WO2006066950A2 - Tricyclic aminoalcohols, methods for producing the same and their use as anti-inflammatory agents - Google Patents

Abstract

The invention relates to the tricyclic aminoalcohols of general formula (I), to methods for producing the same and to their use as anti-inflammatory agents.

Description

 Tricyclic amino alcohols, process for their preparation and their use as anti-inflammatory agents

The invention relates to tricyclic amino alcohols, processes for their preparation and their use as anti-inflammatory agents. From the prior art WO 02/10143 and WO 03/082827 open-chain non-steroidal anti-inflammatory agents are known. 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 a comparable effect as the compounds described in the prior art.

The present invention relates to compounds 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-ι-Cio) -alkyl group, a (C _r Cio) alkoxy group, a (CrCio) -alkylthio group, a (CrC ₅₎ perfluoroalkyl group, a cyano group, a nitro group or R ¹ and R ² together form a group selected from the groups -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _{n +} 2 -, - 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 ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently hydrogen, C-ι-C may be ₅ -alkyl or (CO) -C -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 _r Cio-alkyl group, by one or more groups selected from 1-3 hydroxy groups, halogen atoms, 1-3 (CrC ₅₎ - alkoxy substituted C _r Cio-alkyl group, 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, wherein R ₃ ¹⁰ C _r C ₆ alkyl or benzyl), (CrCs) alkoxy groups, hydroxy groups, halogen atoms, (CrC ₃ ) - Exoalkylidengruppen 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 one to two keto groups, it being possible for this group to be linked via any position with the amine of the ring system and optionally hydrogenated at one or more sites t can be

R ^{5 is} a (C ₁ -C ₅ ) -alkyl group or an optionally partially or completely fluorinated (C ₁ -C ₅ ) -alkyl group, a (C ₃ -C ₇ ) -cycloalkyl group, a (C ₃ -C ₇ ) -cycloalkyl (C ₁ -C ₈ ) -alkyl group, (C ₃ -C 7) cycloalkyl (C ₂ -C ₈₎ alkenyl ₍₈ -C) alkyl group, a heterocyclyl group, a heterocyclyl, heterocyclyl (C ₂ - Ce) alkenyl group, an aryl group, an aryl (-C ₈₎ alkyl group,

Aryl (C ₂ -C ₈ ) alkenyl group, aryl (C ₂ -C ₈ ) alkynyl group, optionally 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 or more nitrogen atoms and / or oxygen atoms and / or sulfur atoms containing mono- or bicyclic heteroaryl group, a heteroaryl (-C ₈₎ alkyl group, or a heteroaryl (C ₂ -C ₈₎ alkenyl group which groups via any position with the chromium system may be linked and may optionally be hydrogenated at one or more sites,

R ⁶ and R ⁷ independently represent a hydrogen atom, a halogen atom, a (Ci-C ₅ ) alkyl group which may be substituted with 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 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C _r Cio) - alkyl, (Ci-Cio) Alkoxy group, a (C 1 -C 10) -alkythio group, a (C 1 -C 8) -perfluoroalkyl group, a cyano group, a nitro group, or R ¹ and R ² together form a group selected from the group -O- (CH ₂ ) _n -O-, -O - (CH ₂ ) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) _n + 2- _> where n = 1 or 2 and the terminal atoms are linked to directly adjacent ring carbon atoms, or NR ⁸ R ⁹ , where R ⁸ and R ⁹ independently of one another may be hydrogen, C 1 -C 6 -alkyl or (CO) -CrC ₅ -alkyl, R ^{3 is} a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 10) alkyl group, a (Ci-Ci ₀₎ alkoxy group, a (CrCio) -alkylthio group, a _(Ci-C5) perfluoroalkyl group, a cyano group,

R ^{4 is} a C 1 -C 18 -alkyl group, represented by one or more groups selected from the group consisting of 1-3 hydroxy groups, halogen atoms, C 1 -C 15 -alkoxy substituted CiC-io-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 (Ci-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, 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 (Ci-C ₅₎ alkyl group or an optionally partially or completely fluorinated (Ci-C ₅₎ alkyl group, an aryl group, an aryl (-C ₈₎ alkyl, 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 represent a hydrogen atom, a halogen atom , a methyl or ethyl group which may be substituted with 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 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted _(Ci-C5) - alkyl group, a (C ₁ -C ₅₎ alkoxy 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} -, 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 (C 1 -C 10) -alkyl group which is substituted by 1 to 3 hydroxyl groups, halogen atoms and is optionally substituted by one or more groups selected from 1 to 2 keto groups, 1 to 2 (C 1 -C ₅ ) - Substituted alkyl groups, 1-2 (Ci-C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (CrC ₃ ) -Exoalkylidengruppen

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, these groups being attached via any position with the amine of the Ringsystems can be linked and optionally at one or more

Bodies can be hydrogenated,

R ^{5 is} a (Ci-C ₅ ) alkyl group or an optionally partially or completely fluorinated (d-CsJ-alkyl group R ⁶ and R ^{7 are} independently a hydrogen atom, a halogen atom, a methyl or ethyl group, with OR ⁸ , SR ⁸ , N (R ⁹ ) ₂ may be substituted, wherein R ⁸ and R ^{9 are} independently hydrogen, C-ι-C ₅ alkyl or

(CO) -CrC ₅ alkyl, p is 1, 2 or 3 and X is an oxygen, a sulfur atom, a CH ₂ or NR ⁹ group.

A preferred subject of the present invention are stereoisomers of the general formula (I) according to claim 1, wherein R ¹ , R ² and R ³ are each independently a hydrogen atom, a

Hydroxy group, a halogen atom, an optionally substituted (Ci-Ci ₀ ) -

Alkyl group, a (CrCio) alkoxy group, a cyano group

R ^{4 is} optionally selected from one or more groups

1-2 keto groups, 1-2 (CrC ₅ ) alkyl groups, 1-2 (CrCsJ alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C ₃ ) -exxalkylidengruppen substituted, 1-3 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2

Sulfur atoms and / or mono- or bicyclic containing 1-2 keto groups

Heteroaryl group, which group can be linked via any position with the amine of the ring system and optionally at one or more

Bodies can be hydrogenated,

R ^{5 is} a (dC ₅ ) -alkyl group or an optionally partially or completely fluorinated (CrCsJ-alkyl group

R ⁷ and R ^{8 are} independently a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2

X represents an oxygen or a sulfur atom. Another object of the present invention are stereoisomers of the general formula (I) wherein

R ¹ , R ² and R ³ 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 cyano group

R ^{4 is} optionally substituted by one or more groups selected from 1-2 keto groups, 1-2 (Ci-C ₅ ) alkyl groups, 1-2 (C-ι-C ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (dC ₃₎ -Exoalkylidengruppen substituted phenyl, phthalidyl, isoindolyl, dihydroindolyl, Dihydroisoindolyl-, Dihydroisochinolinyl-, thiophthalidyl, Benzoxazinonyl-, Phthalazinonyl-,

Quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, 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 are} independently of one another a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2 and

X represents an oxygen or a sulfur atom.

A particularly preferred subject of the invention are stereoisomers according to claims 1-5, wherein

R ¹ , R ² and R ³ independently represent a hydrogen atom or a

Halogen atom,

R ^{4 is} optionally selected from one or more groups

(C 1 -C ₅ ) -alkyl groups, hydroxyl groups, halogen atoms, substituted, optionally containing 1-2 nitrogen atoms and / or 1 keto group-containing bicyclic heteroaryl group, which group can be linked via any position with the amine of the ring system and optionally hydrogenated at one or more sites can be, R ^{5 is} a fluorinated (CrC ₃ ) alkyl group

R ⁶ and R ⁷ independently represent a hydrogen atom, or a (CrC ₂ ) alkyl group, p 2 and X represents an oxygen or a sulfur atom.

A very particularly preferred subject of the invention are stereoisomers of general formula I, wherein

R ¹ , R ² and R ³ independently of one another represent a hydrogen atom or a halogen atom,

R ^{4 is} optionally selected from one or more groups

1-2 keto groups, 1-2 (Ci-C ₅ ) -alkyl groups, 1-3 hydroxy groups, 1-3

Halogen atoms, substituted phthalazinonyl, quinolinyl, isoquinolinyl,

Isoquinolonyl, quinolonyl, quinazolinyl, dihydroindolonyl, indazolyl, which groups can be attached at any position with the amine of the

Ringsystems can be linked and optionally at one or more

Bodies can be hydrogenated,

R ^{5 is} a fluorinated (CrC ₃ ) alkyl group

R ⁶ and R ⁷ independently of one another represent a hydrogen atom, or a (C ₁ -C ₂ ) -alkyl group, p 2 and

X represents an oxygen or a sulfur atom.

A very particularly preferred subject of the invention are stereoisomers of general formula I, wherein

R ¹ , R ² and R ³ independently represent a hydrogen atom or a

Halogen atom,

R ^{4 is} optionally selected from one or more groups

1-2 keto groups, 1-2 (d-CsJ-alkyl groups, 1-3 hydroxy groups, 1-3 halogen atoms, substituted phthalazinonyl, quinolinyl, quinolonyl,

Chinazolinylgruppe, whereby these groups over an arbitrary position with the

Amine of the ring system can be linked and optionally at one or can be hydrogenated several sites, R ^{5 is} a fluorinated (Ci-C ₃ ) alkyl group

R ⁶ and R ⁷ independently of one another represent a hydrogen atom, or a (C ₁ -C ₂ ) -alkyl group, p 2 and

X represents an oxygen or a sulfur atom.

The third fused ring containing X ₁ [(Chbjp] and the substituent R ⁷ can be 5-, 6- or 7-membered, p can therefore assume values of 1-3, p = 2 is preferred.

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

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

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 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 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, (Ci-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 , where 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. Particularly preferred for R ⁶ and R ^{7 is} a hydrogen atom and the unsubstituted C 1 -C ₃ -alkyl group, most preferably a hydrogen atom and the methyl group. The alkoxy groups can be straight-chain or branched and are, for example, 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, are, for example, the partially or fully 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 and the pentafluoroethyl group, most preferably the trifluoromethyl 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 may form a ring in which both aryl substituents together represent a chain selected from among

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 Hs) ₂ , NH (C ₃ H ₇ ), N ( C ₃ H ₇ ) ,, NH (C ₄ H ₉ ), N (C ₄ H ₉ ) 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 by one or more groups selected from hydroxy, halo, (CrC ₅₎ alkyl, (C ₁ - C _δ J-alkoxy optionally substituted saturated cyclic group having from 3 to 7 ring carbon atoms, for example 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 _I - (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 (CrC 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 heterocyclyl group is not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine. Come as substituents

Hydroxy groups, halogen atoms, (CrC ₅ ) alkyl groups, (Ci-Cs) alkoxy groups in question.

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 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. Suitable substituents for both groups Ci-C coming ₃ alkyl, hydroxy, -C ₃ - alkoxy, d-Cs-alkylthio, halogen, cyano, COO (Ci-C ₅₎ alkyl, COOH, NR ⁹ R ^10, nitro, in 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, in addition to or in addition to the abovementioned substituents, keto, (C ₁ -C ₃ ) - Wear exoalkylidene. 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 linked to a skeleton via a C 1 -C ₈ -alkyl group, where the alkyl group can 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 which is linked to the skeleton via a C ₂ -C 6 -alkynyl group, where the alkynyl group may be straight-chain or branched.

By mono- or bicyclic heteroaryl group R ⁴ and R ⁵ , which may be hydrogenated at one or more sites, are meant any mono- or bicyclic aromatic ring systems which contain at least one heteroatom and at most seven heteroatoms. Preference is given to ring systems having 1-5 heteroatoms. Suitable heteroatoms are 1-4 nitrogen atoms, 1-2 oxygen atoms and 1-2 sulfur atoms, which can occur in all subcombinations in the ring system as long as they do not exceed the number specified for the respective heteroatom and, in total, the maximum number of seven heteroatoms. For example, they include compounds of formula I wherein R ⁴ or R ^{5 is} furanyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl , Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, azaindolizinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, 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; The heteroaryl groups contain a keto group, so it can take various positions within the ring system. All chemically possible regioisomers are included in this definition: for example, "quinolonyl" includes both quinoline-2 (1H) one and quinoline-3 (4H) one and quinoline-4 (1H) one. If the heteroaryl groups are partially or fully hydrogenated then belong

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-pyridine 4-ylidenaminyl, chromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz [1 , 4] oxazinyl, 1, 2-dihydro [1, 3] benzoxazin-4-onyl, 3,4-dihydrobenz [1,4] oxazin-4-onyl, 3,4-dihydro-2H-benzo [1, 4 ] thiazinyl, 4H-benzo [1,4] thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-quinazolin-4-onyl, 3 , 4-Dihydro-1H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetrahydro [1,5] naphthyridinyl, dihydro-1H- [1,5] naphthyridyl, 1H- [ 1, 5] naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl, 1,2-dihydropyrido [3,2-d] [1,3] oxazine-4- onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihyd o-2H-isoindolyl, 1, 2-dihydroindazolyl, 1 H -pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1 H -pyrrolo [2,3-b] pyridyl, 2,2-dihydro- 1 H-pyrrolo [2,3-b] pyridin-3-onyl, to the present invention.

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), (CIC ₅ ) Alkoxy groups, hydroxy groups,

Halogen atoms, (CrC ₃ ) substituted exoalkylidene, optionally 1-3 nitrogen atoms and / or 1 -2 oxygen atoms and / or 1 -2 sulfur atoms and / or 1-2 keto groups containing mono- or bicyclic Heteroaryl group, which group may be linked via an arbitrary position with the amine of the ring system and may optionally be hydrogenated at one or more points means.

A particularly preferred subject of the invention are compounds of general formula I according to claims 1-5, wherein R ^{4 is} optionally substituted by one or more groups selected from (C 1 -C ₅ ) -alkyl groups, hydroxy groups, halogen atoms, optionally substituted 1-2 nitrogen atoms and or bicyclic heteroaryl group containing 1 keto group, 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.

A preferred subject of the invention are compounds of general formula I according to claims 1-5, wherein R ⁴ is optionally substituted by -C ₅ - alkyl, halogen, hydroxy, C _r C ₅ alkoxy, keto, or (Ci-C ₃₎ substituted Exoalkyliden 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.

A preferred object is compounds of general formula I according to claims 1-5, wherein R ^{4 is} a phenyl or naphthyl, phthalidyl, thiophthalidyl, benzoxazinonyl optionally substituted by C 1 -C ₅ -alkyl, halogen, hydroxy, C 1 -C ₅ -alkoxy. , Phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7- or 1, 8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, Benzimidazole or indolyl group.

A particularly preferred subject of the invention are compounds of the general formula I in which R ^{4 is} a quinolinyl, quinolinyl, quinazolinyl, phthalazinonyl or quinolonyl group which is optionally substituted by C 1 -C ₃ -alkyl, halogen, hydroxyl. 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 6 -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 general formula I, according to claims 1-5, wherein R ^{5 is} a (Ci-CsJ-alkyl group or an optionally partially or fully fluorinated (CrC ₅ ) alkyl group, a (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇₎ cycloalkyl (CrC ₈₎ alkyl (C ₃ -C ₇₎ cycloalkyl (C ₂ -C ₈₎ alkenyl group, a heterocyclyl group, a heterocyclyl (Ci-C ₈₎ alkyl, heterocyclyl ( C ₂ -C ₈ ) alkenyl group, an aryl group, an aryl (Ci-C ₈ ) alkyl group, aryl (C ₂ -C ₈ ) alkenyl group.

A particular subject of the invention are compounds of general formula I according to claims 1-5, 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 4) alkyl group. C ₈₎ alkyl aryl (C ₂ -Cβ) alkenyl group, a (C ₃ - C ₇₎ cycloalkyl group, a (C ₃ -C ₇₎ cycloalkyl _(Ci-C8) alkyl, (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 1-5, in which R ^{5 represents} a (CrC ₃ ) alkyl group or an optionally partially or fully fluorinated (Ci-C ₃ ) alkyl group. Particular preference is given to compounds of general formula I according to claims 1-5, in which R ^{5 is} a fully fluorinated (C ₁ -C ₃ ) -alkyl group, very particularly preferably a CF ₃ group.

Another object of the invention are compounds of formula I, wherein R ^{4 is} a C _r Cio-alkyl group which may optionally be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted

Phenyl group, an optionally represented by 1-2 keto groups, 1-2 (C 1 -C ₅ ) -alkyl groups, 1-2 (C ₁ -C 6 -alkoxy groups, 1-3 halogen atoms, 1-2 (C ₁ -C ₃ ) - Exoalkylidene-substituted 1-4 nitrogen atoms and / or 1-2 oxygen atoms and / or 1-2 sulfur atoms containing mono- or bicyclic heteroaryl group, 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 RRR, RRS, RSR, RSS, SRR, SRS ₁ SSR, SSS), both as racemates or mixtures of diastereomers. as well as in enantiomerically pure or diastereomerically pure form. The enantiomers or diastereomers can be obtained by methods known to the person skilled in the art, for example by chromatography of the racemate or the diastereomer mixture on a chiral solid phase. 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.

The compounds according to the invention can also be present on the hydroxy group as ether or ester, which can be prepared by methods known to the person skilled in the art.

For example, for the ether, methyl ether, ethyl ether, propyl ether,

Isopropyl ether methoxymethyl ether, ethoxymethyl ether, ethoxyethylether ganannt. The esters are derived from inorganic acids or organic acids.

The organic acids may be cyclic, straight-chain or branched, saturated or unsaturated, carbocyclic or heterocyclic, substituted or unsubstituted. Preferably, the radicals are derived from d-Cg carboxylic acids.

Examples of suitable acids which are suitable for esterification are sulfuric acid, formic acid, acetic acid, propionic acid, butanoic acid,

Pentanoic acid, called pivalic acid.

Inorganic acids are, for example, H ₂ SO 4, H ₂ SO ₃ , H ₂ SO ₂ , H ₃ PO ₄ . 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 ) are converted from the corresponding chromanones, thiochromanones, cyclic ketones or cyclic aminoketones cyclic styrenes of the general formula (III) by an optionally enantioselectively led ene reaction with optionally chiral Lewis acids in the compounds of general formula (IV). By reduction and amination, the imine (V) is produced by methods known to those skilled in the art,

Wittig-type olefination

(II) (III)

(Hl) (IV)

(R6 = H)

(IV) (V)

Lewis acid

(V) (I) then either without further reagent or by addition of inorganic or organic acids or Lewis acids at temperatures in the range of -70 ⁰ C to + 80 ⁰ C (preferably in the range of -30 ⁰ C to + 80 ⁰ C. ) is cyclized to the compounds of general formula (I).

Under Lewis acid according to the invention are understood as meaning all known to those skilled Lewis acids such as TiCl _4, Ti (OR3) _4, TiCl ₂ (OR 3) _2, TiBr ₂ (OR 3) _2, PdCl _4, Pd (OR 3) _4, PdCl ₂ (OR3) _2, PdBr ₂ (OR 3) _2, ZnCl _2, ZnBr _2, SnCl _4, AlCl _3, AlBr _3, AIEtCI _2, AlMe ₂ Cl, BBr _3, BCl _3, Bl _3, BF _3, BBrMe _2, Cu Salts z. B. Cu (OTf) ₂ , CuCl ₂ , CuBr ₂ , Yb (OTf) ₃ , preferably BBr ₃ .

A particular subject of the invention are the amines R ⁴ NH ₂ , 5-amino-7-fluoro-2-methylquinazoline, 5-amino-8-fluoro-2-methylquinazoline and 5-amino-7,8-difluoro-2-methylquinazoline , 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. 1. hydrogenation

2. reduction

3. oxidation

(VI) (VII for R ⁶ = H))

Compounds of type (VII), for example, can be reacted with a compound of the general formula CqF2q + i-Si (CH ₃₎ 3 ■ wherein q may be = 1, 2, 3 or 4, in the presence of a catalyst or with an alkyl metal compound of the type R ⁵ A, wherein A is magnesium halogen or lithium, for example a Grignard reagent or a lithium alkyl, to implement 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).

(VIII)

(VII)

By oxidation of compounds of general structure (VIII) according to literature methods (J. Org. Chem. 54 (1989) pp. 661-668) new compounds of type (IX) are obtained.

(IX)

(VlIl)

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.

(IX) (X)

Compounds of general formula (XI) can be prepared by reacting compounds of general formula (X) with a suitable reducing agent, e.g. Diisobutylaluminum hydride are obtained.

(X)

These new 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 obtained by reaction with e.g. an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, in the presence of a suitable copper salt or mixed organo copper (eg Tetrahedron Lett., 31 (1990) pp. 7425-7428; J. Organomet. Chem. 502 (1995) pp. C5-C7 ) and subsequent reduction eg be reacted with diisobutylaluminum hydride to give a compound of formula VII, which are analogous to the preparation process b) into which the compounds of general formula (I) are converted.

(VI) (VII) d) Compounds of the general formula (IX) may, for example, with alkenyl-metallo-R ¹² R ¹³ (C) = CH-A, where A is magnesium halogen or lithium and R ¹² , R ^{13 is} hydrogen or CrCβ-alkyl, such as Vinylmagnesium Grignard compounds will be 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.

(X)

An object of the invention are the intermediates for the processes described above, in particular the compounds of formulas III, IV and V wherein the radicals have the meanings given in claim 1 and the process steps for their preparation.

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. Compared to the reference substance [ ³ H] -dexamethasone, the substances show a high affinity to the GR. Thus, for the compound of Example 2, an IC ₅₀ (GR) = 20 nM and IC ₅₀ (PR)> 1 μM.

As a major molecular mechanism for the anti-inflammatory effect of glucocorticoids, the GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is mediated by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (for review see Cato 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 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, Glucocorticoids: Immunological Foundations, Pharmacology and Therapy Guidelines,

Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998]. Cause of this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and free amino acids resulting from the breakdown of proteins (catabolic effect of glucocorticoids). A key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after administration of the test substances, the liver is removed and the TAT activity in the Homogenate measured. The compounds of general formula I do not or only to a limited extent induce tyrosine aminotransferase in doses in which they are anti-inflammatory in this test.

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

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

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

- Bronchitis of different origin

- 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, e.g. systemic lupus erythematosus,

Scleroderma, Polymyositis, Dermatomyositis-Sjögren Syndrome, Still's Syndrome, Felty's 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 nephritides (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) 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, 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 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 states of shock, eg anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) Substitution therapy in: - congenital primary adrenal insufficiency, eg congenital adrenogenital syndrome

Acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, postinfectious, tumors, metastases, etc. - congenital secondary adrenal insufficiency, e.g. congenital hypopitotitarism

Acquired secondary adrenal insufficiency, 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 vomiting.

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

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

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 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 treatment is one of the invention

Compounds or mixtures thereof and at least one pharmaceutical excipient and / or carrier.

In general, satisfactory results are expected in animals when the daily doses range from 1 μg to 100,000 μg of the compound of the invention per kg of body weight. For larger mammals, such as humans, a recommended daily dose is in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg body weight, more preferably a dose of 10 to 10,000 μg per kg body weight. For example, this one will

Dose expediently administered several times a day. For the treatment of an acute shock (e.g., anaphylactic shock), single doses well above the above doses may be given.

The formulation of pharmaceutical preparations based on the new

Compounds are prepared in a manner known per se by processing the active ingredient with the carriers customarily used in galenicals, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and converting them into the desired administration 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. Furthermore, the invention relates to the compounds of general formula I as therapeutic agent together with pharmaceutically acceptable and acceptable excipients and carriers.

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 6-r (7-Fluoro-2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) -2,3,3a, 4,6,6-hexahydrobenzorodeclene-5-ol

3- (2-Chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propanal 20 g (307 mmol) of zinc dust and 710 mg (2.5 mmol) of lead (II) chloride are suspended in 200 ml of THF and at room temperature 11.2 ml (100 mmol) of dibromomethane are added. Stirring is continued for a further 60 minutes and 33 ml (33 mmol) of a 1 M titanium (IV) chloride solution in dichloromethane are added dropwise over 40 minutes while cooling with ice. After one hour, are added firmly in several portions at room temperature 4.4 g (30 mmol) chroman-4-one, wherein the reaction heated to 30 ⁰ C. The mixture is stirred for a further 3 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 2.75 g of 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) Ethyltrifluorpyruvat are added and the mixture is heated over 2 hours at 110 ⁰ C After cooling, column chromatography on silica gel (hexane / ethyl acetate 20%) and purified immediately 1.15 g of ethyl 3- (2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate are obtained. 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. Is taken up in 10 ml of diethyl ether and cooled to -5 ⁰ C. over 10 minutes in portions 78 mg (2.0 mmol) Lithium aluminum hydride firmly added. 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. 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 ) ₁ 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, 1 H).

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%), 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 -70 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 to warm and stirred for 4 hours at ⁰ -4o 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. The phases are separated, washed with saturated sodium chloride solution and dried 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), 6.50 (dd, 1H) ₁ 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%) yield 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) ₁ 4.26 (ddd, 1H), 4.50 (ddd, 1 H), 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-r (2-methyl-quinolin-5-yl) -aminol-5- (trifluoromethyl) -2,3,3a, 4.5.6-hexahydrobenzofeerychol-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 are added together with 5.0 g (29.6 mmol) Bezyltrimethylammoniumhydroxid 4 days at 80 ⁰ C stirred. At room temperature, ice is added and 2N hydrochloric acid is added. The mixture is stirred for 10 minutes, extracted with ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solution, dried Sodium sulfate and the solvent is removed in vacuo. 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, it is diluted with ice-water and stirred for 10 minutes. It is extracted with ethyl acetate, washed with saturated ammonium chloride solution and dried over sodium sulfate. After removal of the solvent under reduced pressure gives 6.5 g of 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 stirred at 70 ^° C. for four hours. After cooling overnight, it is poured onto ice water. It is extracted with ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solution and dried over sodium sulfate. After removal of the solvent in vacuo, 5.5 g of 8-fluorochroman-4-one are obtained 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 28.6 ml (253 mmol) of dibromomethane are added at room temperature. 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. To 281 mg (0.98 mmol) of 1,1'-bi-2-naphthol are added 0.98 ml (0.49 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene 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) Ethyltrifluorpyruvat are added and the mixture is heated for 3 hours at 12O ⁰ C. After cooling, it is immediately purified by column chromatography on silica gel (hexane / Ethyl acetate 0-20%) to give 0.69 g of ethyl 3- (8-fluoro-2H-chromen-4-yl) -2-hydroxy-2- (trifluoromethyl) propionate. 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 transferred over 185 mg (4.9 mmol) of lithium aluminum hydride are added in portions 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).

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 are added analogously to Example 1 corresponding 3- (8-fluorochroman-4-yl) -1 - [(2-methylquinolin-5-yl) imino] -2- (trifluoromethyl) propan-2-ol. The imine is taken up in 3.6 ml of dichloromethane and treated at -5O ⁰ C with 0.90 ml (0.90 mmol) of a 1 M boron tribromide solution. The mixture is allowed to warm to ⁰ ° C. for 60 minutes and the solution is poured into a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatography Silica gel (hexane / 2-propanol 10-20%) gives 25 mg of the desired

Product as a mixture of two diastereomers.

Diastereomer 1

¹ H-NMR (300 MHz, CDCl ₃ ); δ = 1.70-1.86 (m, 2H) ₁ 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, 1 H), 2.23 (m, 1 H), 2.73 (s, 3H), 3:00 (m, 1 H) ₁ 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-r (2-methylquinazoline-5-vnamino1-5- (trifluoromethyl) -2,3,3a.4.5.6-hexahydrobenzordeichromene-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 refluxed in 75 ml of phosphoryl chloride for 20 hours. After cooling, pour into sat. NaHCO ₃ solution and extracted with ethyl acetate. The organic phase is dried and the solvent removed. This gives 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) are dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. Are added 2 g of palladium on carbon and 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 of toluene are added 89 .mu.l (0.42 mmol) of titanium tetraethylate and the mixture is heated to 110 ⁰ 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 chromatographed on 50 ° C to be cooled. 0.67 ml (0.67 mmol) of a 1 M boron tribromide solution are added dropwise over 5 minutes

Dichloromethane and removes the cooling bath. After two hours, pour the solution, which is 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 γ-Fluoro-5-hydroxy-5- (trifluoromethyl) -2,3,3a.4,5,6-hexahydrobenzorde1-chromene

-vπamino) -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, 1 H), 7.88 (t, 1 H) ₁ 8.3 (d, 1 H), 8.56 (d, 1 H) 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 of DMF are added 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 washed with water and brine. It is dried and the solvent removed in vacuo. Recrystallization from ethyl acetate gives 2.35 g of 5-nitrophthalazin-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-phthalazine-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, 1 H), 8.62 (d, 2H), 8.75 (s, 1 H) 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 in vacuo away. 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 ) Analogously to Example 3, 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 give the corresponding {[3- (8-fluorochroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propylidene] amino} -2-methylphthalazin-1-one. The imine is taken up in 3.4 ml dichloromethane and treated at -50 ⁰ C with 0.83 ml (0.83 mmol) of a 1 M boron tribromide solution. The mixture is allowed to come to 0 ⁰ C for one hour and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 15 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (hexane / 2-propanol 15%) gives 28 mg of the desired 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) ₁ 4.53 (ddd, 1H), 4.84 (d, 1H), 5.15 (d, 1H), 6.65 (dd, 1H), 6.93 (dd, 1H) ₁ 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) ₁ 6.78 (dd, 1H), 6.81 (d, 1H), 6.89 (dd, 1H), 7.52 ( t, 1 H), 7.78 (d, 1 H), 8.26 (s, 1 H).

Example 5 5- / Ir 5 -hydroxy-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrozodelchromene-6-vnamino) -quinoline-2 (1 H) -one

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

Analogously to Example 1, 600 mg (2.18 mmol) of 3- (chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal with 386 mg (2.39 mmol) of 5-aminoquinoline-2 (1 H) -one zum corresponding 5 - {[3- (chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propylidene] amino} quinoline-2 (1H) -one. 100 mg of imine is taken up in 2 ml dichloromethane and treated with a 1 M TiCLrLosung 0 ⁰ C and 2.4 ml (2:40 mmol). The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (dichloromethane / 2-propanol 0-5%) gives 18 or 14 mg of the desired product as separated diastereomers. Diastereomer 1

¹ H-NMR (400 MHz, DMSO); δ = 1.43 (dd, 1H), 1.60 (dq, 1H), 2.19 (dd, 1H), 2.55 (dd, 1H), 2.98 (m, 1H), 4.02 (t, 1H), 4.28 ( ddd, 1H), 4.78 (d, 1H), 6.02 (d, 1H), 6.23 (d + s, 2H), 6.38 (d, 1H), 6.55 (d, 1H), 6.65 (d, 1H ), 7.00 (t, 1 H), 7.13 (t, 1 H) ₁ 8.15 (d, 1 H), 11.52 (s, 1 H). Diastereomer 2

¹ H-NMR (400 MHz, DMSO); δ = 1.63 (dq, 1H), 1.80 (dd, 1H), 1.97 (dd, 1H), 2.19 (dd, 1H), 3.15 (m, 1H), 4.15 (td, 1H), 4.38 (ddd, 1H) ₁ 5.28 (d, 1H), 6.07 (d, 1H), 6.30 (d, 1H), 6.45 (s, 1H), 6.52 (d, 1H), 6.59 ( d, 1H), 6.65 (d, 1H), 6.97 (t, 1H), 7.20 (t, 1H), 8.13 (d, 1H), 11.50 (s, 1H).

Analog can be produced: Example 6

6-r (8-Fluoro-2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzofdelchromene-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 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. It is stirred for a further 30 min at RT and heated after the addition of 4.09 g (58.9 mmol)

Hydroxylammonium chloride in 19 ml of water over 45 min at 125 ⁰ 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 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. 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 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).

Example 76- (7,8-Difluoro-2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) - 2.3.3a.4.5.6-hexahydrobenzor-1-ene-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 -7O ⁰ C 156 ml (391 mmol) of a 2.5M butyllithium solution in hexane , 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) 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 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 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).

250 mg (0.91 mmol) of 3- (chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal are reacted with 200 mg (1.02 mmol) of 5-amino-7,8-difluoro-2 analogously to Example 1. methylquinazoline to give the corresponding 3- (chroman-4-yl) -1 - [(7,8-difluoro-2-methylquinazolin-5-yl) imino] -2- (trifluoromethyl) -propan-2-ol. 200 mg of imine is taken up in 4.0 ml dichloromethane and treated solution at -40 ⁰ C and 2.2 ml (21.2 mmol) of a 1 M boron tribromide. The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatography on basic silica gel (hexane / 2-propanol 10-20%), 18 mg of the desired product are obtained as a mixture of two diastereomers. Mixture of diastereomers:

¹ H NMR (300 MHz, CD ₃ OD, selected patterns); δ = 0.87 (m, 1H), 1.15 - 1.30 (m, 3H) ₁ 1.42 (s, 3H), 1.70 - 2.16 (m, 7H), 3.02 - 3-13 (m, 1H) ₁ 4.00 - 4.25 (m, 2H), 6.58 (dd, 1H), 6.72 (t, 1H), 6.80 (m, 1H), 6.95 - 7.18 (m, 2H), 9.47 (s, 1H).

Analog can be prepared: Example 8

5- (y5) -hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzofdelchromene-6-ylamino) -2-methylphthalazin-1-one

Example 9

6-r (2-methylquinazolin-5-yl) -aminol-5- (trifluoromethyl) -2,3,3a, 4,6,6-hexahydrozorothiochromene-5-ol

2-Hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal Can be prepared analogously to Example 1 from thiochroman-4-one, wherein in the hydrogenation Raney nickel instead of palladium on carbon is to be used as a catalyst. Mixture of diastereomers:

¹ H NMR (500 MHz, CD ₃ OD, selected patterns); δ = 0.60-0.72 (m, 1H), 1.40-1.65 (m, 2H), 1.75-2.00 (m, 3H), 2.14-2.28 (m, 3H), 2.49 (dd, 1H), 2.87 (m, 1H), 3.00 (m, 1H), 3.04 - 3.18 (m, 2H), 3.38 - 3.90 (m, 1H, Diaster.A + B), 6.78 (d, 1H, Diaster.A), 6.85 - 7.30 (m, 4H, Diaster A + B), 9.13 (s, 1 H, Diaster A), 9.68 (s, 1 H, Diaster B).

Analogously to Example 1, 183 mg (0.63 mmol) of 2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal with 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline to the corresponding 3- (thiochroman 4-yl) -1 - [(2-methylquinazolin-5-yl) imino] -2- (trifluoro-methyl) -propan-2-ol. 40 mg of imine are dissolved in 2.0 ml

Dichloromethane and treated at -40 ⁰ C with 0.93 ml (0.93 mmol) of a 1 M Bortribromid solution. The mixture is allowed to warm to 0 ⁰ C over 60 min and the solution is poured onto a mixture of ice and saturated Sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (dichloromethane / 2-propanol 2-4%) gives 12 mg of the desired product as a mixture of two diastereomers. Mixture of diastereomers:

¹ H NMR (300 MHz, CD ₃ OD, selected patterns); δ = 1.25 - 1.34 (m, 2H), 1.56 - 75 (m, 1H), 1.95 (t, 1H), 2.22 - 2.34 (m, 1H), 2.38 (dd, 1H), 2.78 (s , 3H), 2.93 - 3.10 (m, 2H), 3.22 (dd, 1 H), 4.59 (s, 1 H, Diaster A), 5.40 (s, 1 H, Diaster B), 6.95 - 7.09 (m , 4H), 7.68 (t, 1H, Diaster.B), 7.78 (t, 1H, Diaster.A), 9.50 - 9.17 (m, 1H).

Analog can be prepared: Example 10

2-Methyl-6-r (2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrozodelithiochromen-5-ol

2-Hydroxy-3- (2-methylthiochroman-4-yl) -2- (trifluoromethyl) propanal Can be prepared analogously to Example 1 from 6-chloro-2-methylthiochroman-4-one, wherein in the hydrogenation Raney nickel instead of palladium is to be used as a catalyst on carbon.

Example 11

5- / y5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzofe1-chelene-6-yl-amino) phthalazine-1 (2H) -one

Analogously to Example 1, 600 mg (2.18 mmol) of 3- (chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) -propanal with 384 mg (2.39 mmol) of 5-amino-2H-phthalazin-1-one to corresponding 5- [3- (chroman-4-yl) -2-hydroxy-2- (trifluoromethyl) propylidene] amino} phthalazine-1 (2H) -one. 210 mg of imine are taken up in 5 ml of dichloromethane and treated at -40 ° C with 2.5 ml (2.5 mmol) of a 1 M BBr ₃ solution. The mixture is allowed to warm to 0 ⁰ C over 60 min and pour the Solution to a mixture of ice and saturated sodium bicarbonate

Solution and stir vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate.

After concentration and chromatography on RP silica gel (MeCN / water 38-50%), 69 or 34 mg of the desired product are obtained as separated

Diastereomers.

Diastereomer 1:

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.49 (dd, 1 H), 1.63 (qd, 1 H), 2.18 (dd, 1 H),

2.54 (dd, 1H), 2.98 (m, 1H), 4.03 (t, 1H), 4.29 (ddd, 1H), 4.88 (d, 1H), 6.20 (s, 1H), 6.41 ( d, 1H), 6.68 (dd, 1H), 6.98 (q, 1H), 7.40 (d, 1H) ₁ 7.47 (t, 1H), 8.58 (s,

1 H), 12.48 (S ₁ 1 H).

Diastereomer 2:

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.63 (qd, 1H), 1.81 (t, 1H), 1.99 (m, 1H),

2.21 (dd, 1H), 3.10-3.20 (m, 1H), 4.16 (td, 1H), 4.48 (ddd, 1H), 5.37 (d, 1H), 6.43 (s, 1H), 6.48 (d, 1 H), 6.60 (d, 1H), 6.18 (d, 1H), 6.98 (t, 1H), 7.24 (d, 1H),

7.39 (d, 1H), 7.53 (t, 1H), 8.55 (s, 1H) ₁ 12.48 (s, 1H).

Example 12 5- / y9-Fluoro-5-hydroxy-3a-methyl-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrobenzor-1-ene-6-yl-1-amino-quinolin-2 (1H) -one

2-Hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propionaldehyde 7.3 g E / Z- (chroman-4-ylidene) -acetic acid ethyl ester (J. Med. Chem. 2001, 44 pp. 1085 - 1098), 100 mg of copper (l) chloride and 5.1 ml of chlorotrimethylsilane in 55 ml of THF are added slowly at ⁰ ° C. with 11.5 ml of methylmagnesium chloride solution [3.3 M in THF], so that the temperature always remains below 5 ^° C. It is stirred for a further hour at ⁰ ° C. and for 10 hours at room temperature. The mixture is mixed with saturated ammonium chloride solution and extracted with ether. The combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90:10) gives ethyl 2- (4-methylchroman-4-yl) acetate as crude product. This is dissolved in 50 ml of THF at 0 ^° C. with 1 g Added lithium aluminum hydride and stirred for 1, 5 hour at ^{0 0} C. The mixture is carefully added to saturated ammonium chloride solution and diluted with ethyl acetate. It is filtered through diatomaceous earth and the aqueous phase extracted with ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo. After chromatography on silica gel (hexane / ethyl acetate 100: 0 → 60:40), 1.2 g of 2- (4-methylchroman-4-yl) ethanol are obtained as a colorless oil. 0.58 ml of oxalyl chloride in 25.0 ml of dichloromethane are mixed at -78 ° C. with 1.0 ml of DMSO in 25.0 ml of dichloromethane. After 5 min. 1.2 g of 2- (4-methylchroman-4-yl) ethanol in 25.0 ml of dichloromethane are added dropwise at -78 ° C. After 15 min. is added 4 ml of triethylamine and slowly warmed to room temperature. It is mixed with water, brine, 1% sulfuric acid and sat. Sodium bicarbonate solution, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 90:10) gives 970 mg of 2- (4-methylchroman-4-yl) -ethanal as a colorless oil. A solution of 870 mg of 2- (4-methyl-chroman-4-yl) ethanal and 2 ml Trifluormethy-Itrimethylsilan in 30 ml THF at 0 ⁰ C with 0.87 ml of tetrabutylammonium fluoride solution (1 M in THF) and stirred for 1 hour. It is again added a spatula tip solid tetrabutylammonium fluoride and treated with water. It is extracted with ethyl acetate, the organic phase washed with brine and dried with sodium sulfate. This gives 1.2 g of 2- (4-methylchroman-4-yl) -1-trifluoromethyl-ethanol as a brown oil (mixture of diastereomers). 7.8 g of Dess-Martin periodinane in 100 ml of dichloromethane are added at 0 ⁰ C with a solution of 1.2 g of 2- (chroman-4-yl) -1-trifluoromethyl-ethanol in 20 ml of dichloromethane and stirred for 1 hour at ⁰ ° C. The approach is with ges.

Sodium bicarbonate solution, diluted with diethyl ether and with sodium thiosulfate solution for 30 min. touched. The organic phase is separated and washed with water. It is dried with sodium sulfate and concentrated in vacuo. This gives 1.1 g of 3- (4-methylchroman-4-yl) -1, 1, 1-trifluoropropan-2-one as a brown oil. A solution of 1.1 g of 3- (4-methylchroman-4-yl) -1, 1, 1-trifluoropropan-2-one in 30 ml of THF is added at room temperature to 9.2 ml of vinylmagnesium bromide solution [1H in THF] at room temperature. It is stirred for 5 hours at room temperature and then sat. ammonium chloride Solution given. The batch is extracted with ethyl acetate and the combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 95: 5) gives 930 g of 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol as an oil. In a solution of 900 mg of 1- (4-methylchroman-4-yl) -2-trifluoromethyl-3-buten-2-ol in 56 ml of dichloromethane and 14 ml of methanol at -70 ⁰ C ozone is introduced until the Solution takes a blue dye. Then argon is passed through the solution for one minute, mixed with 0.42 ml of dimethyl sulfide and stirred at -70 ⁰ C for one hour. It is slowly warmed to room temperature and stirred for a further 10 hours. The batch is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated in vacuo. Chromatography on silica gel (hexane / ethyl acetate 100: 0 → 96: 4) gives 330 mg of 2-hydroxy-3- (4-methylchroman-4-yl) -2-trifluoromethyl-propionaldehyde as a yellow oil (mixture of diastereomers) ,

¹ H-NMR (CDCl ₃ , selected signals): δ = 1.38 (s, 3H, diast. A), 1.43 (s, 3H, diast. B), 1.57-1.65 (m, 2H), 1.81 (ddd, 1 H), 2.13 (ddd, 1 H), 2.37 (d, 1 H, Diaster B), 2.45-2.60 (m), 2.83 (d, 1 H, Diaster B), 3.69 (s, 1 H, Diaster A), 3.86 (s, 1 H, Diaster B), 3.97 (dd, 1 H, Diaster B), 4.08-4.35 (m), 6.78-6.84 (m, 1 H, Diaster A + B) , 6.88-6.95 (m, 1H), 7.07-7.21 (m), 7.23-7.30 (m), 8.88 (s, 1H, Diaster.B), 9.56 (s, 1H, Diaster A).

Analogously to Example 1, 300 mg (1.0 mmol) of 2-hydroxy-3- (4-methylchroman-4-yl) -2- (trifluoromethyl) propionaldehyde with 160 mg (1.0 mmol) of 5-aminoquinoline-2 (1H) - to give the corresponding 5 - {[2-hydroxy-3- (4-methylchroman-4-yl) -2- (trifluoromethyl) -propylidene] amino} quinoline-2 (1H) -one. 250 mg of imine is taken up in 3 ml dichloromethane and treated ₃ solution at -40 ⁰ C 3.0 ml (3.0 mmol) of a 1 M BBr. The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatography on silica gel (Dichloromethane / i-PrOH 0 - 6%) are obtained 81 and 16 mg of the desired

Product as separated diastereomers.

Diastereomer 1:

¹ H-NMR (600 MHz, DMSO-d6): δ = 1.40 (s, 3H), 1.84 (m, 2H), 1.93 (d, 1H), 2.38 (d, 1H), 4.28 (m, 2H ), 5.04 (d, 1H), 6.13 (s, 1H), 6.15 (d, 2H), 6.24 (d, 1H), 6.43

(d, 1H), 6.60 (d, 1H), 6.72 (d, 2H), 7.04 (t, 1H), 7.12 (t, 1H), 8.20 (d, 1H), 11.60

(s, 1H).

Diastereomer 2:

¹ H-NMR (600 MHz, DMSO-d6): δ = 1.51 (s, 3H), 1.76 (m, 1H), 1.88 (dd, 1H), 2.00 (d, 1H), 2.18 (d, 1 H), 4.33 (m, 1 H), 4.41 (m, 1 H), 5.26 (d, 1 H), 6.18 (d, 1 H),

6.34 (s, 1H), 6.37 (d, 1H), 6.48 (d, 1H), 6.57 (d, 1H), 6.68 (d, 1H), 6.70 (d, 1H),

7.01 (t, 1H), 7.22 (t, 1H), 8.24 (d, 1H), 11.67 (s, 1H).

Example 13

5- / 79-fluoro-5-hydroxy-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrobenzofdelithiochromene-6-vinylamino) quinoline-2 (1H) -one

Analogously to Example 1, 700 mg (2.4 mmol) of 2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal with 386 mg (2.4 mmol) of 5-aminoquinoline-2 (1 H) -one to the corresponding 5 - {[2-Hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propylidene] amino} quinoline-2 (1H) -one. 100 mg of imine is taken up in 3 ml dichloromethane and treated ₃ solution at -40 ⁰ C with 2.3 ml (2.3 mmol) of a 1 M BBr. The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (dichloromethane / i-PrOH 2-4%) gives 28 mg of the desired product as a mixture of diastereomers. Mixture of diastereomers:

¹ H-NMR (500 MHz, DMSO-d6, selected signals): δ = 1.57 (ddd, 1H, Diaster.A + B), 1.96 (t, 1H), 2.25 (m, 1H, Diaster.A + B), 3.88 - 3.99 (m, 1H, Diaster. A + B), 3.07 (ddd, 1 H), 3.13 - 3.27 (m, 1 H, Diaster A + B), 4.32 (d, 1 H, Diaster A), 4.57 (brs s, 1 H, Diaster.B), 5.47 (d, 1H, Diaster.B), 6.10 (d, 1H, Diaster.A), 6.37 (d, 1H, Diaster.A), 6.40 (s, Diaster.A), 6.58 (d, 2H, Diaster A + B), 6.90 (d, 1 H ₁ Diaster A), 7.05 (m, 2H, Diaster A + B), 7.25 (t, 1 H), 8.16 (d, 1 H), 11.53 (s, (1 H, Diaster. A + B).

Example 14

6-r (8-Fluoro-2-methyl-quinazolin-5-yl) -amino1-5- (trifluorometh-2.3.3a.4.5.6-hexahydrobenzordeithiochromene-5-ol

328 mg (1.1 mmol) of 2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal with 200 mg (1.1 mmol) of 5-amino-8-fluoroquinazoline are converted into the corresponding 1 - [analogously to Example 1 ( 8-fluoro-2-methylquinazolin-5-yl) imino] -3- (thiochroman-4-yl) -2- (trifluoromethyl) propan-2-ol. 185 mg of imine are dissolved in 5 ml

Dichloromethane and treated at -40 ⁰ C with 4.1 ml (4.1 mmol) of a 1 M BBr ₃ solution. The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. Concentration and chromatography on silica gel (dichloromethane / i-PrOH 2-4%) and re-chromatography on basic silica gel gives 18 mg of the desired product as a mixture of diastereomers. Mixture of diastereomers: ¹ H-NMR (400 MHz, CD ₃ OD, selected signals): δ = 1.12 (t, 1 H), 1:15 to 1:38 (. M, 2H, Diaster A + B), 1:53 - 1.68 (m , 1H), 1.90 (t, 1H), 2.25 (m, 1H), 2.36 (dd, 1H), 2.73 - 2.85 (m, 4H), 2.86 - 3.08 (m, 2H), 3.10 - 3.33 (m, 2H), 5.31 (s, 1H), 6.88 (dd, 1H), 6.90-7.05 (m, 4H), 7.46 (dd, 1H), 7.52 (dd, 1H), 9.54 - 9.68 (m, 1 H, Diaster. A + B).

Example 15

6-r (7.8-Difluoro-2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrobenzordeithiochromene-5-ol 223 mg (0.77 mmol) of 2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal with 150 mg (0.77 mmol) of 5-amino-7,8-difluoroquinazoline are added to the corresponding [(7,8-Difluoro-2-methyl-quinazolin-5-yl) imino] -3- (thiochroman-4-yl) -2- (trifluoromethyl) propan-2-ol. 90 mg of imine are taken up in 4 ml of dichloromethane and treated at -4O ⁰ C with 1.9 ml (1.9 mmol) of a 1 M BBr ₃ solution. The mixture is left for 60 min at 0 ⁰ C erwämen and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatography on silica gel (dichloromethane / i-PrOH 2-4%), 13 mg of the desired product are obtained. ¹ H-NMR (300 MHz, MeOH): δ = 1.63 (qd, 1H), 1.94 (dd, 1H), 2.25 (m, 1H), 2.33 (dd, 1H), 2.78 (s, 3H ), 2.90 - 3.10 (m, 2H), 3.23 (td, 1H), 5.34 (s, 1H), 6.85 (dd, 1H), 7.00 (s, 3H), 9.54 (s, 1H).

Example 16

6-r (7-Fluoro-2-methylquinazolin-5-yl) -amino1-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzordeithiochromene-5-ol

246 mg (0.85 mmol) of 2-hydroxy-3- (thiochroman-4-yl) -2- (trifluoromethyl) propanal with 150 mg (0.85 mmol) of 5-amino-7-fluoroquinazoline are added analogously to Example 1 to the corresponding 1 - [( 7-Fluoro-2-methylquinazolin-5-yl) imino] -3- (thiochroman-4-yl) -2- (trifluoromethyl) propan-2-ol. 70 mg of imine are in 4 ml

Dichloromethane and treated at -40 ⁰ C with 1.56 ml (1.56 mmol) of a 1 M BBr3 solution. The mixture is allowed to warm to 0 ° C over 60 min and the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with EtOAc, washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration and chromatography on silica gel (dichloromethane / i-PrOH 2-4%), 13 mg of the desired product are obtained as a mixture of two diastereomers. Mixture of diastereomers:

¹ H NMR (300 MHz, MeOD, selected signals): δ = 1.20-1.36 (m, 1H), 1.55-1.75 (m, 1H), 1.95 (t, 1H), 2.24 (m, 1H ), 2.37 (dd, 1H), 2.74 (m, 3H), 2.88 - 3.10 (m, 2H), 3.20 (dd, 1H), 5.48 (s, 1H), 6.68 - 6.80 (m, 2H) ₁ 6.90 - 7.04 (m, 2H), 7.20 - 7.45 (m, 1H), 9.40 - 9.55 (m, 1H).

Analogously, it is possible to prepare using the amines described above, in WO 2005/034939 or in WO2003 / 082827:

5-yl-fluoro-5-hydroxy-3a-methyl-5- (trifluoromethyl) -2,3,3a, 4,6- hexahydrobenzor-1-hexene-6-yl-amino) -isoquinoline-1 (2H) -one

5-yl-fluoro-5-hydroxy-3a-methyl-5- (trifluoromethyl) -2,3,3a, 4,6,6-hexahydrozodecelene-6-ylamino) -2-methyl-phthalazin-1-one

6-f (7.8-Difluoro-2-methylquinazolin-5-yl) -amino1-2-methyl-5- (trifluoromethyl) - 2.3.3a.4.5.6-hexahydrobenzorothiochromen-5-ol

6-r (indazol-4-yl) -aminol-2-methyl-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrobenzo [de1thiochromen-5-ol

6-f (8-Fluoro-2-methylquinazolin-5-yl) -aminol-3a-methyl 5- (trifluorometh-D-2.3.3a.4.5.6-hexahydrobenzor-1-ene-5-ol

6-r (8-Fluoro-2-methyl-quinazolin-5-yl) -aminol-2-methyl-5- (trifluorometh-2,3,3a, 4,5,6-hexahydrobenzothel-thiochromen-5-ol

9-Fluoro-6-r (isoquinolin-5-yl) -amino1-5- (trifluoromethyl) -2.3.3a.4.5.6 hexahydrobenzofdeichromene-5-ol

4- / y9-Fluoro-5-hydroxy-5- (trifluoromethine-2.3.3a.4.5.6-hexahydrobenzodelchromene-6-vnamino) -1,3-dihydroidol-2-one ^ / yS-hydroxypropyl-δ-difluoromethvD ^ .S.SaΛ.δ.e-hexahydrobenzordeithiochromene-θ-ylamino) -1, 3-dihydro-din-2-one

9-Fluoro-6-r (1-methyl-indazol-4-yl) -aminol-5- (thfluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzofe1-ene-5-ol

5- / y9-fluoro-5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,5,6-hexahydrobenzofdelchromen-6-ylamino) -2-methylisoquinolin-1-one

5 - // 5-Hydroxy-2-methyl-5- (trifluoromethvn-2.3.3a.4.5.6-hexahydrobenzordeithiochromene-e-ylaminoVI-methoxyquinoline ^ -one

5- (Ir9-Fluoro-5-hydroxy-5- (trifluoromethyl) -2.3.3a, 4.5.6-hexahydrobenzofdelchromen-β-vinylamino-methyl-phthalazin-1-one

5- / Ir9-Fluoro-5-hydroxy-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrobenzo [delchromen-6-yl-amino) -isoquinoline-1 (2H) -one

5- (yl) -hydroxy-3a-methyl-5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrozodelithiochromene-6-vnamino) -2-methylphthalazin-1-one

6-r (2-Methylquinazolin-5-yl) -amino1-3a-methyl 5- (trifluoromethyl) -2.3.3a.4.5.6-hexahydrozodelithiochromen-5-ol

Claims

claims

1. 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 10) -alkyl group, a (C 1 -C 4) -alkoxy group, a (C 1 -C 4) -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 -CKCHz) _n -O-, -O- (CHz) _n -CH ₂ -, -O-CH = CH-, - (CH ₂ ) n ₊ 2, -NH- (CH ₂ ) _{n + 1} , N (Ci-C ₃ -alkyl) - (CH ₂ ) n ₊ i, -NH-N = CH-, wherein n = 1 or 2 and the terminal atoms with direct adjacent ring-carbon atoms are linked, or NR ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently hydrogen, Cr C may be ₅ -alkyl or (CO) -C-ι-C ₅ alkyl, R ³ is a hydrogen atom, hydroxy group, a halogen atom, an optionally substituted (CrCio) -alkyl group, a (C ₁ -C ₀₎ - alkoxy group, a (CrCio) -alkylthio group, a (CrC ₅₎ -

Perfluoroalkyl group, a cyano group,

R ^{4 is} a C 1 -C 10 -alkyl group, a C 1 -C 10 -alkyl group which is substituted by one or more groups selected from C 1-3 -hydroxy groups, halogen atoms, C 1-3 -alkoxy groups, an optionally substituted C 3 -C 7 -cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, an optionally by one or more groups selected from (CrC _ö J-alkyl groups (which may optionally be substituted by 1-3 hydroxy or 1-3 COOR ¹⁰ groups wherein R ¹⁰ is (dC ₆₎ alkyl or Benzyl), (C 1 -C ₅ ) -alkoxy groups, hydroxy groups,

Halogen atoms, (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 keto groups containing mono- or bicyclic heteroaryl group, said group having a 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 (Ci-C ₅ ) alkyl group or an optionally partially or fully fluorinated (Ci-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 (Cr

Csjalkylgruppe, heterocyclyl (C ₂ -C ₈₎ alkenyl ₍₈ CrC) alkyl aryl, aryl, aryl (C ₂ -C ₈₎ alkenyl, aryl (C ₂ -C ₈₎ alkynyl group optionally substituted by one or more keto groups, mono- substituted Exoalkylidengruppen, one or more nitrogen atoms and / or oxygen atoms and / or sulfur atoms containing or bicyclic heteroaryl group, a heteroaryl (C ₁ -C ₅₎ - - alkyl, (CrC ₅₎ -alkoxy groups, halogen atoms, (C ₃ C ₁₎ (-C ₈₎ alkyl group, or a heteroaryl (C ₂ -C ₈₎ alkenyl group which groups may be linked via any position to the amine of the tricyclic system and optionally can be hydrogenated at one or more sites,

R ⁶ and R ⁷ independently 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 is 1, 2 or 3 and

X represents an oxygen atom, a sulfur atom, a CH ₂ - or an NR ⁹ group. 2. stereoisomers of the general formula (I) according to claim 1, wherein

R ¹ and R ^{2 are} independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₁₀₎ - alkyl group, a (CRCI ₀₎ alkoxy, (Ci-Cio) -Alkythiogruppe, a ( C ₁ -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 with directly adjacent ring

Carbon atoms, or NR ⁸ R ⁹ , where R ⁸ and R ^{9 can} independently of one another be hydrogen, C 1 -C ₅ -alkyl or (CO) -CC-C ₅ -alkyl,

R ³ is a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CrCio) -alkyl group, a (C1-C1 ₀₎ -

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, represented by one or more groups selected from 1-3 hydroxy groups, halogen atoms, C 1-3C (C 1 -C 6) -alkoxy substituted C 1 -C 18 -alkyl group, an optionally substituted C 1 -C 4 -alkyl group

Phenyl group, an optionally substituted by 1-2 keto groups, 1-2 (Ci-C ₅ ) - alkyl groups, 1-2 (CrC ₅ ) alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C ₃ ) -Axoalkylidengruppen, 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, these groups via any position with the amine of the tricyclic Systems and may optionally be hydrogenated at one or more sites

R ^{5 is} an (CrCs) alkyl group or an optionally partially or fully fluorinated (CrCs) alkyl group, an aryl group, a

Aryl (Ci-C ₈₎ alkyl, aryl (C ₂ -C ₈₎ alkenyl group, a (C ₃ - C ₇₎ cycloalkyl group, a (C ₃ -C ₇₎ cycloalkyl (Ci-C ₈₎ alkyl (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,

2 or 3 X represents an oxygen, a sulfur atom, a CH ₂ - or an NR ⁹ group.

3. stereoisomers of the general formula (I) according to claim 1, in which R ¹ and R ^2, independently of one another, are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C ₁ -C ₅ ) -alkyl group, a (CrC ₅ ) Alkoxy group, a (CrC 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,

R ⁴ is a d-Cio-alkyl group, a ₍₅ CrC) by 1-3 hydroxy groups, halogen atoms substituted Ci-Ci _o alkyl group, an optionally by one or more groups selected from 1-2 keto groups, 1-2 - 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, 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 points

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 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 , where R ⁸ and R ⁹ independently of one another are hydrogen, C 1 -C ₅ -alkyl or (CO) -CrC ₅ - Alkyl, p 1, 2 or 3 i X represents an oxygen, a sulfur atom, a CH ₂ - or an NR ⁹ group.

4. stereoisomers of the general formula (I) according to claim 1, 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 4) -alkoxy group, a cyano group R ^{4 is} optionally substituted by one or more groups selected from

2 keto groups, 1-2 (CiC _δ J-alkyl groups, 1-2 (d-CsJ-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (Ci-C ₃ ) -Exoalkylidengruppen substituted, 1-3 nitrogen atoms and / or 1 -2-oxygen atoms and / or

Mono- or bicyclic heteroaryl group containing 1 to 2 sulfur atoms and / or 1 to 2 keto groups, it being possible for this group to be linked to the amine of the ring system via an arbitrary position and 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 (CrC ₅ ) alkyl group

R ⁷ and R ⁸ independently of one another denote a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2 X, an oxygen or a sulfur atom.

5. stereoisomers of the general formula (I) according to claim 1, 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 to 2 keto groups, 1 to 2 (C 1 -C ₅ ) -alkyl groups, 1 to 2 (C 1 -C ₅ ) -alkoxy groups, 1 to 3 hydroxy groups, 1 to 3 halogen atoms, 1 to 2 ( CrC ₃ ) -exxalkylidene-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 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 ⁷ and R ^{8 are} independently a hydrogen atom, a halogen atom, a methyl or ethyl group p 1 or 2

X represents an oxygen or a sulfur atom.

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

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

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

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

10. A process for preparing the stereoisomers of general formula I, wherein the radicals, unless otherwise stated, have the meanings defined in claim 1, characterized in that either a)

Stereoisomers of the general formula (III)

(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)

(IV)

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 has the meaning given in claim 1, the compounds of general formula (V) are prepared

(V)

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 - 7O ⁰ C to 80 ° C to compounds of general formula I are cyclized or b) compounds prepared by the skilled person of the general formula (VI)

(VI)

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),

(VII)

which can subsequently be reacted with a silicon compound of the general formula CqF _{2q +} iSi (CH ₃ ) ₃ , where q = 1, 2, 3, or 4, in the presence of a catalyst or with a metalorganic compound of the formula R ⁵ A, where 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)

(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)

(X)

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

(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

(VIII)

with alkenyl-metal-organyls

wherein A is magnesium-halogen or lithium and R ¹² , R ^{13 is} hydrogen or C ¹ -C 6 -alkyl, are reacted to generate compounds of general formula (XII)

(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).

11. Process stage for the preparation of the stereoisomers of the general formula I according to claim 10, 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 are as defined in claim 1

Meanings have optionally be cyclized with the addition of inorganic or organic acids or Lewis acids.

12. Compounds of the general formula V according to claim 11

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.

13. Process stage for the preparation of the compounds of general formula (I), characterized according to claim 10, characterized in that stereoisomers of 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).

14. Compounds of formula IV according to claim 13, wherein R ¹ , R ² , R ³ , R ⁵ , X, and p correspond to the meanings defined in claim 1.

15. Compounds of formula III according to claim 10, wherein R ¹ , R ² , R ³ , R ⁷ , X, p have the meanings defined in claim 1

16. Amines according to claim 10, 5-amino-7-fluoro-2-methylquinazoline, 5-amino-8-fluoro-2-methylquinazoline and 5-amino-7,8-difluoro-2-methylquinazoline.