine gegebenenfalls durch eine oder mehrere Ketogruppen, (C₁-C₅)-Alkylgruppen, (C₁-C₅)-Alkoxygruppen, Halogenatome, (C₁-C₃)-Exoalkylidengruppen substituierte, ein oder mehrere Stickstoffatome und/oder Sauerstoffatome und/oder Schwefelatome enthaltende mono- oder bizyklische Heteroarylgruppe,
eine Heteroaryl(C₁-C₈)alkylgruppe oder eine Heteroaryl(C₂-C₈)alkenylgruppe
wobei diese Gruppen über eine beliebige Position mit dem Tetrahydronaphthalinsystem verknüpft sein können und gegebenenfalls an einer oder mehreren Stellen hydriert sein können,
R⁷ ein Halogenatom, eine (C₁-C₁₀)-Alkylgruppe, die gegebenenfalls durch OR¹⁰, SR¹⁰, N(R¹⁰R¹¹) oder 1–3 Halogenatome substituiert sein kann,
R⁸ und R⁹ unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, eine (C₁-C₅)Alkylgruppe, die mit OR¹⁰, SR¹⁰, N(R¹⁰R¹¹) substituiert sein kann,
eine Cyanogruppe oder gemeinsam mit dem Kohlenstoffatom des Ringsystems einen (C₃-C₆)-Cycloalkylring oder gemeinsam eine gegebenenfalls durch Hydroxy, Halogen oder Cyano substituierte (C₁-C₅)-Alkylidengruppe oder
R⁷ und R⁸ gemeinsam einen annelierten fünf- bis achtgliedrigen gesättigten oder ungesättigten Carbo- oder Heterozyklus, der gegebenenfalls durch 1–2 Ketogruppen, 1–2 (C₁-C₅)-Alkylgruppen, 1–2 (C₁-C₅)-Alkoxygruppen, 1–4 Halogenatome substituiert ist, bedeuten.The present invention relates to compounds of the general formula (I),

wherein
R ¹ and R ² independently represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) alkyl group, an optionally substituted (C ₁ -C ₁₀ ) alkoxy group, a (C ₁ -C ₁₀ ) -alkylthio group, a (C ₁ -C 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} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - ( CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,
or NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
R ³ and R ⁴ independently represent a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀₎ - alkyl group, an optionally substituted (C ₁ -C ₁₀₎ alkoxy, (C ₁ -C ₁₀ ) -alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group,
R ⁵ is a C ₁ -C ₁₀ alkyl, a by one or more groups selected from hydroxy, halogen, (C ₁ to C ₅₎ alkoxy substituted C ₁ -C ₁₀ alkyl,
an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group,
an optionally substituted heterocyclyl group,
an optionally substituted aryl group,
an optionally substituted independently by one or more groups selected from (C ₁ -C ₅₎ alkyl (which may be optionally substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups), (C ₁ -C ₅₎ alkoxy , Hydroxy groups, halogen atoms, 1-2 (C ₁ -C ₃ ) -exxalkylidengruppen substituted, optionally 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic Heteroaryl group, which group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites,
R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, a (C ₃ -C ₇ ) -cycloalkyl group, a (C ₃ -C ₇ ) -cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group, a heterocyclyl group, a heterocyclyl (C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group , an aryl group, an aryl (C ₁ -C ₈ ) alkyl group,
Aryl (C ₂ -C ₈ ) alkenyl group, aryl (C ₂ -C ₈ ) alkynyl group, optionally one or more keto groups (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy groups, halogen atoms, (C ₁ -C ₃ ) -exxalkylidene-substituted mono-, or mono- and / or nitrogen atoms containing one or more oxygen atoms and / or sulfur atoms. or bicyclic heteroaryl group,
a heteroaryl (C ₁ -C ₈ ) alkyl group or a heteroaryl (C ₂ -C ₈ ) alkenyl group
these groups may be linked via any position with the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites,
R ^{7 is} a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group which may optionally be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms,
R ⁸ and R ^{9 are} independently of one another a hydrogen atom, a halogen atom, a (C ₁ -C ₅ ) alkyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ),
a cyano group or together with the carbon atom of the ring system is a (C ₃ -C ₆₎ cycloalkyl ring or together form a optionally substituted by hydroxyl, halo or cyano-substituted (C ₁ -C ₅₎ alkylidene group or
R ⁷ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) -Alkoxygruppen, 1-4 halogen atoms is substituted mean.

Another object of the invention are stereoisomers of the general formula (I) wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (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-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,
or NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
R ³ and R ^{4 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) Alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group,
R ⁵ is a C ₁ -C ₁₀ alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅₎ alkoxy substituted C ₁ -C ₁₀ alkyl group, an optionally substituted Phenyl group, an optionally represented by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 ( C ₁ -C ₃ ) -Exoalkylidengruppen substituted 1-4 nitrogen atoms and / or 1-2-oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, said groups via any position with may be linked to the amine of the tetrahydronaphthalene system and optionally hydrogenated at one or more sites
R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, an aryl (C ₁ -C ₈ ) -alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group
R ^{7 is} a halogen atom, a (C ₁ -C ₁₀ ) -alkyl group which may optionally be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms
R ⁸ and R ⁹ independently of one another represent a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , NR ¹⁰ R ¹¹ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a (C ₁ -C ₅ ) -alkylidengruppe or
R ⁷ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) -Alkoxygruppen, 1-4 halogen atoms is substituted mean.

An object of the present invention are stereoisomers of the general formula (I) wherein
R ¹ and R ^{2 are} independently hydrogen, hydroxy, halogen, optionally substituted (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, cyano
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 and R ⁴ independently of one another represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group,
R ^{5 is} a C ₁ -C ₁₀ alkyl group, one by one or more groups selected from 1-3 hydroxy groups or Halogen atoms substituted C ₁ -C ₁₀ -alkyl group, one optionally by one or more groups selected from 1-2 keto groups, 1-2- (C ₁ -C ₅ ) -alkyl groups, 1-2- (C ₁ -C ₅ ) - Alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-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, benzimidazole or indolyl group,
which groups may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites
R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group
R ^{7 is} a halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms
R ⁸ and R ⁹ independently of one another represent a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ ) ₂ , a cyano group or, together with the carbon atom of the tetrahydronaphthalene ring, a (C ₃ -C ₆ ) -cycloalkyl ring or together a (C ₁ -C ₅ ) alkylidene group or
R ⁷ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) -Alkoxygruppen, 1-4 halogen atoms is substituted mean.

Another object of the present invention are stereoisomers of the general formula (I) wherein
R ¹ and R ² independently represent a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, or together 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 hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group,
R ^{4 is} a hydrogen atom
R ^{5 is} optionally substituted by one or more groups selected from 1-2 keto groups, 1-2- (C ₁ -C ₅ ) -alkyl groups, 1-2- (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1 3 halogen atoms, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-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, benzimidazole or indolyl group,
which groups may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites,
R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group
R ^{7 is} a halogen atom, a methyl or ethyl group,
R ⁸ and R ⁹ independently of one another represent a hydrogen atom, a halogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a methylene or ethylidene, or
R ⁷ and R ⁸ together denote a fused five to eight-membered saturated or unsaturated carbo or heterocycle.

Particular subgroups of the present invention are characterized by the definitions of claims 1 to 4 with the definition of R ⁷ in which R ^{7 is} a (C ₁ -C ₅ ) -alkyl group or a halogen atom and in which R ^{7 is} a (C ₁ -C ₃ ) Alkyl group and particularly preferably wherein R ^{7 represents} a methyl or ethyl group.

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

The alkyl groups R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ may be straight-chain or branched and are, for example, a methyl, ethyl, n-propyl n-butyl, iso-butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl. A C ₁ -C ₃ alkyl group is preferred. They may optionally be substituted by a group selected from 1-3 hydroxy, 1-3 halogen, 1-3 (C ₁ -C ₃ ) alkoxy, and / or 1-3 COOR ¹¹ groups. Preference is given to hydroxy groups.

The alkyl group R ⁵ has the meaning mentioned in the preceding paragraph, but the possible Substituents selected from the group hydroxy, halogen, (C ₁ -C ₅ ) -alkyloxy.

The alkyl groups R ⁸ and R ⁹ have the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group OR ¹⁰ , SR ¹⁰ and N (R ¹⁰ R ¹¹ ), wherein R ¹⁰ and R ^{11 are} hydrogen, C ₁ -C ₅ alkyl or (CO) C ₁ -C ₅ alkyl and alkyl is also as defined above.

The Alkoxy groups can straight-chain or branched and for a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy stand. A methoxy or ethoxy group is preferred.

The Alkylthio groups can straight-chain or branched, and for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.

For a partially or completely fluorinated alkyl group, which may be straight-chain or branched, the following are, for example, the partially or completely fluorinated groups: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1 , 1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, C ₃ F ₇ , C ₃ H ₂ F ₅ , C ₄ F ₉ , C ₅ F ₁₁ . Of these, preferred are the trifluoromethyl or the pentafluoroethyl group. The reagents are commercially available or the published syntheses of the corresponding reagents are state of the art.

The aryl substituents R ¹ and R ² can form a ring in which both aryl substituents together represent a chain selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) -CH ₂ -, -O- CH = CH-, - (CH ₂ ) _{n + 2} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2. The terminal atoms of the groups listed above are linked to directly adjacent aryl ring carbon atoms to form a fused ring.

The substituent NR ¹⁰ R ^{11 is} , for example, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , NH (C ₂ H ₅ ), N (C ₂ H ₅ ) ₂ , NH (C ₃ H ₇ ), N (C ₃ H ₇ ) ₂ , NH (C ₄ H ₉ ), N (C ₄ H ₉ ) ₂ , NH (C ₅ H ₁₁ ), N (C ₅ H ₁₁ ) ₂ , NH (CO) CH ₃ , NH (CO) C ₂ H ₅ , NH (CO) C ₃ H ₇ , NH (CO) C ₄ H ₉ , NH (CO) C ₅ H ₁₁ .

The cycloalkyl group means a saturated cyclic group having 3 to 7 ring carbon atoms, optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy groups, such as cyclopropyl, methylcyclopropyl, Cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.

The cycloalkylalkyl group means, for example, - (CH ₂ ) -cycloalkyl, - (C ₂ H ₄ ) -cycloalkyl, - (C ₃ H ₆ ) -cycloalkyl, - (C ₄ H ₈ ) -cycloalkyl, - (C ₅ H ₁₀ ) - Cycloalkyl, wherein cycloalkyl is defined as described above.

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

A (C ₁ -C ₃ ) -exoalkylidene group is to be understood as meaning a group which is bound to the system (ring or chain) via an exo-double bond. Preference is given to exomethylene.

The alkylidene group R ⁸ / R ⁹ may have 1 to 5 carbon atoms, may be symmetrical or asymmetric and may be optionally substituted by hydroxy, halo or cyano groups.

The heterocyclyl group is not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Suitable substituents are hydroxyl groups, halogen atoms, (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy groups.

Heterocyclylalkyl groups are to be understood as meaning heterocyclyl groups which are bonded to the skeleton via a C ₁ -C ₅ -alkyl group, where the alkyl group may be straight-chain or branched.

Heterocyclylalkenyl groups are heterocyclyl groups which have an unsaturated C ₂ -C ₅ -alkyl group are bonded to the skeleton, wherein the alkenylene groups may be straight-chain or branched.

The aryl group R ⁵ and R ⁶ may be phenyl or naphthyl.

Suitable substituents for both groups are C ₁ -C ₃ -alkyl, hydroxy, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylthio, halogen, cyano, COO (C ₁ -C ₅ ) -alkyl, COOH, N ( R ¹⁰ R ¹¹ ), nitro, into consideration. The degree of substitution may be one or more than one, may include several identical or different substituents. Mono- or disubstituted phenyl and naphthyl groups R ⁵ are preferred.

The aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also carry keto, (C ₁ -C ₃ ) -exoalkyliden. By partially hydrogenated phenyl is meant, for example, cyclohexadienyl, cyclohexenyl, cyclohexyl. A partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetralone.

The arylalkyl group is an aryl group attached to a backbone via a C ₁ -C ₈ alkyl group, which alkyl group may be straight-chain or branched. For example, benzyl or phenethylene may be mentioned.

An arylalkenyl group is an aryl group which is linked to a skeleton via a C ₂ -C ₈ -alkenyl group, where the alkenyl group may be straight-chain or branched.

The arylalkynyl group is an aryl group bonded to the skeleton via a C ₂ -C ₈ alkynyl group, where the alkynyl group may be straight-chain or branched.

By mono- or bicyclic heteroaryl group R ⁵ and R ⁶ , which may be hydrogenated at one or more sites, are meant any mono- or bicyclic aromatic ring systems which contain at least one heteroatom and at most seven heteroatoms. Preference is given to ring systems having 1-5 heteroatoms. Suitable heteroatoms are 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms, which can occur in all subcombinations in the ring system as long as they do not exceed the number specified for the respective heteroatom and, in total, the maximum number of seven heteroatoms. For example, they include compounds of the formula I embedded image in which R ⁵ or R ⁶ furanyl, thiophenyl, 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, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl , Coumarinyl, isocumarinyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxal inyl-, cinnolinyl-, phthalazinyl, 1,7- or 1,8-naphthyridinyl-, means to the present invention and constitutes a particular embodiment of the invention.

If the heteroaryl groups are partially or completely hydrogenated, compounds of the formula I in which R ^{4 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] benzoxazine-4-onyl, 3,4-dihydrobenz [1,4] oxazine-4-onyl , 3,4-dihydro-2H-benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnoline-4-onyl, 3H-quinazoline-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-ony 1, 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] pyridin-3-onyl, to the present invention.

Preference is given to compounds of the formula I in which R ^{5 is} optionally substituted by one or more groups selected from (C ₁ -C ₅ ) -alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups), (C ₁ -C ₅ ) -alkoxy groups, hydroxy groups, halogen atoms, (C ₁ -C ₃ ) -exoalkylidene-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 to 2 keto groups, which group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites.

A preferred subject matter of the invention are compounds of the general formula I in which R ^{5 is} a phenyl optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxyl, C ₁ -C ₅ -alkoxy, keto or (C ₁ -C ₃ ) -exoalkylidene , 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, benzimidazole or indolyl group.

A preferred subject matter of the invention are compounds of the general formula I in which R ^{5 is} a phenyl optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxyl, C ₁ -C ₅ -alkoxy, keto or (C ₁ -C ₃ ) -exoalkylidene , Phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, Quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group.

A preferred object is compounds of the general formula I in which R ^{5 is} a phenyl or naphthyl radical which is optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxyl, C ₁ -C ₅ -alkoxy, phthalidyl, thiophthalidyl or benzoxazinonyl , Phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, Benzimidazole or indolyl group.

If it is a heteroarylalkyl group, it is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is linked to the skeleton via a C ₁ -C ₈ -alkyl group which may be straight-chain or branched.

A heteroarylalkenyl group is to be understood as meaning an optionally also partially hydrogenated heteroaryl group as described above which is bonded to the skeleton via a (C ₂ -C ₈ ) -alkenyl group which may be straight-chain or branched.

If R ⁷ and R ^{8 form} a five- to eight-membered carbocycle or heterocycle (also substituted), then there is a tricyclic system.

Suitable heteroatoms are nitrogen, oxygen or sulfur. Suitable substituents are all radicals defined for R ¹ .

The invention furthermore relates to compounds of the general formula I embedded image in which R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, a (C ₃ -C ₇ ) - Cycloalkyl group, a (C ₃ -C ₇ ) -cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) -cycloalkyl (C ₂ -C ₈ ) alkenyl group, a heterocyclyl group, a heterocyclyl (C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group, an aryl group, an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group.

A particular subject of the invention are compounds of the general formula I, wherein R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, an aryl (C ₁ C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) -cycloalkyl group, a (C ₃ -C ₇ ) -cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ - C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group.

The invention further provides compounds of the general formula I in which R ^{6 represents} a (C ₁ -C ₃ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₃ ) -alkyl group. Particularly preferred are the fully fluorinated alkyl groups.

The invention furthermore relates to compounds of the formula I in which R ^{6 is} a C ₁ -C ₁₀ -alkyl group which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, an optionally by 1-2 keto groups, 1 -2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) exoalkylidene-substituted 1-4 nitrogen atoms and / or 1 Mono- or bicyclic heteroaryl group containing 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms, which groups may be linked to the nitrogen atom via any position and may optionally be hydrogenated at one or more sites.

The Compounds of the invention of general formula I can by the presence of asymmetric centers as stereoisomers Subject of the present invention are all possible Stereoisomers (e.g., RRRR, RRRS, RRSR, RSRR, SRRR, RSRS, RRSS, RSSR, SRRS, SSRR, SRSR, RSSS, SRSS, SSRS, SSSR, SSSS), both as racemates, as well as in enantiomerically pure form.

The Compounds of the invention can also in the form of salts with physiologically acceptable anions, for example, in the form of the hydrochloride, sulfate, nitrate, Phosphates, Pivalates, Maleates, Fumarates, Tartrates, Benzoates, Mesylates, citrates or succinates.

ester or ethers or amides of the compounds of general formula I. or other compounds which in the organism become compounds of the are general subject of the present invention Invention.

• a) indem nach im Stand der Technik bekannten Methoden hergestellten Styrole der allgemeinen Formel (II) durch eine gegebenenfalls enantioselektiv geführte En-Reaktion mit chiralen Lewis Säuren in die Verbindungen der allgemeinen Formel (III) überführt werden. Durch Reduktion und Aminierung wird nach dem Fachmann bekannten Methoden das Imin (IV) erzeugt,
  
  
  das dann entweder ohne weiteres Reagenz in einem Lösungsmittel, vorzugsweise chlorierten Kohlenwasserstoffen, wie z.B. Methylenchlorid oder Dichlorethan oder konzentrierten organischen Säuren, vorzugsweise Eisessig, oder durch Zusetzen von anorganischen oder organischen Säuren oder Lewissäuren unter Temperaturen im Bereich von –70°C bis +80°C (bevorzugt im Bereich von –30°C bis +80°C) zu den Verbindungen der allgemeinen Formel (Ia) (für R⁸ + R⁹ = R^8a = Alkyliden) zyklisiert wird. oder
• b) indem die nach der Methode a) hergestellten Verbindungen der allgemeinen Formel (III) durch Hydrierung in die Verbindung der Formel (V) (für R⁹=H) oder durch dem Fachmann bekannte Methoden der Cyclopropanierung (J.Am.Chem.Soc. 80 (1958) pp. 5323–5324, J.Org.Chem. 50 (1985) pp. 4412–4414) in Verbindungen der Formel (V) (für R⁸-R⁹=CH₂-CH₂) oder durch Hydrohalogenierung (J.Org.Chem. 53 (1988) pp. 1475–1481) in Verbindungen der Formel (V) (für R⁹ = Halogen) umgewandelt werden.
  

The compounds according to the invention are prepared,
either

• a) by styrenes of the general formula (II) prepared by methods known in the art are converted by an optionally enantioselectively conducted ene reaction with chiral Lewis acids in the compounds of general formula (III). By reduction and amination, the imine (IV) is produced by methods known to those skilled in the art,
  
  
  which then either without further reagent in a solvent, preferably chlorinated hydrocarbons such as methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids at temperatures in the range of -70 ° C to + 80 ° C (preferably in the range of -30 ° C to + 80 ° C) to the compounds of general formula (Ia) (for R ⁸ + R ⁹ = R ^8a = alkylidene) is cyclized. or
• b) by the compounds of general formula (III) prepared by the method a) by hydrogenation in the compound of formula (V) (for R ⁹ = H) or by methods known in the art of cyclopropanation (J.Am.Chem.Soc 80 (1958) pp. 5323-5324, J. Org. Chem. 50 (1985) pp. 4412-4414) in compounds of formula (V) (for R ⁸ -R ⁹ = CH ₂ -CH ₂ ) or by Hydrohalogenation (J. Org. Chem. 53 (1988) pp. 1475-1481) into compounds of formula (V) (for R ⁹ = halogen).
  

chlorierten Kohlenwasserstoffen, wie z.B. Methylenchlorid oder Dichlorethan oder konzentrierten organischen Säuren, vorzugsweise Eisessig, oder durch Zusetzen von anorganischen oder organischen Säuren oder Lewissäuren unter Temperaturen im Bereich von –70°C bis +80°C (bevorzugt im Bereich von –30°C bis +80°C) zu den Verbindungen der allgemeinen Formel zur Verbindung (1) zyklisiert wird.By reduction and amination, the imine (VI) is produced analogously to a), which then either without further reagent in a solvent, preferably

chlorinated hydrocarbons, such as methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids at temperatures in the range of -70 ° C to + 80 ° C (preferably in the range of -30 ° C to + 80 ° C) is cyclized to the compounds of the general formula to compound (1).

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 checked using recombinant 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. Thus, for the compound of Example 3, an IC ₅₀ (GR) = 36 nM and IC ₅₀ (PR)> 1 μM were measured.

When essential, molecular mechanism for the anti-inflammatory Effect of glucocorticoids becomes GR mediated inhibition Transcription of cytokines, adhesion molecules, enzymes and other pro - inflammatory Factors considered. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B, causes (to the overview see Cato ACB 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 compound of Example 3 showed inhibition IC ₅₀ (IL8) = 130 nM at 80% efficiency with respect to [ ³ H] -dexamethasone as a standard.

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, the ear weights were used as a measure of the inflammatory edema, the Pe roxidase activity was measured as a measure of granulocytic immigration and elastase activity as a measure of immigration of neutrophilic granulocytes. The compounds of the general formula I inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.

A the most common undesirable Effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoids: Immunology, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998]. reason therefor is the stimulation of gluconeogenesis in the liver by induction the one for this responsible enzymes and free amino acids resulting from the degradation of Proteins (catabolic effect of glucocorticoids) arise. One Key enzyme of the catabolic metabolism in the liver is tyrosine aminotransferase (DID). The activity This enzyme can be determined photometrically from liver homogenates and provides a good measure of the unwanted metabolic Effects of glucocorticoids. To measure TAT induction the animals are killed 8 hours after administration of the test substances, the Liver taken and the TAT activity in the homogenate measured. The compounds of general formula I induce in this test in doses in which they are anti-inflammatory effect, not or only to a small extent the tyrosine aminotransferase.

• (i) Lungenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Chronisch obstruktive Lungenerkrankungen jeglicher Genese, vor allem Asthma bronchiale – Bronchitis unterschiedlicher Genese – Alle Formen der restriktiven Lungenerkrankungen, vor allem allergische Alveolitis, – Alle Formen des Lungenödems, vor allem toxisches Lungenödem – Sarkoidosen und Granulomatosen, insbesondere Morbus Boeck
• (ii) Rheumatische Erkrankungen/Autoimmunerkrankungen/Gelenkerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Alle Formen rheumatischer Erkrankungen, insbesondere rheumatoide Arthritis, akutes rheumatisches Fieber, Polymyalgia rheumatica – Reaktive Arthritis – Entzündliche Weichteilerkrankungen sonstiger Genese – Arthritische Symptome bei degenerativen Gelenkerkrankungen (Arthrosen) – Traumatische Arthritiden – Kollagenosen jeglicher Genese, z.B. systemischer Lupus erythematodes, Sklerodermie, Polymyositis, Dermatomyositis- Sjögren-Syndrom, Still-Syndrom, Felty-Syndrom
• (iii) Allergien, die mit entzündlichen, und/oder proliferativen Prozessen einhergehen: – Alle Formen allergischer Reaktionen, z.B. Quincke Ödem, Heuschnupfen, Insektenstich, allergische Reaktionen auf Arzneimittel, Blutderivate, Kontrastmittel etc., Anaphylaktischer Schock, Urtikaria, Kontakdermatitis
• (iv) Gefäßentzündungen (Vaskulitiden) – Panarteriitis nodosa, Arteriitis temporalis, Erythema nodosum
• (v) Dermatologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Atopische Dermatitis (vor allem bei Kindern) – Psoriasis – Pityriasis rubra pilaris – Erythematöse Erkrankungen, ausgelöst durch unterschiedlichen Noxen, z.B. Strahlen, Chemikalien, Verbrennungen etc. – Bullöse Dermatosen – Erkrankungen des lichenoiden Formenkreises, – Pruritus (z.B. allergischer Genese) – Seborrhoisches Ekzem – Rosacea – Pemphigus vulgaris – Erythema exsudativum multiforme – Balanitis – Vulvitis – Haarausfall wie Alopecia areata – Cutane T – Zell – Lymphome
• (vi) Nierenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Nephrotisches Syndrom – Alle Nephritiden
• (vii) Lebererkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – akuter Leberzellzerfall – akute Hepatitis unterschiedlicher Genese, z.B. viral, toxisch, arzneimittelinduziert – chronisch aggressive und/oder chronisch intermittierende Hepatitis
• (viii) Gastrointestinale Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – regionale Enteritis (Morbus Crohn) – Colitis Ulcerosa – Gastritis – Refluxoesophagitis – Gastroenteritiden anderer Genese, z.B. einheimische Sprue
• (ix) Proktologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Analekzem – Fissuren – Hämorrhoiden – idiopathische Proktitis
• (x) Augenerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – allergische Keratitis, Uveitis, Iritis, – Konjunktivitis – Blepharitis – Neuritis nervi optici – Chorioditis – Ophtalmia sympathica
• (xi) Erkrankungen des Hals-Nasen-Ohren-Bereiches, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – allergische Rhinitis, Heuschnupfen – Otitis externa, z.B. bedingt durch Kontaktexem, Infektion etc. – Otitis media
• (xii) Neurologische Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Hirnödem, vor allem Tumor-bedingtes Hirnödem – Multiple Sklerose – akute Encephalomyelitis – Meningitis – verschieden Formen von Krampfanfällen, z.B. BNS-Krämpfe
• (xiii) Bluterkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Erworbene hämolytische Anämie – Idopathische Thrombocytopenia
• (xiv) Tumorerkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Akute lymphatische Leukämie – Maligne Lymphome – Lymphogranulomatosen – Lymphosarkome – Ausgedehnte Metastasierungen, vor allem bei Mamma- Bronchial- und Prostatakarzinom
• (xv) Endokrine Erkrankungen, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – Endokrine Orbitopathie – Thyreotoxische Krise – Thyreoiditis de Quervain – Hashimoto Thyreoiditis – Morbus Basedow
• (xvi) Organ- und Gewebstransplantationen, Graft-versus-host-disease
• (xvii) Schwere Schockzustände, z.B anaphylaktischer Schock, systemic inflammatory response syndrome (SIRS)
• (xviii) Substitutionstherapie bei: – angeborene primäre Nebenniereninsuffizienz, z.B. kongenitales adrenogenitales Syndrom – erworbene primäre Nebenniereninsuffizienz, z.B. Morbus Addison, autoimmune Adrenalitits, postinfektiös, Tumoren, Metastasen etc. – angeboren sekundäre Nebeniereninsuffizienz, z.B. kongenitaler Hypopitutitarismus – erworbene sekundäre Nebenniereninsuffizienz, z.B. postinfektiös, Tumoren etc.
• (xix) Emesis, die mit entzündlichen, allergischen und/oder proliferativen Prozessen einhergehen: – z.B. in Kombination mit einem 5-HT3-Antagonisten bei Zytostika – bedingten Erbrechen.
• (xx) Schmerzen bei entzündlicher Genese, z.B. Lumbago

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative action, 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 all origins, especially bronchial asthma - Bronchitis of various origins - All forms of restrictive lung diseases, especially allergic alveolitis, - All forms of pulmonary edema, especially toxic pulmonary edema - sarcoidosis and granulomatosis, 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 - reactive arthritis - inflammatory soft tissue diseases of other origin - arthritic symptoms degenerative joint diseases (arthrosis) - Traumatic arthritis - collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis - Sjögren syndrome, still syndrome, Felty syndrome
• (iii) Allergies associated with inflammatory and / or proliferative processes: All forms of allergic reactions, eg, edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis
• (iv) vasculitis - panarteritis nodosa, temporal arteritis, erythema nodosum
• (v) Dermatological disorders associated with inflammatory, allergic and / or proliferative processes: - atopic dermatitis (especially in children) - psoriasis - pityriasis rubra pilaris - erythematous diseases caused by different noxae, eg radiation, chemicals, burns etc. - Bullous dermatoses - Lichenoid disorders - Pruritus (eg allergic origin) - Seborrhoeic dermatitis - Rosacea - Pemphigus vulgaris - Erythema exudativum multiforme - Balanitis - Vulvitis - Hair loss such as Alopecia areata - Cutaneous T - cell lymphoma
• (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes: - nephrotic syndrome - all nephritides
• (vii) liver disease associated with inflammatory, allergic and / or proliferative processes: acute hepatic cell disintegration acute hepatitis of various causes, eg 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 - gastroenteritis of other genesis, eg 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 - choroiditis - ophthalmia 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, eg due to contact xem, infection, etc. - otitis media
• (xii) Neurological diseases associated with inflammatory, allergic and / or proliferative processes: - brain edema, especially tumor-related cerebral edema - multiple sclerosis - acute encephalomyelitis - meningitis - various forms of seizures, eg BNS cramps
• (xiii) Blood disorders associated with inflammatory, allergic and / or proliferative processes: - Acquired hemolytic anemia - Idopathic thrombocytopenia
• (xiv) tumors associated with inflammatory, allergic and / or proliferative processes: - acute lymphoblastic leukemia - malignant lymphoma - lymphogranulomatosis - lymphosarcoma - extensive metastases, especially in breast, bronchial and prostate cancers
• (xv) Endocrine disorders associated with inflammatory, allergic and / or proliferative processes: - endocrine orbitopathy - thyrotoxic crisis - thyreitis de Quervain - Hashimoto's thyroiditis - Graves' disease
• (xvi) Organ and tissue transplants, graft-versus-host disease
• (xvii) Severe shock states, eg, anaphylactic shock, systemic inflammatory response syndrome (SIRS)
• (xviii) Substitution therapy in: - congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome - acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc. - congenital secondary adrenal insufficiency, eg congenital hypopitotitarism - acquired adrenal insufficiency, eg post-infectious, Tumors etc.
• (xix) Emesis associated with inflammatory, allergic and / or proliferative processes: - eg in combination with a 5-HT3 antagonist in cytostatic - induced vomiting.
• (xx) Pain in inflammatory genesis, eg lumbago

Furthermore can the compounds of the invention of general formula I for the therapy and prophylaxis of others above unnamed disease states be used for today synthetic glucocorticoids are used (see Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998).

All The aforementioned indications (i) to (xx) are described in detail in Hatz, HJ, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998.

For the therapeutic Effects in the above disease states is the appropriate dose different and depends for example, the potency the compound of general formula I, the host, the route of administration and the nature and severity of the conditions to be treated, as well as from use as a prophylactic or therapeutic.

The The invention further relates to the use of the claimed compounds / stereoisomers for the manufacture of a medicament.

• (i) die Verwendung eines der erfindungsgemäßen Verbindung gemäß Formel I oder deren Gemisch zur Herstellung eines Medikaments zur Behandlung von einer ERKRANKUNG;
• (ii) ein Verfahren zur Behandlung von einer ERKRANKUNG, welches Verfahren eine Verabreichung einer Verbindungsmenge gemäß der Erfindung umfaßt, wobei die Menge die Krankheit unterdrückt, und wobei die Verbindungsmenge einem Patienten gegeben wird, der ein solches Medikament benötigt;
• (iii) eine pharmazeutische Zusammensetzung zur Behandlung von einer ERKRANKUNG, welche Behandlung eines der erfindungsgemäßen Verbindungen oder deren Gemisch und wenigstens einen pharmazeutischen Hilfs- und/oder Trägerstoff umfaßt.

The invention further provides

• (i) the use of one of the compounds of the invention of formula I or a mixture thereof for the manufacture of a medicament for the treatment of a DISEASE;
• (ii) a method of treating a DISEASE, which method comprises administering a compounding amount according to the invention, wherein the amount suppresses the disease, and wherein the compounding amount is given to a patient in need of 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 the In general, satisfactory results can be expected in animals when the daily Doses a range of 1 μg up to 100,000 μg the compound of the invention per kg of body weight include. For larger mammals, for example, to humans, is a recommended daily dose in the range of 1 μg up to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, more preferred a dose of 10 to 10,000 μg per kg of body weight. For example, this dose is conveniently administered several times a day. For the treatment of acute shock (e.g., anaphylactic shock) can Single doses are given that are well above the above doses lie.

The Formulation of pharmaceutical preparations based on the new Compounds are carried out in a conventional manner by the active ingredient with those used in galenics Excipients fillers, Decomposers, binders, humectants, lubricants, Absorbents, diluents, Taste Correctives, Colorants etc., processed and in the desired Transferred application form. there is on Remington's Pharmaceutical Science, 15th ed Mack Publishing Company, East Pennsylvania (1980).

For the oral In particular, tablets, dragees, capsules, pills, Powders, granules, lozenges, suspensions, emulsions or solutions in Question.

For the parenteral Application injection and infusion preparations are possible.

For intra-articular injection can appropriately prepared crystal suspensions are used.

For intramuscular injection can aqueous and oily injection solutions or suspensions and entprechende Depotpräparationen use.

For the rectal Application can the new compounds in the form of suppositories, capsules, solutions (e.g. in the form of clysters) and ointments both to the systemic, as well used for local therapy.

to pulmonary application of the new compounds may be in the form of aerosols and inhalants.

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

For the topical Application are formulations in gels, ointments, greases, creams, Pastes, powders, milk and tinctures possible. The dosage of the compounds of general formula I should be 0.01% -20% in these preparations, to achieve a sufficient pharmacological effect.

The Invention also the compounds of the invention the general formula I as a therapeutic agent. Farther belongs to the invention, the compounds of the invention the general formula I as a therapeutic agent together with pharmaceutically acceptable and acceptable excipients and carriers.

Also comprises The invention relates to a pharmaceutical composition containing one of the pharmaceutically active compounds of the invention or their Mixture or its pharmaceutically acceptable salt and pharmaceutically compatible Excipients and carriers contains.

experimental part

example 1

6-fluoro-1 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2,5-diol

5-amino-8-fluoro-2-methylquinazoline

To a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water is a 50 ° C warm solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml conc. hydrochloric acid (37%), which was previously stirred at this temperature for 1 h. Man stirs another 30 min at RT and heated after the addition of 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water over 45 min at 125 ° C and keeps them Temperature for 5 min. After cooling and another hour is the fancy light brown precipitate filtered off, washed with water and dried. 3.0 g (15.0 mmol) of the hydroxylimine as an intermediate, the portionwise in 15 ml conc. sulfuric acid be solved at 60 ° C. After complete The addition is heated at 80 ° C for 2 hours and at 90 ° C for 4 hours. Allow to cool and pouring the solution on 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dries over Sodium sulfate and concentrated. After chromatography on silica gel with Hexane-ethyl acetate (0-45 %), 1.2 g (7.1 mmol) of 4,7-difluoroisine are obtained. To the Isatin in 30 ml of a 1 molar sodium hydroxide solution are over 10 min Dripped 1.8 ml of a 30% hydrogen peroxide solution. After 2 hours Stirring RT is at 0 ° C chilled and 5 ml of 4 molar hydrochloric acid are added and 50 ml Diluted with water. It is extracted with ethyl acetate, dried over sodium sulfate, concentrated and receives so quantitatively 1.27 g of the 3,6-difluoroanthranilic acid, which without further purification is implemented.

The 3,6-difluoroanthranilic acid is heated to 100 ° C. in 8 ml of acetic anhydride for 45 minutes. After cooling, the resulting acetic acid and excess acetic anhydride are removed azeotropically with toluene in vacuo. The residue is added under ice-cooling with 40 ml of a 25% ammonia solution and Stirred for 72 hours. Dilute with water and acidify with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and concentrated. The resulting 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus-pentachloride are heated in 20 ml of phosphoryl chloride over 12 h at 125 ° C. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives, quantitatively, 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which are dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine. 600 mg of palladium on carbon are added and the mixture is shaken for 2 h (480 ml of hydrogen uptake) under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration through Celite from the catalyst, washing with 100 ml of ethanol, and evaporated. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline are obtained. To 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF are added 890 mg (13.7 mmol) of sodium azide and the mixture is heated for 8 h 125 ° C. The solvent is removed in vacuo and chromatographed on silica gel with ethyl acetate to give 52 mg of product.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).

4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal

19.6 ml of propionic acid chloride are added dropwise at 0 ° C. to 20 ml (213 mmol) of 2-fluorophenol in 24 ml of pyridine. It is stirred for 1.5 hours at room temperature and then 200 ml of 1M hydrochloric acid are added. It is extracted several times with dichloromethane, washed with water, dried with sodium sulfate and concentrated in vacuo. This gives 38.4 g of propionic acid (2-fluorophenyl) ester as a crude product, which are added dropwise in 30 ml of dichlorobenzene to 29 g of aluminum trichloride. The reaction mixture is stirred at 100 ° C for 18 hours. After cooling, it is diluted with dichloromethane, poured carefully onto cold 4M hydrochloric acid and vigorously stirred for 10 minutes. It is extracted several times with dichloromethane, washed with water, dried with sodium sulfate and concentrated in vacuo. Chromatographic purification on silica gel (hexane / ethyl acetate 0% -40%) gives 16.7 g (99 mmol) of 1- (3-fluoro-2-hydroxyphenyl) -propan-1-one. To 16.7 g of 1- (3-fluoro-2-hydroxyphenyl) -propan-1-one in 150 ml of acetone are added 25.1 g (89 mmol) of potassium carbonate and 10.9 ml (70 mmol) of methyl iodide. The mixture is heated for 6 hours at 70 ° C and then distilled off the solvent to about 80%. The residue is added to water and extracted several times with diethyl ether. It is washed with water and dried over sodium sulfate. The solvent is removed in vacuo to give 16.8 g (92 mmol) of 1- (3-fluoro-2-hydroxyphenyl) -propan-1-one.
¹ H-NMR (CDCl ₃ ): δ = 1.18 (t, 3H), 2.97 (q, 2H), 3.99 (s, 3H), 7.02 (ddd, 1H), 7.20 (dd, 1H), 7.34 (d, 1H).

58 g (890 mmol) of zinc powder and 1.21 g of lead dichloride are suspended in 600 ml of tetrahydrofuran and 54 ml of dibromomethane are slowly added dropwise. The mixture is stirred for 30 minutes and the mixture is cooled to 0 ° C. 103 ml (103 mmol) of a 1M titanium tetrachloride solution in dichloromethane are added so that the internal temperature does not exceed 10 ° C. The mixture is stirred for 30 minutes and at 0.degree. C., 18.8 g (103 mmol) of 1- (3-fluoro-2-hydroxyphenyl) -propan-1-one in 85 ml of tetrahydrofuran are added. After 1 hour, dilute with diethyl ether and pour the reaction mixture carefully onto a cold 4M hydrochloric acid, the temperature r rising to about 35 ° C. It is extracted several times with diethyl ether, washed with water and dried over sodium sulfate. The solvent is removed in vacuo and after chromatographic purification on silica gel (hexane / ethyl acetate 0% -5%), 4.8 g (26.6 mmol) of 1-fluoro-2-methoxy-3- (1-methylpropenyl) -benzene are obtained as E / Z mixture. To 3.6 g (20 mmol) of 1-fluoro-2-methoxy-3- (1-methylpropenyl) benzene in 4 ml of dichloroethane are added 6.8 g (40 mmol) of ethyl trifluoropyrate and 1.2 g (2 mmol) yterbium triflate and the mixture is heated 20 hours at 140 ° C. After cooling, the mixture is chromatographed directly on silica gel (hexane / ethyl acetate 20%) to give 4.1 g (11.7 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent -4-enoic acid ethyl ester as stereoisomer mixture. 0.9 g (2.5 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoic acid ethyl ester are dissolved in 20 ml of methanol and 0.5 ml of acetic acid and 50 mg of palladium on carbon (10%) are added. Shake under the reaction mixture under a hydrogen atmosphere for 5 hours. It is then filtered through Celite, washed with dichloromethane and methanol and the solvent is removed in vacuo. After two coevaporations with toluene, 850 mg of crude 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanoic acid ethyl ester, which is cooled to -5 ° C in 30 ml of diethyl ether and to which portionwise 182 mg (4.8 mmol) of lithium aluminum hydride are solidified. The mixture is stirred for 1 hour at 0 ° C and poured into saturated ammonium chloride solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. After chromatographic purification on silica gel (hexane / ethyl acetate 20%), 290 mg (0.9 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal are obtained as stereoisomer mixture.
¹ H-NMR (CDCl _3): δ = 0.80-0.90 (d, 3H), 1:32 to 1:58 (d, 3H), 2.40-2.65 (dq, 1H), 3.10-3.70 (dq, 1H), 3.90 (s , 3H), 6.85-7.10 (m, 3H), 9.00-9.70 (s, 1H).

280 mg (0.90 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal, 100 mg (0.56 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.4 ml of titanium tetraethylate are stirred in 8 ml of toluene at 100 ° C. for 2 h. After cooling, it is poured onto water and stirred vigorously. The suspension is filtered through Celite, rinsing thoroughly with ethyl acetate. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is dried over sodium sulfate, the solvent is removed in vacuo and 360 mg of 4- (3-fluoro-2-methoxyphenyl) 1 - [(8-fluoro-2-methylquinazolin-5-yl) -imino] -3-methyl-2 - (trifluoromethyl) -pentan-2-ol as a crude product. 7.7 mL (7.7 mmol) of a 1M boron tribromide solution are added dropwise at -30 ° C. to 360 mg (0.6 mmol) of imine in 20 mL of CH ₂ Cl ₂ . The cooling bath is removed and after 30 minutes the mixture is treated with saturated NaHCO ₃ solution, the phases are separated, the aqueous phase is extracted with CH ₂ Cl ₂ , the combined organic phases are dried (Na ₂ SO ₄ ) and concentrated in vacuo. Column chromatography on silica gel (hexane / ethyl acetate / methanol 43:43:12%) and subsequent crystallization from chloroform afford 40 mg (0.09 mmol) of product as a racemic mixture of the main diastereomer.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 1.20 (d, 3H), 1.49 (d, 3H), 2.47 (dq, 1H), 2.83 (s, 3H), 3.58 (dq, 1H), 5.17 (s, 1H), 6.75 (dd, 1H), 6.88 (dd, 1H), 6.90 (dd, 1H), 7.58 (dd, 1H), 9.60 (s, 1H).

Example 2

5 - {[6-fluoro-3,4-dimethyl-2,5-dihydroxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} quinolin-2 (1H) -one

5-aminoquinoline-2 (1H) -one

4.5 g of 5-nitroquinoline-2 (1H) -one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) are dissolved in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as catalyst Hydrogenated under atmospheric pressure with hydrogen until complete reaction. The catalyst is removed by filtration through diatomaceous earth and the reaction solution is concentrated in vacuo. 3.8 g of the title compound are obtained as a yellow solid.
¹ H-NMR (DMSO): δ = 5.85 (bs, 2H), 6.27 (d, 1H), 6.33 (d, 1H), 6.43 (d, 1H), 7.10 (t, 1H), 8.07 (d, 1H ), 11.39 (br, 1H)

290 mg (0.94 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal, 150 mg (0.94 mmol) of 5-aminoquinoline-2 (1H) -one and 0.4 ml of titanium tetraethylate are stirred in 8 ml of toluene at 100 ° C. for 2 h. After cooling, it is poured onto water and stirred vigorously. The suspension is filtered through Celite, rinsing thoroughly with ethyl acetate. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is dried over sodium sulfate, the solvent is removed in vacuo and 480 mg of 4- (3-fluoro-2-methoxyphenyl) 5 - {[(3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- ( trifluoromethyl) pentanyl] imino} quinoline-2 (1H) -one as crude product. 9.5 ml (9.5 mmol) of a 1M boron tribromide solution are added dropwise at -35 ° C. over 10 minutes to 480 mg of imine in 19 ml of CH ₂ Cl ₂ . It is allowed to warm for 2 hours to -20 ° C and pour the approach into cold ges. NaHCO ₃ solution. It is rinsed with ethyl acetate, the phases are separated, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na ₂ SO ₄ ) and concentrated in vacuo. Column chromatography on silica gel (hexane / ethyl acetate / methanol 43:43:12%) and subsequent HPLC (Gemini C18 5μ, water + 0.1% TFA / acetonitrile 38-50%) provide 30 mg of product as a racemic mixture of the main diastereomer.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 1.14 (d, 3H), 1.44 (d, 3H), 2.39 (dq, 1H), 3.52 (dq, 1H), 5.07 (s, 1H), 6.46 (d, 1H), 6.63 (d, 1H), 6.67 (d, 1H), 6.70 (dd, 1H), 7.36 (t, 1H), 8.15 (d, 1H).

Example 2A / 2B

5 - {[6-Fluoro-3,4-dimethyl-2,5-dihydroxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] -amino} -quinolin-2 (1H) -one cleaved by preparative chiral HPLC (Chiracel OD 5μ) in the enantiomerically pure compounds:
Enantiomer 1: analytical HPLC: R _t = 8.4 min (Chiralcel OD 5μ, 250 x 4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 ml / min flow)
Enantiomer 2: analytical HPLC: R _t = 15.1 min (Chiralcel OD 5μ, 250 x 4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 ml / min flow)

Example 3

6-fluoro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaghthalin-2,5-diol

5-amino-7-fluoro-2-methychinazolin

17 g (70.5 mmol) 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I Fagervall, L.-G. Larsson, S.B. Ross, Eur. Med. Chem. 34 (1999) 137-151), 9.2 g acetamidine hydrochloride, 13.48 potassium carbonate and 10.4 g molecular sieve (4A) are combined in 70 ml of butyronitrile. One heats up vigorous stirring 17 Hours at 145 ° C and remove the solvent in a vacuum. After chromatography of the residue on silica gel with hexane / ethyl acetate (0-70%) receives 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline.

1 g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline are dissolved in 74 ml of toluene and cooled to -70 ° C. 9.5 ml (11.4 mmol) of a 1.2 M disobutylaluminum hydride solution in toluene are added dropwise over 30 minutes. The reaction mixture is allowed to warm to -40 ° C and stirred for 4 hours at -40 ° C. Water is slowly added and stirred for 30 minutes at room temperature until a precipitate forms, which is removed by filtration through Celite. The phases are separated, washed with saturated sodium chloride solution and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 64 mg of the product are obtained.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.83 (s, 3H), 4.67 (br., 2H), 6.50 (dd, 1H), 6.93 (dd, 1H), 9.23 (s, 1H).

261 mg (0.85 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal, 150 mg (0.85 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.5 ml of titanium tetraethylate are stirred in 8 ml of toluene at 100 ° C. for 2 h. After cooling, it is poured onto water and stirred vigorously. The suspension is filtered through Celite, rinsing thoroughly with ethyl acetate. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is dried over sodium sulfate, the solvent is removed in vacuo, giving 4- (3-fluoro-2-methoxyphenyl) 1 - [(7-fluoro-2-methylquinazolin-5-yl) -imino] -3-methyl-2- ( trifluoromethyl) -pentan-2-ol as a crude product. 8.5 ml (8.5 mmol) of a 1M boron tribromide solution are added dropwise at -35 ° C. over 10 minutes to the imine in 17 ml of CH ₂ Cl ₂ . It is allowed to warm for 2 hours to -20 ° C and pour the approach into cold ges. NaHCO ₃ solution. It is rinsed with ethyl acetate, the phases are separated, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na ₂ SO ₄ ) and concentrated in vacuo. Column chromatography on silica gel (hexane / ethyl acetate / methanol 43:43:12%) and subsequent chromatography on an amino phase provide 55 mg (0.0 mmol) of product as a racemic mixture of the main diastereomer.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 1.17 (d, 3H), 1.46 (d, 3H), 2.44 (dq, 1H), 2.73 (s, 3H), 3.54 (dq, 1H), 5.15 (s, 1H), 6.69 (dd, 1H), 6.73 (d, 1H), 6.74 (d, 1H), 6.87 (dd, 1H), 9.47 (s, 1H).

Example 3A / 3B

6-fluoro-1 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2,5-diol is cleaved by preparative chiral HPLC (Chiracel OD 5μ) into the enantiomerically pure compounds:
Enantiomer 1: analytical HPLC: R _t = 7.9 min (Chiralcel OD 5μ, 250 x 4.6 mm, hexane / ethanol 5 => 20% in 30 minutes, 1 ml / min flow)
Enantiomer 2: analytical HPLC: R _t = 13.6 min (Chiralcel OD 5μ, 250 x 4.6 mm, hexane / ethanol 5 => 20% in 20 minutes, 1 ml / min flow)

Analog can be made become:

Example 4

5 - {[6-fluoro-2,5-dihydroxy-3,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl] amino} -2-methylphthalazin-1-one

5-amino-2-methyl-phthalazin-1-one

3-bromo-4-nitro-phthalide

5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are heated in 80 ml of benzotrifluoride under reflux and exposure to light until complete reaction. It is added to water, extracted with dichloromethane, washed several times with water, dried and the solvent removed in vacuo. This gives 7.24 g of 3-bromo-4-nitro-phthalide as a solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ = 7.26 (s, 1H), 7.88 (t, 1H), 8.3 (d, 1H), 8:56 (d, 1H) 5-nitro-phthalazin-one 1- :
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100 ° C for 1 h. Then 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF are added and it is stirred at 100 ° C for a further 4 h. It is added to water, extracted several times with ethyl acetate and the org. Phase washed with water and brine. It is dried and the solvent removed in vacuo. After recrystallization from ethyl acetate gives 2.35 g of 5-nitro-phthalazin-1-one as a solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ), δ = 8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs, 1H)
2-methyl-5-nitro-phthalazin-1-one

1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate are stirred for 10 min. stirred at room temperature in 60 ml of DMF. 1.1 ml of methyl iodide are added and the mixture is stirred overnight. It is added to water, extracted several times with ethyl acetate and the org. Phase washed with water and brine. It is dried and the solvent removed in vacuo. This gives 1.57 g of 2-methyl-5-nitro-phthalazin-1-one as a yellow solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ), δ = 3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H) 5-amino-2-methyl phthalazine-on-1

1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under atmospheric pressure. It is filtered through diatomaceous earth and the solvent removed in vacuo. This gives 1.26 g of 5-amino-2-methyl-phthalazin-1-one as a yellow solid.
¹ H-NMR (300 MHz, _CDCl3), = 3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 1H), 7.8 (d, 1H), 8.16 (s, 1H)

The desired Product can analogously to Example 1 from 5-amino-2-methyl-phthalazin-1-one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal getting produced.

Example 5

6-fluoro-1 - [(2-methylquinazolin-5-yl) amino] -3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2,5-diol

5-amino-2-methylquinazoline

12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (MT Bogert, VJ Chambers J. Org. Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are dissolved in 75 ml Phosphoryl chloride heated under reflux for 20 hours. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) are dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. 2 g of palladium on carbon are added and the mixture is stirred with ice-cooling for 4 hours under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration through Celite from the catalyst, washing with 200 ml of ethanol, and evaporated. Chromatography on silica gel with ethyl acetate-ethanol (0-10%) gives 530 mg of the product.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.87 (s, 3H), 4.52 (br, 2H), 6.77 (d, 1H), 7.33 (d, 1H), 7.65 (t, 1H), 9.40 (s, 1H).

The desired Product can be prepared analogously to Example 1 from 5-amino-2-methylquinazoline and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal getting produced.

Example 6

1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] -6-fluoro-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2,5 diol

5-amino-7,8-difluoro-2-methylquinazoline

To 41.7 g (180 mmol) of 2,2-dimethyl-N- (3,4,5-trifluorophenyl) -propionamide in 385 ml of THF are added dropwise at -70 ° C 156 ml (391 mmol) of a 2.5M butyllithium solution in hexane , The mixture is stirred for one hour and then 38.6 ml of DMF are added dropwise in 90 ml of THF, during which the solution is allowed to warm to -60 ° C. Man stirs for another hour at -70 ° C and then poured the cold reaction solution to a mixture of 2 kg of ice and 400 ml of concentrated hydrochloric acid. The mixture is stirred vigorously and extracted several times with diethyl ether after one hour. The organic phase is washed neutral with water and dried over sodium sulfate. Concentration gives 49.3 g (188 mmol) of crude 4,5,6-trifluoro-2-N-pivaloylaminobenzaldehyde, which is treated with 26 g (275 mmol) acetamidine hydrochloride, 38.3 g (277 mmol) potassium carbonate and 30 g molecular sieve (4A ) is combined in 206 ml of butyronitrile. The mixture is heated with vigorous stirring for 18 hours at 145 ° C and the solvent is removed in vacuo. Chromatography of the residue on silica gel with hexane / ethyl acetate (0-100%) gives 9.1 g of 7,8-difluoro-5-N-pivaloylamino-2-methylquinazoline.

2.0 g (7.2 mmol) of 7,8-difluoro-5-N-pivaloylamino-2-methyquinazoline are dissolved in 140 ml of toluene and cooled to -70 ° C. Over 30 minutes, 24 ml (28.8 mmol) of a 1.2 M diisobutylaluminum hydride solution in toluene are added dropwise. The reaction mixture is allowed to warm for 2 hours to -25 ° C and stirred for 2 hours at -25 ° C. Isopropanol is added slowly followed by water and stirred for 12 hours at room temperature until a precipitate forms, which is removed by filtration through Celite. It is washed thoroughly with a methylene chloride methanol mixture and concentrated. The residue is stirred vigorously in 200 ml of ethyl acetate and 50 ml of methanol together with 100 g of silica gel and 20 g of manganese dioxide. It is filtered through Celite, washed with a good with a methylene chloride-methanol mixture and concentrated. Chromatography on silica gel (hexane-ethyl acetate 0-100%) gives 370 mg of the product.
¹ H-NMR (300 MHz, CD ₃ OD); δ = 2.81 (s, 3H), 6.64 (dd, 1H), 9.52 (s, 1H).

158 mg (0.51 mmol) of 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal, 100 mg (0.51 mmol) of 5-amino-7,8-difluoro-2 Methylquinazoline and 0.4 ml of titanium tetraethylate are stirred in 6 ml of toluene at 100 ° C for 2 h. After cooling, it is poured onto water and stirred vigorously. The suspension is filtered through Celite, rinsing thoroughly with ethyl acetate. The phases of the filtrate are separated and it is extracted again with ethyl acetate. It is dried over sodium sulfate, the solvent is removed in vacuo and 1 - [(7,8-difluoro-2-methylquinazolin-5-yl) -imino] -4- (3-fluoro-2-methoxyphenyl) -3-methyl- 2- (trifluoromethyl) -pentan-2-ol as a crude product. 5 mL (5 mmol) of a 1M boron tribromide solution are added dropwise at -35 ° C. over 10 minutes to the imine in 10 mL CH ₂ Cl ₂ . It is allowed to warm for 2 hours to -20 ° C and pour the approach into cold ges. NaHCO ₃ solution. It is rinsed with ethyl acetate, the phases are separated, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na ₂ SO ₄ ) and concentrated in vacuo. Column chromatography on silica gel (hexane / ethyl acetate / methanol 43:43:12%) and subsequent preparative thin-layer chromatography on an amine phase (Merck NH ₂ ) provide 10 mg (0.02 mmol) of product as a racemic mixture of the main diastereomer.
¹ H-NMR (300 MHz, CD ₃ OD): δ = 1.17 (d, 3H), 1.45 (d, 3H), 2.44 (dq, 1H), 2.77 (s, 3H), 3.53 (dq, 1H), 5.10 (s, 1H), 6.69 (dd, 1H), 6.83 (dd, 1H), 6.86 (dd, 1H), 9.51 (s, 1H).

Example 7

6-fluoro-1 - [(2-methylquinolin-5-yl) amino] -3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-2,5-diol

The desired Product can be prepared analogously to Example 1 from 5-amino-2-methylquinoline and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal getting produced.

Example 8

6-chloro-5-methoxy-1 - [(2-methylquinazolin-5-yl) amino] -3-methyl-4-metylen-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-2-ol

4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enal

To 250 mmol of 2-chlorophenol, dissolved in 200 ml of dichloromethane (DCM) and 38 ml of pyridine, are slowly added dropwise 265 mmol of propionic acid chloride. After stirring for 2 h, the batch is quenched with 1 M hydrochloric acid and extracted with DCM. The organic phases are washed with NaCl solution and dried with sodium sulfate. After removal of the solvent, 46 g of crude product are obtained, which is taken up in 40 ml of 1,2-dichlorobenzene. This solution is added dropwise at RT to a solution of 33 AlCl ₃ in 40 ml of 1,2-dichlorobenzene. The mixture is stirred at 100 ° C for 18 h, cooled, diluted with DCM and added to ice / hydrochloric acid (4 m). The phases are separated, the aqueous phase extracted with DCM and the combined organic phases washed with NaCl solution and dried with sodium sulfate. After removal of the solvent, 49 g of a mixture of regioisomeren products. When stirred with hexane, 18 g of the para compound remain undissolved. The hexane solution is concentrated. 22 g of this isomerically enriched intermediate the dissolved in acetone, at RT carefully added 240 mmol of potassium carbonate and 144 mmol of methyl iodide and stirred at 80 ° C for 18 h. After cooling, the reaction mixture is poured into water and extracted with diethyl ether. After drying with sodium sulfate and stripping off the solvent, the crude product is purified by column chromatography on silica gel (eluent: hexane / ethyl acetate 4: 1). 18 g of the desired 1- (3-chloro-2-methoxy-phenyl) -propan-1-one are obtained.

56.2 Zinc powder and 1.22 g of lead (II) chloride are placed in 800 ml of THF and at RT slowly added dropwise 53 ml of dibromomethane. After stirring for 30 minutes slowly added dropwise 100 mmol of titanium (IV) chloride. After another 30 min stirring 100 mmol of 1- (3-chloro-2-methoxy-phenyl) -propan-1-one are added dropwise and stirred at RT for 4 h. You dilute with diethyl ether, the reaction mixture is added to ice / hydrochloric acid (4 m), separates the phases, extracted with diethyl ether and dried with Sodium sulfate. The crude product solution is slow on a rotary evaporator at a bath temperature of 45 ° C. concentrated and finally Completely concentrated. The crude product is chromatographed on silica gel with hexane / ethyl acetate 7: 3 chromatographed. You get 16.7 g of 1-chloro-2-methoxy-3- (1-methylpropenyl) benzene.

1.0 g of this styrene derivative are initially charged with 1.30 g of trifluoropyruvate (1.5 equivalents) in 2.5 ml of dichloroethane, 82 mg (0.1 equiv.) Of iron (III) chloride are added and the mixture is heated to 90 ° C. for about 10 hours. It is diluted with water and DCM and the phases are separated. The aqueous phase is extracted with DCM, the combined organic phases are washed intensively with water and sat. NaCl solution and dried with sodium sulfate. After separating off the solvents, the crude product is purified by chromatography. This gives 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-4-pentenoic acid ethyl ester as a mixture of isomers. 225 mg of this ester are mixed at -20 ° C. in 7 ml of THF with 24 mg of LiAlH ₄ . The mixture is stirred for about 4 h at 0 ° C, a further 20 mg of LiAlH ₄ are added and stirred for a further 2 d. The mixture is poured onto ice-water, diluted with THF, ethyl acetate and water, and the phases are separated. The water phase is acidified with 2 M hydrochloric acid, extracted again and the combined organic phases with water and sat. NaCl solution and dried with sodium sulfate. After chromatographic purification, 209 mg of 4- (3-chloro-2-methoxy-phenyl) -3-methyl-2-trifluoromethyl-pent-4-ene-1,2-diol and 85 mg of 4- (3-chloro 2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4-enal. The diol obtained is dissolved in DCM, added 0.22 ml of DMSO, 0.87 ml of triethylamine and 600 mg of sulfur trioxide-pyridine complex and stirred at RT for 7 h. The reaction mixture is partitioned between ammonium chloride solution and ethyl acetate, the phases are separated, extracted with ethyl acetate, washed with NaCl solution and dried with sodium sulfate. After chromatographic purification, 110 mg of further 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4-enal are obtained as a slightly yellowish oil.

113 mg of aldehyde are initially charged with 83 mg (1.5 equiv.) Of 5-amino-2-methylquinazoline in toluene, 0.18 ml of titanium tetraethylate are added dropwise and the mixture is heated to reflux for about 5 hours. After cooling, it is diluted with ethyl acetate, sodium bicarbonate solution is added, precipitates formed are filtered through kieselguhr and the phases are separated. The aqueous phase is extracted with ethyl acetate, the combined organic phases with sat. NaCl solution and dried with sodium sulfate. After separating off the solvents, the crude product is purified by chromatography. This gives 60 mg of 4- (3-chloro-2-methoxy-phenyl) -1,1,1-trifluoro-3-methyl-2- (2-methylquinazolin-5-ylmino) -methylpent-4-en-2-ol as a mixture of isomers. The imine is taken up in DCM and added dropwise at -20 ° C 1.3 ml of titanium tetrachloride solution (1 m in DCM). It is allowed to come to 0 ° C and the mixture after 4 h stir on ice water. It is extracted with DCM, washed thoroughly with water and dried with sodium sulfate. The crude product is filtered through a little silica gel with DCM / MeOH. 17 mg of 6-chloro-5-methoxy-3-methyl-4-methylene-1- (2-methylquinazolin-5-ylamino) -2-trifluoro-methyl-1,2,3,4-tetrahydronaphthalene-2 are obtained. ol as isomeric mixture.
¹ H-NMR (300 MHz, CDCl ₃ ): δ (major isomer) = 1.13 (d, 3H), 2.88 (s, 3H), 3.79 (s, 3H), 5.02 (d, 1H), 5.14 (d, 1H ), 5.80 (s, 1H), 5.95 (s, 1H), 6.89 (d, 1H), 7.07 (m, 1H), 7.19 (dd, 1H), 7.38 (m, 1H), 7.75 (m, 1H) , 9.45 (s, 1H); MS (ESI): 464/466 (M + H), 482/484 (M + H + H ₂ O), 496/498 (M + H + MeOH).

Analog can be made become:

6-chloro-1 - [(7,8-difluoro-2-methylquinazolin-5-yl) amino] -5-metoxy-3-methyl-4-metylen-2- (trifluoromethyl) -1,2,3,4 tetrahydronaphthalen-2-ol

The desired Product can analogously to Example 8 from 5-amino-7,8-difluoro-2-methylquinazoline and 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethylpent-4-enal getting produced.

6-chloro-5-methoxy-1 - [(2-methylquinolin-5-yl) amino] -3-methyl-4-metylen-2- (trifluoromethyl) -1,2,3,4-tetrahydronaghthalin-2-ol

The desired Product can be prepared analogously to Example 8 from 5-amino-2-methylquinoline and 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4-enal getting produced.

Example 9

6,7,8,8a, 9,10-hexahydro-10 - [(2-methyl-quinazolin-5-yl) amino] -9- (trifluoromethyl) phenanthrene-9-ol

Ethyl 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) -propionate

870 mg (5.5 mmol) of 1-phenyl-1-cyclohexene, 1.87 g (11 mmol) and 310 mg (0.5 mmol) of ytterbium triflate are dissolved in 2 ml of 1,2-dichloroethane and boiled under reflux for 19 h. After cooling to room temperature, the solution is concentrated in vacuo and purified by column chromatography. 2 diastereomers are obtained: 312 mg diastereomer A and 293 mg diastereomer B.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.07 (t, 3H), 1.59-1.67 (m, 1H), 1.72-1.85 (m, 1H), 2.10-2.34 (m, 4H), 3.01- 3.11 (m, 1H), 3.57 (bs, 1H), 3.61-3.70 (m, 1H), 3.80 (s, 1H), 5.97 (t, 1H), 7.17-7.29 (m, 5H).

3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) propionaldehyde

300 mg (0.91 mmol) of ethyl 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) propionate is dissolved in 11 ml of diethyl ether and cooled to -10 ° C. under a nitrogen atmosphere. 69 mg (1.82 mmol) of lithium aluminum hydride are added in several portions. The reaction is stirred at -10 ° C. for 1 h and at 0 ° C. for 1 h. For workup, the reaction mixture is poured into saturated ammonium chloride solution and the aqueous phase extracted three times with ethyl acetate. The collected organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered off and concentrated in vacuo. The crude product obtained is purified by column chromatography, giving 120 mg of product.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.62-1.73 (m, 1H), 1.80-1.92 (m, 1H), 2.00-2.14 (m, 1H), 2.20-2.28 (m, 2H), 2.31-2.41 (m, 1H), 3.66 (bs, 1H), 3.78 (d, 1H), 6.05 (t, 1H), 7.14-7.20 (m, 2H), 7.24-7.33 (m, 3H), 9.05 ( quint, 1H).

112 mg (0.39 mmol) of 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohex-2-enyl) propionaldehyde, 62 mg (0.39 mmol) of 5-amino-2-methylquinazoline and 210 μl (1 mmol) of titanium tetraethylate were dissolved in 2 ml of toluene and refluxed under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was poured onto water, diluted with ethyl acetate and filtered through Celite. The aqueous phase is extracted twice with ethyl acetate. The collected organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After purification by column chromatography on silica gel, 50 mg of 1,1,1-trifluoro-3- (2-methyl-quinazolin-5-yl-imino) -2 - (- 2-phenylcyclohex-2-enyl) -propane are obtained. 2-ol.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.70-1.78 (m, 1H), 1.81-1.91 (m, 1H), 2.26-2.39 (m, 3H), 2.54 (d, 1H), 2.91 ( s, 3H), 3.67 (bs, 1H), 4.97 (s, 1H), 5.78 (d, 1H), 6.12 (t, 1H), 6.99-7.02 (m, 1H), 7.09 (t, 2H), 7.18 -7.20 (m, 2H), 7.53 (t, 1H), 7.68 (s, 1H), 7.74 (d, 1H), 9.49 (s, 1H).

47 mg (0.11 mmol) of 1,1,1-trifluoro-3- (2-methyl-quinazolin-5-yl-imino) -2- (2-phenylcyclohex-2-enyl) -propan-2-ol dissolved in 2 ml of dichloromethane and cooled to -20 ° C under a nitrogen atmosphere. 440 μl (0.44 mmol, 1 M solution in dichloromethane) are slowly added to the reaction. The mixture is stirred for 2 h at room temperature. For work-up, it is poured onto saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The collected organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography and preparative HPLC. 20 mg of product are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.40 (bs, 1H), 1.80-18.7 (m, 2H), 1.94 (bs, 1H), 2.20 (bs, 2H), 2.69 (s, 3H), 3.04 (bs, 1H), 5.62 (d, 1H), 6.11 (s, 1H), 6.76 (bs, 1H), 6.90 (d, 1H), 7.00 (d, 1H), 7.05 (d, 1H ), 7.17 (t, 1H), 7.23-7.25 (m, 2H), 7.71-7.25 (m, 2H), 9.63 (s, 1H).

Analog can be made become:

10 - [(7,8-difluoro-2-methyl-quinazolin-5-yl) amino] -6,7,8,8a, 9,10-hexahydro-9- (trifluoromethyl) -phenanthrene-9-ol

The desired product can be prepared analogously to Example 9 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohex-2-enyl) propionaldehyde.

5 - {[10- [6,7,8,8a -one, 9,10-hexahydro-9- (trifluoromethyl) -9-hydroxy-phenanthrenyl] amino) quinolin-2 (1H)

The desired Product can be prepared analogously to Example 9 from 5-aminoquinoline-2 (1H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) propionaldehyde getting produced.

6,7,8,8a, 9,10-hexahydro-10 - [(2-methyl-quinolin-5-yl) amino] -9- (trifluoromethyl) phenanthrene-9-ol

The desired Product can be prepared analogously to Example 9 from 5-amino-2-methyl-quinoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) propionaldehyde getting produced.

3,3a, 4,5-tetrahydro-5 - [(2-methyl-quinazolin-5-yl) amino] -4- (trifluoromethyl) -2H-benz [e] inden-4-ol

The desired Product can be prepared analogously to Example 9 from 5-amino-2-methyl-quinoline and 1-phenyl-1-cyclopentene getting produced.

5 - [(7,8-difluoro-2-methyl-quinazolin-5-yl) amino] -3,3a, 4,5-tetrahydro hydro-4- (trifluoromethyl) -2H-benz [e] inden-4-ol

The desired Product can be prepared analogously to Example 9 from 5-amino-7,8-difluoro-2-methylquinazoline and 1-phenyl-1-cyclopentene.

Example 10

4b, 5,6,7,8,8a, 9,10-octahydro-10 - [(2-methyl-quinazolin-5-yl) amino] -9- (trifluoromethyl) phenanthrene-9-ol

3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde

500 mg (1.52 mmol) of ethyl 3,3,3-trifluoro-2-hydroxy- (2-phenyl-cyclohex-2-enyl) -propionate are dissolved in 20 ml of methanol and treated with 300 μl of acetic acid and 30 mg of palladium on activated carbon ( 10%). The flask is evacuated and then filled with hydrogen. The reaction was stirred for 5 h at room temperature. For workup, it is filtered through Celite and concentrated in vacuo. This gives 492 mg of crude 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl-propionic acid ethyl ester, which is used directly in the subsequent reaction without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.23 (t, 3H), 1.41-1.59 (m, 2H), 1.70-1.87 (m, 3H), 1.90-2.00 (m, 1H), 2.09- 2.19 (m, 1H), 2.20-2.29 (m, 1H), 2.73-2.77 (m, 1H), 2.91-2.95 (m, 1H), 3.32 (s, 1H), 3.78-3.87 (m, 1H), 4.07-4.09 (m, 1H), 7.17-7.28 (m, 5H).

485 mg (1.47 mmol) of ethyl 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohexyl) propionate are dissolved in 18 ml of diethyl ether and cooled to -10 ° C. under a nitrogen atmosphere. 111 mg (2.94 mmol) of lithium aluminum hydride are added in several portions, stirred for 1 h at -10 ° C and allowed to thaw for 3 h to room temperature. For working up, it is poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered off and concentrated in vacuo. The crude product was purified by column chromatography on silica gel. 200 mg of product are obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.40-2.20 (m, 8H), 2.82-2.86 (m, 1H), 3.05-3.09 (m, 1H), 3.58 (s, 1H), 7.14- 7.31 (m, 5H), 8.87 (s, 1H).

190 mg (0.66 mmol) of 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohexyl) propionaldehyde, 106 mg (0.66 mmol) of 5-amino-2-methyl-quinazoline and 350 μl (1.7 mmol) of titanium tetraethylate are dissolved in 3.5 ml of toluene and boiled under nitrogen atmosphere for 3 h under reflux. After cooling to room temperature, the reaction mixture is poured onto water, diluted with ethyl acetate and filtered through Celite. The aqueous phase is extracted twice with ethyl acetate. The collected organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After purification by column chromatography, 69 mg of 1,1,1-trifluoro-3- (2-methyl-quinazolin-5-ylamino) - (2-phenyl-cyclohexyl) -propan-2-ol are obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.44-2.16 (m, 8H), 2.74-2.81 (m, 1H), 2.92 (s, 3H), 3.29 (q, 1H), 4.77 ( s, 1H), 6.61 (dd, 1H), 7.04-7.12 (m, 3H), 7.33 (d, 2H), 7.53 (s, 1H), 7.70 (t, 1H), 7.83 (d, 1H), 9.37 (s, 1H).

66 mg (0.15 mmol) of 1,1,1-trifluoro-3- (2-methyl-quinazolin-5-yl-imino) -2 - (- 2-phenylcyclo hex-2-enyl) -propanol are dissolved in 3 ml of dichloromethane and cooled to -20 ° C. under a nitrogen atmosphere. 620 μl of a boron tribromide solution (0.62 mmol, 1 M solution in dichloromethane) are slowly added to the reaction. The mixture is stirred for 2 h at room temperature. For working up, it is poured onto saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The collected organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography, giving 33 mg of the desired product.
¹ H-NMR (500 MHz, CDCl _3): δ = 0.83-0.93 (m, 1H), 1.41-1.75 (m, 6H), 1.83-1.95 (m, 2H), 2.57-2.65 (m, 2H), 2.85 (s, 3H), 3.18 (bs, 1H), 4.78 (d, 1H), 5.78 (d, 1H), 6.46 (d, 1H), 7.21 (t, 1H), 7.29 (t, 1H), 7.37 (t, 1H), 7.45 (d, 1H), 7.61 (t, 1H), 9.43 (s, 1H).

Analog can be made become:

10 - [(7,8-difluoro-2-methyl-quinazolin-5-yl) amino] -4b, 5,6,7,8,8a, 9,10-octahydro-9- (trifluoromethyl) -phenanthrene-9 -oil

The desired Product can be prepared analogously to Example 10 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohexyl) propionaldehyde getting produced.

5 - {[10- [4b, 5,6,7,8,8a, 9,10-octahydro-9-hydroxy-9- (trifluoromethyl) phenanthrenyl] amino} quinolin-2 (1H) -one

The desired Product can be prepared analogously to Example 10 from 5-aminoquinoline-2 (1H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde getting produced.

4b, 5,6,7,8,8a, 9,10-octahydro-10 - [(2-methyl-quinolin-5-yl) amino] -9- (trifluoromethyl) phenanthrene-9-ol

The desired Product can be prepared analogously to Example 10 from 5-amino-2-methyl-quinoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde getting produced.

2,3,3a, 4,5,9b-hexahydro-5 - [(2-methyl-quinazolin-5-yl) amino] -4- (trifluoromethyl) -1Hbenz [e] inden-4-ol

The desired Product can be prepared analogously to Example 10 from 5-amino-2-methyl-quinazoline and 1-phenyl-1-cyclopentene.

5 - [(7,8-difluoro-2-methyl-quinazolin-5-yl) amino] -2,3,3a, 4,5,9b-hexahydro-4- (trifluoromethyl) -1H-benz [e] indene -4-ol

The desired Product can be prepared analogously to Example 10 from 5-amino-7,8-difluoro-2-methylquinazoline and 1-phenyl-1-cyclopentene.

Claims (13)

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, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ - C ₁₀ ) -alkylthio group, a (C ₁ -C 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} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} independently gig with each other may be hydrogen, C ₁ -C ₅ alkyl or (CO) -C ₁ -C ₅ alkyl, R ³ and R ^{4 are} independently a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) -alkylthio group, a (C ₁ -C ₅ ) -perfluoroalkyl group, R ^{5 is} a C ₁ C ₁₀ alkyl group, a C ₁ -C ₁₀ alkyl group substituted by one or more groups selected from hydroxy groups, halogen atoms, (C ₁ -C ₅ ) alkoxy groups, an optionally substituted (C ₃ -C ₇ ) cycloalkyl group, a optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally independently selected from one or more groups selected from (C ₁ -C ₅ ) alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups), (C ₁ -C ₅ ) alkoxy groups, hydroxy groups, halo enatomen, 1-2 (C ₁ -C ₃₎ substituted -Exoalkylidengruppen, optionally comprising 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, wherein this group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites, R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) Alkyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group , a heterocyclyl group, a heterocyclyl (C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group, an aryl group, an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, aryl (C ₂ -C ₈ ) alkynyl group, optionally by one or more keto groups, (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy group mono- or bicyclic heteroaryl group containing one or more nitrogen atoms and / or oxygen atoms and / or sulfur atoms, a heteroaryl (C ₁ -C ₈ ) -alkyl group or a heteroaryl (C ₂ -), halogen atoms, (C ₁ -C ₃ ) -exoxyalkylidene-substituted -C ₈ ) alkenyl group wherein these groups may be linked via any position with the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites, R ^{7 is} a halogen atom, a (C ₁ -C ₁₀ ) alkyl group, optionally substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms may be substituted, R ⁸ and R ^{9 are} independently a hydrogen atom, a halogen atom, a (C ₁ -C ₅ ) alkyl group, with OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) may be substituted, a cyano group or together with the carbon atom of the ring system a (C ₃ -C ₆ ) -cycloalkyl ring or together an optionally substituted by hydroxy, halogen or cyano substituted (C ₁ -C ₅ ) - alkylidene or R ⁷ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C mean ₅₎ -alkoxy groups, 1-4 halogen atoms. 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 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-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ¹⁰ R ¹¹ , where R ¹⁰ and R ^{11 can be,} independently of one another, hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl, R ³ and R ^4, independently of one another, represent a hydrogen atom, a hydroxyl group, a halogen atom, a gege optionally substituted (C ₁ -C ₁₀ ) alkyl group, (C ₁ -C ₁₀ ) alkoxy group, (C ₁ -C ₁₀ ) alkylthio group, (C ₁ -C ₅ ) perfluoroalkyl group, cyano group, R ⁵ a C ₁ -C ₁₀ alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅₎ alkoxy substituted C ₁ -C ₁₀ alkyl group, an optionally substituted phenyl group, an optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -Exoalkylidengruppen substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, these groups via any position with the amine be linked to the Tetrahydronaphthalinsystems and optionally be hydrogenated at one or more sites R ^{6 is} a (C ₁ -C ₅ ) alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) -cycloalkyl group , a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) -cycloalkyl (C ₂ -C ₈ ) alkenyl group R ^{7 is} a halogen atom, a (C ₁ -C ₁₀ ) - Alkyl group optionally substituted with OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms, R ⁸ and R ^{9 are} independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group associated with OR ¹⁰ , SR ¹⁰ , NR ¹⁰ R ¹¹ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a (C ₁ -C ₅ ) -alkylidengruppe or R ⁷ and R ⁸ together fused five- to eight-membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) alkoxy groups, 1-4 halogen atoms is substituted mean. 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 ₅ ) alkyl group, a (C ₁ -C ₅ ) alkoxy group, a cyano group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -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 and R ⁴ are each independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) - alkyl group, a (C ₁ -C ₁₀₎ alkoxy group, R ⁵ is a C ₁ -C ₁₀ alkyl group, a C by one or more groups selected from 1-3 hydroxy groups or halogen atoms substituted C ₁ -C ₁₀ alkyl group, optionally substituted by one or more groups selected from 1-2 keto groups, 1-2- (C ₁ -C ₅ ) -alkyl groups, 1-2- (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, Phenyl-, phthalidyl-, isoindolyl-, dihydroindolyl-, dihydroisoindolyl-, dihydroisoquinolinyl-, thiophthalidyl-, benzoxazinonyl-, phthalazinonyl-, quinolinyl-, isoquinolinyl-, quinolonyl-, isoquinolonyl- substituted 1-2 (C ₁ -C ₃ ) -exoxyalkylidene groups -, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, these groups having any position with R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group R ^{7 is} a halogen atom, R ⁶ can be hydrogen bonded to the amine of the tetrahydronaphthalene system and optionally be hydrogenated at one or more sites. a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms R ⁸ and R ^{9 are} independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl Gr uppe which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ ) ₂ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a (C ₁ -C ₅ ) - alkylidene or R ⁷ and R ⁸ together form a fused five to eight membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) alkoxy groups, 1-4 halogen atoms is substituted mean. Stereoisomers of the general formula (I),

wherein R ¹ and R ² independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, a (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group, or together 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 hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, R ^{4 is} a hydrogen atom R ^{5 is} optionally substituted by one or more groups selected from 1-2 keto groups, 1-2- (C ₁ -C ₅ ) -alkyl groups, 1-2- (C ₁ -C ₅ ) -alkoxy groups, 1-3 Phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, hydroxy, 1-3 halogen, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-substituted phenyl, isoquinolinyl , Quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl groups, these being Groups may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites, R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) Alkyl group R ^{7 is} a halogen atom, a methyl or ethyl group, R ⁸ and R ^{9 are} independently a hydrogen atom, a halogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a methylene or ethylidene, or R ⁷ and R ⁸ together denote a fused five to eight-membered saturated or unsaturated carbo or heterocycle. Use of the stereoisomers according to one of the preceding claims for the manufacture of a medicament. Use of the stereoisomers of claims 1-4 for the preparation a medicine for the treatment of inflammatory Diseases. Pharmaceutical preparations containing at least a stereoisomer according to claim 1-4 or mixtures thereof and pharmaceutically acceptable Carrier. Stereoisomers of the general formula I, according to one the claims 1-4 in Form of salts with physiologically acceptable anions. A process for the preparation of the stereoisomers of general formula I in which the radicals, unless otherwise stated, have the meanings defined in claim 1, characterized in that either Stereoisomers of the general formula (II)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ^{8 have} the meanings given in claim 1, by an optionally enantioselectively conducted ene reaction with α-keto acids R ⁶ (CO) COOR ¹⁰ in the presence of optionally chiral Lewis acids in compounds of the general formula (III)

be converted by reduction and reaction with amines of the formula R ⁵ -NH ₂ , wherein R ^{5 has} the meaning given in claim 1, the compounds of general formula (IV) are prepared

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{7 have} the meanings given in claim 1 and R ^8a corresponds to the common meaning of R ⁸ and R ⁹ as the alkylidene group, then either without further reagent or by adding inorganic or organic acids or Lewis acids are cyclized at temperatures of -70 ° C to 80 ° C to compounds of the general formula (I) or b) in compounds of the formula (III) prepared by a) by hydrogenation of the radical R ⁹ = H, by methods of cyclopropanation the radical R ⁹ with the common meaning of R ⁸ and R ⁹ = CH ₂ -CH ₂ or by hydrohalogenation the radical R ⁹ = halogen is introduced and thus compounds of the general formula V are prepared,

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ^{10 have} the meanings given in claim 1, by reduction and reaction with amines of the formula R ⁵ -NH ₂ , wherein R ^{5 is} the has the meaning given in claim 1, the compounds of general formula (VI) are prepared,

which are cyclized either without further reagent or by addition of inorganic or organic acids or Lewis acids at temperatures of -70 ° C to 80 ° C to compounds of general formula I. Process stage for the preparation of the stereoisomers of the general formula I according to claim 9, characterized in that stereoisomers of the general formula VI,

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meanings defined in claim 1 optionally cyclized with the addition of inorganic or organic acids or Lewis acids. Compounds of the general formula VI according to Claim 9

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meanings defined in claim 1. Process stage for the preparation of the compounds of the general formula (I), according to claim 9, characterized in that stereoisomers of the general formula (V)

be reduced and reacted with a corresponding amine of the formula R ⁵ -NH ₂ to imine of the general formula (VI). Compounds of formula V according to claim 9, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ correspond to the meanings defined in claim 1.