WO2006100100A1 - Tetrahydronaphthalene derivatives, method for their production and their use as anti-inflammatory agents - Google Patents

Abstract

The invention relates to tetrahydronaphthalene derivatives of general formula (I), to a method for their production and to their use as anti-inflammatory agents.

Description

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

The invention relates to tetrahydronaphthalene derivatives, processes for their preparation and their use as anti-inflammatory agents. The prior art WO 02/10143 discloses open-chain non-steroidal anti-inflammatory agents. These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.

The prior art compounds still have disadvantages such that one skilled in the art is further motivated to seek new compounds that bind to the glucocorticoid receptor.

There have now been found compounds which have at least a comparable effect as the compounds described in the prior art.

The present invention relates to compounds of the general formula (I),

worin R >1¹ ■ u ,nnΛd D R² unabhängig voneinander ein Wasserstoffatom, eine Hydroxy- Gruppe, ein Halogenatom, eine gegebenenfalls substituierte (C₁-C₁₀)- Alkylgruppe, eine gegebenenfalls substituierte (C-ι-Cio)-Alkoxygruppe, eine (Cr Cio)-Alkylthiogruppe, eine (CrCs^Perfluoralkylgruppe, eine Cyanogruppe, eine Nitrogruppe oder R¹ und R² zusammen eine Gruppe ausgewählt aus den Gruppen -O-

in which R 1 ^1, and R ² independently of one another denote a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, an optionally substituted (C ₁ -C ₁₀ ) -alkoxy group, a (C 1 -C 10) -alkylthio group, a (C 1 -C 6) perfluoroalkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O-

(CHs) _n -O-, -O- (CHa) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) n ₊ 2 -, - NH- (CH ₂ ) n ₊ i, N (C _r C ₃ alkyl) - (CH _{2) n} + i, -NH-N = CH-, wherein 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 hydrogen, -C ₅ - alkyl or (CO) -C ₁ -C ₅ -alkyl may be,

R ³ and R ⁴ independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C 1 -C 10) -alkyl group, an optionally substituted (C 1 -C 10) -alkoxy group, a (C 1 -C ₁₀ ) alkylthio group, a (CrC-s) perfluoroalkyl group, R ⁵ a CRCI _O alkyl group, by a plurality of groups or is selected from hydroxy, halogen, (CrC ₅₎ alkoxy groups substituted C _r Cio-alkyl group, an optionally substituted (C ₃ -C ₇₎ cycloalkyl group, an optionally substituted heterocyclyl, an optionally substituted aryl group, an optionally substituted independently by one or more groups selected from (C _r C ₅₎ alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1 -3 COOR ¹⁰ groups), (C 1 -C 5) -alkoxy groups, hydroxy groups, halogen atoms, 1-2 (C 1 -C ₃ ) -oxoalkylidene-substituted, optionally 1-4 nitrogen atoms and / or 1-2 acid mono- or bicyclic heteroaryl group containing one or more sulfur atoms and / or 1-2-keto groups, which group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites, R ⁶ 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-ι-C ₈₎ alkyl, heterocyclyl (C ₂ - C ₈₎ alkenyl group, an aryl group, an aryl ( -C ₈₎ alkyl aryl (C ₂ -C ₈₎ alkenyl, aryl (C ₂ -C ₈₎ alkynyl group, an optionally by one or more keto groups, (C-ι-C ₅₎ alkyl, (CrC ₅₎ alkoxy , Halogen atoms, (Ci-C ₃ ) -exxalkylidengruppen substituted, one or more nitrogen atoms and / or oxygen atoms and / or sulfur elatome-containing mono- or bicyclic heteroaryl group, a heteroaryl (Ci-C ₈ ) alkyl group or a heteroaryl (C ₂ -C ₈ ) alkenyl group wherein these groups via an arbitrary position with the Tθtrahydronaphthalinsystem can be linked and may optionally be hydrogenated at one or more sites,

R ^{7 is} a halogen atom, a (Ci-Cio) alkyl group which may optionally be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms, R ⁸ and R ^{9 are} independently a hydrogen atom, a Halogen atom, a (C ₁ -C ₅ ) alkyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ), a cyano group or together with the carbon atom of the ring system a (C ₃ -C ₆ ) cycloalkyl ring or together an optionally substituted by hydroxy, halogen or cyano (-C-Cs) alkylidene group or R ⁷ and R ⁸ together a fused five to eight-membered saturated or unsaturated carbo or heterocycle, optionally substituted by 1-2 keto groups, 1-2 (Ci -C ₅ ) alkyl groups, 1-2 (CrC ₅ ) alkoxy groups, 1-4 halogen atoms substituted. 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 -Cio) -Alkoxygruppe, a (Ci-C-ιo) -Alkythiogruppe, a (Cr C ₅ ) - perfluoroalkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups

-O- (CH ₂ ) _n -O-, -O- (CH ₂ ) n -CH ₂ -, -O-CH = CH-, - (CH ₂ W-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring-carbon atoms, or NR ¹⁰ R ^11, wherein R ¹⁰ and R ¹¹ are independently hydrogen, -C ₅ - alkyl or (CO) -C-C may be ₅ alkyl,

R ³ and R ⁴ independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C ₁₀ ) -alkyl group, a (C 1 -C ₁₀ ) -alkoxy group, a (C 1 -C ₁₀ ) -alkylthio group, a ( CrC ₅ ) - perfluoroalkyl group, a cyano group, R ^{5 is} a C 1 -C 6 -alkyl group, a C 1 -C 6 -alkyl group substituted by one or more groups selected from among 1 to 3 hydroxyl groups, halogen atoms, 1-3 (C 1 -C ₅ ) -alkoxy groups, an optionally substituted phenyl group, optionally by 1-2 keto groups, 1-2 (Ci-C ₅ ) -alkyl groups, 1-2 (Ci-C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C ₃ ) -Exoalkylidengruppθn substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, which groups may be linked via an arbitrary position with the amine of the tetrahydronaphthalene and may optionally be hydrogenated at one or more sites , R ⁶ is a (CrCsJ alkyl group or an optionally partially or completely fluorinated (C-ι-C ₅₎ alkyl group, an aryl group, an aryl (CrC alkyl group ₈₎ aryl (C ₂ -C alkenyl group _8), 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 (Ci-Ci _O ) alkyl group which may optionally be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms R ⁸ and R ^{9 is} independently a hydrogen atom, a Halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , NR ¹⁰ R ¹¹ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a (CrC ₅ ) Alkylidene group or R ⁷ and R ⁸ together form an annelated 5- to ⁸ -membered saturated or unsaturated carbo or heterocycle optionally substituted by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (C 1 -C ₅ ) Alkoxy groups, 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 a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted _(Ci-C5) - alkyl, (Ci-C ₅₎ alkoxy group, a cyano group or R ¹ and R ² together ^form a A group selected from the group consisting of -O- (CHz) _n -O-, -O- (CH ₂ ) n -CH ₂ -, -O-CH = CH-, - (CH ₂ W, 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 are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 4) -alkoxy group,

^R5 is a Ci-C ₁₀ alkyl group, by one or more groups selected from 1-3 hydroxy groups or halogen atoms substituted C ₁ -C ₁₀ - alkyl group, optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 - (C-ι-C ₅₎ alkyl groups, 1-2- (-C ₅₎ -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C ₃₎ -Exoalkylidengruppen 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 (Ci-CsJ-alkyl group or a 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 are} independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ ) ₂ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C ₃ -C ₆ ) -cycloalkyl ring or together a (CrC ₅ ) alkylidene group or

R ⁷ and R ⁸ together form a fused 5- to ⁸ -membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (Ct-C ₅ ) - Alkoxy groups, 1-4 halogen atoms is substituted mean. Another object of the present invention are stereoisomers of the general formula (I) wherein

R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, a (Ci-CsJ-alkyl group, a (Ci-CsJ-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 W-, where n = 1 or 2 and linking the terminal atoms 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 among 1-2 keto groups, 1-2- (C 1 -C ₅ ) -alkyl groups, 1-2- (C 1 -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CiC- ₃ ) -exxalkylidengruppen 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, dihydroindolone, dihydroisoindolonyl, benzimidazole or indolyl group, which groups may be linked via any position with the amine of the tetrahydronaphthalene system and optionally at one or more sites R ^{6 is} a (CrC ₅ ) -alkyl group or an optionally partially or completely fluorinated (Ci-CsJ-alkyl group R ^{7 is} a halogen atom, a methyl or ethyl group, R ⁸ and R ⁹ are each 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 eth yliden, or

R ⁷ and R ⁸ together form a fused five to eight-membered saturated or unsaturated carbo or heterocycle, bθdeuten.

Another object of the present invention are stereoisomers of the general formula (I) wherein

R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-C ₅ ) -

Alkyl group, a (CrC ₅ ) alkoxy group, a cyano group or

R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-

, -O- (CH ₂ ) _H -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and link the terminal atoms to directly adjacent ring carbon atoms are,

R ³ and R ⁴ independently of one another represent a hydrogen atom, a hydroxyl

Group, a halogen atom, an optionally substituted (C ₁ -C ₅ ) -

Alkyl group, a (CrC ₅ ) alkoxy group,

^R5 is a Ci-C ₁₀ alkyl group, a substituted by one or more groups selected from 1-3 hydroxy groups or halogen atoms, C ₁ -C- ₁₀ -

Alkyl group, one optionally by one or more groups selected from 1-2 keto groups, 1-2- (CrC ₅ ) alkyl groups, 1-2- (CrC ₅ ) alkoxy groups, 1-3

Hydroxy, 1-3 halogen, 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, chromenyl,

Isochromenyl, chromenonyl, isochromenonyl, 1, 7 or 1, 8-naphthyridinyl, dihydroindolonyl, Dihydroisoindolonyl-, benzimidazole or indolyl group, which groups via any position with the amine of

Tetrahydronaphthalinsystems may be linked and may optionally be hydrogenated at one or more sites

R ^{6 is} a (C 1 -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C 1 -C ₅ ) -alkyl group

R ^{7 is} a halogen atom, a methyl or ethyl group which is linked to OR ¹⁰ , SR ¹⁰ ,

N (R ¹⁰ R ¹¹ ) or 1-3 halogen atoms may be substituted R ⁸ and R ^{9 are} independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ ) ₂ , a cyano group or together with the carbon atom of the tetrahydronaphthalene ring a (C C ₃ -C ₆ -cycloalkyl ring or together form a (C 1 -C ₅ ) -alkylidene group or

R ⁷ and R ⁸ together form a fused five- to eight-membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (C 1 -C ₅ ) -alkoxy groups, 1-4 halogen atoms is substituted mean. Another object of the present invention are stereoisomers of the general formula (I) wherein

R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, a (CiC ₅ ) alkyl group, a (Ci-C ₅ ) alkoxy, 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 with direct linked to adjacent ring carbon atoms,

R ^{3 is} a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C ₅ ) -alkyl group, a (C 1 -C ₅ ) -alkoxy group, R ^{4 is} a hydrogen atom

R ^{5 is} optionally substituted by one or more groups selected from 1-2 keto groups, 1-2- (C 1 -C ₅ ) -alkyl groups, 1-2- (C 1 -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 Halogen atoms, 1-2 (CrC ₃ ) -oxoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl,

Dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, chromenyl, isochromenyl, chromenonyl, isochromenonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl , Phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, these groups being attached via any position with the amine of the R ^{6 is} a fully fluorinated (Ci-Cs) alkyl group R ^{7 is} a methyl or ethyl group, R ⁸ and R ^{9 are} independently a hydrogen atom, a methyl or ethyl group or together form a methylene or ethylidene group, or R ⁷ and R ⁸ together denote a fused five to eight-membered saturated or unsaturated Carbozyklus. A preferred subject of the present invention are stereoisomers of the general formula (I) wherein

R ¹ and R ^{2 are} independently hydrogen, hydroxy, halogen, (C 1 -C ₅ ) alkyl, (C 1 -C ₅ ) alkoxy, R ^{3 is} hydrogen, halogen, R ^{4 is} hydrogen

R ^{5 is} optionally substituted by 1-2 keto groups, 1-2 (Ci-C ₅ ) alkyl groups, 1-2 (Ci-C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CrC ₃ ) - 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, which groups linked via any position with the amine of Tetrahydronaphthalinsystems and optionally hydrogenated at one or more sites R ⁶ fully fluorinated (Ci-Cs) alkyl group R ^{7 is} a methyl or ethyl group,

R ⁸ and R ⁹ independently of one another represent a hydrogen atom, a methyl or ethyl group or together a methylene or ethylidene group, or R ⁷ and R ⁸ together denote a fused five- to six-membered saturated or unsaturated carbocycle.

A preferred subject of the present invention are stereoisomers of the general formula (I) wherein R ¹ and R ² independently of one another represent a hydrogen atom, a hydroxyl

A group, a halogen atom, a (Ci-C ₅ ) alkyl group, a (C-ι-C ₅ ) alkoxy group,

R ^{3 is} a hydrogen atom, a halogen atom,

R ^{4 is} a hydrogen atom R ^{5 is} optionally independently of one another by one or more

Groups selected from a keto group, a (C-ι-C ₅ ) alkyl group, 1-2

Substituted halogen atoms

Quinazolinyl, quinolonyl, isoquinolonyl, phthalazinonyl, phthalazinyl,

Quinolinyl, isoquinolinyl, dihydroindolyl, dihydroisoindolyl, dihydroindolonyl, dihydroisoindolonyl, isochromenyl, isochromenonyl

R ⁶ fully fluorinated (C-ι-C ₃ ) alkyl group

R ^{7 is} a methyl or ethyl group,

R ⁸ and R ^{9 are} independently hydrogen, methyl or

Ethyl group or together a methylene or ethylidene group, or R ⁷ and R ⁸ together denote a fused five- to six-membered saturated or unsaturated Carbozyklus.

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.

definitions

The term halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom. As a substituent for R ⁵ is most preferably the fluorine atom.

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

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

The alkyl groups R ⁸ and R ⁹ have the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group OR ¹⁰ , SR ¹⁰ and N (R ¹⁰ R ¹¹ ), wherein R ¹⁰ and R ^{11 are} hydrogen, dC ₅ alkyl or (CO) CrC ₅ alkyl and alkyl is also as defined above. The alkoxy groups can be straight-chain or branched and are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy , 2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group is preferred.

The alkylthio groups may be straight-chain or branched and may be a methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio , 2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.

For a partially or fully 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 Fn. 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 aromatic part of the tetrahydronaphthalene system may be substituted 1-4 times, preferably 1-2 times. Suitable substituents are the definitions of the patent claims mentioned for R ¹ , R ² , R ³ and R ⁴ , for R ¹ and R ² independently of one another a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 4) -alkyl group , an optionally substituted (C 1 -C 10) -alkoxy group, a (C 1 -C 10) - Alkylthio group, a (CrC ₅₎ perfluoroalkyl group, a cyano group, a nitro group, preferably each independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₅₎ - alkyl group, an optionally substituted (CrC ₅₎ Alkoxy group, a (C ₁ -C ₅ ) alkylthio group, a (C ₁ -C ₃ ) perfluoroalkyl group, more preferably independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₃ ) alkyl group, an optionally substituted one (CrC ₃ ) alkoxy, a (CrC ₃ ) alkylthio group, a (CrC ₃ ) perfluoroalkyl group, most preferably substituents independently selected from the group hydroxy group, halogen atom, (CrC ₃ ) alkyl group and (CrC ₃ ) alkoxy. A particular subject of the invention are compounds of general formula I according to one of the claims, wherein R ¹ and R ² independently of one another particularly preferably a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CrC ₃ ) alkyl group, an optionally substituted (-C ₃₎ alkoxy, (CrC ₃₎ alkylthio group, a (-C ₃₎ perfluoroalkyl group, most preferably a hydroxy group, a halogen atom, a (-C ₃₎ alkyl group or a (C ₁ -C ₃₎ - Alkoxy group mean. If the text speaks of "basic structure", then the tetrahydronaphthalene system is meant.

The 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 VCH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, - NH- (CH ₂ ) n ₊ i, N (CrC ₃ -alkyl) - (CH ₂ ) n + i, -NH-N = CH-, wherein 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 Hs) ₂ , NH (C ₃ H ₇ ), N ( C ₃ Hy) ₂ , NH (C ₄ H ₉ ), N (C ₄ Hg) ₂ , NH (C ₅ H ₁₁ ), N (C ₅ Hn) ₂ , NH (CO) CH ₃ , NH (CO) C ₂ H ₅ , NH (CO) C ₃ H ₇ , NH (CO) C ₄ H ₉ , NH (CO) C ₅ H ₁₁ . The cycloalkyl group means a saturated cyclic group having 3 to 7 ring carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (C 1 -C ₅ ) -alkyl groups, (C 1 -C ₅ ) -alkoxy groups , Methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.

The cycloalkylalkyl group means, for example, - (CH ₂ ) -cycloalkyl, - (C ₂ H ₄ ) -cycloalkyl, - (C ₃ H ₆ ) -cycloalkyl, - (C ₄ H ₈ ) -cycloalkyl, - (C ₅ H ₁₀ ) - Cycloalkyl, wherein cycloalkyl is defined as described above. 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. As (Ci-C ₃ ) -Exoalkylidengruppe is to be understood a group which is bound via an exodo double bond to the system (ring or chain). 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 linked to the skeleton via a C 1 -C ₅ -alkyl group, where the alkyl group may be straight-chain or branched.

Heterocyclylalkenyl groups are heterocyclyl groups which are bonded to the skeleton via an unsaturated C ₂ -Cs-alkyl group, where the alkenylene groups may be straight-chain or branched. Diθ aryl group R ⁵ and R ⁶ may be phenyl or naphthyl. Suitable substituents for both groups come CrC ₃ alkyl, hydroxy, -C ₃ - alkoxy, _Ci-C3 alkylthio, halo, cyano, COO (C _r C ₅₎ alkyl, COOH, N (R ¹⁰ R ^11), nitro, into consideration. The degree of substitution may be one or more than one, may include several identical or different substituents. Mono- or disubstituted phenyl and naphthyl groups R ⁵ are preferred.

The aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also carry keto, (CrC ₃ ) - Exoalkyliden. 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 which is linked to a skeleton via a C 1 -C ₈ -alkyl group, where the 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.

A monocyclic or bicyclic heteroaryl group R ⁵ and R ⁶ which may be hydrogenated at one or more sites is understood as meaning all monocyclic or bicyclic aromatic ring systems which contain at least one heteroatom and at most seven heteroatoms. Preference is given to ring systems having 1-5 heteroatoms. Suitable heteroatoms are 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms, which can occur in all subcombinations in the ring system as long as they do not exceed the number specified for the respective heteroatom and, in total, the maximum number of seven heteroatoms. Besoners preferred are heterocyclic systems which have 1-3 heteroatoms in ring system and contain at least one nitrogen atom. For example, belong to it Compounds of the formula I in which R ⁵ or R ^{6 is} furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl , Pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl , Benzofuranyl, benzimidazolyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl,. Dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, coumarinyl, isocumarinyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, , Cinnolinyl-, phthalazinyl, 1, 7- or 1, 8-Naphthyridinyl-, means to the present invention and constitute a particular embodiment of the invention. Heterocyclic ring systems containing directly adjacent to each other more oxygen or sulfur atoms are not subject matter the invention.

When the heteroaryl groups are partially or completely hydrogenated, compounds of the formula I in which R ^{5 is} tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, chromenyl, isochromenyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl , Decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazin-4-onyl, 3,4-dihydrobenz [1,4] oxazine 4-onyl, 3,4-dihydro-2H-benzo [1, 4] thiazinyl, 4H-benzo [1, 4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H-Quinazolin-4-onyl, 1H-Quinazolin-4-onyl, 3,4-Dihydro-1H-quinoxaline-2-onyl, 2,3,1,3,3,4-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 - Dihydro pyrido [3,2-d] [1,3] oxazin-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro-2H -isoindolyl, 1, 2-

Dihydroindazolyl, 1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl, 2,2-dihydro-1H-pyrrolo [2,3-b] 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 to 3 hydroxyl or 1 to 3 COOR ¹⁰ groups), C ₅ ) alkoxy groups, hydroxy groups, halogen atoms, (C ₁ -C ₃ ) exoalkylidene-substituted mono- or bicyclic heteroaryl groups which optionally contain 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups , which group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more points means.

Particular 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 to ₃ hydroxyl or 1 to 3 COOR ¹⁰ groups), (C 1 -C 4) -C ₅ ) -alkoxy groups, hydroxy groups, halogen atoms, (CrC ₃ ) exoalkylidene-substituted, optionally 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group where this group may be linked via any position with the amine of the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites and contains at most 3 heteroatoms in the monocyclic ring system and at most 4 heteroatoms in the bicyclic ring system. A preferred subject matter of the invention are compounds of the general formula I ₁ in which R ^{5 is} a phenyl, phthalidyl or isoindolyl radical which is optionally substituted by C ₁ -C ₅ -alkyl, halogen, hydroxyl, C 1 -C ₅ -alkoxy, keto or (C 1 -C ₃ ) -exoalkylidene , Dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group. A preferred subject of the invention are compounds of general formula I, wherein R ^{5 is} optionally substituted with C 1 -C ₅ -alkyl, halogen, hydroxy, C 1 -C ₅ -alkoxy, keto or (C ₁ -C ₃ ) -exoalkylidene-substituted phenyl, phthalidyl, isoindolyl , Dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, Cinnolinyl, phthalazinyl, 1, 7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group. A preferred subject of the invention are compounds of general formula I, wherein R ^{5 is} an optionally independently of one another with one or more Ci-C ₅ alkyl, halogen, hydroxy, Ci-C ₅ alkoxy, keto or (d C ₃ ) Exoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl , Chromenyl, isochromenyl, chromenonyl, isochromenonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7 or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group. A preferred subject of the invention are compounds of general formula I, wherein R ^{5 is} an optionally independently of one another with one or more CrC ₅ alkyl, halogen, hydroxy, Ci-C ₅ alkoxy, keto or (C _r C ₃ ) Exoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, coumarinyl, isocoumarinyl, chromenyl, isochromenyl, chromenonyl, isochromenonyl, quinolinyl -, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl means.

A preferred object are compounds of the general formula I in which R ^{5 is} a phenyl or naphthyl radical which is optionally substituted by C 1 -C ₅ -alkyl, halogen, hydroxyl, C 1 -C ₅ -alkoxy, phthalidyl, thiophthalidyl, Benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl , Benzimidazole or indolyl group. Very particular preference is given to compounds of the general formula I according to one of the claims, in which R ⁵ denotes a quinazolinyl, quinolonyl, isoquinolonyl, phthalazinonyl, optionally substituted by C ₁ -C ₃ -alkyl, halogen, hydroxyl, C ₁ -C ₃ -alkoxy Phthalazinyl, quinolinyl, isoquinolinyl, dihydroindolyl, dihydroisoindolyl, isochromenonyl group. In particular, compounds of general formula I according to one of the claims, wherein R ^{5 is} a quinazolinyl, quinolonyl, isoquinolonyl, phthalazinonyl, quinolinyl, dihydroindolyl optionally substituted by C 1 -C ₃ -alkyl, halogen, hydroxy, C 1 -C ₃ -alkoxy , Dihydroisoindolyl-, Isochromenonylgruppe, subject of the present invention. 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 bonded to the skeleton via a C 1 -C ₈ -alkyl group which may be straight-chain or branched.

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

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 . When R ⁷ and R ^{8 form} a carbocycle, a five- to six-membered carbocycle is preferred.

The invention further provides compounds of the general formula I in which R ^{6 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, a (C ₃ -C ₇ ) -cycloalkyl group, a (C ₃ -C ₇ ) -cycloalkyl (C ₁ -C ₈ ) -alkyl group, (C ₃ -C ₇ ) - Cycloalkyl (C ₂ -C ₈₎ alkenyl group, a heterocyclyl group, a heterocyclyl (CRC8) alkyl, heterocyclyl (C2-C8) alkenyl group, an aryl group, an aryl (-C ₈₎ alkyl, aryl (C ₂ -C 8) alkenyl means.

An object of the invention are compounds of general formula I ₁ wherein R ^{6 is} a (C-ι-C ₅ ) alkyl group or an optionally partially or fully fluorinated (Ci-C ₅ ) alkyl group, an aryl group, an aryl (Ci-C ₈₎ alkyl, aryl (C ₂ -C ₈₎ alkenyl group, a (C ₃ -C ₇₎ - cycloalkyl, (C ₃ -C ₇₎ cycloalkyl (Ci-C alkyl group _8), (C ₃ -C ₇₎ - Cycloalkyl (C-2-C ₈ ) alkenyl group means. Another object of the invention are compounds of general formula I, in which R ^{6 represents} a (Ci-C ₃ ) alkyl group or an optionally partially or fully fluorinated (Ci-C ₃ ) alkyl group. Particularly preferred are the fully fluorinated alkyl groups. Most preferred is the CF ₃ group. The invention further provides compounds of the formula I in which R ^{6 is} a C ¹ -C 10 -alkyl group which may optionally be substituted by 1 to 3 hydroxyl groups, halogen atoms, an optionally substituted phenyl group, an optionally by 1 to 2 keto groups, 1 to 2 (CrC ₅ ) alkyl groups, 1-2 (CrC ₅ ) alkoxy groups, 1-3 halogen atoms, 1-2 (Cr C ₃ ) exoalkylidene-substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 Mono- or bicyclic heteroaryl group containing sulfur atoms, which groups may be linked via any position with the nitrogen atom and may optionally be hydrogenated at one or more sites, means. The compounds of the general formula I according to the invention can exist as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible stereoisomers (eg: RRRR, RRRS, RRSR, RSRR, SRRR, RSRS, RRSS, RSSR, SRRS, SSRR, SRSR, RSSS, SRSS, SSRS, SSSR, SSSS), both as racemates, as well in enantiomerically pure form, both as pure diastereomers and as diastereomeric mixtures. The compounds according to the invention may also be present in the form of salts with physiologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate. Esters or ethers or amides of the compounds of the general formula I or other compounds which metabolize in the organism to compounds of the general formula I are likewise provided by the present invention.

The compounds according to the invention are prepared either a) by converting styrenes of the general formula (II) prepared by methods known in the prior art into the compounds of the general formula (III) by means of an optionally enantioselectively conducted ene reaction with chiral Lewis acids. As chiral Lewis acids it is possible to use: (R) - or (S) -SEGPHOS-PdCl ₂ (Mikami et al., Tetrah. Asymm., 2004, 15, 3885-89), (R) - or (S) -BINOL- Ti (OiPr) ₂ (Ding et al Tetrah. Lett. 2004, 45, 2009-12), (R) - or (S) -Cu ^f BuBOX,), (R) - or (S) -Cu 'PrBOX , (R) - or (S) -Cu PhBOX, (R) - or (S) -Cu AdaBOX (Evans et al., J. Am. Chem. Soc., 2000, 122, 7936-43), (R) - or (S) -Ph-pybox Sc (OTf) ₃ (Evans et al., J. Am. Chem. Soc., 2005, 127, 8006-7), (R) - or (S) - Pr-pybox Yb ( OTf) _3, (R) - or (S) - ^f-Bu pybox Yb (OTf) _3, (R) - or (S) -Ph-pybox Yb (OTf) ₃ (Qian et al Tetrah Asymm 2000th.. , 11, 2347-57). By reduction and amination, the imine (IV) is produced by methods known to those skilled in the art,

catalyst

(II) (Hl)

(III) (IV)

Lewis acid

(IV) (Ia) 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 ⁰ C to + 80 ° C (preferably in the range of -30 ⁰ C to +80 ⁰ C) is cyclized to the compounds of general formula (Ia) (for R ⁸ + R ⁹ = R ^8a = alkylidene), or b) in that the compounds of the general formula (III) prepared by the method a) are hydrogenated into the compound of the formula (V) (for R ⁹ = H) or by methods of cyclopropanation known to the skilled person (J. Am (1958) pp. 5323-5324, J. Org. Chem. 50 (1985) pp. 4412-4414) in compounds of the 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) become.

(III) (V) By reduction and amination, the imine (VI) is produced analogously to a), which then either without further reagent in a solvent, preferably

(V) (VI) chlorinated hydrocarbons, such as methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids at temperatures ranging from -70 ⁰ C to +80 ⁰ C (preferably in the range from -30 ⁰ C to +80 ⁰ C) is cyclized to the compounds of general formula to compound (I).

Lewis acid

(VI) (I)

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

Reference substance [ ³ H] -dexamethasone, the substances show a high affinity for GR. Thus, for the compound of Example 3, an IC ₅ o (GR) = 36 nM and IC ₅ o (PR)> 1 μM were measured. As a major molecular mechanism for the anti-inflammatory effect of glucocorticoids, the GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is caused by a Interaction of the GR with other transcription factors, eg AP-1 and NF-kappa-B, effects (for a review 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 ICso (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 ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration. The compounds of the general formula I inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.

One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and by free amino acids, which arise from the degradation of proteins (catabolic effect of glucocorticoids). A key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be photometric can be determined from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after administration of the test substances, the liver is removed and the TAT activity in the homogenate is measured. The compounds of general formula I do not or only to a limited extent induce tyrosine aminotransferase in doses in which they are anti-inflammatory in this test.

Because of their anti-inflammatory and additional anti-allergic, immunosuppressive and anti-proliferative effect, the compounds of the general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans: The term "DISEASE" stands for the following indications:

(i) Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes:

- Chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma

- Bronchitis of various origins - All forms of restrictive lung diseases, especially allergic alveolitis,

- All forms of pulmonary edema, especially toxic pulmonary edema

- Sarcoidoses and granulomatoses, in particular Boeck's disease (ii) Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes:

- All forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica - reactive arthritis

- Inflammatory soft tissue diseases of other causes

- Arthritic symptoms in degenerative joint disease (arthrosis)

- Traumatic arthritis - Collagenosis of any genesis, eg systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjögren syndrome, StNI syndrome, Felty syndrome

(iii) allergies associated with inflammatory and / or proliferative processes:

All forms of allergic reactions, e.g. Quincke edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, 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

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

- Bull's-eye dermatoses

- diseases of the lichenoid type, - pruritus (eg allergic genesis)

- Seborrheic dermatitis

- Rosacea

- Pemphigus vulgaris

- Erythema exudativum multiforme - Balanitis

- vulvitis

- Hair loss like alopecia areata

- Cutaneous T - cell lymphomas

(vi) kidney disease associated with inflammatory, allergic and / or proliferative processes:

- Nephrotic syndrome

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

- Acute liver cell decay

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

- Chronic aggressive and / or chronic intermittent hepatitis

(viii) Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes:

- regional enteritis (Crohn's disease) - ulcerative colitis

- Gastritis

- Reflux esophagitis

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

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

- Anal eczema

- fissures

- Hemorrhoids

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

- allergic keratitis, uveitis, iritis,

- conjunctivitis

- Blepharitis - neuritis nervi optici

- Chorioditis

- Ophtalmia sympathica

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

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

- Otitis media (xii) neurological disorders associated with inflammatory, allergic and / or proliferative processes:

- Cerebral edema, especially tumor-related cerebral edema

- multiple sclerosis - acute encephalomyelitis

- Meningitis

various forms of seizures, e.g. BNS-seizures

(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

- Lymphogranulomatoses

- Lymphosarcomas

- Extensive metastases, especially in breast bronchial and prostate carcinoma (xv) Endocrine disorders associated with inflammatory, allergic and / or proliferative processes:

- endocrine orbitopathy

- Thyrotoxic crisis

- Thyreoiditis 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 for: congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome Acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.

- congenital secondary adrenal insufficiency, e.g. congenital hypopituitarism - acquired secondary adrenal insufficiency, e.g. postinfectious, tumors etc.

(xix) emesis associated with inflammatory, allergic and / or proliferative processes:

- e.g. in combination with a 5-HT3 antagonist in cytostatic - induced vomiting.

(xx) Pain in inflammatory genesis, e.g. lumbago

In addition, the compounds of the general formula I according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic glucocorticoids are used today (see Hatz, HJ, Glucocorticoids: Immunological Principles, Pharmacology and Therapy Guidelines, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart , 1998).

All 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-mentioned disease states, the appropriate dose will vary and depends, for example, on the potency of the compound of general formula I, the host, the mode of administration and the nature and severity of the conditions to be treated, as well as the prophylactic use or therapeutic.

The invention further relates to combination therapies or combined compositions wherein a glucocorticoid receptor (GR) agonist of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof, administered either simultaneously (optionally in the same composition) or sequentially together with one or more medicaments for the treatment of any of the above-mentioned conditions. For example, for the treatment of rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive pulmonary disease), asthma or allergic rhinitis, a GR agonist of the present invention may be combined with one or more drugs to treat such a condition. Where such a combination is administered by inhalation, the drug to be combined may be selected from the following list:

A PDE4 inhibitor including an isoform PDE4D inhibitor;

• a selective ß.sub2. Adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,

Pirbuterol or indacaterol;

A muscarinic receptor antagonist (for example an M1, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;

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

• an inhibitor of p38 kinase function.

For another object of the present invention, such combination with a GR agonist of formula (I) or a pharmaceutically acceptable salt thereof is employed for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (e.g. for example, aminophylline or theophylline), which may also be administered by inhalation or orally.

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

The compounds of the general formula I according to the invention are particularly suitable for the preparation of a medicament for the therapy or prophylaxis of inflammatory diseases.

In particular, the use of the compounds according to the invention for the manufacture of a medicament for the treatment of a disorder mentioned under i), ii), iii), iv), v) and x) is an object of the present invention.

In general, satisfactory results are expected in animals when the daily doses range from 1 μg to 100,000 μg of the compound of the invention per kg of body weight. For larger mammals, such as humans, a recommended daily dose is in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg body weight, more preferably a dose of 10 to 10,000 μg per kg body weight. For example, this dose is conveniently administered several times a day. For the treatment of an acute shock (eg anaphylactic shock) single doses may be given that are well above the doses mentioned above. The formulation of the pharmaceutical compositions based on the novel compounds is carried out in a conventional manner by the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinflussern, binders, humectants, lubricants, absorbents, diluents, Geschmackskorrigentien, colorants, etc. processed and converted into the desired application form. Reference may be made to Remington ^'s Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions in question.

For parenteral administration, injection and infusion preparations are possible.

For intraarticular injection appropriately prepared crystal suspensions may be used.

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

For rectal administration, the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy.

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

For local application to the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses, the new compounds may be used as drops, ointments and tinctures in appropriate pharmaceutical preparations. For topical application, formulations in gels, ointments, greases, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be in these preparations 0.01% - 20% in order to achieve a sufficient pharmacological effect.

The invention also encompasses the compounds of general formula I according to the invention as therapeutic active ingredient. The invention further relates to the compounds of the general formula I according to the invention as a therapeutic active ingredient together with pharmaceutically acceptable and acceptable auxiliaries and excipients.

The invention also includes a pharmaceutical composition containing one of the pharmaceutically active compounds of the invention or their mixture or their pharmaceutically acceptable salt and pharmaceutically acceptable excipients and carriers.

Experimental part

example 1

2-Fluoro-5-f (8-fluoro-2-methylquinazoline-5-diamino-5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) -dahthalene-1,6-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, a 50 ⁰ C warm solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml of conc , Hydrochloric acid (37%), which was previously stirred at this temperature for 1 h. The mixture is stirred for a further 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 ⁰ C and keeps this temperature for 5 min. After cooling and for a further hour, the precipitated light brown precipitate is filtered off, washed with water and dried. 3.0 g (15.0 mmol) of the hydroxylimine are obtained

Intermediate, the portions in 15 ml of conc. Sulfuric acid are dissolved at 60 ⁰ C. After complete addition, the mixture is heated for 2 hours at 8O ⁰ C and 4 hours at 90 ⁰ C. It is allowed to cool and the solution is poured onto 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dried 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-difluoroisin obtained. 1.8 ml of a 30% strength hydrogen peroxide solution are added dropwise to the isatin in 30 ml of a 1 molar sodium hydroxide solution over a period of 10 minutes. After stirring for 2 hours at RT is cooled to 0 ⁰ C and 5 ml of a 4 molar hydrochloric acid are added and diluted with 50 ml of water. One extracts with

Ethyl acetate, dried over sodium sulfate, concentrated and so quantitatively 1.27 g of 3,6-Difluoranthranilsäure, which is reacted without further purification. 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 thus obtained 1, 03 g (5.25 mmol) 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated to 125 ⁰ C in 20 ml of phosphoryl chloride over 12 h. 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 To 20 ml (213 mmol) of 2-fluorophenol in 24 ml of pyridine at 0 ⁰ C 19.6 ml of propionyl chloride dripped. It is stirred for 1.5 hours at room temperature and then 200 ml of 1 M 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 4 M 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) potassium carbonate and 10.9 ml (70 mmol) of methyl iodide. The mixture is heated for 6 hours at 70 ⁰ 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 ⁰ C. 103 ml (103 mmol) of a 1 M titanium tetrachloride solution in dichloromethane are added so that the internal temperature does not exceed 1O ⁰ C. The mixture is stirred for 30 minutes and at 0 ⁰ C, 18.8 g (103 mmol) of 1- (3-fluoro-2-hydroxyphenyl) -propan-1-one in 85 ml of tetrahydrofuran to. After 1 hour, dilute with diethyl ether and pour the reaction mixture carefully onto a cold 4 M hydrochloric acid, the Temperaturr rises 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) Ethyltrifluorpyruvat and 1.2 g (2 mmol) Ytterbiumtriflat and the mixture is heated for 20 hours at 14O ⁰ C. After cooling the mixture is directly chromatographed on silica gel (hexane / ethyl acetate 20%) and gives 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 charcoal (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 removes the solvent 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 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), 1.32-1.58 (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. To 360 mg (0.6 mmol) imine in 20 mL CH ₂ CI ₂ at -30 ⁰ C 7.7 ml (7.7 mmol) of a 1 M boron tribromide solution was dropped. The cooling bath is removed and after 30 minutes the mixture is mixed 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 yield 40 mg (0.09 mmol) of product as a racemic mixture of the main diastereomer.

¹ H-NMR (300 MHz ₁ 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- (r6-Fluoro-3,4-dimethyl-2,5-dihydroxy-2- (trifluoromethyl) -1, 2,3,4-tetramvonaphthalene-1-vinylamino) quinoline-2 (1H) -one 5-aminoquinoline-2 ( 1 H) -on

4.5 g of 5-nitroquinoline-2 (1 H) -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 Catalyst hydrogenated under normal 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 (1 H) -one and 0.4 ml of titanium tetraethylate are stirred in 8 ml of toluene for 2 h at 100 ⁰ C. 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 the

Vacuum to give 480 mg of 5 - {[(3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentylidene] amino} quinoline-2 (1 H) -one as a crude product. To 480 mg imine in 19 mL CH ₂ CI ₂ of a 1 M boron tribromide solution are added dropwise at -35 ⁰ C for 10 minutes, 9.5 mL (9.5 mmol). It is allowed to warm for 2 hours - 2O ⁰ C and poured the approach into cold ges. NaHCO _ß 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, 1 H), 6.46 (d, 1H), 6.63 (d, 1H), 6.67 (d, 1H), 6.70 (dd, 1H) ₁ 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} quinoline-2 (1H) -one is cleaved by preparative chiral HPLC (Chiralcel OD 5μ) into the enantiomerically pure compounds:

Enantiomer 1: analytical HPLC: R _t = 8.4 min (Chiralcel OD 5μ, 250x4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 ml / min flow) Enantiomer 2: analytical HPLC: R _t = 15.1 min (Chiralcel OD 5μ, 250x4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 ml / min flow)

Example 3

2-fluoro-5 | ^" (7-fluoro-2-methylquinazolin-5-yl) aminol-5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) naphthalene-1,6-diol

5-Amino-7-fluoro-2-methyyninazoline 17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (Florval, I. Fagervall, L.-G-Larsson, SB Ross, Eur. J. Med. Chem. 34 (1999) 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) are combined in 70 ml of butyronitrile. The mixture is heated with vigorous stirring for 17 hours at 145 ° C and the solvent is removed in vacuo. After chromatography of the residue on silica gel with hexane / ethyl acetate (0-70%) to obtain 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methychinazolin. 1g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methychinazolin are dissolved in 74 ml toluene and cooled to -7O ⁰ C. 9.5 ml (11.4 mmol) of a 1, 2 M disobutylaluminum hydride solution in toluene are added dropwise over 30 minutes. Allow the reaction mixture to -40 ⁰ C warm and stirred for 4 hours at -40 ⁰ C. It is slowly water was added and stirred for 30 minutes at room temperature until a precipitate forms which is removed by filtration through Celite. Separate the phases, wash with saturated sodium chloride solution and Dries over sodium sulfate. Chromatography on silica gel with hexane-ethyl acetate (0-100%) gives 64 mg of the product. ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.83 (s, 3H), 4.67 (br., 2H) ₁ 6.50 (dd, 1H), 6.93

(dd, 1H), 9.23 (s, 1H). 261 mg (0.85 mmol) 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 for 2 h at 100 ⁰ C. 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 crude product. To the imine in 17 ml of CH ₂ CI ₂ at -35 to ⁰ C over 10 minutes 8.5 mL (8.5 mmol) of a 1 M boron tribromide solution was dropped. It is allowed to warm for 2 hours - 2O ⁰ C and poured 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 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

2-Fluoro-5 - [(7-fluoro-2-methylquinazolin-5-yl) amino] -5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) naphthalene-1, 6 Diol is cleaved by preparative chiral HPLC (Chiralcel OD 5μ) into the enantiomerically pure compounds:

Enantiomer 1: analytical HPLC: R _t = 7.9 min (Chiralcel OD 5μ, 250x4.6 mm, hexane / ethanol 5 => 20% in 30 minutes, 1 ml / min flow) Enantiomer 2: analytical HPLC: R _t = 13.6 min (Chiralcel OD 5μ, 250x4.6 mm, hexane / ethanol 5 => 20% in 20 minutes, 1 ml / min flow)

Analog can be prepared: Example 4

5- (r6-Fluoro-2,5-dihydroxy-3,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-vinylamino) -2-methyl-phthalazin-1-one

5-amino-2-methyl-phthalazine-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-

Bromsuccinimide 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, 1 H), 7.88 (t, 1 H), 8.3 (d, 1 H), 8.56 (d,

1H)

5-nitro-phthalazine-1-one;

18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100 ⁰ C for 1 h. Then 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml

Added DMF and it is stirred at 100 ⁰ C for a further 4 h. It is added to water, extracted several times with ethyl acetate and the org. Phase with water and

Sole washed. 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, 1 H),

13.13 (bs, 1 H)

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 given to water, with

Essigester extracted several times and the org. Phase with water and brine washed. 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, 1 H) 5-amino-2- methyl-phthalazine-1-one:

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, CDCl ₃ ), = 3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 1H), 7.8 (d, 1H), 8.16 (s, 1H )

The desired product can be prepared analogously to Example 1 from 5-amino-2-methyl-phthalazin-1 -one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal ,

Example 5

2-Fluoro-5.6.7.8-tetrahydro-7,8-dimethyl-5-r (2-methylquinazolin-5-yl) -aminol-6- (trifluoromethyl) -naphthalene-1,6-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 become in 75 ml of phosphoryl chloride heated for 20 hours under reflux. 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.

Example 6

5-r (7.8-Difluoro-2-methylquinazoline-5-vinylamino-2-fluoro-5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) -naphthalene-1,6-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 THF ⁰ C 156 mL (391 mmol) of a 2.5M butyl lithium solution in hexane are added dropwise at -70 , The mixture is allowed to stir for a Sunde and then added dropwise to 38.6 ml of DMF in 90 ml THF, during which the solution is allowed to warm to -60 ⁰ C. The mixture is stirred for a further hour at -70 ⁰ C and then poured the cold reaction solution onto 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 ⁰ 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-methychinazolin are dissolved in 140 ml toluene and cooled to -7O ⁰ 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

-25 ⁰ C. It is slowly isopropanol and then water was added and stirred for 12 hours at room temperature until a precipitate forms which is removed by filtration through Celite. One washes well with one Methylene chloride Methanol Mixture after 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 ⁰ 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 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. To the imine in 10 mL CH ₂ CI ₂ at -35 ⁰ C a 1 M boron tribromide solution are added dropwise over 10 minutes 5 ml (5 mmol). It is allowed to warm for 2 hours - 20 ⁰ C and poured 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 2-Fluoro-5-r (2-methylquinoline-5-vinylamino-5,6,7,8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) naphthalene-1,6-diol The desired product can be prepared analogously to Example 1 from 5-amino-2-methylquinoline and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) ρentanal.

Example 8

6-Chloro-5-methoxy-1-r (2-methylquinazolin-5-yl) -amino1-3-methyl-4-methylene-2- (trifluoromethvn-1,2,3,4-tetrahydronaphthalene-2-ol

4- (3-Chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enal To 250 mmol 2-chlorophenol dissolved in 200 ml dichloromethane (DCM) and 38 ml 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% AIICI ₃ in 40 ml of 1, 2-dichlorobenzene. The mixture is stirred at 100 ⁰ 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 are dissolved in acetone, carefully added at RT 240 mmol of potassium carbonate and 144 mmol of methyl iodide and stirred at 8O ⁰ 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 g of zinc powder and 1.22 g of lead (II) chloride are initially charged in 800 ml of THF, and 53 ml of dibromomethane are slowly added dropwise at RT. After stirring for 30 minutes, 100 mmol of titanium (IV) chloride are slowly added dropwise. After further stirring for 30 minutes, 100 mmol of 1- (3-chloro-2-methoxy-phenyl) -propan-1-one added dropwise and stirred at RT for 4 h. It is diluted with diethyl ether, the reaction mixture is added to ice / hydrochloric acid (4 m), the phases are separated, extracted with diethyl ether and dried with sodium sulfate. The crude product solution is slowly concentrated on a rotary evaporator at a bath temperature of 45 ° C and finally completely concentrated. The crude product is chromatographed on silica gel with hexane / ethyl acetate 7: 3. This gives 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 trifluoropyrrugate (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 added at -2O ⁰ C in 7 ml of THF with 24 mg LiAlH. ₄ The mixture is stirred for about 4 h at 0 ⁰ C, a further 20 mg of LiAIH _{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-methoxyphenyl) -3-methyl-2-trifluoromethyl-pent-4-en-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 gives 110 mg of further 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4-enal 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 washed with

Essigester extracted, 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. 60 mg of 4- (3-chloro-2-methoxyphenyl) -3-methyl-1 - [(2-methylquinazolin-5-yl) imino) -2- (trifluoromethyl) pent-4-ene-2-one are obtained. ol as a mixture of isomers. The imine is taken up in DCM and stored at -20 ⁰ C 1.3 ml of titanium tetrachloride solution (1 M in DCM) was added dropwise. It is allowed to come to 0 ⁰ C and are the mixture after 4 h stirring 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).

The following can be prepared analogously: a) 6-chloro-r (7,8-difluoro-2-methylquinazoline-5-vamoyl ^' 1-5-metoxy-3-methyl-4-methylene-2- (trifluoromethyl) -1.2,3,4 -tetrahvdronaphthalin-2-ol

The desired product can be prepared analogously to Example 8 from 5-amino-7,8-difluoro-2-methylquinazoline and 4- (3-chloro-2-methoxyphenyl) -2-hydroxy-3-methyl-2-trifluoromethyl-pent-4- be made enal.

b) θ-Chloro-δ-methoxy-i-methvithinoline-δ-diamino-S-methyl-methyl-2- (trifluoromethyl) -1,3,3,4-tetrahydronaphthalene-2-ol The desired product can be prepared analogously to Example 8 from 5-amino-2-methylquinoline and ΦCS-Chlor ^ -methoxyphenyO ^ -hydroxy-S-methyl ^ -trifluoromethyl-pent-enal.

Example 9

6,7,8,8a, 9,10-Hexahydrod-10-r (2-methylquinazolin-5-yl) amino 1-9- (trifluoromethyl) -phenanthren-9-ol

3,3,3-Thfluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) -propionic acid ethyl ester 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. To give 2 diastereomers: 312 mg diastereomer A and 293 mg of diastereomer B. ¹ H-NMR (300 MHz, CDCI _3): δ = 1:07 (t, 3H) ₁ 1:59 - 1.67 (m, 1 H) ₁ 1.72 - 1.85 ( m, 1 H) ₁ 2.10 - 2.34 (m, 4H) ₁ 3.01 - 3.11 (m, 1 H) ₁ 3.57 (bs, 1 H) ₁ 3.61 - 3.70 (m, 1 H) ₁ 3.80 (s, 1 H) ₁ 5.97 (t, 1 H) ₁ 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 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) - propionic acid ethyl ester is dissolved in 11 ml diethyl ether and cooled under nitrogen to -10 ⁰ C. 69 mg (1.82 mmol) of lithium aluminum hydride are added in several portions. The reaction is 1 hour at -10 ⁰ C and stirred for 1 h at 0 ⁰ C. 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, 1 H) ₁ 1.80 - 1.92 (m, 1 H) ₁ 2.00 - 2.14 (m, 1 H) ₁ 2.20 - 2.28 (m, 2H), 2.31 - 2.41 (m, 1H), 3.66 (bs, 1H) ₁ 3.78 (d, 1 H) ₁ 6.05 (t, 1 H) ₁ 7.14 - 7.20 (m, 2H) ₁ 7.24 - 7.33 (m , 3H) ₁ 9.05 (quint, 1H). 112 mg (0.39 mmol) of 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) propionaldehyde, 62 mg (0.39 mmol) of 5-amino-2-methyl-quinazoline and 210 μl (1 mmol) of titanium tetraethylate were dissolved in 2 ml of toluene and boiled under reflux for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured onto water, washed with

Diluted 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-phenyl-cyclohex-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) ₁ 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 ⁰ 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 workup is on saturated

Sodium bicarbonate solution poured 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).

The following can be prepared analogously: a) 10-r (7,8-Difluoro-2-methylquinazoline-5-vinylamino1-6.7.8.8a.9,10-hexahydro-9- (trifluoromethyl) -phenanthren-9-ol The desired product can be prepared analogously to Example 9 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohex-2-enyl) - propionaldehyde become.

b) 5- (πO-r6.7.8,8a.9,10-hexahydro-9- (trifluoromethyl) -9-hydroxy-phenanthrenyl-amino} quinolin-2 (1H) -one

The desired product can be prepared analogously to Example 9 from 5-aminoquinoline-2 (1 H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohex-2-enyl) propionaldehyde.

c) 6.7,8.8a.9.10-hexahydro-10-r (2-methylquinolin-5-yl) -aminol-9- (trifluoromethyl) -phenanthren-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-phenylcyclohex-2-enyl) propionaldehyde.

d) 3.3a.4.5-Tetrahvdro-5-r (2-methyl-quinazolin-5-vinylamino) -4- (trifluoromethyl) -2H-benz [elinden-4-ol

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

e) 5-r (7,8-Difluoro-2-methyl-quinazolin-5-yl) -aminol-3.3a.4.5-tetrahydro-4- (trifluoromethyl) -2H-benzoindeninden-4-ol

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

Example 10

4b.5.6.7, 8,8a, 9,10-octahydro-10-r (2-methylquinazoline-5-vino-1-1- (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-phenylcyclohex-2-enyl) propionate are dissolved in 20 ml of methanol and treated with 300 μl of acetic acid and 30 mg of palladium on charcoal (10%) provided. 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 3,3,3-trifluoro-2-hydroxy-2- (2-phenylcyclohexyl) - propionic acid ethyl ester are dissolved in 18 ml diethyl ether and cooled under nitrogen to -10 ⁰ C. 111 mg (2.94 mmol) of lithium aluminum hydride are added in several portions, stirred for 1 h at -10 ⁰ C and allowed to thaw for 3 h to room temperature. to

Work-up 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-ylimino) - (2-phenyl-cyclohexyl) propan-2-ol. 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-methylquinazolin-5-yl-imino) -2 - (- 2-phenylcyclohex-2-enyl) -propanol are dissolved in 3 ml of dichloromethane and cooled to -20 ⁰ 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, 1 H).

The following can be prepared analogously: a) 10-r (7,8-difluoro-2-methylquinazoline-5-vinylamino) -4b.5.6.7.8.8a.9.10-octahydrod-9- (trifluoromethyl) -phenanthren-9-ol

The desired product can be prepared analogously to Example 10 from 5-amino-7,8-difluoro-2-methylquinazoline and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) - propionaldehyde.

b) 5-1 π Q-r4b.5,6,7,8,8a, 9,10-octahydro-9-hydroxy-9- (trifluoromethyphenanthrenylamino) quinoline-2 (1 H) -one

The desired product can be prepared analogously to Example 10 from 5-aminoquinoline-2 (1 H) -one and 3,3,3-trifluoro-2-hydroxy-2- (2-phenyl-cyclohexyl) propionaldehyde. c) 4b.5.6.7, 8,8a, 9,10-octahydro-10-r (2-methylquinoline-5-vnamino-9- (trifluoromethoxy-phenanthrene-9-ol

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

d) 2.3.3a A5.9b-Hexahydro-54 (2-methyl-quinazolin-5-yl) -aminol-4- (trifluoromethyl) -1H-benzerinden-4-ol

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

e) 5-r (7,8-Difluoro-2-methyl-quinazolin-5-vinylamino-1,2,3,3a, 4,5,9b-hexahydrod-4- (trifluoromethyl) -1H-benzoindene-4-ol

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

Example 11

(3aQr.4α, 5Q; 9άQf) 2.3.3a.4.5.9b-hexahydro-8-fluoro-5-r (2-methylquinazolin-5-yl) -aminol-4- (trifluoromethyl) -1H-benzerinden-4 , 9-Diol (1a, 2a) -2- (3-fluoro-2-methoxyphenyl) -a-hydroxy-a- (trifluoromethyl) cyclopentane-acetaldehyde:

2.62 g (15.5 mmol) of 3-fluoro-2-methoxyphenyl) boronic acid, 7.14 g (nonafluorobutyl) cyclopent-1-enyl ester 720 mg (42 mmol) of lithium chloride, 2.68 g (19.4 mmol) of potassium carbonate and tetrakis (triphenylphosphine) palladium are dissolved in 8 ml of toluene and 8 ml 1-

Propanol dissolved. The mixture is heated for 6 hours at 110 ⁰ C and added after cooling in water. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over Na ₂ SO _4. After removal of the solvent, the residue is purified by column chromatography on silica gel (hexane / diisopropyl ether, 0-10%). 1.9 g of 6- (cyclopent-1-enyl) -2-fluoroanisole are obtained. To 613 mg (0.99 mmol) of ytterbium trifluoromethanesulfonate are added 2.6 ml (19.7 mmol) Ethyl trifluoropyrrnate and 1.9 g (9.9 mmol) of 6- (cyclopent-1-enyl) -2-fluoroanisole in 10 ml of dichloromethane. The reaction mixture is stirred at 140 ^° C. for 16 hours and the reaction mixture is purified by column chromatography on silica gel (hexane / diisopropyl ether 0-10%). 391 mg of ethyl 2- (3-fluoro-2-methoxyphenyl) -α-hydroxy-α- (trifluoromethyl) cyclopent-2-enacetate are obtained

Mixture of diastereomers. 211 mg (0:58 mmol) of ethyl 2- (3-fluoro-2-methoxy- Phenyo-α-hydroxy-α ^ ^ trifluormethyOcyclopent -enacetat are dissolved in 18 ml of diethyl ether under argon and cooled to -25 ⁰ C. 52 mg ( 1.4 mmol) of lithium aluminum hydride are added in portions as a solid and it is rested for 1.5 hours as the temperature rises to -2O ⁰ C. 1 ml of ethyl acetate is added, after 10 minutes it is poured onto a mixture of ice and saturated ammonium chloride solution and stirred vigorously separates the phases and extracts repeatedly with ethyl acetate and diethyl ether The combined organic extracts are filtered through Celite, washed with saturated sodium chloride solution and dried over Na ₂ SO _{4 to give} 182 mg of 2- (3-fluoro-2-methoxyphenyl) -α- Hydroxy-α- (trifluoromethyl) cyclopent-2-enacetaldehyde 114 mg (0.36 mmol) of 32- (3-fluoro-2-methoxyphenyl) -α-hydroxy-α- (trifluoromethyl) cyclopent-2-enacetaldehyde are dissolved in 11 ml of methanol and 0.1 ml of acetic acid and 20 mg of palladium on carbon ( 10%) are added. The suspension is shaken under a hydrogen atmosphere at normal pressure until complete reaction. The mixture is filtered through Celite, rinsing thoroughly with ethyl acetate. After removal of the solvent, 108 mg of the saturated aldehyde are obtained as a mixture of 2 diastereomers. The diastereomers can be separated by column chromatography on silica gel (hexane / diisopropyl ether 0-15%) of one another: ^[• / ^^^^^ - (S-fluoro ^ -methoxyphenyO-α-hydroxy-α- ^ rifluormethyl) - cyclopentanacetaldehyd: ¹ H NMR (300 MHz ₁ CDCl ₃ ); δ = 1.78 (m, 2H), 1.98 (m, 2H), 2.15 (m, 3H), 2.88 (ddd, 1H), 3.95 (s, 3H), 3.97 (s, 1H), 4.46 (s, 1H), 6.84-6.99 (m, 3H), 9.06 (s, 1H). [yα (7 → J, 2α] -2- (3-fluoro-2-methoxyphenyl) -α-hydroxy-α- (trifluoromethyl) cyclopentane acetaldehyde: ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.60 (m, 2H), 1.80-2.35 (m, 5H), 3.26 (ddd, 1H), 3.62 (s, 1H), 3.95 (s, 3H), 6.84-6.99 (m, 3H), 9.18 (s , 1 H). 117 mg (0.37 mmol) of [7α (S * J, 2α] -2- (3-fluoro-2-methoxyphenyl) -α-hydroxy-α- (trifluoromethyl) cyclopentane acetaldehyde, 65 mg (0.41 mmol) of 5-amino-2 methylquinazoline and 0.2 ml of titanium tetraethylate are stirred in 10 ml of toluene for 2 hours at 100 ^° C. After cooling, it is poured into water and stirred vigorously The suspension is filtered through celite while being washed thoroughly with ethyl acetate The phases of the filtrate are separated It is extracted once more with ethyl acetate, dried over sodium sulphate and the solvent is removed in vacuo to give 116 mg of ['-'('S * j _J 2 O;] - 2- (3-fluoro-2-methoxyphenyl) -α- {[(methylquinazolin-5-yl) imino] methyl} -α- (trifluoromethyl) -. cyclopentanemethanol as crude to 116 mg of crude imine CH ₂ Cl 2 at -30 ⁰ C in 20 ml 2.2 ml (2.2 mmol) of a 1 M boron tribromide The mixture is allowed to warm to room temperature and stirred for 12 hours, poured into saturated NaHCO ₃ solution, the phases are separated, and the aqueous phase is extracted with CH ₂ Cl ₂ , dried the combined organic phases (Na ₂ SO ₄ ) and concentrated in vacuo. Column chromatography on silica gel (hexane / ethyl acetate 0-80%) gives 62 mg of product.

¹ H NMR (300MHz, DMSO [d6]); δ = 1.32 (m, 1H), 1.46 (m, 1H), 1.67 (m, 2H), 1.76 (m, 1H), 2.42 (m, 1H), 2.50 (m, 1H), 2.67 (s, 3H), 3.28 (d, 1H), 3.57 (ddd, 1H), 5.14 (d, 1H), 6.01 (s, 1H), 6.61 (dd, 1H), 6.89 (m, 2H), 7.05 (d, 1H), 7.63 (t, 1H), 9.41 (s, 1H), 9.65 (s, 1H).

Example 12

(3aα4 ^, 5 ^, 9 £) α) -2,3,3a, 4,5,9b-hexahydro-8-fluoro-5-r (2-methylquinazolin-5-yl) -aminol-4- (trifluoromethyl) -1 H-benzerinden-4,9-diol 65 mg (0.2 mmol) [7c <ft * J, 2α] -2- (3-fluoro-2-methoxyphenyl) -α-hydroxy-α- (trifluoromethyl) cyclopentane acetaldehyde, 36 mg (0.23 mmol) of 5-amino-2-methylquinazoline and 0.11 ml of titanium tetraethylate are stirred in 5 ml of toluene at 100 ^° C. for 2 hours. 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 sulphate and the solvent is removed in vacuo to give 100 mg of [1 a (R *), 2a] -2- (3-fluoro-2-methoxyphenyl) -α - {[(methylquinazolin-5-yl) imino] methyl} -α- (trifluoromethyl) - cyclopentanmethanol as crude product. To 100 mg of crude imine in 12 ml CH ₂ Cl ₂ 1.9 ml (1.9 mmol) of a 1 M boron tribromide solution was added dropwise at -30 ⁰ C. It is allowed to warm to room temperature and stirred for 2 hours. You pour in ges. 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 0-75%) yield 43 mg of product.

¹ H NMR (300MHz, DMSO [dβ]); δ = 1.38 (m, 2H), 1.74 (m, 1H), 1.85 (m, 1H), 2.11 (m, 1H), 2.64 (m, 1H), 2.67 (s, 3H), 2.78 ( ddd, 1H), 3.12 (d, 1H), 3.16 (ddd, 1H), 5.29 (d, 1H), 5.99 (s, 1H), 6.61 (dd, 1H), 6.72 (d, 1H), 6.90 (m, 2H), 7.01 (d, 1H), 7.60 (t, 1H), 9.46 (s, 1H), 9.67 (s, 1H).

Example 13

(3ao;, 4g, 5α, 9fcα) -8-fluoro-5- | ^" (7-fluoro-2-methylquinazoline-5-diamino-2,3,3a, 4,9,5-hexahydrod-4- (trifluoromethyl) -1H-benzoindene-4,9-diol

108 mg (0.34 mmol) of [1a (S *), 2a] -2- (3-fluoro-2-methoxyphenyl O-α-hydroxy-α-rifluoromethylcyclopentane-acetaldehyde, 66 mg (0.37 mmol) of sodium are obtained analogously to Example 11). Amino-7-fluoro-2-methylquinazoline and 0.2 ml of titanium tetraethylate are converted to the corresponding imine 156 mg of crude imine thus obtained are analogously to Example 11 at -30 ⁰ C addition temperature and then 2 hours at room temperature with 2.8 ml_ (2.8 mmol) 1 M boron tribromide Chromatography on silica gel (hexane / ethyl acetate 0-80%) gives 66 mg of the desired product ¹ H-NMR (300 MHz, CD ₃ OD), δ = 1.49 (m, 2H), 1.70 (m, 1 H) ₁ 1.80 (m, 1H), 1.94 (m, 1H), 2.57 (m, 1H), 2.64 (ddd, 1H), 2.75 (s, 3H), 3.72 (ddd, 1H) , 5.13 (s, 1H), 6.65 (dd, 1H), 6.66 (d, 1H), 6.76 (d, 1H), 6.84 (dd, 1H), 9.50 (s, 1H).

Example 14

(3aa.4 ^ .5 ^ 9άcy) -8-fluoro-5-r (7-fluoro-2-methylquinazoline-5-vinylamino-2,3,3a, 4,5,9b-hexahydrod-4- (trifluoromethyl) -1 H-Benzoindene-4,9-diol Analogously to Example 12, 130 mg (0.4 mmol) of [1 a (R *), 2a] -2- (3-fluoro-2-methoxyphenyl O-α-hydroxy-α-rifluoromethylcyclopentane acetaldehyde, 79 mg (0.44 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.22 ml of titanium tetraethylate converted to the corresponding imine. 205 mg of crude imine thus obtained are cyclized analogously to Example 12 at -3O ⁰ C addition temperature and then 2 hours at room temperature with 3.7 ml_ (3.7 mmol) 1 M boron tribromide solution to the desired product. Chromatography on silica gel (hexane / ethyl acetate 0-75%) gives 49 mg of the desired product.

¹ H-NMR (300 MHz, CD ₃ OD); δ = 1.52 (m, 2H), 1.84 (m, 1H), 1.97 (m, 1H), 2.22 (m, 1H), 2.70-2.86 (m, 2H), 2.74 (s, 3H), 3.35 (ddd, 1H), 5.17 (s, 1H), 6.61 (d, 1H), 6.65 (dd, 1H), 6.74 (d, 1H), 6.84 (dd, 1H), 9.50 (s, 1 H).

Example 15

5- {r (3aor.4α5Qr., 9ibQ;) - 8-fluoro-2.3.3a, 4.5.9b-hexahydro-4,9-dihydroxy-4- (trifluoromethyl) -1H-benz [einden-5-vnamino quinoline-2 (1H) -one Analogously to Example 11, 108 mg (0.34 mmol) of [1a (S *), 2a] -2- (3-fluoro-2-methoxyphenyl O-α-hydroxy-α-rifluoromethylcyclopentane acetaldehyde, 66 mg (0:37 mmol) of 5-aminoquinoline-2 (1 H) -one and 0:18 ml of titanium tetraethylate to form the corresponding imine. 147 mg thus obtained crude imine are prepared analogously to example 11 at -30 ⁰ C addition temperature and subsequently for 2 hours at room temperature with 2.8 mL (2.8 mmol) 1 M boron tribromide solution Cyclized on silica gel (hexane / ethyl acetate 0-100%) gives 72 mg of the desired product ¹ H-NMR (300 MHz, CD ₃ OD); δ = 1.45 ( m, 1H), 1.57 (m, 1H), 1.64 (m, 1H), 1.77 (m, 1H), 1.95 (m, 1H), 2.55 (m, 1H), 2.63 (ddd, 1H), 3.70 (ddd, 1H), 5.04 (s, 1H), 6.48 (d, 1H), 6.52 (d, 1H), 6.65 (d, 1H), 6.66 (dd, 1H), 6.80 (dd, 1H), 7.32 (t, 1H), 8.19 (d, 1 H).

Example 16

5- (r6-Fluoro-2,5-dihydroxy-3,4-dimethyl 2- (trifluoromethine-1,2,3,4-tetrahydronaphthalene-1-ylamino-iso-1-chloro-1-one

As usual, the imine is produced by means of the aldehyde described in Example 1. After cyclization with boron tribromide, 38.3 mg of the nonpolar diastereomer of 5 - {[6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1 -yl] amino} isochromen-1-one and 9.1 mg of the polar diastereomer of 5 - {[6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] amino} isochromen-1-one.

Non-polar diastereomer: ¹ H-NMR (300 MHz, CD ₃ OD), δ = 1, 18 (3H), 1, 45 (3H), 2.39 (1H), 3.51 (1H), 5.03 ( 1H), 6.63-6.72 (1H), 6.80 (1H) ₁ 6.87 (1H), 7.19 (1H), 7.32 (1H), 7.41 (1H) , 7.58 (1H).

Polar diastereomer: ¹ H-NMR (300 MHz, CD ₃ OD), δ = 1, 28 (3H), 1, 43 (3H), 2.32 (1 H), 3.20 (1 H), 5, 09 (1H), 6.63-6.72 (1H), 6.79 (1H), 6.85 (1H), 7.20 (1H), 7.35 (1H), 7.40 (1H), 7.55 (1H).

Example 17

8-Fluoro-5- (r6-fluoro-2,5-dihydroxy-3,4-dimethyl 6- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-vnamino> quinoline-2 (1H) -one 5-amino -8-fluoroquinoline-2 (1H) -one: 7.8 g (43 mmol) of 5,8-difluoroquinoline-2 (1H) -one and 1.18 g (8.2 mmol) of Cu ₂ O are dissolved in 620 ml of ethylene glycol under 8 bar with gaseous NH ₃ added

Reaction mixture is heated to 190 ⁰ C for 19 h. After cooling the reaction mixture and removing the solvent, the crude product is purified by column chromatography (silica gel, hexane, CH ₂ Cl ₂ / MeOH 0-5%). 1.03 g of 5-amino-8-fluoroquinoline-2 (7H) -one is obtained as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO-d6); δ = 5.58 (s, 2H), 6.23 (dd, 1H), 6.31 (d, 1H), 7.03 (dd, 1H), 8.05 (dd, 1H), 11.28 (s, 1H).

The desired product can be prepared analogously to Example 15 from 5-amino-8-fluoroquinoline-2 (1 H) -one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal getting produced.

¹ H-NMR (400 MHz, CD ₃ OD); δ = 1.18 (d, 3H), 1.48 (d, 3H), 2.45 (m, 1H), 3.55 (m, 1H), 5.04 (s, 1H), 6.53 (d, 1H), 6.58 ( dd, 1H), 6.73 (m, 1H), 6.87 (dd, 1H), 7.24 (dd, 1H), 8.16 (d, 1H).

Example 18

5- (r6-Fluoro-2,5-dihydroxy-3,4-dimethyl 2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1 _" -vinyl) isoquinolin-1 (2H) -one The desired product can be prepared analogously to Example 15 from 5-aminoisoquinoline-1 (2H) -one and 4- (3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal.

Nonpolar diastereomer: ¹ H-NMR (300 MHz, CD ₃ OD), δ = 1, 29 (3H), 1, 44 (3H), 2.35 (1H), 3.20 (1H), 5.09 (1H), 6.69-6.87 (3H), 7.10 (2H), 7.38 (1H), 7.66 (1H). Polar diastereomer: ¹ H-NMR (300 MHz, DMSO [d6]), polar δ = 1, 02 (3H), 1, 35 (3H), 2.31 (1H), 3.43 (1H), 5.05 (1H), 5.78 (1H), 6.23 (1H), 6.51-6.61 (1H) ₁ 6.69 (1H), 6.91 (1H) ₁ 7.02-7.15 (2H), 7.26 (1H), 7.49 (1H), 9.4 (1H), 11, 18 (1H).

Example 19

5- (r7-fluoro-2,5-dihydroxy-3,4-dimethyl 2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylamino} isoquinolin-1 (2H) -one

1- (4-fluoro-2-hydroxyphenyl) propan-1-one:

100 g (892 mmol) of 3-fluorophenol are dissolved in 1, 4 L of pyridine and treated at 0 ⁰ C dropwise with 99 g (1, 07 mol) of propionyl chloride. After stirring overnight at room temperature, the mixture is poured onto two liters of ice-water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with saturated brine, dried over sodium sulfate and the solvent is removed by rotary evaporation. The remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 148.7 g (99.1%) of propionic acid 3-fluorophenyl ester are isolated. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1, 29 (3H), 2.60 (2H), 6.81-6.69 (3H), 7.30-7.39 (1H) , 15.38 g (115.36 mmol) of aluminum trichloride are placed in 48 mL of 1, 2-dichlorobenzene. At room temperature, 20 g (118.93 mmol) of propionic acid 3-fluorophenyl ester dissolved in 41 ml of 1,2-dichlorobenzene are then added dropwise. In this case, a slight warming occurs. The reaction mixture is then stirred at 100 ^° C. for 18 hours. After cooling, the batch is added to 4N hydrochloric acid and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with brine, dried and the solvent is removed by rotary evaporation. Chromatography of the residue on silica gel (eluent ethyl acetate / hexane) gives 16.75 g (83.75%) of the desired product. ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1, 25 (3H) ₁ 3.00 (2H) ₁ 6.55-6.70 (2H) ₁ 7.70-7.83 (1H) , 12.7 (1H).

Ethyl 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoate: 16.75 g (99.6 mmol) of 1- (4-fluoro 2-hydroxyphenyl) propan-1-one are added in 124 ml of acetone with 27.53 g (199.2 mmol) of potassium carbonate and 28.27 g (199.2 mmol) of iodomethane. After four hours of refluxing, the mixture is filtered through a glass fiber filter and the filtrate evaporated. The remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 1.84 g (92.8%) of 1- (4-fluoro-2-methoxyphenyl) -propan-1-one are isolated: ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 1.18 (3H) , 2.97 (2H), 3.91 (3H), 6.62-6.76 (2H), 7.79 (1H). 56 g (858.4 mmol) of Zn and 1.04 g (3.73 mmol) of PbCl ₂ are initially charged at room temperature in 545 ml of THF. 111. 43 g (641 mmol) of dibromomethane are slowly added dropwise to this mixture, and the batch is stirred for 30 minutes at room temperature. After cooling to 0 ⁰ C 93.3 ml of a one molar solution of titanium (IV) chloride solution in dichloromethane are slowly added dropwise, in such a way that the temperature does not exceed 1O ⁰ C increases. After stirring for 30 minutes at room temperature, the mixture is cooled again to ⁰ ° C. and 17 g (93.21 mmol) of the above-described 1- (4-fluoro-2-methoxyphenyl) propan-1-one dissolved in 75 ml of THF , dripped. After one hour of stirring at room temperature (heating to about 28 ° C, water bath cooling), the reaction mixture is diluted with 150 ml of diethyl ether and then added carefully to 4N HCl. The temperature is kept at 28-30 ⁰ C and stirred vigorously for 15 minutes. After three extractions with diethyl ether, the combined organic phases are washed twice with brine, dried over sodium sulfate and the solvent is removed by rotary evaporation. The crude product is chromatographed on silica gel (eluent ethyl acetate / hexane) on the same day and the resulting 4-fluoro-2-methoxy-1- (1-methylenepropyl) benzene (9.58 g = 56.97%) stored in the refrigerator.

¹ H-NMR (300 MHz ₁ CDCl ₃ ): δ = 1.00 (3H), 2.45 (2H), 3.81 (3H), 4.98 (1H), 5.15 (1H) ₁ 6.52-6.78 (2H), 7.09 (1H). 3.3 g (5.32 mmol) of ytterbium (III) trifluoromethanesulfonate are initially charged in 118 ml of dichloromethane. After dropwise addition of 18.08 g (106.31 mmol) Ethyltrifluorpyruvat 9.58 g (53.16 mmol) of the previously described alkene, dissolved in 30 ml dichloromethane, added dropwise and the mixture then stirred for two days at room temperature. For workup is the

Reaction mixture with 25 mL of water and the organic phase separated. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane). There are 14.33 g (76.96%) of a mixture of (E / Z) - ethyl 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hex-4-enoate and ethyl 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoate, which is thus used in the next reaction. 4- (4-Fluoro-2-methoxy-phenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentanal. 14.3 g (40.9 mmol) of the mixture obtained from the reaction step described above is dissolved in 320 ml of diethyl ether dissolved and at 0 to 5 ° C in portions with 1, 55 g (40.91 mmol) of lithium aluminum hydride. After four hours of stirring at room temperature, after cooling the batch to a temperature between 0 and 5 ° C carefully 30 mL saturated sodium bicarbonate solution is added dropwise. After vigorous stirring for 30 minutes, the batch is filtered through a glass fiber filter. The filtrate is extracted three times with methyl tert-butyl ether and the combined organic extracts washed with brine, dried over sodium sulfate and the solvent was removed by rotary evaporation. After chromatography of the residue on silica gel (eluent ethyl acetate / hexane) 11, 03 g (87.47%) of the desired compound as a mixture of (E / Z) 4- (4-fluoro-2-methoxyphenyl) -2-

(trifluoromethyl) hex-4-ene-1,2-diol and 4- (4-fluoro-2-methoxyphenyl) -3-methyl-2-

(trifluoromethyl) pent-4-ene-1, 2-diol. MS (Cl) m / e (relative intensity): 326

(100%)

4.86 g (15.76 mmol) of the mixture described in the previous section are dissolved in a 1: 1 mixture of tetrahydrofuran and ethanol (total 486 mL) and treated with 0.5 g (1, 8 mmol) Pd / calcium carbonate. After uptake of 335 ml of hydrogen and a reaction time of two and one-quarter hours, the catalyst is filtered off and the filtrate is evaporated in a rotary evaporator. To Chromatography of the residue on flashmaster (eluent ethyl acetate / hexane) gives 4.46 g (89.13%) of the hydrogenated compounds. 1 g (3.22 mmol) of the mixture of 4- (4-fluoro-2-methoxyphenyl) -2- (trifluoromethyl) -hexane-i, 2-diol and 4- (4-fluoro-2-methoxyphenyl) -3- methyl-2- (trifluoromethyl) pentan-i, 2-diol is oxidized under Swernbedingungen at -70 ⁰ C. At still -7O ⁰ C 2.46 ml of triethylamine are added dropwise for refurbishing and the batch is brought to room temperature. After addition of 10 ml of water, the mixture is stirred for 15 minutes. The dichloromethane phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The combined organic extracts are washed with 10% sulfuric acid, saturated sodium bicarbonate solution and brine. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane). 732.8 mg (73.76%) are isolated as a mixture of 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexanal and 4- (4-fluoro-2-methoxyphenyl) - 2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal. 500 mg (1.62 mmol) of the mixture of 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexanal and 4- (4-fluoro-2-methoxyphenyl) -2-hydroxy 3-methyl-2- (trifluoromethyl) pentanal are added in 10 mL glacial acetic acid with 259.79 mg (1.62 mmol) 5-amino-isoquinolin-1 (2H) -one and three days at

Room temperature stirred. The reaction mixture is evaporated to dryness and the residue is stripped three times with toluene and twice with dichloromethane. Chromatography of the residue on the flashmaster gives 322.9 mg (44.2%) of the mixture of the two imines. 322.9 mg (0.72 mmol) of the mixture of 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} isoquinoline-1 (described in the previous section) ( 2H) -one and 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino} isoquinolin-1 (2H) -one are shown in Figure 3, Submitted to 2 mL dichloromethane and treated dropwise at ^{0 0} C with 7.2 mL of a 1 M solution of boron tribromide in dichloromethane. After four hours of stirring at 0 to 5 ° C, the reaction mixture is carefully added to a mixture of ice and saturated sodium bicarbonate solution. After three extractions with ethyl acetate, the combined extracts are washed with brine washed, dried over sodium sulfate and the solvent was removed by rotary evaporation. After extensive chromatography on silica gel, 2.8 mg (1.8%) of the desired compound are obtained.

¹ H-NMR (400 MHz ₁ CD ₃ OD): δ = 1, 18 (3H), 1, 49 (3H), 2.37 (1H) ₁ 3.40 (1H) ₁ 5.02 (1 H) ₁ 6.40 (2H) ₁ 6.78 (1H), 7.03 (1H) ₁ 7.12 (1H), 7.49 (1H), 7.69 (1H).

Example 20

5-r (7.8-Difluoro-2-methylquinazolin-5-yl) -aminol-3-fluoro-5.6.7.8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) -naphthalene-1,6-diol 226.5 mg (0 , 46 mmol) of a mixture of 1 - [(7,8-difluoro-2-methylquinazolin-5-yl) imino] -4- (4-fluoro-2-methoxyphenyl) -2- (trifluoromethyl) hexan-2-ol and 1 - [(7,8-difluoro-2-methylquinazolin-5-yl) imino] -4- (4-fluoro-2-methoxyphenyl) -3-methyl-2- (trifluoromethyl) -pentan-2-ol are as described Usually cyclized with the help of boron tribromide (reaction temperature -40 to -1O ⁰ C). After chromatography, 19.4 mg (17.6%) of the desired product are isolated.

¹ H-NMR (400 MHz, CD ₃ OD): δ = 0.77 (3H) ₁ 1, 43 (3H), 2.25 (1H), 3.92 (1H), 5.30 (1H) , 6.81 (1H), 6.89-6.99 (1H), 7.24 (1H), 9.55 (1H).

Example 21 5- (r7-Fluoro-2,5-dihydroxy-3,4-dimethyl 2- (trifluoromethvn-1,2,3,4-tetrahydronaphthalene-1-ylaminol isochromen-i-one

366.1 mg (0.42 mmol) of a mixture of 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} isochromene-1-one and 5- {[4- (4-Fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino} -isochromen-1-one are cyclized as usual with the aid of boron tribromide. After extensive chromatography, finally, 6.8 mg (1, 9%) of the desired product are isolated.

¹ H-NMR (400 MHz, CD ₃ OD): δ = 1, 18 (3H), 1, 49 (3H), 2.37 (1H), 3.40 (1H), 5.02 (1 H), 6.38-6.48 (2H), 6.80 (1H), 7.18 (1H), 7.35 (1H), 7.43 (1H), 7.60 ( 1 H).

Example 22

5- (r7-Fluoro-2,5-dihydroxy-3,4-dimethyl 2- (trifluoromethine-1,2,3,4-tetrahydronaphthalene-1-vinylamino) quinoline-2 (1H Von 314.4 mg (0.7 mmol) of a mixture of 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} quinoline-2 (1H) - on and 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino} -quinoline-2 (1H) -one are prepared as described with boron tribromide cycled. After chromatography, 2 mg (1.31%) of the desired compound are obtained. ¹ H-NMR (300 MHz, CD ₃ OD): δ = 0.59 (3H), 1, 34 (3H), 2.08 (1H), 3.88 (1H), 4.95 (1H), 6 , 51 (1H), 6.69 (1H), 6.73-6.92 (2H), 7.12 (1H), 7.32 (1H), 8.12 (1H).

Example 23 5-Ir7-Fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,3,3,4-tetrahydronaphthalene-1-vinylamino) -2,3-dihydroidino-1-olone 301 mg (0 , 68 mmol) of a mixture of 5 - {[4- (4-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} -2,3-dihydroisoindol-1-one and 5- { [4- (4-Fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino} -2,3-dihydro-isoindol-1-one is cyclized as described with boron tribromide. After chromatography, 5.4 mg (3.71%) of the desired compound are obtained.

¹ H-NMR (400 MHz, CD ₃ OD): δ = 1, 12 (3H), 1, 40 (3H), 2.38 (1H), 3.40 (1H), 4.20-4 , 34 (2H), 5.01 (1H), 6.38-6.49 (2H), 6.99 (1H), 7.15 (1H), 7.38 (1H).

Example 242,3-Difluoro-7,8-dimethyl-5-r (2-methylquinazolin-5-yl) -amino 1-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

4- (3,4-Difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal: Analogously to Example 1 can from 2,3-difluorophenol 1, 2-difluoro-3-methoxy-4 - (1-methylpropenyl) benzene can be prepared as E / Z mixture.

To 3.27 g (16.5 mmol) of 2,3-difluoro-6- (1-methylpropenyl) anisole, 4.35 ml (33 mmol) of ethyl trifluoropyruvate and 3.5 g of molecular sieve at ⁰ ° C. for 30 minutes 747 mg (820 μmol) of [Cu ( S, S) -2,2-bis (4,5-dihydro-4-phenyloxazolin-2-yl) propane) (H ₂ O) 2] ((SbF ₆ ) ₂ ) is added dropwise to 40 ml of dichloromethane Reaction mixture for 16 hours at room temperature and cleans the

Reaction mixture by column chromatography on silica gel (hexane / ethyl acetate 10-20%). This gives 3.03 g of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoic acid ethyl ester as a mixture of Diastereomers. 3:03 g (45.3 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoic acid ethyl ester in 85 ml diethyl ether are cooled to -20 ⁰ C and Over 10 minutes, 625 mg (16.5 mmol) of lithium aluminum hydride are added in portions. It is stirred for 2 hours at 0 ⁰ C and poured into saturated ammonium chloride solution. 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 washed with saturated sodium chloride solution, dried over sodium sulfate, the solvent is removed in vacuo and, after column chromatography on silica gel (hexane / ethyl acetate 10-50%) gives 0.48 g of 4- (3,4-difluoro-2-methoxyphenyl) -3 -methyl-2- (trifluoromethyl) pent-4-ene-1, 2-diol and 2.1 g of the corresponding aldehyde. 0.95 g (2.9 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -3-methyl-2- (trifluoromethyl) pent-4-ene-1,2-diol are dissolved in 100 ml of ethanol and 100 mg of palladium on charcoal (10%) are added. The suspension is under a hydrogen atmosphere at 100 bar until complete

Reaction stirred. The mixture is filtered through Celite, rinsing thoroughly with ethanol. After removal of the solvent and column chromatography on silica gel (hexane / ethyl acetate 30-60%), 0.62 g of 4- (3,4-difluoro-2-methoxyphenyl) -3-methyl-2- (trifluoromethyl) pentane-1 are obtained, 2- diol as a mixture of diastereomers. To 1.2 g (3.7 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -3-methyl-2- (trifluoromethyl) pentane-1,2-diol in 30 ml of dichloromethane and 7.4 ml of DMSO are added 2.55 ml ( 18.4 mmol) of triethylamine and in portions over 10 min 1.17 g (7.4 mmol) of pyridine SO ₃ complex. The mixture is stirred for 16 hours and admixed with a mixture of saturated ammonium chloride solution and tartaric acid solution. The mixture is stirred for a further 20 minutes, the phases are separated and it is extracted with diethyl ether. It is washed with water and dried over sodium sulfate. The solvent is removed in vacuo and after column chromatography on silica gel (hexane / diisopropyl ether 20-60%). This gives 608 mg as a mixture of 3 of the 4 possible stereoisomers of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal.

Stereoisomer 1: ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.04 (d, 3H), 1.17 (d, 3H), 2.54 (dq, 1H), 2.92 (dq, 1H), 3.82 (s, 1H), 3.97 (s, 3H), 6.84 (m , 2H), 9.69 (s, 1H). Stereoisomer 2: ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 0.97 (d, 3H), 1.34 (d, 3H), 2.30 (dq, 1H), 3.54 (dd, 1H), 3.97 (s, 3H), 4.59 (s, 1H), 6.78 (m , 2H), 9.50 (s, 1H). Stereoisomer 3: ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.03 (d, 3H), 1.22 (d, 3H), 2.65 (dq, 1H), 3.07 (dq, 1H), 3.97 (s, 3H), 4.19 (s, 1H), 6.78 - 6.86 (m, 2H), 9.63 (s, 1H).

140 mg (0.43 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal and 72 mg (0.45 mmol) of 5-amino-2-methylquinazoline are dissolved in Dissolved 1 ml of toluene and 0.33 ml (0.86 mmol) of titanium butoxide are added. The reaction mixture is heated for 2 hours at 100 °, poured into water after cooling 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 washed with saturated sodium chloride solution, dried over sodium sulfate, the solvent is removed in vacuo to give 181 mg of 4- (3,4-difluoro-2-methoxyphenyl) -3-methyl-1 - [(2-methylquinazolin-5-yl ) imino] -2-

(trifluoromethyl) pentan-2-ol as a crude product. The crude imine is dissolved in 8 ml CH ₂ Cl ₂ and cooled to -45 ° C. 0.66 ml (0.66 mmol) of a 1 M BBr ₃ solution in dichloromethane are slowly added dropwise over 5 min and allowed to warm to 0 ⁰ C over 2 hours. The reaction solution is poured onto a mixture of saturated NaHCO ₃ solution and ice. It is extracted several times with ethyl acetate, washed with saturated NaCl solution and dried over Na ₂ SO ₄ . Column chromatographic purification on silica gel (hexane / ethyl acetate 30-100%) gives 64 mg of the desired product as two separate diastereomers. Diastereomer 1: ¹ H-NMR (300MHz, DMSO [d6]]); δ = 1.15 (d, 3H), 1.36 (d, 3H), 2.15 (dq, 1H), 2.73 (s, 3H), 2.89 (dq, 1H), 5.21 (d, 1H) ₁ 6.02 (s , 1H), 6.66 (dd, 1H), 6.72 (d, 1H), 6.94 (d, 1H), 7.10 (d, 1H), 7.66 (t, 1H), 9.70 (s, 1 H), 10:19 (s, 1 H). Diastereomer 2: ¹ H NMR (300MHz, CD ₃ OD); δ = 1.28 (d, 3H), 1.41 (d, 3H), 2.37 (dq, 1H), 2.75 (s, 3H), 3.12 (dq, 1H), 5.21 (s, 1H), 6.60 (dd , 1H), 6.95 (d, 1H), 7.14 (d, 1H), 7.75 (t, 1H), 9.56 (s, 1H).

Example 24A / 24B (δ ^ ö ^ Z ^ δ ^^. S-Difluoro-δ.θ.T.δ-tetrahydro-r.δ-dimethyl-δ-p-mθthylchinazolin- 5-yl) amino] -6- (trifluoromethyl) naphthalene -1, 6-diol (diastereomer 1) is cleaved by preparative chiral HPLC (Chiralpak AD-H 5μ) into the enantiomerically pure compounds:

Enantiomer 1: analytical HPLC: R _t = 4.88 min (Chiralpak AD-H 5μ, 250x4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 mL / min flow) Enantiomer 2: analytical HPLC: R _t = 7.62 min (Chiralpak AD-H 5μ, 250x4.6 mm, hexane / ethanol 5 => 50% in 20 minutes, 1 ml / min flow)

Example 25

5- (r5.6-Difluoro-1.2.3,4-tetrahydro-3,4-dimethyl-2.5-dihvdroxy-6-

(trifluoromethydnaphthalene-1-vinylamino) quinoline-2 (1H) -one

Analogously to Example 25, 164 mg (0.43 mmol) of 4- (3,4-difluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal and 72 mg (0.45 mmol) of 5-aminoquinoline -2 (1 H) -one condensed to the corresponding imine, which can then be cyclized analogously to Example 25 with boron tribromide to 2 diastereomers. Diastereomer 1: ¹ H NMR (300MHz, CD ₃ OD); δ = 1.15 (d, 3H), 1.34 (d, 3H), 2.24 (dq, 1H), 3.10 (dq, 1H), 4.94 (d, 1H), 5.96 (d, 1H), 6.27 ( d, 1H), 6.52 (d, 1H), 6.54 (dd, 1H), 6.67 (d, 1H), 7.30 (t, 1H), 8.21 (d, 1H).

Diastereomer 2: ¹ H NMR (300MHz, CD ₃ OD); δ = 1.28 (d, 3H), 1.39 (d, 3H), 2.33 (dq, 1H), 3.12 (dq, 1H), 5.05 (s, 1H), 6.46 (d, 1H), 6.59 ( d, 1H), 6.65 (d, 1H), 6.67 (d, 1H), 7.36 (t, 1H), 8.15 (d, 1H).

Analog can be produced:

5-r (7,8-Difluoro-2-methylquinazolin-5-yl) -amino1-2,3-difluoro-5.6.7.8-tetrahydro-7,8-dimethyl-6- (trifluoromethyl) naphthalene-1,6-diol

2,3-Difluoro-5,6,7,8-tetrahydro-7,8-dimethyl-5-r (2-methylquinoline-5-vino-1-6- (trifluoromethyl) -naphthalene-1,6-diol

5-fr2.3-difluoro-1,6-dihydroxy-7,8-dimethyl-6- (trifluoromethine-5.6.7.8-tetrahydronaphthalene-5-ylamino) isoquinoline-1 (2HV-on Example 26

5- (r7-Chloro-6-fluoro-2,5-dihydroxy-3,4-difnethyl-2- (trifluoromethvn-1, 2,3,4-tetrahydronaphthalene-1-ylaminolinoquinolin-i (2H) -one, 4- (triethyl) 4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentanal:

3.69 g (5.96 mmol) of ytterbium (III) trifluoromethanesulfonate are initially charged in 132 ml of dichloromethane. After dropwise addition of 20.28 g (119.25 mmol) Ethyltrifluorpyruvat be 12.38 g (59.63 mmol) of a mixture of 4-chloro-3-fluoro-2-methoxy-1- (1-methylene-propyl) benzene and 4-chloro-3-fluoro-2-methoxy-1- (1-methyl-prop-1-ene) benzene, dissolved in 33 ml dichloromethane, added dropwise and the mixture was then stirred for four days at room temperature. For workup, the reaction mixture is mixed with 28 ml of water and the organic phase is separated off. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate / hexane). A total of 13.54 g (59.1%) of a mixture of (E / Z) -ethyl-4- (4-chloro-3-fluoro-2-methoxy-phenyl) -2-hydroxy-2- (trifluoromethyl) - hex-4-enoate and ethyl 4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enoate, which differed in different fractions Contains ratios of the two compounds. 5.63 g (14.64 mmol) of a portion of the above-described mixture of the two esters is dissolved in 53.4 mL diethyl ether and treated at -5 ⁰ C in portions with 416.5 mg (10.97 mmol) of lithium aluminum hydride and then three Stirred between -5 ° C and 0 ° C for hours. The reaction mixture is treated dropwise at 0 ⁰ C with 11 mL of saturated sodium bicarbonate solution. After removal of the cold bath, the batch is vigorously stirred for two hours at room temperature. After filtration of the mixture through a glass fiber filter and washing with diethyl ether, the solvent is spun off. The remaining residue is chromatographed on silica gel (eluent ethyl acetate / hexane). 877.6 mg (35.2%) of 4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pent-4-enal ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.44 (3H), 3.47 (1H), 3.92 (3H), 4.00 (1H), 5.21 (1H), 5 , 44 (1H), 6.68 (1H), 6.99 (1H), 9.45 (1H). To the prehydrogenated catalyst (platinum dioxide, 140 mg, 0.62 mmol) is added 700 mg (2.05 mmol) of the aldehyde described above in 70 mL of ethanol. After uptake of 330 mL hydrogen and a reaction time of two and a half hours, the reaction mixture is passed through a glass fiber filter. After washing the filter residue with ethanol, the solvent is removed by rotary evaporation. There remain 422 mg (59.9%) of the desired product (as a mixture of diastereomers), which is still used raw. MS (Cl) m / e (relative intensity): 360 (100%). 170 mg (0.5 mmol) of 4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentanal are dissolved in 2.12 ml of glacial acetic acid with 79.5 mg (0.5 mmol) of 5-amino-isoquinolin-1 (2H) -one and stirred for four days at room temperature. The reaction mixture is evaporated to dryness and the residue is stripped three times with toluene. Chromatography of the residue on silica gel (eluent ethyl acetate / hexane) gives 150.9 mg (62.7%) of the desired imine. MS (Cl) m / e (relative intensity): 485 (20%).

5 - {[7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1-yl] amino} -isoquinoline-1 (2H) -one, nonpolar diastereomer and 5 - {[7-chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1 -yl] amino} -isoquinoline-1 (2H) -one, polar diastereomer 220 mg (0.45 mmol) of the imine described above are dissolved in dichloromethane and treated at 0 ⁰ C with 4.5 mL of einmolaren boron tribromide solution in dichloromethane. After three and a half hours of stirring at ice bath temperature, the reaction mixture is poured onto a mixture of ice and saturated sodium bicarbonate solution. After dilution with ethyl acetate, the mixture is stirred vigorously for two hours and the organic phase is separated off. The aqueous phase is extracted again with ethyl acetate and the combined organic extracts are then washed with water and brine. After drying over sodium sulfate, the solvent is removed by rotary evaporation and the residue is chromatographed on flashmaster (amine phase, eluent methanol / dichloromethane). Obtained are 13.3 mg (6.23%) of the nonpolar diastereomer and 3.4 mg (1.59%) of the polar diastereomer of 5 - {[7-chloro-6-fluoro-2,5-dihydroxy-3, 4-dimethyl-2- (trifluoromethyl) -i, 2,3,4-tetrahydronaphthalene-1-yl] amino} -isoquinoline-1 (2H) -one. Nonpolar diastereomer: ¹ H-NMR (400 MHz, CD ₃ OD), δ = 1, 18 (3H), 1, 39 (3H),

2.28 (1H), 3.13 (1H), 4.95 (1H), 6.73 (2H), 6.88 (1H), 7.19 (1H), 7.32 (1H) H), 7.68 (1H).

Polar diastereomer: ¹ H-NMR (400 MHz, CD ₃ OD), δ = 1, 29 (3H), 1, 42 (3H), 2.36 (1 H), 3.16 (1 H), 5, 08 (1H), 6.74 (1H), 6.80 (1H), 7.00 (1H), 7.12 (1H), 7.39 (1H), 7.69 ( 1 H).

Example 27

5-ff7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylaminol .3-dihydro-2H-indol-2-one

195 mg (0.41 mmol) of 5 - {[4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino} -1, 3 dihydro-2H-indol-2-one are cyclized as described. Isolated are 10.1 mg (5.34%) of the nonpolar and 4.7 mg (2.48%) of the polar diastereomer of 5 - {[7-chloro-6-fluoro-2,5-dihydroxy-3,4 -dimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-i -yl] amino} -1,3-dihydro-2H-indol-2-one.

Nonpolar diastereomer: ¹ H-NMR (400 MHz, CD ₃ OD), δ = 1, 18 (3H), 1, 35 (3H) ,. 2.20 (1H), 3.09 (1H), 3.20-3.48 (2H), 4.90 (1H), 6.19 (1H), 6.31 (1H) , 6.81 (1H), 7.02 (1H). Polar diastereomer ¹ H-NMR (400 MHz, CD ₃ OD), δ = 1, 28 (3H), 1, 40 (3H),

2.29 (1H), 3.12 (1H), 3.28-3.38 (2H), 4.93 (1H), 6.34 (1H), 6.50 (1H), 6 , 83 (1H), 7.09 (1H).

Example 28 5- (r7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethane-1.2.3.4-tetrahydronaphthalene-1-ylaminol iso-chromene-i -one 371.9 mg (0.76 mmol) of a A mixture of 5 - {[4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) pentylidene] amino} isochromen-1-one and 5 - {[ 4- (4-Chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} -isochromen-1-one are cyclized with boron tribromide as described several times to isolate 1.5 mg (0.83%) of the desired compound. ¹ H-NMR (400 MHz, CD ₃ OD): δ = 1, 13 (3H), 1, 43 (3H), 2.39 (1H), 3.48 (1H), 5.02 (1 H), 6.74 (1H), 6.80 (1H), 7.20 (1H), 7.38 (1H), 7.43 (1H), 7.60 (1H) ,

Example 29 5 - ([7-Chloro-6-fluoro-2,5-dihydroxy-3,4-dimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1-ylaminoquinoline-2 (1H) - on 264.3 mg (0.54 mmol) of a mixture of 5 - {[4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-3-methyl-2- (trifluoromethyl) -pentylidene] -amino } - isoquinoline-1 (2H) -one and 5 - {[4- (4-chloro-3-fluoro-2-methoxyphenyl) -2-hydroxy-2- (trifluoromethyl) hexylidene] amino} isoquinoline-2 (1H ) -on are cyclized using boron tribromide to isolate 7.4 mg (5.8%) of the desired compound.

¹ H-NMR (400 MHz, CD ₃ OD): δ = 1, 13 (3H), 1, 43 (3H), 2.39 (1H), 3.49 (1H), 5.04 (1H), 6, 49 (1H), 6.63 (1H), 6.70 (1H), 6.78 (1H), 7.39 (1H), 8.15 (1H).

By analogy with the preceding instructions, it is also possible to prepare: a) 5- (r7-chloro-2,5-dihydroxy-3,4,6-trimethyl-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylaminolinoquinoline-i ( 2H) -one

b) 5- (r7-Chloro-2,5-dihydroxy-3,4,6-trimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1-vinylamino) -2,3-dihydro-isoindole-1 - on

c) 5- (r7-chloro-2,5-dihydroxy-3,4,6-trimethyl-2- (trifluoromethvn-1, 2,3,4-tetrahydronaphthalene-1-ylaminol isochromene-i-one

d) 3-Chloro-2,7,8-trimethyl-5-r (2-methylquinazolin-5-yl) -amino 1-6- (trifluoromethyl) -5,6,7,8-tetrahydronaphthalene-1,6-diol

e) 5- (r7-chloro-2,5-dihydroxy-3,4,6-trimethyl-2- (trifluoromethyl) -1, 2,3,4-tetrahydronaphthalene-1-vinylamino) quinoline-2 (1H) -one fi 5-fr2.5-pihvdroxy-3,4-dimethyl-7- (2-vn-2- (trifluoromethvh-1.2.3.4-tetrahydronaphthalene-1-ynaminoisoquinoline-1 (2H) -one

α) 5- (r2,5-Dihydroxy-3,4-dimethyl-7- (drop-2-vπ-2- (trifluoromethine-1.2.3.4-tetrahydronaphthalene-1-vnamino) -2,3-dihydro-1-isoindole-1-one

h) 5- (r2,5-Dihydroxy-3,4-dimethyl-7- (prop-2-yl) -2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylamino} isochromen-1-one

i) 5- (r2,5-Dihydroxy-3,4-dimethy [-7- (prop-2-vn-2- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalene-1-ylamino) quinoline-2 (1H) -one

i) 5.6.7.8-Tetrahvdro-5-f (2-methylquinazoline-5-vinyl-amino-7,8-dimethyl-3- (prop-2-yl) -6- (trifluoromethyl) -naphthalene-1,6-diol

k) 5-fr6-fluoro-3,4-diethyl-2,5-dihydroxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-1-vinylaminolquinoline-2 (1H) -one

I) 2-Fluoro-5-r (2-methylquinazoline-5-vinylamino-7-8-diethyl-5.6.7.8-tetrahydro-6- (trifluorometh- naphthalene-1,6-diol

Claims

claims 1. stereoisomers of the general formula (I),

wherein R ¹ and R ² independently of one another represent a hydrogen atom, a hydroxyl Group, a halogen atom, an optionally substituted (C ₁ -C 10) - Alkyl group, an optionally substituted (C-ι-Cio) alkoxy, a (CrCi ₀ ) alkylthio group, a (Ci-C ₅ ) perfluoroalkyl group, a Cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O- , -O- (CH ₂ ) n -CH 2 -, -O-CH = CH-, - (CH ₂ ) _{n +} 2 -, - NH- (CH ₂ ) _{n +} i, N (C _r C ₃ -alkyl) - (CH ₂ ) _n + i _> -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 Hydrogen, _Δ CrC alkyl or (CO) -C-C may be ₅ alkyl, R ³ and R ^{4 are} independently a hydrogen atom, a hydroxy Group, a halogen atom, a cyano group, an optionally substituted (Ci-C-io) alkyl group, an optionally substituted (Cr Cio) -alkoxy group, a (Ci-Cio) -alkylthio group, a (C ₁ -C ₅ ) - Perfluoroalkyl group, R ⁵ a CRCI _O alkyl group, by one or more groups selected from hydroxy, halogen, (Ci-CsJ-alkoxy substituted CRCI _O alkyl group, an optionally substituted (C ₃ -C ₇₎ cycloalkyl group, an optionally substituted Heterocyclyl group, an optionally substituted aryl group, optionally independently of one another by one or more Groups selected from (C 1 -C ₅ ) -alkyl groups (which may be optionally substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups), (C 1 -C ₅ ) -alkoxy groups, hydroxy groups, halogen atoms, 1-2 (Ci -C ₃ ) - Exoalkylidengruppen substituted, optionally 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 Mono- or bicyclic heteroaryl group containing 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, R ^{6 is} a (C 1 -C 5) -alkyl group or an optionally partially or completely fluorinated (C 1 -C 4) alkyl group 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 , alkyl group, a heterocyclyl group, a heterocyclyl (C ₁ -C ₈₎ heterocyclyl, (C ₂ -C ₈₎ alkenyl group, an aryl group, an aryl (Ci-C ₈₎ alkyl, aryl, alkenyl (C ₂ -C ₈₎ Aryl (C ₂ -C ₈₎ alkynyl group, an optionally by one or more keto groups, (CrC ₅₎ alkyl, _(Ci-C5) -alkoxy groups, halogen atoms, (Ci-C ₃₎ substituted -Exoalkylidengruppen, one or more nitrogen atoms and / or oxygen atoms and / or sulfur atoms containing mono- or bicyclic heteroaryl group, a heteroaryl (Ci-C ₈₎ alkyl group, or a heteroaryl (C ₂ -C ₈₎ alkenyl group which groups may be linked via any position to the Tetrahydronaphthalinsystem and optionally can be hydrogenated at one or more sites, R ^{7 is} a halogen atom, a (C 1 -C 10) -alkyl group, which may be replaced 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 (Ci-C ₅ ) alkyl group, with OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ), a cyano group or together with the carbon atom of the ring system a (C ₃ -C ₆ ) -cycloalkyl ring or together an optionally substituted by hydroxy, halogen or cyano substituted (CrCsJ-alkylidene group or R ⁷ and R ⁸ together form a fused five- to eight-membered saturated or unsaturated carbo or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (C 1 -C ₅ ) -alkoxy groups, 1-4 halogen atoms is substituted mean. 2. stereoisomers of the general formula (I),

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Ci ₀ ) - alkyl group, a (CrCio) alkoxy group, a (CrCio) -Alkythio group, a (Ci-C ₅ ) - Perfluoralkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) n -CH ₂ -, -O-CH = CH-, - (CH ₂ W -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} independently hydrogen, CrC ₅ -alkyl or (CO) -C _r C ₅ alkyl may be, R ³ and R ^{4 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Ci ₀₎ - alkyl group, a (CrCio) alkoxy, (CRCI ₀₎ alkylthio group, a (CrC ₅₎ Perfluoroalkyl group, a cyano group, R ⁵ is a C _r Cio-alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (CrC ₅₎ - alkyl substituted CRCI _O alkyl group, an optionally substituted phenyl group, an optionally substituted by 1-2 keto groups, 1-2 (CiC ₅ ) alkyl groups, 1-2 (Ci-C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C3 ) -Axoalkylidengruppen 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 linked via an arbitrary position with the amine of the tetrahydronaphthalene system may be hydrogenated and optionally hydrogenated at one or more sites R ^{6 is} a (Ci-C- ₅ ) alkyl group or an optionally partially or fully fluorinated (Ci-CsJ-alkyl group, an aryl group, a Aryl (Ci-C ₈₎ alkyl, aryl (C ₂ -C ₈₎ alkenyl group, a (C ₃ -C ₇₎ - cycloalkyl, (C ₃ -C ₇₎ cycloalkyl alkyl group (Ci-C _8), (C ₃ -C ₇ ) - Cycloalkyl (C ₂ -C ₈ ) alkenyl group R ^{7 is} a halogen atom, a (C-ι-C-io) alkyl group, optionally with OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ R ¹¹ ) or 1 -3 halogen atoms may be substituted 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 -Ce ) - Cycloalkylring or together a (C-ι-C ₅ ) -Alkylidengruppe or R ⁷ and R ⁸ together form a fused 5- to ⁸ -membered saturated or unsaturated carbo- or heterocycle which is optionally substituted by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (C 1 -C ₅ ) - Alkoxy groups, 1-4 halogen atoms is substituted mean. 3. stereoisomers of the general formula (I),

(I) wherein R ¹ and R ² independently represent 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 Groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ XrCH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and the R ³ and R ⁴ are each independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C 5) - bonded to terminal atoms with directly adjacent ring carbon atoms Alkyl group, a (CrC ₅ ) alkoxy group, R ^{5 is} a C ₁ -C 20 -alkyl group, a C ₁ -C -alko group which is substituted by one or more groups selected from among _{1 to 3} hydroxyl groups or halogen atoms, and optionally by one or more Groups selected from 1-2 keto groups, 1-2- (Ci-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 ) -exxalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl , Thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, Benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, chromenyl, isochromenyl, chromenonyl, isochromenonyl, 1, 7 or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl groups, wherein these groups over any position with the amine of Tetrahydronaphthalene system may be linked and may optionally be hydrogenated at one or more sites R ^{6 is} a (Ci-C ₅ ) alkyl group or an optionally partially or fully fluorinated (Ci-CsJ-alkyl group R ^{7 is} a halogen atom, a methyl or ethyl group, the with 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 methyl or ethyl group substituted with OR ¹⁰ , SR ¹⁰ , N (R ¹⁰ ) ₂ substituted may be a cyano group or together with the carbon atom of Tetrahydronaphthalinringes a (C ₃ -Ce) - cycloalkyl or together a (C-ι-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 (CrC ₅ ) alkyl groups, 1-2 (CrCs) alkoxy groups, 1 -4 halogen atoms substituted. 4. stereoisomers of the general formula (I),

wherein R ¹ and R ² independently of one another represent a hydrogen atom, a hydroxyl Group, a halogen atom, a (C-ι-C ₅ ) alkyl group, a (CrC 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 W, 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 ₅ ) -alkyl group, a (C 1 -C ₅ ) - alkoxy, R ^{4 is} a hydrogen atom R ^{5 is} optionally substituted by one or more groups selected from 1-2 Substituted keto groups, 1-2- (-C ₅₎ alkyl, 1-2- (-C ₅₎ -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CrC ₃₎ -Exoalkylidengruppen Phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, Chromenyl, isochromenyl, chromenonyl, isochromenonyl, 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 completely fluorinated (C 1 -C ₅ ) -alkyl group R ^{7 is} a methyl or ethyl group, R ⁸ and R ^{9 are} independently a hydrogen atom, a methyl or ethyl group or together a methylene or ethylidene group, or R ⁷ and R ⁸ together denote a fused five to eight-membered saturated or unsaturated Carbozyklus. 5. Use of the stereoisomers according to one of the preceding claims for the preparation of a medicament. 6. Use of the stereoisomers of claims 1-4 for the manufacture of a medicament for the treatment of inflammatory diseases. 7. Pharmaceutical preparations containing at least one stereoisomer according to claim 1-4 or mixtures thereof and pharmaceutically acceptable carriers. 8. stereoisomers of the general formula I, according to any one of claims 1-4 in the form of salts with physiologically acceptable anions. 9. A process for the preparation of the stereoisomers of general formula I, wherein the radicals, unless otherwise stated, those defined in claim 1 Meanings, characterized in that either a) Stereoisomers of the general formula (II)

(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)

(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

In which 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 alkylidene group, then either without further reagent or by adding inorganic or organic acids or Lewis acids at temperatures b) in compounds of the formula (III) prepared by a) by hydrogenation of the radical R ⁹ = H, by methods of cyclopropanation of the radical R ⁹ from -70 ⁰ C to 80 ⁰ C to compounds of the general formula (I) 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,

(V) in which 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 , where R ^{5 has} the meaning given in claim 1, the compounds of the general formula (VI) are prepared,

(VI) which are cyclized either without further reagent or by adding inorganic or organic acids or Lewis acids at temperatures of -70 ⁰ C to 8O ⁰ C to compounds of the general formula I. 10. The process step for preparing stereoisomers of the general formula according to claim 9, characterized in that stereoisomers of general formula Vl ₁

(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. 11.Verbindungen the general formula VI according to claim 9

(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. 12. 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)

(V) be reduced and reacted with a corresponding amine of the formula R ⁵ -NH ₂ to imine of the general formula (VI). 13. 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.

(V)