DE102004063227A1 - Tricylic amino alcohols, process for their preparation and their use as anti-inflammatory agents - Google Patents

Abstract

The invention relates to tricyclic amino alcohols of the general formula I, DOLLAR F1 process for their preparation and their use as anti-inflammatory agents.

Description

The The invention relates to tricyclic amino alcohols, processes for theirs Production and its use as an anti-inflammatory.

Out The prior art WO02 / 10143 and WO 03/082827 are open-chain non-steroidal anti-inflammatory drugs known. These compounds show effect dissociation in the experiment between anti-inflammatory and undesirable metabolic effects and are superior to the nonsteroidal glucocorticoids described so far or at least have an equally good effect.

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

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

worin
R¹ und R² unabhängig voneinander ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine gegebenenfalls substituierte
(C₁-C₁₀)-Alkylgruppe, eine (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, eine (C₁-C₅)-Perfluoralkylgruppe, eine Cyanogruppe, eine Nitrogruppe oder
R¹ und R² zusammen eine Gruppe ausgewählt aus den Gruppen -O-(CH₂)_n-O-, -O-(CH₂)_n-CH₂-, -O-CH=CH-, -(CH₂)_n+2-, -NH-(CH₂)_n+1, N(C₁-C₃-alkyl)-(CH₂)_n+1, -NH-N=CH-, wobei n = 1 oder 2 ist und die endständigen Atome mit direkt benachbarten Ring-Kohlenstoffatomen verknüpft sind,
oder NR⁸R⁹, wobei R⁸ und R⁹ unabhängig voneinander Wasserstoff, C₁-C₅-Alkyl oder (CO)-C₁-C₅-Alkyl sein können,
R³ ein Wasserstoffatom, eine Hydroxy-Gruppe, ein Halogenatom, eine gegebenenfalls substituierte (C₁-C₁₀)-Alkylgruppe, eine (C₁-C₁₀)-Alkoxygruppe, eine (C₁-C₁₀)-Alkylthiogruppe, eine (C₁-C₅)-Perfluoralkylgruppe, eine Cyanogruppe,
R⁴ eine C₁-C₁₀-Alkylgruppe, eine durch eine oder mehrere Gruppen ausgewählt aus 1-3 Hydroxygruppen, Halogenatome, 1-3 (C₁-C₅)-Alkoxygruppen substituierte C₁-C₁₀-Alkylgruppe, eine gegebenenfalls substituierte (C₃-C₇)-Cycloalkylgruppe, eine gegebenenfalls substituierte Heterocyclylgruppe, eine gegebenenfalls substituierte Arylgruppe,
eine gegebenenfalls durch eine oder mehrere Gruppen ausgewählt aus (C₁-C₅)-Alkylgruppen (welche gegebenenfalls substituiert sein können durch 1-3 Hydroxy oder 1-3 COOR¹⁰-Gruppen, wobei R¹⁰ C₁-C₆-Alkyl oder Benzyl bedeutet), (C₁-C₅)-Alkoxygruppen, Hydroxygruppen, Halogenatome, (C₁-C₃)-Exoalkylidengruppen substituierte, gegebenenfalls 1-4 Stickstoffatome und/oder 1-2 Sauerstoffatome und/oder 1-2 Schwefelatome und/oder 1-2 Ketogruppen enthaltende mono- oder bizyklische Heteroarylgruppe, wobei diese Gruppe über eine beliebige Position mit dem Amin des Ringsystems verknüpft sein kann und gegebenenfalls an einer oder mehreren Stellen hydriert sein kann,
R⁵ eine (C₁-C₅)-Alkylgruppe oder eine gegebenenfalls teilweise oder vollständig fluorierte (C₁-C₅)-Alkylgruppe, eine (C₃-C₇)Cycloalkylgruppe, eine (C₃-C₇)Cycloalkyl(C₁-C₈)alkylgruppe, (C₃-C₇)Cycloalkyl(C₂-C₈)alkenylgruppe, eine Heterocyclylgruppe, eine Heterocyclyl(C₁-C₈)alkylgruppe, Heterocyclyl(C₂-C₈)alkenylgruppe, eine Arylgruppe, eine Aryl(C₁-C₈)alkylgruppe, Aryl(C₂-C₈)alkenylgruppe, Aryl(C₂-C₈)alkinylgruppe eine gegebenenfalls durch eine oder mehrere Ketogruppen, (C₁-C₅)-Alkylgruppen, (C₁-C₅)-Alkoxygruppen, Halogenatome, (C₁-C₃)-Exoalkylidengruppen substituierte, ein oder mehrere Stickstoffatome und/oder Sauerstoffatome und/oder Schwefelatome enthaltende mono- oder bizyklische Heteroarylgruppe,
eine Heteroaryl(C₁-C₈)alkylgruppe oder eine Heteroaryl(C₂-C₈)alkenylgruppe wobei diese Gruppen über eine beliebige Position mit dem Tetrahydronaphthalinsystem verknüpft sein können und gegebenenfalls an einer oder mehreren Stellen hydriert sein können,
R⁶ und R⁷ unabhängig voneinander ein Wasserstoffatom, ein Halogenatom, eine (C₁-C₅)Alkylgruppe, die mit OR⁸, SR⁸, NR⁸R⁹ substituiert sein kann,
p 1-3 und
X ein Sauerstoff-, ein Schwefelatom, eine CH₂- oder eine NR⁹-Gruppe bedeuten.The present invention relates to compounds of the general formula (I),

wherein
R ¹ and R ² independently represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted
(C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) -alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, a nitro group or
R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,
or NR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
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, a (C ₁ -C ₁₀ ) -alkylthio group, a ( C ₁ -C ₅ ) perfluoroalkyl group, a cyano group,
R ⁴ is a C ₁ -C ₁₀ alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅₎ alkoxy substituted C ₁ -C ₁₀ alkyl group, an optionally substituted (C ₃ -C ₇ ) -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group,
an optionally substituted by one or more groups selected from (C ₁ -C ₅ ) alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups, wherein R ^{10 is} C ₁ -C ₆ alkyl or benzyl means), (C ₁ -C ₅ ) -alkoxy groups, hydroxy groups, halogen atoms, (C ₁ -C ₃ ) -exoalkylidene-substituted, optionally 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or Mono- or bicyclic heteroaryl group containing keto groups, which group may be linked via any position with the amine of the ring system and may optionally be hydrogenated at one or more sites,
R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) -alkyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group, a heterocyclyl group, a heterocyclyl (C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group, an aryl group , an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, aryl (C ₂ -C ₈ ) alkynyl group, a given if one or more nitrogen atoms and / or oxygen atoms are substituted by one or more keto groups, (C ₁ -C ₅ ) -alkyl groups, (C ₁ -C ₅ ) -alkoxy groups, halogen atoms, (C ₁ -C ₃ ) -oxoalkylidene groups, and / or or sulfur atoms-containing mono- or bicyclic heteroaryl group,
a heteroaryl (C ₁ -C ₈ ) alkyl group or a heteroaryl (C ₂ -C ₈ ) alkenyl group, where these groups may be linked via any position with the tetrahydronaphthalene system and may optionally be hydrogenated at one or more sites,
R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a halogen atom, a (C ₁ -C ₅ ) -alkyl group which may be substituted by OR ⁸ , SR ⁸ , NR ⁸ R ⁹ ,
p 1-3 and
X represents an oxygen, a sulfur atom, a CH ₂ - or an NR ⁹ group.

Another object of the invention are stereoisomers of the general formula (I) wherein
R ¹ and R ² independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a (C ₁ -C ₁₀ ) -Alkythio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _{n is} -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl,
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, a (C ₁ -C ₁₀ ) -alkylthio group, a ( C ₁ -C ₅ ) perfluoroalkyl group, a cyano group,
R ^{4 is} a C ₁ -C ₁₀ alkyl group, substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅ ) alkoxy-substituted C ₁ -C ₁₀ alkyl group, an optionally substituted phenyl group , an optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) alkyl groups, 1-2 (C ₁ -C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -Exoalkylidengruppen, substituted 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, said groups via any position with the Amine of the ring system may be linked and may optionally be hydrogenated at one or more sites
R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, an aryl (C ₁ -C ₈ ) -alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group
R ⁶ and R ⁷ independently of one another are a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ⁸ , SR ⁸ , N (R ⁹ ) ₂ ,
p 1-3 and
X represents an oxygen, a sulfur atom, a CH ₂ - or an NR ⁹ group.

An object 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 hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₅ ) -alkyl group, a (C ₁ -C ₅ ) -alkoxy group,
or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -,
where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms,
R ^{3 is} a 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 (C ₁ -C ₁₀₎ alkyl group, a by 1-3 hydroxy groups, halogen atoms, substituted (C ₁ -C ₁₀₎ alkyl group, an optionally by one or more groups selected from 1-2 keto groups, 1-2 ( C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-substituted phenyl-, naphthyl- , 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 ring system and may optionally be hydrogenated at one or more sites
R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group
R ⁶ and R ⁷ independently of one another are a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ⁸ , SR ⁸ , N (R ⁹ ) ₂ , where R ⁸ and R ⁹ independently of one another are hydrogen, C ₁ - C ₅ alkyl or (CO) -C ₁ -C ₅ alkyl,
p 1, 2 or 3 and
X represents an oxygen, a sulfur atom, a CH ₂ or NR ⁹ group.

Another object of the present invention are stereoisomers of the general formula (I) wherein
R ¹ , R ² and R ³ independently represent a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) -alkyl group, a (C ₁ -C ₁₀ ) -alkoxy group, a cyano group
R ^{4 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, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl , Isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl groups, which groups may be substituted by any of Position may be linked to the amine of the ring system and may optionally be hydrogenated at one or more sites,
R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group
R ⁶ and R ⁷ independently represent a hydrogen atom, a halogen atom, a methyl or ethyl group
p 1 or 2 and
X represents an oxygen or a sulfur atom.

The third fused ring containing X, [(CH ₂ ) _p ] and the substituent R ⁷ may be 5-, 6- or 7-membered; p can therefore assume values of 1-3.

X may represent an oxygen atom, a sulfur atom, an NR ⁹ or a CH ₂ group. The oxygen atom and the sulfur atom are preferred, and the oxygen atom is particularly preferred.

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

The alkyl groups R ¹ , R ² , R ³ , R ⁵ , R ⁸ and R ⁹ may be straight-chain or branched and may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso Butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A C ₁ -C ₃ alkyl group is preferred. They may optionally be substituted by a group selected from 1-3 hydroxy, 1-3 halogen, 1-3 (C ₁ -C ₃ ) alkoxy, and / or 1-3 COOR ¹⁰ groups. Preference is given to hydroxy groups.

The alkyl group R ⁴ has the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group hydroxy, halogen, (C ₁ -C ₅ ) alkoxy.

The alkyl groups R ⁶ and R ⁷ have the meaning mentioned in the preceding paragraph, but the possible substituents are selected from the group OR ⁹ , SR ⁹ and NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 are} hydrogen, C ₁ -C ₅ alkyl or (CO) C ₁ -C ₅ alkyl and alkyl is also as defined above.

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

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

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

The aryl substituents R ¹ and R ² can form a ring in which both aryl substituents together represent a chain selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O -CH = CH-, - (CH ₂ ) _{n + 2} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2. 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 ⁸ R ^{9 is} , for example, NH ₂ , NH (CH ₃ ), N (CH ₃ ) ₂ , NH (C ₂ H ₅ ), N (C ₂ H ₅ ) ₂ , NH (C ₃ H ₇ ), N (C ₃ H ₇ ) ₂ , NH (C ₄ H ₉ ), N (C ₄ H ₉ ) ₂ , NH (C ₅ H ₁₁ ), N (C ₅ H ₁₁ ) ₂ , NH (CO) CH ₃ , NH (CO) C ₂ H ₅ , NH (CO) C ₃ H ₇ , NH (CO) C ₄ H ₉ , NH (CO) C ₅ H ₁₁ .

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

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

Cycloalkylalkenyl group means, for example, - (CH = CH) -cycloalkyl, - [C (CH ₃ ) = CH] -cycloalkyl, - [CH = C (CH ₃ )] -cycloalkyl, - (CH = CH-CH ₂ ) -cycloalkyl, - (CH ₂ -CH = CH) -cycloalkyl, - (CH = CH-CH ₂ -CH ₂ ) -cycloalkyl, - (CH ₂ -CH = CH-CH ₂ ) -cycloalkyl, - (CH ₂ -CH ₂ - CH = CH) -cycloalkyl, - (C (CH ₃ ) = CH-CH ₂ ) -cycloalkyl, - (CH = C (CH ₃ ) -CH ₂ ) -cycloalkyl.

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

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

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

Heterocyclylalkenyl groups are heterocyclyl groups which are linked to the skeleton via an unsaturated C ₂ -C ₅ -alkyl group, where the alkenyl groups may be straight-chain or branched.

The aryl group R ⁴ and R ⁵ may be phenyl or naphthyl.

Substituents for both groups are C ₁ -C ₃ -alkyl, hydroxy, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkylthio, halogen, cyano, COO (C ₁ -C ₅ ) -alkyl, COOH, NR ⁹ R ¹⁰ , 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 ⁴ are preferred.

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

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

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

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

A mono- or bicyclic heteroaryl group R ⁴ and R ⁵ 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. For example, they include compounds of the formula I embedded image in which R ⁴ or R ^{5 are} furanyl, thiophenyl, pyrazolyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, Indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, Furanopyrimidinyl, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl , Quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl- to the present invention and provide a particular embodiment of Invention.

If the heteroaryl groups are partially or completely hydrogenated, compounds of the formula I in which R ^{4 is} tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4- Aminopyridyl, 1H-pyridin-4-ylideneaminyl, chromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydroquinone 2H-benz [1,4] oxazinyl, 1,2-dihydro [1,3] benzoxazin-4-onyl, 3,4-dihydrobenz [1,4] oxazin-4-onyl, 3,4-dihydro-2H- benzo [1,4] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-quinazolin-4 onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] -naphthyridyl, 1H- [ 1,5] naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazin-4-onyl , Octahydro-1H-indolyl, 2,3-dihydro-1H-in dolyl, 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.

If it is a heteroarylalkyl group R ⁵ , 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.

Another object of the invention are compounds of the general formula I, according to claims 1-4, wherein R ^{5 is} a (C ₁ -C ₅ ) alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) alkyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group, a heterocyclyl group, a heterocyclyl ( C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group, an aryl group, an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group.

A preferred object is compounds of the general formula I according to claims _{1 to} ⁴ , in which R ^{4 is} a phenyl or naphthyl, phthalidyl radical which is unsubstituted or substituted by C ₁ -C ₅ -alkyl, halogen, hydroxyl, C ₁ -C ₅ -alkoxy. , 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 particular subject of the invention are compounds of general formula I according to claims 1-4, wherein R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group , an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group.

Another object of the invention are compounds of general formula I according to claims 1-4, in which R ^{5 is} a (C ₁ -C ₃ ) alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₃ ) alkyl group. Particularly preferred are the fully fluorinated alkyl groups.

The invention further provides compounds of the formula I in which R ^{4 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 -2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -oxoalkylidene-substituted 1-4 nitrogen atoms and / or Mono- or bicyclic heteroaryl group containing 1-2 oxygen atoms and / or 1-2 sulfur atoms, which groups may be linked to the nitrogen atom via any position and may optionally be hydrogenated at one or more sites.

Particular preference is given to compounds of the formula I in which R ^{4 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 ₅ ) -alkoxy groups, hydroxy groups, halogen atoms, (C ₁ -C ₃ ) exoalkylidene-substituted, optionally containing 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups mono- or bicyclic heteroaryl group, which group may be linked via an arbitrary position with the amine of the ring system and may optionally be hydrogenated at one or more sites means.

A preferred subject of the invention are compounds of general formula I according to claims 1-4, wherein R ^{4 is} an optionally 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, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl quinazolinyl , Quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group.

The Compounds of the invention of general formula I can by the presence of asymmetric centers as stereoisomers Subject of the present invention are all possible Stereoisomers (e.g., RRR, RRs, RSR, RSS, SRR, SRS, SSR, SSS), both as racemates, as well as in enantiomerically pure form.

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

The Compounds of the invention can also present at the hydroxy group as an ether or ester, according to the methods known in the art can be produced.

• a) indem die nach dem Fachmann bekannten Methoden (z.B. J.Chem. Soc.,Perkin Trans.1 (1999) pp. 2911-2922; Org. Lett. 6 (2004) pp. 3047–3050) aus den entsprechenden Chromanonen, Thiochromanonen, cyclischen Ketonen oder cyclischen Aminoketonen hergestellten cyclischen Styrole der allgemeinen Formel (III) durch eine gegebenenfalls enantioselektiv geführte En-Reaktion mit gegebenenfalls chiralen Lewis Säuren in die Verbindungen der allgemeinen Formel (IV) überführt werden. Durch Reduktion und Aminierung wird nach dem Fachmann bekannten Methoden das Imin (V) erzeugt,
  
  das dann entweder ohne weiteres Reagenz oder durch Zusetzen von anorganischen oder organischen Säuren oder Lewissäuren unter Temperaturen im Bereich von –70°C bis +80°C (bevorzugt im Bereich von –30°C bis +80°C) zu den Verbindungen der allgemeinen Formel (I) zyklisiert wird.
• b) nach bekannter Vorschrift lassen sich Vorstufen vom Typ der allgemeinen Formel (VI) herstellen (J. Med. Chem. 44 (2001) pp. 1085–1098). Nach für den Fachmann bekannten Methoden können diese Verbindungen durch Reduktion der Doppelbindung z.B. mit Wasserstoff an Palladium/Kohle, Reduktion des Esters z.B. mit Lithiumaluminiumhydrid und Oxidation der resultierenden Alkohole zu Verbindungen der allgemeinen Formel (VII) umgesetzt werden.

The compounds according to the invention are prepared,

• a) by the methods known to those skilled in the art (eg J.Chem.Soc., Perkin Trans.1 (1999) pp. 2911-2922; Org. Lett. 6 (2004) pp. 3047-3050) from the corresponding chromanones, Thiochromanonen, cyclic ketones or cyclic aminoketones produced cyclic styrenes of the general formula (III) by an optionally enantioselectively conducted ene reaction with optionally chiral Lewis acids in the compounds of general formula (IV) are converted. By reduction and amination, the imine (V) is produced by methods known to those skilled in the art,
  
  which then either without further reagent or by adding inorganic or organic acids or Lewis acids at temperatures in the range of -70 ° C to + 80 ° C (preferably in the range of -30 ° C to + 80 ° C) to the compounds of the general Formula (I) is cyclized.
• b) according to known instructions, precursors of the type of general formula (VI) can be prepared (J. Med. Chem. 44 (2001) pp. 1085-1098). According to methods known to those skilled in the art, these compounds can be converted into compounds of the general formula (VII) by reducing the double bond, for example with hydrogen over palladium / carbon, reducing the ester, for example with lithium aluminum hydride and oxidizing the resulting alcohols.

Compounds of the type (VII) can be, for example, with a compound of the general formula C _q F _{2q + 1} -Si (CH ₃ ) ₃ , where q = 1, 2, 3 or 4, in the presence of a catalyst or with an alkyl metal compound of the type R ⁵ A, where A is magnesium-halogen or lithium, for example, a Grignard reagent or a lithium alkyl, to give a compound of formula (VIII). Suitable catalysts are fluoride salts or basic compounds such as alkali metal carbonates (J. Am. Chem. Soc. 111 (1989) pp.393).

By Oxidation of compounds of general structure (VIII) according to Literature Methods (J. Org. Chem. 54 (1989) pp. 661-668) obtained new compounds of type (IX).

Compounds of the general formula (X) can be prepared by reacting compounds of the general formula (IX), for example with TMSCN or MCN, where M can be a metal such as, for example, sodium, potassium or copper (J. Med. Chem. 46 (2003 ) pp. 2494-2501). It may optionally be R ^{11 is} a hydrogen atom or a trialkylsilyl group.

links of the general formula (XI) by reacting compounds of general formula (X) with a suitable reducing agent, e.g. diisobutylaluminum to be obtained.

• c) Verbindungen der allgemeinen Formel (VII) können durch Umsetzung mit z.B. einer Alkylmetallverbindung, beispielsweise einem Grignard-Reagenz oder einem Lithiumalkyl, in Anwesenheit eines geeigneten Kupfersalzes oder gemischten Kupferorganyls (z.B. Tetrahedron Lett. 31 (1990) pp.7425–7428; J. Organomet. Chem. 502 (1995) pp. C5-C7) und anschließender Reduktion z.B. mit Diisobutylaluminiumhydrid zu einer Verbindung der Formel VII umgesetzt werden, die analog des Herstellungsverfahrens b) in die die Verbindungen der allgemeinen Formel (I) überführt werden.
  
• d) Verbindungen der allgemeinen Formel (IX) können z.B. mit Alkenyl-Metallorganylen R¹²R¹³(C)=CH-A, wobei A Magnesium-Halogen oder Lithium bedeutet und R¹², R¹³ Wasserstoff oder C₁-C₆-Alkyl bedeuten, wie z.B. Vinylmagnesium-Grignard Verbindungen umgesetzt werden. Dabei erhält man Verbindungen der allgemeinen Formel (XII). Durch Oxidation der Doppelbindung z.B. durch Ozon oder durch Übergangsmetall-Oxyde wie z.B. Osmiumtetraoxid mit anschließender Spaltung unter Verwendung eines geeigneten Oxidationsmittels wie z.B. Natriumperjodat können Verbindungen der allgemeinen Formel (X) erhalten werden.
  

These novel compounds of the general formula (XI) can then be converted analogously to the preparation process a) into the compounds of the general formula (I).

• c) Compounds of the general formula (VII) can be prepared by reaction with, for example, an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, in the presence of a suitable copper salt or mixed copper organyl (eg Tetrahedron Lett., 31 (1990) pp.7425-7428; Organomet. Chem. 502 (1995) pp. C5-C7) and subsequent reduction, for example, with diisobutylaluminum hydride a compound of formula VII are reacted analogously to the preparation process b) into which the compounds of general formula (I) are converted.
  
• d) Compounds of the general formula (IX) can be reacted, for example, with alkenyl-organometallene R ¹² R ¹³ (C) CHCH-A, where A is magnesium, halogen or lithium and R ¹² , R ^{13 is} hydrogen or C ₁ -C ₆ -alkyl mean, such as vinylmagnesium Grignard compounds are implemented. This gives compounds of the general formula (XII). By oxidation of the double bond, for example by ozone or by transition metal oxides such as osmium tetraoxide with subsequent cleavage using a suitable oxidizing agent such as sodium periodate, compounds of general formula (X) can be obtained.
  

The binding of the substances to the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is checked using recombinant receptors. Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays. In comparison to the reference substance [ ³ H] -dexamethasone, the substances show a high affinity for GR. Thus, for the compound of Example 2, an IC ₅₀ (GR) = 20 nM and IC ₅₀ (PR)> 1 μM.

When essential, molecular mechanism for the anti-inflammatory Effect of glucocorticoids becomes GR mediated inhibition the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory Factors considered. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (to overview see Cato ACB and Wade E, BioEssays 18, 371-378 1996).

The compounds of the general formula I according to the invention inhibit lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1. The concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits. The compound of Example 2 showed inhibition of IC ₅₀ (IL8) = 37 nM at 70% 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 topical or sys simultaneously or two hours before the croton oil applied in a mixture. 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.

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

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

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

• (i) Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes:
• - Chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma
• - Bronchitis of different origin
• - 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, especially 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, still syndrome, Felty syndrome
• (iii) allergies associated with inflammatory and / or proliferative processes:
• - All forms of allergic reactions, eg 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
• - Erythematous diseases caused by different noxious agents, eg radiation, chemicals, burns etc.
• - Bull's-eye dermatoses
• - diseases of the lichenoid type,
• - pruritus (eg allergic genesis)
• - Seborrheic dermatitis
• - Rosacea
• - Pemphigus vulgaris
• - Erythema exudative 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 various causes, eg viral, toxic, drug-induced
• - Chronic aggressive and / or chronic intermittent hepatitis
• (viii) Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes:
• - regional enteritis (Crohn's disease)
• - Ulcerative colitis
• - Gastritis
• - Reflux esophagitis
• - Gastroenteritides of other genesis, eg native Sprue
• (ix) proctological diseases associated with inflammatory, allergic and / or proliferative processes:
• - Anal eczema
• - fissures
• - Hemorrhoids
• - idiopathic proctitis
• (x) eye 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, eg due to contact xem, 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, eg BNS cramps
• (xiii) Blood disorders associated with inflammatory, allergic and / or proliferative processes:
• - Acquired hemolytic anemia
• - Idopathic thrombocytopenia
• (xiv) tumors associated with inflammatory, allergic and / or proliferative processes:
• - Acute lymphocytic leukemia
• - Malignant lymphomas
• - Lymphogranulomatoses
• - Lymphosarcomas
• - Extensive metastases, especially in breast, bronchial and prostate cancers
• (xv) Endocrine disorders associated with inflammatory, allergic and / or proliferative processes:
• - 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) replacement therapy in:
• - congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome
• Acquired primary adrenal insufficiency, eg Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc.
• - congenital secondary adrenal insufficiency, eg congenital hypopitotitarism
• Acquired secondary adrenal insufficiency, eg postinfectious, tumors etc.
• (xix) emesis associated with inflammatory, allergic and / or proliferative processes:
• - eg in combination with a 5-HT3 antagonist in cytostatic - induced vomiting.
• (xx) Pain in inflammatory genesis, eg lumbago

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

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

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

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

The invention further provides

• (i) the use of one of the compounds of the invention of formula I or a mixture thereof for the manufacture of a medicament for the treatment of a DISEASE;
• (ii) a method of treating a DISEASE, which method comprises administering a compounding amount according to the invention, wherein the amount suppresses the disease, and wherein the compounding amount is given to a patient in need of such a drug;
• (iii) a pharmaceutical composition for the treatment of a DISEASE, which comprises treatment of one of the compounds of the invention or their mixture and at least one pharmaceutical excipient and / or carrier.

in the In general, satisfactory results can be expected in animals when the daily Doses a range of 1 μg up to 100,000 μg the compound of the invention per kg of body weight include. For larger mammals, for example, to humans, is a recommended daily dose in the range of 1 μg up to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, more preferred a dose of 10 to 10,000 μg per kg of body weight. For example, this dose is conveniently administered several times a day. For the treatment of acute shock (e.g., anaphylactic shock) can Single doses are given that are well above the above doses lie.

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

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

For the parenteral Application injection and infusion preparations are possible.

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

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

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

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

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

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

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

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

experimental part

Example 1 6 - [(7-Fluoro-2-methylquinazolin-5-yl) amino] -5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzo [de] chromen-5-ol

3- (2-chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal

20 g (3 07 mmol) of zinc dust and 710 mg (2.5 mmol) of lead (II) chloride suspended in 200 ml of THF and at room temperature 11.2 ml (100 mmol) of dibromomethane was added. One stirs another 60 minutes and 33 ml (33 mmol) of a 1 M titanium (IV) chloride solution is added dropwise Dichloromethane over 40 minutes with ice cooling to. After one hour at room temperature 4.4 g (30 mmol) Chroman-4-on was added in several portions, with the Reaction to 30 ° C heated. Man stirs another 3 hours at room temperature. It is diluted with diethyl ether and The reaction mixture is carefully poured onto a mixture of 4 M hydrochloric acid and Given ice cream. The phases are separated, extracted with diethyl ether, washes with water, dried over sodium sulfate and remove the solvent. The crude product is purified by column chromatography on silica gel (hexane / isopropyl ether 0-20%) to give 2.75 g 4-methylene-chroman.

To 170 mg (0.60 mmol) of 1,1'-bi-2-naphthol are added 0.60 ml (0.3 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene and the red solution is stirred for 2 hours at room temperature. 1.0 g (6.8 mmol) of 4-methylene-chroman and 2.3 (13.6 mmol) of ethyl trifluoropyrate are added and the mixture is heated to 110 ° C. over 2 hours. After cooling, it is purified by column chromatography on silica gel (hexane / ethyl acetate 20%) immediately to give 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate. 100 mg (0.32 mmol) of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate are dissolved in 10 ml of methanol and 20 mg of palladium on carbon 10% are added. The reaction mixture is shaken under a hydrogen atmosphere for 5 hours. The mixture is then filtered through Celite, washed with ethyl acetate and the solvent is removed in vacuo. It is taken up in 10 ml of diethyl ether and cooled to -5 ° C. Over a period of 10 minutes, 78 mg (2.0 mmol) of lithium aluminum hydride are added in portions. The mixture is stirred for 2 hours at room temperature 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 and the solvent is removed in vacuo. The chromatographic Purification on silica gel (hexane / ethyl acetate 0-15%) gives 50 mg of 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal as a mixture of two diastereomers. ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.66 (m, 0.5H), 1.95-2.37 (m, 2.5H), 2.49 (dd, 0.5H), 2.54 (dd, 1H), 2.79 (m, 0.5H), 3.14 (m, 0.5H) , 3.89 (s, 0.5H), 3.99 (s, 0.5H), 4.09-4.22 (m, 2H), 6.78-6.95 (m, 1H), 7.08-7.19 (m, 2H), 9.74 (s, 1H) ,

5-amino-7-fluoro-2-methychinazolin

17 g (70.5 mmol) 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I Fagervall, L. G Larsson, S.B. Ross, Eur. Med. Chem. 34 (1999) 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) are in 70 ml of butyronitrile combined. The mixture is heated with vigorous stirring 17 Hours at 145 ° C and remove the solvent in a vacuum. After chromatography of the residue on silica gel with hexane / ethyl acetate (0-70%) receives 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline.

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

50 mg (0.18 mmol) of 3- (2H-chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal are added together with 20 mg (0.12 mmol) of 5-amino-7-fluoro-2-methyquinazoline in 5 Toluene dissolved and 0.15 ml of titanium tetraethylate are added. The mixture is heated to 100 ° C over 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 sulfate and the solvent is removed in vacuo to give 3- (chroman-4-yl) -1 - [(7-fluoro-2-methylquinazolin-5-yl) imino] -2- (trifluoromethyl) -propane-2 -ol as a crude product. The imine is taken up in 4 ml dichloromethane and cooled to -78 ° C. 1.5 ml (1.5 mmol) of a 1 M titanium tetrachloride solution in dichloromethane are added dropwise over 5 minutes and the cooling bath is removed after 20 minutes. After a further 20 minutes, pour the solution warmed to room temperature on a mixture of ice and saturated sodium bicarbonate solution and stir vigorously for 10 minutes. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (hexane / ethyl acetate 50-100%) gives 9 mg of the desired product.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.78-1.91 (m, 2H), 2.06 (dd, 1H), 2.48 (dd, 1H), 3.34 (m, 1H), 4.26 (ddd, 1H), 4.50 (ddd, 1H), 5.13 ( d, 1H), 5.79 (d, 1H), 6.65 (dd, 1H), 6.74 (d, 1H), 6.82 (d, 1H), 6.94 (dd, 1H), 7.07 (t, 1H), 9.19 (s , 1H).

Example 2 9-Fluoro-6 - [(2-methylquinolin-5-yl) amino] -5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzo [de] chromen-5-ol

3- (8-fluoro-chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal:

33.2 g (296 mmol) 2-fluorophenol and 18.4 ml 281 mmol acrylonitrile together with 5.0 g (29.6 mmol) of benzyltrimethylammonium hydroxide 4 Days at 80 ° C touched. At room temperature, ice is added and 2N hydrochloric acid is added. Man stirs 10 minutes, extracted with ethyl acetate, washed with sat Sodium hydrogen carbonate and sodium chloride solution, dried over sodium sulfate and removes the solvent in the Vacuum. The column chromatographic Separation on silica gel (hexane / ethyl acetate 5-50%) gives 6.4 g of 3- (2-fluorophenoxy) -propionitrile. 6.4 g (38.8 mmol) of 3- (2-fluorophenoxy) -propionitrile are refluxed in 38.6 ml of concentrated hydrochloric acid over 2 hours. at Room temperature is diluted with ice-water and stirred for 10 minutes. you extracted with ethyl acetate, washed with saturated Ammonium chloride solution and dries over Sodium sulfate. After removal of the solvent in vacuo, 6.5 g 3- (2-fluorophenoxy) -propionic acid. 6.5 g (35.6 mmol) of 3- (2-fluorophenoxy) propionic acid are added to 39 g of polyphosphoric acid and four hours at 70 ° C touched. After cooling overnight is poured on ice water. It is extracted with ethyl acetate, washed with saturated Sodium hydrogen carbonate and sodium chloride solution and dried over sodium sulfate. After removal of the solvent obtained in a vacuum 5.5 g of 8-fluorochroman-4-one as a crystalline solid.

29.8 g (456 mmol) of zinc dust and 710 mg (2.5 mmol) of lead (II) chloride are suspended in 450 ml of THF and at room temperature, 28.6 ml (253 mmol) of dibromomethane are added. Stirring is continued for a further 60 minutes and 50.7 ml (50.7 mmol) of a 1 M titanium (IV) chloride solution in dichloromethane are added dropwise over 40 minutes while cooling with ice. After one hour, 8.4 g (50.7 mmol) of 8-fluorochroman-4-one in 500 ml of THF are added dropwise at room temperature. The mixture is stirred for a further 18 hours at room temperature. It is diluted with diethyl ether and the reaction mixture is carefully added to a mixture of 4 M hydrochloric acid and ice. The phases are separated, extracted with diethyl ether, washed with water, dried over sodium sulfate and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane / isopropyl ether 0-20%) to give 0.81 g of 8-fluoro-4-methylene-chroman.

0.98 ml (0.49 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene are added to 281 mg (0.98 mmol) of 1,1'-bi-2-naphthol and the red solution is stirred for 2 hours at room temperature. 0.81 g (4.9 mmol) of 8-fluoro-4-methylene-chroman and 1.21 ml (9.8 mmol) of ethyl trifluoropyrrugate are added and the mixture is heated to 120 ° C. over 3 hours. After cooling, the residue is purified by column chromatography on silica gel (hexane / ethyl acetate 0-20%), giving 0.69 g of 3- (8-fluoro-2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) -propionic acid ethyl ester. 400 mg (1.2 mmol) of ethyl 3- (8-fluoro-2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate are dissolved in 12 ml of methanol and 40 mg of 10% palladium on carbon are added. Shake under the reaction mixture under a hydrogen atmosphere for 40 minutes. It is then filtered through Celite, washed with dichloromethane and the solvent is removed in vacuo. The resulting 330 mg of crude 3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propionic acid ethyl ester are cooled to -5 ° C in 8 ml of diethyl ether and 2 ml of THF and allowed to settle over In portions, 185 mg (4.9 mmol) of lithium aluminum hydride was added firmly. It is stirred for 24 hours at room temperature and poured into water. The phases are separated and extracted several times with ethyl acetate. It is washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic separation on silica gel (hexane / ethyl acetate 0-15%) gives 53 mg of 3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal as a mixture of two diastereomers and 126 mg Alcohol.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.73 (m, 0.5H), 1.99-2.38 (m, 2.5H), 2.47 (dd, 0.5H), 2.53 (dd, 1H), 2.84 (m, 0.5H), 3.16 (m, 0.5H) , 3.90 (s, 0.5H), 4.00 (s, 0.5H), 4.18-4.37 (m, 2H), 6.70-6.97 (m, 3H), 9.75 (s, 1H).

Analogous Example 1 is 53 mg (0.18 mmol) of 3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal with 30 mg (0.19 mmol) of 5-amino-2-methylquinoline to the corresponding 3- (8-fluoro-chroman-4-yl) -1 - [(2-methylquinolin-5-yl) imino] -2- (trifluoromethyl) propan-2-ol implemented. The imine is taken up in 3.6 ml of dichloromethane and at -50 ° C with 0.90 ml (0.90 mmol) of a 1M boron tribromide solution. It is allowed to over 60 min at 0 ° C erwämen and pours the solution on a mixture of ice and saturated sodium bicarbonate solution and stir Fierce for 10 minutes. It is extracted with dichloromethane, with saturated Sodium chloride solution washed and over Dried sodium sulfate. After concentration and chromatography on silica gel (Hexane / 2-propanol 10-20%) receives you want 25 mg Product as a mixture of two diastereomers.

Diastereomer 1

• ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.70-1.86 (m, 2H), 2.10 (m, 1H), 2.47 (dd, 1H), 2.72 (s, 3H), 3.31 (m, 1H), 4.27 (ddd, 1H), 4.40 (d, 1H), 4.60 (ddd, 1H), 5.20 (d, 1H), 6.61 (d, 1H), 6.81 (dd, 1H), 6.97 (dd, 1H), 7.22 (d, 1H), 7.58 (t, 1H ), 7.59 (d, 1H), 7.98 (d, 1H).

Diastereomer 2

• ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.70-1.86 (m, 2H), 2.10 (dd, 1H), 2.23 (m, 1H), 2.73 (s, 3H), 3.00 (m, 1H), 4.24 (ddd, 1H), 4.54 (ddd, 1H), 4.78 (d, 1H), 5.10 (d, 1H), 6.58 (d, 1H), 6.74 (dd, 1H), 6.89 (dd, 1H), 7.22 (d, 1H), 7.48 (d, 1H ), 7.49 (t, 1H), 8.12 (d, 1H).

Example 3

9-fluoro-6 - [(2-methylquinazolin-5-yl) amino-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] chromen-5-ol

5-amino-2-methylquinazoline

12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (MT Bogert, VJ Chambers J. Org. Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are dissolved in 75 ml Phosphoryl chloride heated under reflux for 20 hours. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The orga nische 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).

To 60 mg (0.21 mmol) of 3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal and 39 mg (0.22 mmol) of 5-amino-2-methyl-quinazoline in 4 ml Toluene is added to 89 .mu.l (0.42 mmol) of titanium tetraethylate and the mixture is heated to 110.degree. C. over 2 hours. After cooling, pour on sat. Ammonium chloride solution adds ethyl acetate 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. The crude 3- (8-fluorochroman-4-yl) -1 - [(2-methylquinazolin-5-yl) imino] -2- (trifluoromethyl) propan-2-ol thus obtained is taken up in 2.6 ml of dichloromethane and cooled to -50 ° C. 0.67 ml (0.67 mmol) of a 1 M boron tribromide solution in dichloromethane is added dropwise over 5 minutes and the cooling bath is removed. After two hours, pour the solution, which is at about 0 ° C., onto a mixture of ice and saturated sodium bicarbonate solution and stir vigorously for 15 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatographic separation on silica gel (hexane / 2-propanol 15%) gives 6 mg of the desired product.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.82-1.92 (m, 2H), 2.10 (dd, 1H), 2.50 (dd, 1H), 2.85 (s, 3H), 3.36 (dddd, 1H), 4.29 (ddd, 1H), 4.62 ( ddd, 1H), 5.19 (d, 1H), 5.38 (d, 1H), 6.74 (dd, 1H), 6.87 (dd, 1H), 6.94 (d, 1H), 7.37 (d, 1H), 7.77 (t , 1H), 9.33 (s, 1H).

Example 4

{[9-fluoro-5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] chromen-6-yl] amino} -2-methylphthalazin-1-one

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

3-bromo-4-nitro-phthalide

5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are heated in 80 ml of benzotrifluoride under reflux and exposure to light until complete reaction. It is added to water, extracted with dichloromethane, washed several times with water, dried and the solvent removed in vacuo. This gives 7.24 g of 3-bromo-4-nitro-phthalide as a solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ = 7.26 (s, 1H), 7.88 (t, 1H), 8.3 (d, 1H), 8:56 (d, 1H)

5-nitro-phthalazin-1-one:

18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100 ° C for 1 h. Then 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF are added and it is stirred at 100 ° C for a further 4 h. It is added to water, extracted several times with ethyl acetate and the org. Phase washed with water and brine. It is dried and the solvent removed in vacuo. After recrystallization from ethyl acetate gives 2.35 g of 5-nitro-phthalazin-1-one as a solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ), δ = 8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs, 1H)

2-methyl-5-nitro-phthalazin-1-one

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

5-amino-2-methyl-phthalazin-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, _CDCl3), = 3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 1H), 7.8 (d, 1H), 8.16 (s, 1H)

Analogous Example 3 is 60 mg (0.21 mmol) of 3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal with 39 mg (0.22 mmol) of 5-amino-2-methyl-phthalazin-1-one to the corresponding {[3- (8-fluoro-2H-chromen-4-yl) -2- (trifluoromethyl) propan-2-ol-1-yl] imino} -2-methyl-phthalazin-1-one implemented. The imine is taken up in 3.4 ml of dichloromethane and at -50 ° C with 0.83 ml (0.83 mmol) of a 1 M boron tribromide solution. One lets one over Hour at 0 ° C erwämen and pours the solution on a mixture of ice and saturated sodium bicarbonate solution and stir Violent for 15 minutes. It is extracted with dichloromethane, with saturated Sodium chloride solution washed and over Dried sodium sulfate. After concentration and chromatography on silica gel (Hexane / 2-propanol 15%) you want 28 mg Product as a mixture of two diastereomers.

Diastereomer 1

• ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.40-1.86 (m, 2H), 2.08 (m, 1H), 2.45 (dd, 1H), 3.29 (m, 1H), 3.82 (s, 3H), 4.25 (ddd, 1H), 4.53 (ddd, 1H), 4.84 (d, 1H), 5.15 (d, 1H), 6.65 (dd, 1H), 6.93 (dd, 1H), 7.21 (d, 1H), 7.64 (t, 1H), 7.87 (d, 1H ), 8.18 (s, 1H).

Diastereomer 2

• ¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.40-1.86 (m, 2H), 2.27 (m, 1H), 2.85 (dd, 1H), 2.97 (m, 1H), 3.84 (s, 3H), 4.22 (ddd, 1H), 4.60 (ddd, 1H), 4.65 (d, 1H), 5.43 (d, 1H), 6.78 (dd, 1H), 6.81 (d, 1H), 6.89 (dd, 1H), 7.52 (t, 1H), 7.78 (d, 1H ), 8.26 (s, 1H).

Analog can be made become:

Example 5

{[9-fluoro-5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] chromen-6-yl] amino} -one -quinoline-2 (1H)

5-aminoquinoline-2 (1H) -one:

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

Example 6

6 - [(8-fluoro-2-methylquinazolin-5-yl) amino] -5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] chromen-5-ol

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 ° 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 ° C and holding 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. This gives 3.0 g (15.0 mmol) of the hydroxylimine as an intermediate, the portions in 15 ml of conc. Sulfuric acid are dissolved at 60 ° C. After complete addition, the mixture is heated for 2 hours at 80 ° C and 4 hours at 90 ° C. One lets Cool and pour the solution on 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-difluoroisatin are 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, the mixture is cooled to 0 ° C. and 5 ml of 4 molar hydrochloric acid are added and diluted with 50 ml of water. It is extracted with ethyl acetate, dried over sodium sulfate, concentrated, and thus quantitatively obtained 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 resulting 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus-pentachloride are heated in 20 ml of phosphoryl chloride over 12 h at 125 ° C. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives, quantitatively, 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which are dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine. 600 mg of palladium on carbon are added and the mixture is shaken for 2 h (480 ml of hydrogen uptake) under a hydrogen atmosphere at atmospheric pressure. The solution is freed by filtration through Celite from the catalyst, washing with 100 ml of ethanol, and evaporated. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline are obtained. To 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF are added 890 mg (13.7 mmol) of sodium azide and the mixture is heated for 8 h 125 ° C. The solvent is removed in vacuo and chromatographed on silica gel with ethyl acetate to give 52 mg of product.
¹ H-NMR (300 MHz, CDCl ₃ ); δ = 2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).

Example 7 6- (7,8-Difluoro-2-methylquinazolin-5-yl) amino] -5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzo [de] chromen-5-ol

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

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

2.0 g (7.2 mmol) of 7,8-difluoro-5-N-pivaloylamino-2-methyquinazoline are dissolved in 140 ml of toluene and cooled to -70 ° C. Over 30 minutes, 24 ml (28.8 mmol) of a 1.2 M diisobutylaluminum hydride solution in toluene are added dropwise. The reaction mixture is allowed to warm for 2 hours to -25 ° C and stirred for 2 hours at - 25 ° C. Isopropanol is added slowly followed by water and stirred for 12 hours at room temperature until a precipitate forms, which is removed by filtration through Celite. It is washed thoroughly with a methylene chloride methanol mixture and concentrated. The residue is stirred vigorously in 200 ml of ethyl acetate and 50 ml of methanol together with 100 g of silica gel and 20 g of manganese dioxide. It is filtered through Celite, washed with good with a methylene chloride methanol mixture and concentrated. Chromatography on silica gel with 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).

Example 8

{[5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] chromen-6-yl] amino} -2-methylphthalazin-1-one

Example 9

6 - [(2-methylquinazolin-5-yl) amino-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] thiochromen-5-ol

2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal

can be prepared from thiochroman-4-one analogously to Example 1, wherein in the hydrogenation Raney nickel instead of palladium on carbon as a catalyst to use.

Example 10

2-methyl-6 - [(2-methylquinazolin-5-yl) amino] -5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydro-benzo [de] thiochromen-5-ol

2-hydroxy-3- (2-methylthiochroman-4-yl) -2- (trifluoromethyl) propanal

can prepared analogously to Example 1 from 6-chloro-2-methylthiochroman-4-one Raney nickel instead of palladium in the hydrogenation Coal is to be used as a catalyst.

Claims (15)

Stereoisomers of the general formula (I),

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) alkyl group, a (C ₁ -C ₁₀ ) alkoxy group, a (C ₁ -C ₁₀ ) Alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, a nitro group, or R ¹ and R ² together form a group selected from the group consisting of -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, -NH- (CH ₂ ) _{n + 1} , N (C ₁ -C ₃ -alkyl) - (CH ₂ ) _{n + 1} , -NH-N = CH-, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 are} independently hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl, 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, a (C ₁ -C ₁₀ ) alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, R ^{4 is} a C ₁ -C ₁₀ -alkyl group, a C ₁ -C ₁₀ -alkyl group substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅ ) -alkoxy groups, an optionally substituted (C ₃ -C ₇ ) Cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, optionally one or more groups selected from (C ₁ -C ₅ ) alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups in which R ^{10 is} (C ₁ -C ₆ ) -alkyl or benzyl), (C ₁ -C ₅ ) -alkoxy groups, hydroxyl groups, halogen atoms, (C ₁ -C ₃ ) -exoalkylidene-substituted, optionally _{1 to} 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, this group on any position may be linked to the amine of the tricyclic system and may optionally be hydrogenated at one or more sites, R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or fully fluorinated (C ₁ -C ₅ ) - Alkyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkenyl group, a heterocyclyl group , a heterocyclyl (C ₁ -C ₈ ) alkyl group, heterocyclyl (C ₂ -C ₈ ) alkenyl group, an aryl group, an aryl (C ₁ -C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, aryl (C ₂ C ₈ ) alkynyl group represents an optionally substituted by one or more keto groups, (C ₁ -C ₅ ) alkyl groups, (C ₁ -C ₅ ) alkoxy, halogen atoms, (C ₁ -C ₃ ) Exoalkylidengruppen, one or more nitrogen atoms and mono- or bicyclic heteroaryl group containing oxygen atoms and / or sulfur atoms, a heteroaryl (C ₁ -C ₈ ) alkyl group or a heteroaryl (C ₂ -C ₈ ) alkeny where these groups can be linked to the tetrahydronaphthalene system via an arbitrary position and may optionally be hydrogenated at one or more sites, R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a halogen atom, a (C ₁ -C ₅ ) -alkyl group which reacts with OR ⁸ , SR ⁸ , NR ⁸ R ⁹ may be substituted, p is 1,2 or 3 and X is an oxygen atom, a sulfur atom, a CH ₂ - or an NR ⁹ group. Stereoisomers of the general formula (I),

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) alkyl group, a (C ₁ -C ₁₀ ) alkoxy group, a (C ₁ -C ₁₀ ) -Alkythio group, a (C ₁ -C ₅ ) - perfluoroalkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _{n is} -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n + 2} -, where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ independently of one another may be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl, 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, a (C ₁ -C ₁₀ ) alkylthio group, a (C ₁ -C ₅ ) perfluoroalkyl group, a cyano group, R ⁴ a C C ₁ -C ₁₀ alkyl group selected by one or more groups a us _{1 to 3} hydroxy groups, halogen atoms, 1-3 (C ₁ -C ₅ ) alkoxy-substituted C ₁ -C ₁₀ alkyl group, an optionally substituted phenyl group, an optionally substituted by 1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) -oxoalkylidene groups, substituted 1-3 nitrogen atoms and / or 1 2-oxygen atoms and / or 1-2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic heteroaryl group, which groups may be linked via any position with the amine of the tricyclic system and may optionally be hydrogenated at one or more sites R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, an aryl group, an aryl (C ₁ -C ₈ ) -alkyl group, aryl (C ₂ -C ₈ ) alkenyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₈ ) alkyl group, (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₈ ) alkene R ⁶ and R ⁷ independently of one another represent a hydrogen atom, a halogen atom, a methyl or ethyl group which may be substituted by OR ⁸ , SR ⁸ , N (R ⁹ ) ₂ , p is 1, 2 or 3 X is an oxygen atom Sulfur atom, a CH ₂ - or an NR ⁹ group. Stereoisomers of the general formula (I),

wherein R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₅ ) alkyl group, a (C ₁ -C ₅ ) alkoxy group, a (C ₁ -C ₅ Perfluoroalkyl group, a cyano group, a nitro group, 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 C ₁ -C ₁₀ alkyl group, a substituted by 1-3 hydroxy groups, halogen atoms, C ₁ -C ₁₀ alkyl group, optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 (C ₁ -C ₅₎ - alkyl groups, 1-2 (C ₁ -C ₅₎ -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃₎ -Exoalkylidengruppen substituted phenyl, naphthyl, phthalidyl, isoindolyl, Dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, Ben zothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, which groups link via any position with the amine of the ring system R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group R ⁶ and R ^{7 is} independently of one another a hydrogen atom, and a halogen atom, a methyl or ethyl group which may be substituted by OR ⁸ , SR ⁸ , N (R ⁹ ) ₂ , wherein R ⁸ and R ^{9 are} independently hydrogen, C ₁ -C ₅ alkyl or (CO) -C C ₁ -C ₅ -alkyl, p 1, 2 or 3 X represents an oxygen, a sulfur atom, a CH ₂ - or an NR ⁹ group. Stereoisomers of the general formula (I),

wherein R ¹ , R ² and R ^{3 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀ ) alkyl group, a (C ₁ -C ₁₀ ) alkoxy group, a cyano group R ⁴ one optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 (C ₁ -C ₅ ) -alkyl groups, 1-2 (C ₁ -C ₅ ) -alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, Phenyl-, phthalidyl-, isoindolyl-, dihydroindolyl-, dihydroisoindolyl-, dihydroisoquinolinyl-, thiophthalidyl-, benzoxazinonyl-, phthalazinonyl-, quinolinyl-, isoquinolinyl-, quinolonyl-, isoquinolonyl- substituted 1-2 (C ₁ -C ₃ ) -exoxyalkylidene groups -, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, these groups being via any position may be linked to the amine of the ring system and optionally at one or more Stel R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group R ⁷ and R ^{8 is} independently a hydrogen atom, a halogen atom, a methyl or Ethyl group p 1 or 2 X represents an oxygen or a sulfur atom. Use of the stereoisomers according to one of the preceding claims for the manufacture of a medicament. Use of the stereoisomers of claims 1-4 for the manufacture of a medicament for the treatment of inflammatory Diseases. Pharmaceutical preparations containing at least a stereoisomer according to claims 1-4 or mixtures thereof and pharmaceutically compatible Carrier. Stereoisomers of the general formula I, according to one the claims 1-4 in the form of salts with physiologically acceptable anions. A process for the preparation of the stereoisomers of general formula I in which the radicals, unless stated otherwise, have the meanings defined in claim 1, characterized in that either a) stereoisomers of general formula (III)

wherein R ¹ , R ² , R ³ , R ⁷ , X and p have the meanings given in claim 1, by an optionally enantioselectively conducted ene reaction with α-keto acids R ⁵ (CO) COOR ¹⁰ in the presence of optionally chiral Lewis acids in Compounds of the general formula (IV)

be converted, the radical R ⁶ = H is introduced by hydrogenation and by reduction and reaction with amines of the formula R ⁴ -NH ₂ , wherein R ^{4 has} the meaning given in claim 1, the compounds of general formula (V) are prepared

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , X and p have the meanings given in claim 1, which then either without further reagent or by addition of inorganic or organic acids or Lewis acids at temperatures of - From 70 ° C. to 80 ° C. to give compounds of general formula I or b) compounds of general formula (VI) prepared by a method known to the person skilled in the art

by reduction of the double bond or by reaction with an R ⁶ -containing cuprate reagent in which R ^{6 has} the meanings given in claim 1, reduction of the ester and, if appropriate, oxidation are converted into compounds of the general formula (VII),

which can subsequently be reacted with a silicon compound of the general formula C _q F _{2q + 1} -Si (CH ₃ ) ₃ , where q = 1, 2, 3 or 4, in the presence of a catalyst or with a metalloorganylene of the formula R ⁵ A, wherein R ^{5 has} the meanings given in claim 1 and A is magnesium-halogen or lithium, is converted to a compound of general formula (VIII)

which after oxidation and reaction with a compound of formula M-CN wherein M may represent sodium, potassium, copper or trimethylsilyl, is converted into a compound of general formula (X)

which is converted after reduction into a compound of the general formula (XI),

which can be reacted and cyclized analogously to process a) with an amine R ⁴ -NH ₂ , or c) compounds of the general formula VIII

with alkenyl-organometallene R ¹² R ¹³ (C) = CH-A, where A is magnesium, halogen or lithium and R ¹² , R ^{13 are} hydrogen or C ₁ -C ₆ -alkyl, to give compounds of the general formula XII)

which can be converted by oxidative cleavage of the double bond into compounds of the general formula (X), which can be reacted analogously to variant b) to give compounds of the general formula (I). Process stage for the preparation of the stereoisomers of the general formula I according to claim 9, characterized in that stereoisomers of the general formula V

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and p have the meanings defined in claim 1 optionally cyclized with the addition of inorganic or organic acids or Lewis acids. Compounds of the general formula V according to claim 9

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

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

Compounds of formula III according to claim 9, wherein R ¹ , R ² , R ³ , R ⁷ , X, p have the meanings defined in claim 1

Amines according to claim 9, 5-amino-7-fluoro-2-methylquinazoline, 5-amino-8-fluoro-2-methylquinazoline and 5-amino-7,8-difluoro-2-methylquinazoline,