AU2005318354A1 - Tricyclic aminoalcohols, methods for producing the same and their use as anti-inflammatory agents - Google Patents

Description

VERIFICATION OF TRANSLATION I, Melissa Stanford, a translator with Chillson Translating Service, 3530 Chas Drive, Hampstead, Maryland, 21074, hereby declare as follows: That I am familiar with the German and English languages; That I am capable of translating from German to English; That the translation attached hereto is a true and accurate translation of German language Application PCT/EP2005/013943 filed December 20, 2005 titled, "TRICYCLIC AMINO ALCOHOLS, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS ANTI INFLAMMATORY AGENTS:' That all statements made herein of my own knowledge are true and that all statements made on information and belief are believed to be true; And further that these statements were made with the knowledge that willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such willful false statements may jeopardize the validity of the application or any registration resulting therefrom. By Executed this &2. day of o? 0o 7 Witness WO 2006/066950 PCT/EP2005/013943 Tricyclic Amino Alcohols, Process for their Production and their Use as Anti-Inflammatory Agents The invention relates to tricyclic amino alcohols, process for their production 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. In the experiment, these compounds show dissociations of action between anti-inflammatory actions and undesirable metabolic actions and are superior to the previously described, nonsteroidal glucocorticoids or have at least just as good an action. The compounds of the prior art still exhibit drawbacks such that one skilled in the art is motivated to search in addition for new compounds that bind to the glucocorticoid receptors. Compounds have now been found that have an action that is comparable to the compounds that are described in the prior art. This invention relates to compounds of general formula (I), R e R R R, OH

HN'R

4 R) in which 2

R

1 and R 2 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-Cl 0 )-alkyl group, a

(C

1 -Clo)-alkoxy group, a (C-Clo 0 )-alkylthio group, a (CI-Cs) perfluoroalkyl group, a cyano group, a nitro group or R1 and R2 together mean a group that is selected from the groups -O-(CH 2 )n-O-, -O-(CH2)n-CH2-, -O-CH=CH - , -(CH2)n+2-, -NH-(CH2)n+3, N(CI-C3-alkyl)

(CH

2 )n+I 1 , -NH-N=CH-, whereby n = 1 or 2, and the terminal atoms are linked to directly adjacent ring-carbon atoms, or NR 8

R

9 , whereby R 8 and

R

9 , independently of one another, can be hydrogen, CI-Cs-alkyl or (CO) Ci-Cs-alkyl,

R

3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Clo)-alkyl group, a (Ci 1 -Clo)-alkoxy group, a (CI-Co 10

)

alkylthio group, a (CI-C 5 )-perfluoroalkyl group, or a cyano group,

R

4 means a CI-Cl 0 -alkyl group, a CI-Ci 0 -alkyl group that is substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Ci-Cs)-alkoxy groups; an optionally substituted (C 3

-C

7 )-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (CI-Cs) alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR'o groups, whereby R1 0 means Ci-C 6 -alkyl or benzyl), (CI-C 5

)

alkoxy groups, hydroxy groups, halogen atoms, or (CI-C 3 )-exoalkylidene groups and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen 3 atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (C 1 -Cs)-alkyl group, a (C 3

-C

7 )-cycloalkyl group, a(C3-C7) cycloalkyl(CI-Cs)alkyl group, a (C 3

-C

7 )-cycloalkyl(C 2 -Cs)alkenyl group, a heterocyclyl group, a heterocyclyl(C -Cs)alkyl group, a heterocyclyl(C2

C

8 )alkenyl group, an aryl group, an aryl(C 1 -Cs)alkyl group, an aryl(C 2 Cs)alkenyl group, an aryl(C 2

-C

8 )alkinyl group; a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more keto groups, (CI-Cs)-alkyl groups, (CI-Cs)-alkoxy groups, halogen atoms, or (CI-C 3

)

exoalkylidene groups and that contains one or more nitrogen atoms and/or oxygen atoms and/or sulfur atoms; a heteroaryl(CI-Cs)alkyl group or a heteroaryl(C 2

-C

8 )alkenyl group, whereby these groups can be linked via any position to the chromene system and optionally can be hydrogenated at one or more sites, 6 7 R and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, or a (C 1 -Cs)alkyl group, which can be substituted with OR 8 , SR , or

NR'R

9 , p means 1-3, and X means an oxygen atom, a sulfur atom, a CH 2 group or an NR 9 group. Stereoisomers of general formula (1), in which R1 and R 2 , independently of one another, mean a hydrogen atom, a hydroxy 4 group, a halogen atom, an optionally substituted (C-C 0 lo)-alkyl group, a (CI-Co 10 )-alkoxy group, a (C 1

-C

0 lo)-alkylthio group, a (C 1

-C

5

)

perfluoroalkyl group, a cyano group, or a nitro group or RI and R 2 together mean a group that is selected from the groups -0

(CH

2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH-, -(CH 2 )n+ 2 -, whereby n = I or 2, and the terminal atoms are linked to directly adjacent ring-carbon atoms, or NR 8R 9 , whereby R 8 and R 9 , independently of one another, can be hydrogen, CI-C 5 -alkyl or (CO)-C 1

-C

5 -alkyl,

R

3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -Clo)-alkyl group, a (C 1 -Clo)-alkoxy group, a (CI-Clo) alkylthio group, a (C 1 -Cs)-perfluoroalkyl group, or a cyano group,

R

4 means a CI-C 10 -alkyl group; a C

I

-C

0 lo-alkyl group that is substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (CI-Cs)-alkoxy groups; an optionally substituted phenyl group; a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1 2 keto groups, 1-2 (CI-Cs)-alkyl groups, 1-2 (Ci-Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (CI-C 3 )-exoalkylidene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a (CI-Cs)-alkyl group or an optionally partially or completely 5 fluorinated (C 1 -Cs)-alkyl group, an aryl group, an aryl(CI-Cs)alkyl group, an aryl(C 2

-C

8 )alkenyl group, a (C 3

-C

7 )cycloalkyl group, a (C 3 C 7 )cycloalkyl(Ci-Cs)alkyl group, or a (C 3

-C

7 )cycloalkyl(C 2

-C

8 )alkenyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, or a methyl or ethyl group that should be substituted with OR8, SR8, or

N(R

9

)

2 , p means 1-3, and X means an oxygen atom, a sulfur atom, or a Cl-I 2 group or an NR 9 group, are another subject of the invention. Stereoisomers of general formula (1), in which

R

1 and R 2 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Cs)-alkyl group, or a (CI-Cs)-alkoxy group, or R' and R 2 together mean a group that is selected from the groups

-O-(CH

2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH-l-, or -(CH2)n+2-, whereby n = 1 or 2, and the terminal atoms are linked to directly adjacent ring-carbon atoms,

R

3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1

-C

0 lo)-alkyl group, or a (CI-C 0 lo)-alkoxy group,

R

4 means a (C 1 -Co 10 )-alkyl group, a (C 1 -Clo)-alkyl group that is substituted by 1-3 hydroxy groups or halogen atoms; a phenyl, naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, 6 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 that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (C 1 -Cs)-alkyl groups, 1-2 (CI-Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (CI-C 3 )-exoalkylidene groups, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, a methyl or ethyl group, which should be substituted with OR 8 , SR 8 or

N(R

9

)

2 , whereby R 8 and R 9 , independently of one another, can be hydrogen, C 1 -Cs-alkyl or (CO)-C 1 -Cs-alkyl, p means 1, 2 or 3, and X means an oxygen atom, a sulfur atom, or a CH 2 group or NR 9 group, are a subject of this invention. Stereoisomers of general formula (I) according to claim 1, in which 1 2 3

R

1 , R and R , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-C 0 lo)-alkyl group, a

(CI-C

0 lo)-alkoxy group, or a cyano group, 7

R

4 means a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (Ci Cs)-alkyl groups, 1-2 (CI-Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (C 1

-C

3 )-exoalkylidene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or I 2 keto groups, whereby this group can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (C 1 -Cs)-alkyl group,

R

7 and R 8 , independently of one another, mean a hydrogen atom, a halogen atom, or a methyl or ethyl group, p means 0 or 1, X means an oxygen atom or a sulfur atom, are a preferred subject of this invention. Stereoisomers of general formula (1), in which R', R 2 and R 3 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-C 0 lo)-alkyl group, a (CI-Clo)-alkoxy group, or a cyano group,

R

4 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- 8 or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (Ci-Cs)-alkyl groups, 1-2

(C

1 -Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2

(CI-C

3 )-exoalkylidene groups, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a (C 1 -Cs)-alkyl group or an optionally partially or completely fluorinated (C 1

-C

5 )-alkyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, a methyl group or an ethyl group, p means I or 2, and X means an oxygen atom or a sulfur atom, are another subject of this invention. Stereoisomers according to claims 1-5, in which I 2 3 R', R and R , independently of one another, mean a hydrogen atom or a halogen atom,

R

4 means a bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (CI-Cs)-alkyl groups, hydroxy groups, or halogen atoms and that optionally contains I1-2 nitrogen atoms and/or 1 keto group, whereby this group can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites, 9

R

5 means a fluorinated (CI-C 3 )-alkyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom or a (C I-C 2

)

alkyl group, p means 2, and X means an oxygen atom or a sulfur atom, are an especially preferred subject of the invention. Stereoisomers of general formula I, in which R', R 2 and R 3, independently of one another, mean a hydrogen atom or a halogen atom,

R

4 means a phthalazinonyl, quinolinyl, isoquinolinyl, isoquinolonyl, quinolonyl, quinazolinyl group, dihydroindolonyl-, or indazolyl- that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (C 1

-C

5 )-alkyl groups, 1-3 hydroxy groups, or 1-3 halogen atoms, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a fluorinated (CI-C 3 )-alkyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom, or a (CI-C2) alkyl group, p means 2, and X means an oxygen atom or a sulfur atom, are a quite especially preferred subject of the invention. Stereoisomers of general formula 1, in which 10 R', R 2 , and R 3 , independently of one another, mean a hydrogen atom or a halogen atom,

R

4 means a phthalazinonyl, quinolinyl, quinolonyl, or quinazolinyl group that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (CI-Cs)-alkyl groups, 1-3 hydroxy groups, or 1-3 halogen atoms, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites,

R

5 means a fluorinated (CI-C 3 )-alkyl group,

R

6 and R 7 , independently of one another, mean a hydrogen atom, or a (CI-C2) alkyl group, p means 2, and X means an oxygen atom or a sulfur atom, are a quite especially preferred subject of the invention. The third fused ring that contains X, [(CH 2 )p] and the substituent R 7 can be 5-, 6 or 7-membered; p therefore can assume values of 1-3; p = 2 is preferred. X can mean an oxygen atom, a sulfur atom, an NR 9 group or a CH 2 group. The oxygen atom and the sulfur atom are preferred; the oxygen atom is especially preferred. The designation halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred. The alkyl groups R', R 2 , R 3 , R 5 , R 8 and R 9 can be straight-chain or branched and stand for, for example, a 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 CI-C 3 -alkyl 11 group is preferred. They optionally can be substituted by a group that is selected from 1 3 hydroxy atoms, 1-3 halogen atoms, 1-3 (CI-C 3 )alkoxy groups and/or 1-3 COORIO groups. Hydroxy groups are preferred. The alkyl group R 4 has the meaning that is mentioned in the preceding paragraph, but the possible substituents are selected from the group hydroxy, halogen, and (CI-C 5

)

alkoxy. The alkyl groups R 6 and R 7 have the meaning that is mentioned in the preceding paragraph, but the possible substituents are selected from the group OR 9 , SR 9 and NR 8

R

9 , whereby R 8 and R 9 mean hydrogen, CI-Cs-alkyl or (CO)C 1 -Cs-alkyl, and alkyl is also defined as above. For R 6 and R 7 , a hydrogen atom and the unsubstituted C 1

-C

3 -alkyl group are especially preferred, and a hydrogen atom and the methyl group are quite especially preferred. The alkoxy groups can be straight-chain or branched and stand for, for example, a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, or n pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group is preferred. The alkylthio groups can be straight-chain or branched and stand for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio group or ethylthio group is preferred. For a partially or completely fluorinated alkyl group, which can be straight-chain or branched, for example the following partially or completely fluorinated groups are 12 considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1 -difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, C 3

F

7 , C 3

H

2 Fs,

C

4

F

9 , and CsFI 1 . Of the latter, the trifluoromethyl group and the pentafluoroethyl group are preferred; the trifluoromethyl group is especially preferred. The reagents are available commercially or the published syntheses of the corresponding reagents are part of the prior art. The aryl substituents R' and R 2 can form a ring by both aryl substituents together meaning a chain that is selected from the groups -O-(CH 2 )n-O-, -O-(CH 2 )n-CH 2 -, -0 CH=CH-, -(CH 2 )n+ 2 -, -NH-(CH 2 )n+ 1 , N(CI-C 3 -alkyl)-(CH 2 )n+1, or -NH-N=CH--, whereby n = 1 or 2. The terminal atoms of the above-cited groups are linked to directly adjacent aryl ring-carbon atoms, such that an annelated ring is produced. The substituent NR 8

R

9 means, for example, NH 2 , NH(CH 3 ), N(CH 3

)

2 , NH(C 2

H

5 ),

N(C

2

H

5

)

2 , NH(C 3

H

7 ), N(C 3

H

7

)

2 , NH(C 4

H

9 ), N(C 4

H

9

)

2 , NH-(C 5 H I), N(CsH 1)2,

NH(CO)CH

3 , NH(CO)C 2 Hs, NH(CO)C 3

H

7 , NH(CO)C 4

H

9 , or NH(CO)CsHI,. The cycloalkyl group means a saturated cyclic group with 3 to 7 ring-carbon atoms, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and methylcycloheptyl, that is optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (C 1 -Cs)-alkyl groups, or (CI-Cs)-alkoxy groups. The cycloalkylalkyl group means, for example, -(CH 2 )-cycloalkyl, -(C 2

H

4

)

cycloalkyl, -(C 3

H

6 )-cycloalkyl, -(C 4 H8)-cycloalkyl, or -(CsH lo)-cycloalkyl, whereby cycloalkyl is defined as described above.

13 The cycloalkylalkenyl group means, for example, -(CH=CH)-cycloalkyl,

-[C(CH

3 )=CH]-cycloalkyl, -[CH=C(CH3)]-cycloalkyl, -(CH=CI-CH-CH 2 )-cycloalkyl,

-(CH

2 -CH=CH)-cycloalkyl, -(CH=CH-CH-1 2

-CH

2 )-cycloalkyl, -(CH 2

-CH=CH-CH

2

)

cycloalkyl, -(CH 2

-CH

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

)=CH-CH

2 )-cycloalkyl, or

-(CH=C(CH

3 )-CH2)-cycloalkyl. A (CI-C 3 )-exoalkylidene group is defined as a group that is bonded via an exo double bond to the system (ring or chain). Exomethylene is preferred. The heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine. As substituents, hydroxy groups, halogen atoms, (CI-Cs)-alkyl groups and (CI-Cs)-alkoxy groups are suitable. Heterocyclylalkyl groups are defined as heterocyclyl groups that are bonded via a CI-Cs-alkyl group to the skeleton, whereby the alkyl group can be straight-chain or branched. Heterocyclylalkenyl groups are heterocyclyl groups that are bonded via an unsaturated C 2

-C

5 -alkyl group to the skeleton, whereby the alkenyl groups can be straight-chain or branched. The aryl groups R 4 and R 5 can be phenyl or naphthyl. As substituents for the two groups, Ci-C 3 -alkyl, hydroxy, C 1

-C

3 -alkoxy, Cs-C 3 alkylthio, halogen, cyano, COO(C,-Cs)alkyl, COOH, NR 9R io and nitro are considered. The degree of substitution can be single or multiple and can contain several of the same or different substituents. Mono- or disubstituted phenyl and naphthyl groups R 4 are preferred.

14 The aryl groups can be partially hydrogenated, and then in addition or as an alternative to the above-cited substituents can also carry keto, (Ci-C 3 )-exoalkylidene. Partially hydrogenated phenyl is defined as, e.g., cyclohexadienyl, cyclohexenyl, or cyclohexyl. A partially hydrogenated substituted naphthalene system is, for example, 1 tetralone or 2-tetralone. The arylalkyl group is an aryl group that is bonded via a CI-Cs-alkyl group to a skeleton, whereby the alkyl group can be straight-chain or branched. For example, benzyl or phenethylene can be mentioned. An arylalkenyl group is an aryl group that is bonded via a C 2 -Cs-alkenyl group to a skeleton, whereby the alkenyl group can be straight-chain or branched. The arylalkinyl group is an aryl group that is bonded via a C 2

-C

8 -alkinyl group to the skeleton, whereby the alkinyl group can be straight-chain or branched. Monocyclic or bicyclic heteroaryl groups R 4 and R 5 , which can be hydrogenated at one or more sites, are defined as all monocyclic or bicyclic aromatic ring systems that contain at least one heteroatom and at most seven heteroatoms. Ring systems with 1-5 heteroatoms are preferred. As heteroatoms, 1-4 nitrogen atoms, 1-2 oxygen atoms and 1 2 sulfur atoms that 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 sum the maximum number of seven heteroatoms, are suitable. For example, compounds of formula I, in which R 4 or R 5 means 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, 15 benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, indolizinyl, isobenzofuranyl, azaindolinyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl are thus part of this invention and represent a special embodiment of the invention. If the heteroaryl groups contain a keto group, it can occupy various positions within the ring system. All chemically possible regioisomers are included in this definition: e.g., "quinolonyl" includes both quinolin-2(1 H)-one and quinolin-3(41-H)one and quinolin-4(1 H)one. If the heteroaryl groups are partially or completely hydrogenated, compounds of formula I in which R 4 means tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, I H-pyridin-2-onyl, I H-pyridin-4-onyl, 4 aminopyridyl, I H-pyridin-4-ylideneaminyl, chromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro- I H 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, I H-cinnolin-4-onyl, 3H-quinazolin 4-onyl, 1 H-quinazolin-4-onyl, 3,4-dihydro- l H-quinoxalin-2-onyl, 2,3-1,2,3,4 tetrahydro[1,5]naphthyridinyl, dihydro- I H-[ 1,5]naphthyridyl, 1H--[ 1,5]naphthyrid-4-onyl, 16 5,6,7,8-tetrahydro- 1H-naphthyridin-4-onyl, 1,2-dihydropyrido[3,2-d][1,3]oxazin-4-onyl, octahydro- I H-indolyl, 2,3-dihydro- I H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro 2H-isoindolyl, 1,2-dihydroindazolyl, I H-pyrrolo[2,3-b]-pyridyl, 2,3-dihydro-lH pyrrolo[2,3-b]pyridyl, or 2,2-dihydro- I H-pyrrolo[2,3-b]pyridin-3-onyl are part of this invention. Compounds of formula I, in which R 4 means a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (CI-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy groups or 1-3 COORIO groups), (CI-Cs)-alkoxy groups, hydroxy groups, halogen atoms, or (CI-C 3 )exoalkylidene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the ring system, and optionally can be hydrogenated at one or more sites, are especially preferred. Compounds of general formula I according to claims 1-5, in which R 4 means a bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C 1 -Cs)-alkyl groups, hydroxy groups, or halogen atoms, or that optionally contains 1-2 nitrogen atoms and/or 1 keto group, whereby this group can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites, are an especially preferred subject of the invention. Compounds of general formula I according to claims 1-5, in which R 4 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, 17 phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group, which optionally is substituted with C 1 -Cs-alkyl, halogen, hydroxy, Cl-C 5 -alkoxy, keto or (C 1

-C

3 )exoalkylidene, are a preferred subject of the invention. Compounds of general formula I according to claims 1-5, in which R 4 is a phenyl or naphthyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with CI-Cs-alkyl, halogen, hydroxy, or C 1 -Cs-alkoxy, are a preferred subject of this invention. Compounds of general formula I, in which R 4 means a quinolinyl, quinazolinyl, phthalazinonyl, or quinolonyl group that optionally is substituted with CI-C 3 -alkyl, halogen or hydroxy, are an especially preferred subject of the invention. If this is a heteroarylalkyl group R 5 , it is understood to include an optionally also partially hydrogenated heteroaryl group as defined above, which is bonded to the skeleton via a C 1 -Cs-alkyl group, which can be straight-chain or branched. A heteroarylalkenyl group is defined as 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 can be straight-chain or branched. Compounds of general formula I, according to claims 1-5, in which R 5 means a

(C

1 -Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group, a (C 3

-C

7 )cycloalkyl group, a (C 3

-C

7 )cycloalkyl(CI-Cs)alkyl group, a (C 3 C 7 )cycloalkyl(C 2

-C

8 )alkenyl group, a heterocyclyl group, a heterocyclyl (Ci-C8)alkyl 18 group, a heterocyclyl(C 2 -C8)alkenyl group, an aryl group, an aryl(CI-Cs)alkyl group, or an aryl(C 2 -C8)alkenyl group, are another subject of the invention. Compounds of general formula I according to claims 1-5, in which R 5 means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (Ci-Cs)-alkyl group, an aryl group, an aryl(C 1 -Cs)alkyl group, an aryl(C 2

-C

8 )alkenyl group, a (C 3 C 7 )cycloalkyl group, a (C 3

-C

7 )cycloalkyl(C 1 -Cs)alkyl group, or a (C 3

-C

7 )cycloalkyl(C 2 Cs)alkenyl group, are a special subject of the invention. Compounds of general formula I according to claims 1-5, in which R 5 represents a

(CI-C

3 )-alkyl group or an optionally partially or completely fluorinated (Ci-C 3 )-alkyl group, are another subject of the invention. Compounds of general formula I according to claims 1-5 in which R 5 means a completely fluorinated (CI-C 3 )-alkyl group are especially preferred and those in which R 5 means a CF 3 group are quite especially preferred. Compounds of formula 1, in which R 4 means a CI-C 1 0 -alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (CI-Cs)-alkyl groups, 1-2 (CI-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 (Ci-C 3 )-exoalkylidene groups and that contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the nitrogen atom and optionally can be hydrogenated at one or more sites, are another subject of the invention. The compounds of general formula I according to the invention can be present as stereoisomers because of the presence of asymmetry centers. All possible stereoisomers 19 (e.g.: RRR, RRS, RSR, RSS, SRR, SRS, SSR, SSS), both as racemates or diastereomer mixtures, and in enantiomer-pure form or diastereomer-pure form, are subjects of this invention. The enantiomers or diastereomers can be obtained according to methods that are known to one skilled in the art, for example by chromatography of the racemate or diastereomer mixture in a chiral solid phase. The compounds according to the invention can also be present in the form of salts with physiologically compatible anions, for example in the form of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate. The compounds according to the invention can also be present in the hydroxy group as ethers or esters that can be produced according to the methods that are known to one skilled in the art. For example, methyl ether, ethyl ether, propyl ether, isopropyl ether, methoxymethyl ether, ethoxymethyl ether, and ethoxyethyl ether can be mentioned for the ether. The esters are derived from inorganic acids or organic acids. The organic acids can be cyclic, straight-chain or branched, saturated or unsaturated, carbocyclic or heterocyclic, substituted or unsubstituted. The radicals are preferably derived from Cl

C

9 -carboxylic acids. For example, sulfuric acid, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, and pivalic acid can be mentioned as acids that are suitable for esterification. Inorganic acids are, for example, H 2

SO

4 , H 2

SO

3 , H 2

SO

2 , and H 3 PO4. The compounds according to the invention are produced by 20 a) the cyclic styrenes of general formula (111) that are produced according to the methods that are known to one skilled in the art (e.g., J. Chem. Soc., Perkin Trans. 1 (1999), pp. 2911-2922; Org. Left. 6 (2004), pp. 3047 3050) from the corresponding chromanones, thiochromanones, cyclic ketones or cyclic aminoketones being converted by an optionally enantioselectively conducted En-reaction with optionally chiral Lewis acids into the compounds of general formula (IV). By reduction and amination, imine (V) is produced according to the methods that are known to one skilled in the art, 21 RI 0 ~Witig-Typ-OIefinieruig R H CH& R3r~ , H)~ R OR Katalysator 0

R

3

R

3 (Iii)(IV) O H 01. Hydrierung ( 6=H) OR 3. R&NHI , R 0 26 6R (IV) (V A1' Lewis SAure zFIO RI Re R R R3 HN.% A (VMI [Key:] Wittig-Typ-Olefinierung =Wittig-Type Olefination Katalysator =Catalyst Hydrierung = Hydrogenation Reduktion = Reduction 22 Lewis Stiure = Lewis acid said imine then is cyclized either without additional reagent or by adding inorganic or organic acids or Lewis acids under temperatures in the range of-70 0 C to +80 0 C (preferably in the range of-30'C to +80 0 C) to form the compounds of general formula (1). Lewis acid, in terms of the invention, is defined as all Lewis acids that are known to one skilled in the art, for example, TiC14, Ti(OR3) 4 , TiCI 2 (OR3) 2 , TiBr 2 (OR3) 2 , PdCI 4 , Pd(OR3) 4 , PdCI 2 (OR3) 2 , PdBr 2 (OR3) 2 , ZnCI 2 , ZnBr 2 , SnCl 4 , AICI 3 , AIBr 3 , AIEtCI 2 , AIMe 2 CI, BBr 3 , BCI 3 , B1 3 ,

BF

3 , BBrMe 2 , Cu salts, e.g., Cu(OTf) 2 , CuCI 2 , CuBr 2 , Yb(OTf) 3 , preferably BBr 3 . 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 are a special subject of the invention. b) it being possible to produce precursors of the type of general formula (VI) according to known instructions (J. Med Chem. 44 (2001), pp. 1085 1098). According to methods that are known to one skilled in the art, these compounds can be reacted by reduction of the double bond, e.g., with hydrogen on palladium/carbon, reduction of the ester with, e.g., lithium aluminum hydride and oxidation of the resulting alcohols to form compounds of general formula (VII).

23 1.X (yHdr R erung X-f( Ha) p 7 Rut R CO 2 R 3. O idation R R R R R R (VI) (VII fOr Re = H)) [Key:] Hydrierung = Hydrogenation Reduktion = Reduction Fir = for Compounds of type (VII) can be reacted with, e.g., a compound of general formula CqF2q+I-Si(CH3)3, whereby q can be I, 2, 3 or 4, in the presence of a catalyst or with an alkyl metal compound of type R 5 A, whereby A means magnesium-halogen or lithium, for example a Grignard reagent or a lithium alkyl, to form a compound of formula (VIII). As a catalyst, fluoride salts or basic compounds such as alkali carbonates are suitable (J. Am. Chem. Soc. 111 (1989), pp. 393).

X

4 ( H,), 2 X+( A H _6 10 _M R - Re R Re A R (Rvii) (vi) (VII) (Vill) 24 By oxidation of compounds of general formula (VIll) according to processes in the literature (J. Org. Chem. 54 (1989), pp. 661-668), new compounds of type (IX) are obtained. R' R 1 R R RR X4f-(CH 2 )9 IH R v P16 RN R6 ------- alp 2

R

6 R (vill) (Ix) Compounds of general formula (X) can be produced by reaction of the compounds of general formula (IX), e.g., with TMSCN or MCN, whereby M can stand for a metal, such as, e.g., sodium, potassium or copper (J. Med Chem. 46 (2003), pp. 2494-2501). In this case, R1 can optionally be a hydrogen atom or else a trialkylsilyl group. R 7 9 7

R

1 R X H 2 ), ,X- (CH) A 2 R Rs - Re CN R R R I ] R (IX) (X) Compounds of general formula (XI) can be obtained by reaction of the compounds of general formula (X) with a suitable reducing agent, such as, e.g., diisobutyl aluminum hydride.

25 R? A H 2 ) R , X ( H) H R3 2 2 \- R R R R CN O R R (XI) (x) These new compounds of general formula (XI) can then be converted analogously to production process a) into the compounds of general formula (I). c) it being possible to react compounds of general formula (VII) 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 copper organyl compound (e.g., Tetrahedron Lett. 31 (1990), pp. 7425-7428; J. Organomet. Chem. 502 (1995), pp. C5-C7) and subsequent reduction with, e.g., diisobutyl aluminum hydride, to form a compound of formula VII and said compounds being converted into the compounds of general formula (I) analogously to production process b). A R I X+( H) A X4_( H2, 2 COzR H RR R (M) (VII) d) it being possible to react compounds of general formula (IX) with, e.g., alkenyl metal organyl compounds RI 2

R

13 (C)CH-A, whereby A means magnesium-halogen or lithium, and R 1 2 , R 13 mean hydrogen or CI-C6- 26 alkyl, such as, e.g., vinylmagnesium-Grignard compounds. In this case, compounds of general formula (XII) are obtained. By oxidation of the double bond, e.g., by ozone or by transition-metal oxides, such as, e.g., osmium tetraoxide, with subsequent cleavage with use of a suitable oxidizing agent, such as, e.g., sodium periodate, compounds of general formula (X) can be obtained.

R

7

R

7 sX f( H2), HgP R 2R R 5 Ra (IX) R (XII) 13 R( X ( H)p H 2 R R5 R (x) The intermediate products that have gone through the above-described processes, in particular the compounds of formulas Ill, IV and V in which the radicals have the meanings that are indicated in Claim I as well as the process stages for the production thereof, are a subject of the invention. The binding of the substances to the glucocorticoid receptor (GR) and additional steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is examined with the assistance of recombinantly produced receptors. Cytosol preparations of Sf9 cells that had been infected with recombinant 27 baculoviruses that code for the GR are used for the binding studies. In comparison to the reference substance [ 3 H]-dexamethasone, the substances show a high affinity to the GR. Thus, for the compound of Example 2, IC 5 0 (GR) was equal to 20 nmol and 1Cs 5 0 (PR) was > I pmol. The GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is considered to be an essential molecular mechanism for the anti-inflammatory action of glucocorticoids. This inhibition is produced by an interaction of the GR with other transcription factors, e.g., AP-I and NF kappa-B (for an overview, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378, 1996). The compounds of general formula 1 according to the invention inhibit the secretion of the cytokine IL-8, triggered by lipopolysaccharide (LPS), in the human monocyte cell line THP-1. The concentration of the cytokines was determined in the supernatant by means of commercially available ELISA kits. The compound of Example 2 showed an inhibition 1Cs 5 0 (IL8) = 37 nmol with a 70% efficiency relative to [ 3

H]

dexamethasone as a standard. The anti-inflammatory action of the compounds of general formula I was tested in the animal experiment by tests in the croton-oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). To this end, croton oil in ethanolic solution was administered topically to the animals' ears. The test substances were also administered topically or systemically at the same time or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a yardstick for the inflammatory edema, the peroxidase activity as a yardstick for the invasions of granulocytes, and the elastase 28 activity as a yardstick for the invasion of neutrophilic granulocytes. In this test, the compounds of general formula I inhibit the three above-mentioned inflammation parameters both after topical administration and after systemic administration. One of the most frequent undesirable actions of a glucocorticoid therapy is the so called "steroid diabetes" [cf. Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien [Glucocorticoids: Immunological Principles, Pharmacology and Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes that are responsible for this and by free amino acids that are produced from the degradation of proteins (catabolic action of glucocorticoids). A key enzyme of the catabolic metabolism in the liver is the tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measurement for thc undesirable metabolic actions of the glucocorticoids. For measurement of TAT induction, the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity in the homogenate is measured. In this test, at doses at which they have an anti-inflammatory action, the compounds of general formula I induce little or no tyrosine aminotransferase. Based on their anti-inflammatory action and, in addition, anti-allergic, immunosuppressive and anti-proliferative action, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this case, the term "DISEASE" stands for the following indications: 29 (i) Lung diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Chronic, obstructive lung diseases of any origin, primarily bronchial asthma - Bronchitis of different origins - All forms of restrictive lung diseases, primarily allergic alveolitis - All forms of pulmonary edema, primarily toxic pulmonary edema - Sarcoidoses and granulomatoses, especially Boeck's disease (ii) Rheumatic diseases/autoimmune diseases/joint diseases that are accompanied by 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 origins - Arthritic symptoms in the case of degenerative joint diseases (arthroses) - Traumatic arthritides - Collagenoses of any origin, e.g., systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, Sj6gren's syndrome, Still's syndrome, Felty's syndrome (iii) Allergies that are accompanied by inflammatory and/or proliferative processes: 30 - All forms of allergic reactions, e.g., Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis (iv) Vascular inflammations (vasculitides) - Panarteritis nodosa, temporal arteritis, erythema nodosum (v) Dermatological diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Atopic dermatitis (primarily in children) - Psoriasis - Pityriasis rubra pilaris - Erythematous diseases, triggered by different noxae, e.g., radiation, chemicals, burns, etc. - Bullous dermatoses - Diseases of the lichenoid group, - Pruritis (e.g., of allergic origin) - Seborrheal eczema - Rosacea - Pemphigus vulgaris - Erythema exudativum multiforme - Balanitis - Vulvitis 31 - Hair loss such as alopecia areata - Cutaneous T-cell lymphoma (vi) Kidney diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Nephrotic syndrome - All nephritides (vii) Liver diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Acute liver cell decomposition - Acute hepatitis of different origins, e.g., viral, toxic, pharmaceutical agent induced - Chronic aggressive hepatitis and/or chronic intermittent hepatitis (viii) Gastrointestinal diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Regional enteritis (Crohn's disease) - Colitis ulcerosa - Gastritis - Reflux esophagitis - Ulcerative colitis of other origins, e.g., native sprue 32 (ix) Proctologic diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Anal eczema - Fissures - Hemorrhoids - Idiopathic proctitis (x) Eye diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Allergic keratitis, uveitis, iritis - Conjunctivitis - Blepharitis - Optic neuritis - Chorioiditis - Sympathetic ophthalmia (xi) Diseases of the ear-nose-throat area that are accompanied by inflammatory, allergic and/or proliferative processes: - Allergic rhinitis, hay fever - Otitis externa, e.g., caused by contact dermatitis, infection, etc. - Otitis media 33 (xii) Neurological diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Cerebral edema, primarily tumor-induced cerebral edema - Multiple sclerosis - Acute encephalomyelitis - Meningitis - Various forms of convulsions, e.g., infantile nodding spasms (xiii) Blood diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Acquired hemolytic anemia - Idiopathic thrombocytopenia (xiv) Tumor diseases that are accompanied by inflammatory, allergic and/or proliferative processes: - Acute lymphatic leukemia - Malignant lymphoma - Lymphogranulomatoses - Lymphosarcoma - Extensive metastases, primarily in breast, bronchial and prostate cancers (xv) Endocrine diseases that are accompanied by inflammatory, allergic and/or proliferative processes: 34 - Endocrine orbitopathy - Thyreotoxic crisis - De Quervain's thyroiditis - Hashimoto's thyroiditis - Basedow's disease (xvi) Organ and tissue transplants, graft-versus-host disease (xvii) Severe shock conditions, e.g., anaphylactic shock, systemic inflammatory response syndrome (SIRS) (xviii) Substitution therapy in: - Innate primary suprarenal insufficiency, e.g., congenital adrenogenital syndrome - Acquired primary suprarenal insufficiency, e.g., Addison's disease, autoimmune adrenalitis, meta-infective tumors, metastases, etc. - Innate secondary suprarenal insufficiency, e.g., congenital hypopituitarism - Acquired secondary suprarenal insufficiency, e.g., meta-infective tumors, etc. (xix) Vomiting that is accompanied by inflammatory, allergic and/or proliferative processes: 35 - e.g., in combination with a 5-HT3 antagonist in cytostatic-agent-induced vomiting. (xx) Pains of inflammatory origins, e.g., lumbago. The invention also relates to combination therapies or combined compositions, in which a glucocorticoid receptor (GR) agonist of formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that contains a GR agonist of formula (1) or a pharmaceutically acceptable salt thereof, is administered either simultaneously (optionally in the same composition) or in succession together with one or more pharmaceutical agents for treating one of the above-mentioned pathologic conditions. For example, for treating rheumatoid arthritis, osteoarthritis, COPD (chronic obstructive lung disease), asthma or allergic rhinitis, a GR agonist of this invention can be combined with one or more pharmaceutical agents for treating such a condition. Where such a combination is administered by inhalation, the pharmaceutical agent to be combined can be selected from the following list: * A PDE4 inhibitor including an inhibitor of the isoform PDE4D; * A selective P.sub2.adrenoceptor agonist, such as, for example, metaproterenol, isopropterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterolmesylate, pirbuterol or indacaterol; * A muscarine receptor antagonist (for example, an M 1, M2 or M3 antagonist, such as, for example, a selective M3 antagonist), such as, for 36 example, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepin, or telenzepin; * A modulator of the chemokine receptor function (such as, for example, a CCRI receptor antagonist); or, * An inhibitor of the p38 kinase function. For another subject of this invention, such a combination with a GR agonist of formula (I) or a pharmaceutically acceptable salt therefore is used for treatment of COPD, asthma or allergic rhinitis and can be administered by inhalation or orally in combination with xanthin (such as, for example, aminophylline or theophylline), which can also be administered by inhalation or orally. Moreover, the compounds of general formula I according to the invention can be used for treatment and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this respect Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998). All previously mentioned indications (i) to (xx) are described in more detail in Hatz, H. J., Glucocorticoide: lmmunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998. For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose varies and depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity of the conditions that are to be treated, as well as the use as a prophylactic agent or therapeutic agent.

37 In addition, the invention provides: (i) The use of one of the compounds of general formula I according to the invention or mixture thereof for the production of a medication for treating a DISEASE; (ii) A process for treating a DISEASE, said process comprises an administration of an amount of the compound according to the invention whereby the amount suppresses the disease, and whereby the amount of compound is given to a patient who requires such a medication; (iii) A pharmaceutical composition for treating a DISEASE, said treatment comprises one of the compounds according to the invention or mixture thereof and at least one pharmaceutical adjuvant and/or vehicle. In general, satisfactory results can be expected in animals when the daily doses comprise a range of I pg to 100,000 pg of the compound according to the invention per kg of body weight. In the case of larger mammals, for example the human, a recommended daily dose lies in the range of I pg to 100,000 pg per kg of body weight. Preferred is a dose of 10 to 30,000 pg per kg of body weight, and more preferred is a dose of 10 to 10,000 pg per kg of body weight. For example, this dose is suitably administered several times daily. To treat acute shock (e.g., anaphylactic shock), individual doses that are considerably above the above-mentioned doses can be given. The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, 38 moisturizers, lubricants, absorbents, diluents, flavoring correctives, coloring agents, etc., that are commonly used in galenicals and converted into the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15 th Edition, Mack Publishing Company, East Pennsylvania (1980). For oral administration, especially tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable. For parenteral administration, injection and infusion preparations are possible. For intra-articular injection, correspondingly prepared crystal suspensions can 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 can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both for systemic and for local treatment. For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants. For local application to eyes, outer ear channels, middle ears, nasal cavities, and paranasal sinuses, the new compounds can be used as drops, ointments and tinctures in corresponding pharmaceutical preparations. For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01%-20% in these preparations to achieve a sufficient pharmacological action.

39 The invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients. In addition, the compounds of general formula I according to the invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles. The invention also comprises a pharmaceutical composition that contains one of the pharmaceutically active compounds according to the invention or mixture thereof or pharmaceutically compatible salt thereof and pharmaceutically compatible adjuvants and vehicles.

40 Experiments Example 1 6-[(7-Fluoro-2-methyiquinazolin-5-yl)aminol-5-(trifluoromethyl) 2,3,3a,4,5,6-hexahydrobenzo[de]chromen-5-ol 3-(2-Chroman-4-yl)-2-hydroxy-2-(trifluoromethyl)propanal 20 g (307 mmol) of zinc dust and 710 mg (2.5 mmol) of lead(ll) chloride are suspended in 200 ml of THF, and 11.2 ml (100 mmol) of dibromomethane is added at room temperature. It is stirred for another 60 minutes, and 33 ml (33 mmol) ofa I M titanium(IV) chloride solution in dichloromethane is added in drops over 40 minutes while being cooled with ice. After one hour, 4.4 g (30 mmol) of chroman-4-one is added in solid form in several portions at room temperature, whereby the reaction is heated to 30'C. It is stirred for another 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 on sodium sulfate, and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane/isopropyl ether 0-20%), and 2.75 g of 4-methylene chroman is obtained. 0.60 ml (0.3 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene is added to 170 mg (0.60 mmol) of 1,1'-bi-2-naphthol, and the red solution is stirred for 2 hours at room temperature. 1.0 g (6.8 mmol) of 4-methylene-chroman and 2.3 (13.6 mmol) of ethyl trifluoropyruvate are added, and the mixture is heated for 2 hours to 1 10 0 C. After cooling, it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 20%), and 1.15 g of 3-(2H-chromen-4-yl)-2-hydroxy-2- 41 (trifluoromethyl)-propionic acid ethyl ester is obtained. 100 mg (0.32 mmol) of 3-(2H chromen-4-yl)-2-hydroxy-2-(trifluoromethyl)-propionic acid ethyl ester is dissolved in 10 ml of methanol, and 20 mg of palladium on carbon at a ratio of 10% is added. The reaction mixture is shaken under hydrogen atmosphere for 5 hours. Then, it is filtered through Celite, rewashed with ethyl acetate, and the solvent is removed in a vacuum. It is taken up in 10 ml of diethyl ether and cooled to -5'C. Over 10 minutes, 78 mg (2.0 mmol) of lithium aluminum hydride is added in solid form in portions. It is stirred for 2 hours at room temperature and poured into saturated ammonium chloride solution. The suspension is filtered through Celite and is thoroughly rewashed 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 on sodium sulfate, and the solvent is removed in a vacuum. Chromatographic purification on silica gel (hexane/ethyl acetate 0-15%) yields 50 mg of 3-(2H-chromen-4-yl)-2-hydroxy-2-(trifluoromethyl) propanal as a mixture of two diastercomers. 'H-NMR (300 MHz, CDCI 3 ); 6 = 1.66 (m, 0.5H), 1.95-2.37 (m, 2.5H), 2.49 (dd, 0.5H), 2.54 (dd, I H), 2.79 (m, 0.5H), 3.14 (m, 0.5H), 3.89 (s, 0.5H), 3.99 (s, 0.5H), 4.09-4.22 (m, 2H), 6.78-6.95 (m, 1 H), 7.08-7.19 (m, 2H), 9.74 (s, 1 H). 5-Amino-7-fluoro-2-methylquinazoline 17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I. Fagervall, L.-G. Larsson, S. B. Ross, Eur. J Med Chem. 34 (1999) 137-151), 9.2 gof acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) are added together in 70 ml of butyronitrile. While being stirred vigorously, it is 42 heated for 17 hours to 145 0 C, and the solvent is removed in a vacuum. After chromatography of the residue on silica gel with hexane/ethyl acetate (0-70%), 4.5 g of 7 fluoro-5-N-pivaloylamino-2-methyquinazoline is obtained. I g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methylquinazoline is dissolved in 74 ml of toluene and cooled to -70 0 C. 9.5 ml (11.4 mmol) of a 1.2 M diisobutyl aluminum hydride solution in toluene is added in drops over 30 minutes. The reaction mixture is allowed to heat to -40'C, and it is stirred for 4 hours at -40 0 C. Water is slowly added, and it is stirred for 30 minutes at room temperature until a precipitate is formed, which is removed by means of filtration through Celite. The phases are separated, washed with saturated sodium chloride solution and dried on sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 64 mg of the product is obtained. 1 H-NMR (300 MHz, CDCI 3 ): 8 = 2.83 (s, 3H), 4.67 (br., 21-1), 6.50 (dd, 1H), 6.93 (dd, I H), 9.23 (s, I H). 50 mg (0.18 mmol) of 3-(2H-chroman-4-yl)-2-hydroxy-2-(trifluoromethyl) propanal is dissolved together with 20 mg (0.12 mmol) of 5-amino-7-fluoro-2 methylquinazoline in 5 ml of toluene, and 0.15 ml of titanium tetraethylate is added. The mixture is heated for 2 hours to 100°C. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite and thoroughly rewashed with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum, and 3-(chroman-4-yl)- 1 -[(7-fluoro-2-methylquinazolin-5-yl)imino]- 2

-

43 (trifluoromethyl)-propan-2-ol is obtained as a crude product. The imine is taken up in 4 ml ofdichloromethane and cooled to -78 0 C. 1.5 ml (1.5 mmol) ofa I M titanium tetrachloride solution in dichloromethane is added in drops over 5 minutes, and after 20 minutes, the cooling bath is removed. After another 20 minutes, the solution that is heated to room temperature is poured into a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 10 minutes. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 50-100%), 9 mg of the desired product is obtained. 'H-NMR (300 MHz, CDCI 3 ): 6 = 1.78-1.91 (m, 2H), 2.06 (dd, 11H), 2.48 (dd, I H), 3.34 (m, 1H), 4.26 (ddd, 1H), 4.50 (ddd, I H), 5.13 (d, I H), 5.79 (d, 1H), 6.65 (dd, 1 H), 6.74 (d, 1 H), 6.82 (d, I H), 6.94 (dd, I H), 7.07 (t, 11-1), 9.19 (s, IH-). Example 2 9-Fluoro-6-[(2-methylquinolin-5-yl)aminol-5-(trifluoromethyl) 2,3,3a,4,5,6-hexahydrobenzo[de]chromen-5-ol 3-(8-Fluoro-chroman-4-yl)-2-hydroxy-2-(trifluoromethyl)-propanal. 33.2 g (296 mmol) of 2-fluorophenol and 18.4 ml (281 mmol) of acrylonitrile are stirred together with 5.0 g (29.6 mmol) of benzyltrimethylammonium hydroxide for 4 days at 80 0 C. At room temperature, it is mixed with ice, and 2N hydrochloric acid is added. It is stirred for 10 minutes, extracted with ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solution, dried on sodium sulfate, and the solvent is removed in a vacuum. Column-chromatographic separation on silica gel (hexane/ethyl acetate 5-50%) yields 6.4 g of 3-(2-fluorophenoxy)-propionitrile. 6.4 g 44 (38.8 mmol) of 3-(2-fluorophenoxy)-propionitrile is 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 on sodium sulfate. After the solvent is removed in a vacuum, 6.5 g of 3-(2-fluorophenoxy)-propionic acid is obtained. 6.5 g (35.6 mmol) of 3-(2-fluorophenoxy)-propionic acid is added to 39 g of polyphosphoric acid, and it is stirred for four hours at 70 0 C. After cooling overnight, it is poured into ice water. It is extracted with ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum, 5.5 g of 8-fluorochroman-4-one is obtained as a crystalline solid. 29.8 g (456 mmol) of zinc dust and 710 mg (2.5 mmol) of lead(ll) chloride are suspended in 450 ml of THF, and 28.6 ml (253 mmol) ofdibromomethane is added at room temperature. It is stirred for another 60 minutes, and 50.7 ml (50.7 mmol) ofa I M titanium(IV) chloride solution in dichloromethane is added in drops over 40 minutes while being cooled with ice. After one hour, 8.4 g (50.7 mmol) of 8-fluorochroman-4 one in 500 ml of TIHF is added in drops at room temperature. It is stirred for another 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 on sodium sulfate, and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane/isopropyl ether 0-20%), and 0.81 g of 8-fluoro-4-methylene-chroman is obtained.

45 0.98 ml (0.49 mmol) of a 0.5 M titanium tetraisopropylate solution in toluene is added to 281 mg (0.98 mmol) of 1,1 '-bi-2-naphthol, and the red solution is stirred for 2 hours at room temperature. 0.81 g (4.9 mmol) of 8-fluoro-4-methylene-chroman and 1.21 ml (9.8 mmol) ofethyltrifluoropyruvate are added, and the mixture is heated over 3 hours to 120'C. After cooling, it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-20%), and 0.69 g of 3-(8-fluoro-2H-chromen-4-yl)-2 hydroxy-2-(trifluoromethyl)-propionic acid-ethyl ester is obtained. 400 mg (1.2 mmol) of 3-(8-fluoro-2H-chromen-4-yl)-2-hydroxy-2-(trifluoromethyl)-propionic acid ethyl ester is dissolved in 12 ml of methanol, and 40 mg of palladium on carbon at a ratio of 10% is added. It is shaken under the reaction mixture under hydrogen atmosphere for 40 minutes. Then, it is filtered through Celite, rewashed with dichloromethane, and the solvent is removed in a vacuum. The thus obtained 330 mg of crude 3-(8-fluoro chroman-4-yl)-2-hydroxy-2-(trifluoromethyl)-propionic acid ethyl ester is cooled to -5 0 C in 8 ml ofdiethyl ether and 2 ml of THF, and 185 mg (4.9 mmol) of lithium aluminum hydride is added in solid form in portions. It is stirred for 24 hours at room temperature and poured into water. The phases are separated, and it is extracted several times with ethyl acetate. It is washed with saturated sodium chloride solution, dried on sodium sulfate, and the solvent is removed in a vacuum. Chromatographic separation on silica gel (hexane/ethyl acetate 0-15%) yields 53 mg of 3-(8-fluoro-chroman-4-yl)-2-hydroxy 2-(trifluoromethyl)-propanal as a mixture of two diastereomers and 126 mg of alcohol. 'H-NMR (300 MHz, CDCI 3 ): 5 = 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, I H).

46 Analogously to Example 1, 53 mg (0.18 mmol) of 3-(8-fluoro-chroman-4-yl)-2 hydroxy-2-(trifluoromethyl)-propanal is reacted with 30 mg (0.19 mmol) of 5-amino-2 methylquinoline to form the corresponding 3-(8-fluoro-chroman-4-yl)-l-[(2 methylquinolin-5-yl)imino]-2-(trifluoromethyl)-propan- 2 -ol. The imine is taken up in 3.6 ml of dichloromethane and treated at -50 0 C with 0.90 ml (0.90 mmol) ofa I M boron tribromide solution. It is allowed to heat over 60 minutes to 0 0 C, 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 on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/2-propanol 10-20%), 25 mg of the desired product is obtained as a mixture of two diastereomers. Diastereomer I 'H-NMR (300 MHz, CDCI 3 ): 8 = 1.70-1.86 (m, 2H), 2.10 (m, 1-H), 2.47 (dd, I H), 2.72 (s, 3H), 3.31 (m, I H), 4.27 (ddd, I H), 4.40 (d, I H), 4.60 (ddd, IH), 5.20 (d, 1H), 6.61 (d, IH), 6.81 (dd, 1 H), 6.97 (dd, 1H), 7.22 (d, 1H), 7.58 (t, I H), 7.59 (d, IH), 7.98 (d, I H). Diastereomer 2 'I-I-NMR (300 MHz, CDCI 3 ): 8 1.70-1.86 (m, 2H), 2.10 (dd, I H), 2.23 (m, I H), 2.73 (s, 3H), 3.00 (m, I H), 4.24 (ddd, IH-), 4.54 (ddd, 1H), 4.78 (d, 11-1), 5.10 (d, I H), 47 6.58 (d, 1H), 6.74 (dd, IH), 6.89 (dd, 1H), 7.22 (d, IH), 7.48 (d, IH), 7.49 (t, IH), 8.12 (d, I H). Example 3 9-Fluoro-6-[(2-methylquinazolin-5-yl)amino]-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[de]chromen-5-ol 5-Amino-2-methylquinazoline 12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert, V. J. Chambers .1. Org Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are refluxed over 20 hours in 75 ml of phosphoryl chloride. After cooling, it is poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) in 225 ml of ethyl acetate and 22.5 ml of triethylamine are dissolved, is obtained. 2 g of palladium on carbon is added, and it is stirred while being cooled with ice for 4 hours under hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration through Celite, and it is rewashed with 200 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with ethyl acetate-ethanol (0-10%), 530 mg of the product is obtained. H-NMR (300 MHz, CDCI 3 ): 8 = 2.87 (s, 3H), 4.52 (br., 2H), 6.77 (d, 1H), 7.33 (d, 1 H), 7.65 (t, I H), 9.40 (s, IH-). 89 pul (0.42 mmol) of titanium tetraethylate is added to 60 mg (0.21 mmol) of 3 (8-fluoro-chroman-4-yl)-2-hydroxy-2-(trifluoromethyl)propanal and 39 mg (0.22 mmol) 48 of 5-amino-2-methyl-quinazoline in 4 ml of toluene, and the mixture is heated to I 10 0 C over 2 hours. After cooling, it is poured into saturated ammonium chloride solution, ethyl acetate is added, and vigorous stirring is continued. The suspension is filtered through Celite, and it is rewashed thoroughly with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. The thus obtained crude 3-(8-fluoro-chroman-4-yl)- I -[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl) propan-2-ol is taken up in 2.6 ml of dichloromethane and cooled to -50 0 C. 0.67 ml (0.67 mmol) ofa 1 M boron tribromide solution in dichloromethane is added in drops over 5 minutes, and the cooling bath is removed. After two hours, the solution that is approximately 0 0 C is poured into a mixture of ice and saturated sodium bicarbonate solution, and it is stirred vigorously for 15 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatographic separation on silica gel (hexane/2 propanol 15%), 6 mg of the desired product is obtained. H-NMR (300 MHz, CDCI 3 ): 8= 1.82-1.92 (m, 2H), 2.10 (dd, 11-1), 2.50 (dd, 11-1), 2.85 (s, 31-1), 3.36 (dddd, 1H), 4.29 (ddd, 1H), 4.62 (ddd, IH), 5.19 (d, IH), 5.38 (d, 1H), 6.74 (dd, I H), 6.87 (dd, I H), 6.94 (d, 1 H), 7.37 (d, I H), 7.77 (t, 1 H), 9.33 (s, 1 H). Example 4 (f9-Fluoro-5-hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6-hexahydrobenzo[de]chromen-6 yllaminol}-2-methylphthalazin- I -one 5-Amino-2-methyl-phthalazin- I-one: 3-Bromo-4-nitro-phthalide 49 5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg ofbenzoyl peroxide are refluxed in 80 ml of benzotrifluoride with exposure to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid. '-H-NMR (300 MHz, CDCI 3 ), 8 = 7.26 (s, I H), 7.88 (t, I H), 8.3 (d, I H), 8.56 (d, I H) 5-Nitro-phthalazin-I -one: 18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100'C for I hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100oC. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-l-one is obtained as a solid. 'H-NMR (300 MHz, DMSO-d 6 ), 6 = 8.05 (t, IH), 8.57-8.66 (m, 21-1), 8.73 (s, IH), 13.13 (bs, IH) 2-Methyl-5-nitro-phthalazin- 1-one 1.6 g of 5-nitro-phthalazin- I-one and 2.31 g of potassium carbonate are stirred for 10 minutes at room temperature in 60 ml of DMF. 1.1 ml of methyl iodide is added, and it is stirred overnight. It is added to water, extracted several times with ethyl acetate, and 50 the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one is obtained as a yellow solid. 'H-NMR (300 MHz, DMSO-d 6 ), 8 = 3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H) 5-Amino-2-methyl-phthalazin- I-one 1.57 g of 2-methyl-5-nitro-phthalazin-I-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin- I-one is obtained as a yellow solid. 'H-NMR (300 MHz, CDCI 3 ), = 3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 11-1), 7.8 (d, I H), 8.16 (s, 1 H) Analogously to Example 3, 60 mg (0.21 mmol) of 3-(8-fluoro-chroman-4-yl)-2 hydroxy-2-(trifluoromethyl)propanal is reacted with 39 mg (0.22 mmol) of 5-amino-2 methyl-phthalazin-1-one to form 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 ofdichloromethane and treated at -50'C with 0.83 ml (0.83 mmol) ofa I M boron tribromide solution. It is allowed to heat over one hour to 0 0 C, and the solution is poured into 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 on sodium sulfate. After concentration by 51 evaporation and chromatography on silica gel (hexane/2-propanol 15%), 28 mg of the desired product is obtained as a mixture of two diastereomers. Diastereomer 1 'H-NMR (300 MHz, CDCI 3 ); 8 = 1.40-1.86 (m, 2H), 2.08 (m, 1 H), 2.45 (dd, I H), 3.29 (m, 1 H), 3.82 (s, 3H), 4.25 (ddd, I H), 4.53 (ddd, 1 H), 4.84 (d, I H), 5.15 (d, 1H), 6.65 (dd, 1H), 6.93 (dd, I H), 7.21 (d, I H), 7.64 (t, I H), 7.87 (d, 11-1), 8.18 (s, I H). Diastereomer 2 'H-NMR (300 MHz, CDCI 3 ); 8 = 1.40-1.86 (m, 2H), 2.27 (m, 11-1), 2.85 (dd, 1H), 2.97 (m, 1H), 3.84 (s, 3H), 4.22 (ddd, 1H), 4.60 (ddd, 1H), 4.65 (d, 1H), 5.43 (d, 1H), 6.78 (dd, I H), 6.81 (d, 1 H), 6.89 (dd, 11-1H), 7.52 (t, 1 H), 7.78 (d, 1IH-), 8.26 (s, I H). Example 5 5-{{5-Hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6-hexahydrobenzo[de]chromen-6 yllamino}-quinolin-2-(1 H)-one 5-A minoquinolin-2(1H)-one: 4.5 g of 5-nitroquinolin-2(I H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.

52 H-NMR (DMSO): 8 = 5.85 (bs, 2H), 6.27 (d, IH), 6.33 (d, 1H), 6.43 (d, 1H1), 7.10 (t, 1 H), 8.07 (d, 1 H), I 1.39 (br, I H) Analogously to Example 1,600 mg (2.18 mmol) of 3-(chroman-4-yl)-2-hydroxy 2-(trifluoromethyl)-propanal is reacted with 386 mg (2.39 mmol) of 5-aminoquinolin 2(1 Fl)-one to form the corresponding 5-{ [3-(chroman-4-yl)-2-hydroxy-2 (trifluoromethyl)-propylidene]amino}quinolin- 2 (I H)-one. 100 mg of imine is taken up in 2 ml of dichloromethane and treated at 0 0 C with 2.4 ml (2.40 mmol) ofa I M TiCl 4 solution. It is allowed to heat to 0 0 C over 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/2-propanol 0-5%), 18 or 14 mg of the desired product is obtained as separated diastereomers. Diastereomer 1 'H-NMR (400 MHz, DMSO); 8 = 1.43 (dd, IH), 1.60 (dq, 1-H), 2.19 (dd, I H), 2.55 (dd, 1 H), 2.98 (m, 1 H), 4.02 (t, I1-1), 4.28 (ddd, 1 H-),4.78 (d, 1 H), 6.02 (d, I H), 6.23 (d+s, 2H), 6.38 (d, I H), 6.55 (d, I H), 6.65 (d, IH), 7.00 (t, 1H), 7.13 (t, I H), 8.15 (d, I H), 11.52 (s, I H). Diastereomer 2 'H-NMR (400 MHz, DMSO): 8 = 1.63 (dq, IH), 1.80 (dd, IH), 1.97 (dd, IH), 53 2.19 (dd, 1H), 3.15 (m, 1H), 4.15 (td, 1H), 4.38 (ddd, I H), 5.28 (d, I H), 6.07 (d, I H), 6.30 (d, 1 H), 6.45 (s, I H), 6.52 (d, I H), 6.59 (d, I H), 6.65 (d, I H), 6.97 (t, 11-1), 7.20 (t, 11H), 8.13 (d, I H), 11.50 (s, I H). Analogously, there can be produced: Example 6 6-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-5-(trifluoromethyl)-2,3,3a.4,5,6 hexahydrobenzo[de]chromen-5-ol 5-Amino-8-fluoro-2-methylquinazoline A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml of concentrated hydrochloric acid (37%) that is 50'C and that was previously stirred for I hour at this temperature is added 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. It is stirred for another 30 minutes at room temperature, and after the addition of 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water, it is heated over 45 minutes to 125 0 C and kept at this temperature for 5 minutes. After cooling and after another hour, the deposited light-brown precipitate is filtered off, washed with water and dried. 3.0 g (15.0 mmol) of the hydroxylimine is obtained as an intermediate product, which is dissolved in portions in 15 ml of concentrated sulfuric acid at 60 0 C. After the addition is completed, it is heated for 2 hours to 80 0 C and for 4 hours to 90 0 C. It is allowed to cool, and the solution is poured into 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. After 54 chromatography on silica gel with hexane-ethyl acetate (0-45%), 1.2 g (7.1 mmol) of the 4,7-difluoroisatin is obtained. 1.8 ml of a 30% hydrogen peroxide solution is added in drops to isatin in 30 ml ofa 1 molar sodium hydroxide solution over 10 minutes. After 2 hours of stirring at room temperature, it is cooled to 0OC, and 5 ml of a 4 molar hydrochloric acid is added, and it is diluted with 50 ml of water. It is extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation, and 1.27 g of 3,6 difluoroanthranilic acid, which is reacted without further purification, is thus obtained quantitatively. The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid anhydride for 45 minutes to 1 00 0 C. After cooling, the acetic acid and excess acetic acid anhydride that are produced are removed azeotropically with toluene in a vacuum. The residue is mixed with 40 ml of a 25% ammonia solution while being cooled with ice, and it is stirred for 72 hours. It is diluted with water and acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride over 12 hours to 125'C. After cooling, it is poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-mcthylquinazoline, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained quantitatively. 600 mg of palladium on carbon is added, and it is shaken for 2 hours (480 ml of hydrogen absorption) under hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration through Celite, whereby it is rewashed with 100 ml of 55 ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added 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, and the mixture is heated over 8 hours to 125oC. The solvent is removed in a vacuum, it is chromatographed on silica gel with ethyl acetate, and 52 mg of product is obtained. 1 H-NMR (300 MHz, CDCI 3 ); 8 = 2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1 H). Example 7 6-(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-5-(trifluoromethyl) 2,3,3a,4,5,6-hexahvdrobenzo[de]chromen-5-ol 5-Amino- 7,8-difluoro-2-methylquinazoline 156 ml (391 mmol) of a 2.5 M butyllithium solution in hexane is added in drops to 41.7 g (180 mmol) of 2,2-dimethyl-N-(3,4,5-trifluorophenyl)-propionamide in 385 ml of THF at -70 0 C. It is allowed to stir for one hour and then 38.6 ml of DMF in 90 ml of TIHF is added in drops, whereby the solution must heat to -60 0 C. It is stirred for another hour at -70 0 C, and then the cold reaction solution is poured into a mixture of 2 kg of ice and 400 ml of concentrated hydrochloric acid. It is stirred vigorously and extracted several times with diethyl ether after one hour. The organic phase is washed neutral with water and dried on sodium sulfate. After concentration by evaporation, 49.3 g (188 mmol) of crude 4,5,6-trifluoro-2-N-pivaloylaminobenzaldehyde, which is added together 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 obtained. While 56 being stirred vigorously, it is heated for 18 hours to 145 0 C, and the solvent is removed in a vacuum. After chromatography of the residue on silica gel with hexane/ethyl acetate (0-100%), 9.1 g of 7,8-difluoro-5-N-pivaloylamino-2-methylquinazoline is obtained. 2.0 g (7.2 mmol) of 7,8-difluoro-5-N-pivalolylamino-2-methylquinazoline is dissolved in 140 ml of toluene and cooled to -70 0 C. Over 30 minutes, 24 ml (28.8 mmol) of a 1.2 M diisobutyl aluminum hydride solution in toluene is added in drops. The reaction mixture is allowed to heat for 2 hours to -25 0 C, and it is stirred for 2 hours at -25 0 C. Isopropanol and then water are slowly added and stirred for 12 hours at room temperature until a precipitate forms, which is removed by means of filtration through Celite. It is thoroughly rewashed with a methylene chloride-methanol mixture and concentrated by evaporation. The residue is vigorously stirred 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, rewashed thoroughly with a methylene chloride-methanol mixture and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 370 mg of the product is obtained. 'I-l-NMR (300 MHz, CD30D); 8 = 2.81 (s, 3H), 6.64 (dd, 1IH), 9.52 (s, I H). Analogously to Example 1, 250 mg (0.91 mmol) of 3-(chroman-4-yl)-2-hydroxy 2-(trifluoromethyl)-propanal is reacted with 200 mg (1.02 mmol) of 5-amino-7,8 difluoro-2-methylquinazoline to form 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 of dichloromethane and treated at -40 0 C with 2.2 ml (2.21 mmol) ofa 1 M boron tribromide solution. It is allowed to heat over 60 minutes to 0 0

C,

57 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on basic silica gel (hexane/2-propanol 10-20%), 18 mg of the desired product is obtained as a mixture of two diastereomers. Mixtures of diastereomers: 'H-NMR (300 MHz, CD 3 OD, selected signals); 8 = 0.87 (m, 1H), 1.15-1.30 (m, 3H), 1.42 (s, 3H), 1.70-2.16 (m, 71-1), 3.02-3.13 (m, 1 H), 4.00-4.25 (m, 2H), 6.58 (dd, 1 H), 6.72 (t, 1 H), 6.80 (m, 1 H), 6.95-7.18 (m, 2H), 9.47 (s, I H). Analogously, there can be produced: Example 8 5-{[5-Hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6-hexahydrobenzo[de]chromen-6 ylamino}-2-methylphthalazin-1-one Example 9 6-[(2-Methylquinazolin-5-yl)amino]-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[de]thiochromen-5-ol 2-Hydroxy-3-(thiochroman-4-yl)-2-(trifluoromethyl)propanal can be produced from thiochroman-4-one analogously to Example I, whereby in hydrogenation, Raney nickel is to be used as a catalyst instead of palladium on carbon. Mixture of the diastereomers: 58 H-NMR (500 MHz, CD 3 OD), selected signals); 6 = 0.60-0.72 (m, I H), 140-1.65 (m, 2H), 1.75-2.00 (m, 3H), 2.14-1.28 (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, 1 H, diaster. A + B), 6.78 (d, 1 H, diaster. A), 6.85 7.30 (m, 4H, diaster. A+B), 9.13 (s, 11-1, diaster. A), 9.68 (s, 11H, diaster. B). Analogously to Example 1, 183 mg (0.673 mmol) of 2-hydroxy-3-(thiochroman 4-yl)-2-(trifluoromethyl)propanal is reacted with 100 mg (0.63 mmol) of 5-amino-2 methylquinazoline to form the corresponding 3-(thiochroman-4-yl)-1-[(2 methylquinazolin-5-yl)imino]-2-(trifluoro-methyl)-propan- 2 -ol. 40 mg of imine is taken up in 2.0 ml of dichloromethane and treated at -40'C with 0.93 ml (0.93 mmol) ofa 1 M boron tribromide solution. It is allowed to stir over 60 minutes to 0 0 C and the solution is poured in 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 on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/2-propanol 2-4%), 12 mg of the desired product is obtained as a mixture of two diastereomers. Mixture of the diastereomers: 'H-NMR (300 MHz, CD 3 OD, selected signals): 6 = 1.25 - 1.34 (m, 2H), 1.56-75 (m, 1 H), 1.95 (t, I H), 2.22-2.34 (m, I H), 2.38 (dd, 1H), 2.78 (s, 3H1), 2.93 - 3.10 (m, 2H), 3.22 (dd, I H), 4.59 (s, 1 H, diaster. A), 5.40 (s, I H, diaster. B), 6.95 - 7.09 (m, 4H), 7.68 (t, IH, diaster. B), 7.78 (t, IH, diaster. A), 9.50 - 9.17 (m, 1H). Analogously, there can be produced: 59 Example 10 2-Methyl-6-[(2-methylquinazolin-5-yi)amino]-5-(trifluoromethyl)-2,3,3a,4,5, 6 hexahydrobenzo[de]thiochromen-5-ol 2-Hydroxy-3-(2-methylthiochroman-4-yl)-2-(trifluoromethyl)propanal can be produced from 6-chloro-2-methylthiochroman-4-one analogously to Example 1, whereby in hydrogenation, Raney nickel is to be used as a catalyst instead of palladium on carbon. Example 11 5-( [5-Hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6-hexahydrobenzo[de]chromen-6 yl]amino } phthalazin- (2H)-one Analogously to Example 1,600 mg (2.18 mmol) of 3-(chroman-4-yl)-2-hydroxy 2-(trifluoromethyl)-propanal is reacted with 384 mg (2.39 mmol) of 5-amino-2Hphthalazin- 1-one to form the corresponding 5-[3-(chroman-4-yl)-2-hydroxy-2 (trifluoromethyl)-propylidene]amino}phthalazin-I (2H)-one. 210 mg of imine is taken up in 5 ml of dichloromethane and treated at -40 0 C with 2.5 ml (2.5 mmol) ofa 1 M BBr 3 solution. It is allowed to heat for 60 minutes to O'C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on RP silica gel (MeCN/water 38-50%), 69 or 34 mg of desired product is obtained as separated diastereomers.

60 Diastereomer 1: 'H-NMR (300 MHz, DMSO-d6): 8 = 1.49 (dd, I H), 1.63 (qd, Ii), 2.18 (dd, I H), 2.54 (dd, I H), 2.98 (mn, I H), 4.03 (t, I H), 4.29 (ddd, 1 H), 4.88 (d, IH), 6.20 (s, 1IH), 6.41 (d, 1 H), 6.68 (dd, I H), 6.98 (q, I H), 7.40 (d, I H), 7.47 (t, 1 H), 8.58 (s, I H), 12.48 (s, I H). Diastereomer 2: 'H-NMR (300 MHz, DMSO-d6): 8 = 1.63 (qd, I H), 1.81 (t, I H), 1.99 (m, I H), 2.21 (dd, 1 H), 3.10-3.20 (m, 1H), 4.16 (td, 1H), 4.48 (ddd, I H), 5.37 (d, I H), 6.43 (s, IH), 6.48 (d, 1H), 6.60 (d, IH), 6.18 (d, 1H), 6.98 (t, IH), 7.24 (d, 11-1), 7.39 (d, 1H), 7.53 (t, IH), 8.55 (s, 1H), 12.48 (s, 1H). Example 12 5-{ [9-Fluoro-5-hydroxv-3a-methyl-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[de]chromen-6-yI]amino }-quinolin- 2 ( 1H)-one 2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoromethyl-propionaldehyde 7.3 g of E/Z-(chroman-4-ylidene)-ethyl acetate (J. Med. Chem. 2001, 44, pp. 1085-1098), 100 mg of copper (1) chloride and 5.1 ml of chlorotrimethylsilane in 55 ml of THF are mixed slowly at 0 0 C with 11.5 ml of methylmagnesium chloride solution [3.3 M in THF], so that the temperature always remains below 5 0 C. It is stirred for another hour at 0 0 C and for 10 hours at room temperature. The batch is mixed with saturated ammonium chloride solution and extracted with ether. The combined organic phases are washed 61 with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 100:0 - > 90:10), 2-(4 methylchroman-4-yl)-ethyl acetate is obtained as a crude product. The latter is mixed in 50 ml of THF at 0 0 C with I g of lithium aluminum hydride and stirred for 1.5 hours at 0OC. The batch is carefully added to saturated ammonium chloride solution and diluted with ethyl acetate. It is filtered through diatomaceous earth and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography o silica gel (hexane/ethyl acetate 100:0 -> 60:40), 1.2 g of 2-(4-methylchroman-4-yl) ethanol is obtained as a colorless oil. 0.58 ml of oxalyl chloride in 25.0 ml of dichloromethane is mixed at -78 0 C with 1.0 ml of DMSO in 25.0 ml of dichloromethane. After 5 minutes, 1.2 g of 2-(4-methylchroman-4-yl)-ethanoline and 25.0 ml of dichloromethane are added in drops at -78 0 C. After 15 minutes, it is mixed with 4 ml of triethylamine and slowly heated to room temperature. It is washed with water, brine, 1% sulfuric acid and saturated sodium bicarbonate solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 100:0 -> 90:10), 970 mg of 2-(4-methylchroman-4-yl)-ethanal is obtained as a colorless oil. A solution of 870 mg of 2-(4-methylchroman-4-yl)-ethanal and 2 ml of trifluoromethyl-trimethylsilane in 30 ml of THF are mixed at 0OC with 0.87 ml of tetrabutylammonium fluoride solution (1 M in THF) and stirred for 1 hour. A spatula tip full of solid tetrabutylammonium fluoride is added once more and mixed with water. It is extracted with ethyl acetate, the organic phase is washed with brine and dried with sodium sulfate. 1.2 g of 2-(4-methylchroman-4-yl)- I -trifluoromethyl-ethanol is 62 obtained as a brown oil (mixture of the diastereomers). 7.8 g of Dess-Martin periodinane in 100 ml of dichloromethane is mixed at 0 0 C with a solution of 1.2 g of 2-(chroman-4 yl)-l-trifluoromethyl-ethanol in 20 ml of dichloromethane and stirred for I hour at 0 0 C. The batch is mixed with saturated sodium bicarbonate solution, diluted with diethyl ether and stirred with sodium thiosulfate solution for 30 minutes. The organic phase is separated and washed with water. It is dried with sodium sulfate and concentrated by evaporation in a vacuum. 1.1 g of 3-(4-methylchroman-4-yl)- 1,1,1 -trifluoropropan-2 onal is obtained as a brown oil. 9.2 ml of vinylmagnesium bromide solution [IHI in THF] is mixed at room temperature with a solution of 1 .1 g of 3-(4-methylchroman-4-yl)- 1,1,1 trifluoropropan-2-onine in 30 ml of THF. It is stirred for 5 hours at room temperature and then added to saturated ammonium chloride solution. The batch is extracted with ethyl acetate and the combined organic phases are washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 100:0 -> 95:5), 930 g of l-(4-methylchroman-4-yl)-2 trifluoromethyl-3-buten-2-ol is obtained as 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, ozone is introduced at -70 0 C until the solution takes on a blue coloring. Then, argon is directed through the solution for one minute, mixed with 0.42 ml of dimethyl sulfide and stirred for one more hour at -70 0 C. It is slowly heated to room temperature and stirred for 10 more hours. The batch is added to water and extracted with dichloromethane. The combined organic phases are dried and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 63 100:0 -> 96:4), 330 mg of 2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoromethyl propionaldehdye is obtained as a yellow oil (mixture of the diastereomers). 'H-NMR (CDCI 3 , selected signals): 6 = 1.38 (s, 3H, diaster. A), 1.43 (s, 3H, diaster. B), 15.7-1.65 (m, 2H), 1.81 (ddd, IH), 2.13 (ddd, IH), 2.37 (d, 1H, diaster. B), 2.45-2.60 (m), 2.83 (d, I H, diaster. B), 3.69 (s, I H, diaster. A), 3.86 (s, I H, diaster. B), 3.97 (dd, I H, diaster. B), 4.08-4.35 (m), 6.78-6.84 (m, 1-H), diaster. A+B),6.88-6.95 (m, IH), 7.07-7.21 (m), 7.23-7.30 (m), 8.88 (s, IH), diaster. B), 9.56 (s, IH, diaster. A). Analogously to Example 1, 300 mg (1.0 mmol) of 2-hydroxy-3-(4 methylchroman-4-yl)-2-(trifluoromethyl)-propionaldehyde is reacted with 160 mg (1.0 mmol) of 5-aminoquinolin-2(1 H)-one to form the corresponding 5-{ [2-hydroxy-3-(4 methylchroman-4-yl)-2-(trifluoromethyl)-prop-ylidene]amino}quinolin- 2 (I H)-one. 250 mg of imine is taken up in 3 ml of dichloromethane and treated at -40 0 C with 3.0 ml (3.0 mmol) ofa I M BBr 3 solution. It is allowed to heat over 60 minutes to 0 0 C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/i-PrOH 0-6%), 81 or 16 mg of desired product is obtained as separated diastereomers. Diastereomer I: IH-NMR (600 MHIz, DMSO-d6): 8 = 1.40 (s, 3H), 1.84 (m, 2H), 1.93 (d, I H), 2.38 (d, I1-1), 4.28 (m, 2H), 5.04 (d, I H), 6.13 (s, I H), 6.15 (d, 2H), 6.24 (d, I H), 6.43 (d, I H), 6.60 (d, 1 H), 6.72 (d, 2H), 7.04 (t, 1H), 7.12 (t, 1H), 8.20 (d, I H), 11.60 (s, 1 H).

64 Diastereomer 2: 1 H-NMR (600 MHz, DMSO-d6): 8 = 1.51 (s, 3H), 1.76 (m, 1H), 1.88 (dd, 1H), 2.00 (d, 1H), 2.18 (d, 1IH), 4.33 (m, I H), 4.41 (m, 11-1), 5.26 (d, I H), 6.18 (d, I H), 6.34 (s, I H), 6.37 (d, I H), 6.48 (d, 1 H), 6.57 (d, 1 H), 6.68 (d, 1 H), 6.70 (d, 1H1-1), 7.01 (t, 1 H), 7.22 (t, 1 H), 8.24 (d, 1 H), 11.67 (s, 1 H). Example 13 5- { [9-Fluoro-5-hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[de]thiochromen-6-yl]amino}-quinolin- 2 (I H)-one Analogously to Example 1, 700 mg (2.4 mmol) of 2-hydroxy-3-(thiochroman-4 yl)-2-(trifluoromethyl)-propanal is reacted with 386 mg (2.4 mmol) of 5-aminoquinolin 2(1H)-one to form the corresponding 5-{ [2-hydroxy-3-(thiochroman-4-yl)-2 (trifluoromethyl)-propylidene]amino}quinolin- 2 (I H)-one. 100 mg of imine is taken up in 3 ml of dichloromethane and treated at -40 0 C with 2.3 ml (2.3 mmol) ofa I M BBr 3 solution. It is allowed to heat over 60 minutes to 0 0 C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/i-PrOHl 2-4%), 28 mg of the desired product is obtained as a mixture of diastereomers. Mixture of diastereomers: 65 'H-NMR (500 MHz, DMSO-d6, selected signals): 8 - 1.57 (ddd, 1H-, diaster. A+B), 1.96 (t, 1H), 2.25 (m, 1 H, diaster. A+B), 3.88-3.99 (m, 1 H, diaster. A+B), 3.07 (ddd, I H), 3.13-3.27 (m, I H, diaster. A+B), 4.32 (d, I H, diaster. A), 4.57 (br. S, I H, diaster. B), 5.47 (d, IH, diaster. B), 6.10 (d, IH, diaster. A), 6.37 (d, IH, diaster. A), 6.40 (s, diaster. A), 6.58 (d, 2H, diaster. A+B), 6.90 (d, I H, diaster. A), 7.05 (m, 2H, diaster. A+B), 7.25 (t, 1H), 8.16 (d, IH), 11.53 (s, (IH, diaster. A+B). Example 14 6-[(8-Fluoro-2-methylquinazolin-5-yl)aminol-5-(trifluoromethyl)- 2 ,3, 3 a, 4 ,5, 6 hexahydrobenzo[de]thiochromen-5-ol Analogously to Example 1, 328 mg (1.1 mmol) of 2-hydroxy-3-(thiochroman-4 yl)-2-(trifluoromethyl)-propanal is reacted with 200 mg (1.1 mmol) of 5-amino-8 fluoroquinazoline to form the corresponding 1-[(8-fluoro-2-methylquinazolin-5 yl)imino]-3-(thiochroman-4-yl)-2-(trifluoromethyl)propan- 2 -ol. 185 mg of imine is taken up in 5 ml ofdichloromethane and treated at -40 0 C with 4.1 ml (4.1 mmol) ofa 1 M BBr 3 solution. It is allowed to heat for 60 minutes to 0 0 C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/i-PrOH 2-4%) and renewed chromatography on basic silica gel, 18 mg of the desired product is obtained as a mixture of the diastereomers. Mixture of diastereomers: iH-NMR (400 MHz, CD 3 OD, selected signals): 8 = 1.12 (t, IH), 1.15-1.38 (m, 66 2H, diaster. A+B), 1.53-1.68 (m, 1H), 1.90 (t, IH), 2.25 (m, 1H), 2.36 (dd, IH), 2.73-2.85 (m, 4H), 2.86-3.08 (m, 2H), 3.10-3.33 (m, 2H), 5.31 (s, IH), 6.88 (dd, 1H), 6.90-7.05 (m, 4H), 7.46 (dd, 11-H), 7.52 (dd, IH), 9.54-9.68 (m, IH, diaster. A+B). Example 15 6-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino-5-(trifluoromethvyl)-2,3,3a,4,5,6 hexahydrobenzo[de]thiochromen-5-ol Analogously to Example 1, 223 mg (0.77 mmol) of 2-hydroxy-3-(thiochroman-4 yl)-2-(trifluoromethyl)propanal is reacted with 150 mg (0.77 mmol) of 5-amino-7,8 difluoroquinazoline to form the corresponding 1-[(7,8-difluoro-2-methyl-quinazolin-5 yl)imino]-3-(thiochroman-4-yl)-2-(trifluoromethyl)propan- 2 -ol. 90 mg of imine is taken up in 4 ml ofdichloromethane and treated at -40 0 C with 1.9 ml (1.9 mmol) ofa I M BBr 3 solution. It is allowed to heat over 60 minutes to 0 0 C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/i-PrOH 2-4%), 13 mg of the desired product is obtained. 'H-NMR (300 MHz, MeOD): 8 = 1.63 (qd, I H), 1.94 (dd, 1 H), 2.25 (m, I H), 2.33 (dd, IH), 2.78 (s, 3H1), 2.90-3.10 (m, 2H), 3.23 (td, IH), 5.34 (s, 11H), 6.85 (dd, 1H), 7.00 (s, 3H), 9.54 (s, I H).

67 Example 16 6-[(7-Fluoro-2-methylquinazolin-5-yli)amino]-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[de]thiochromen-5-ol Analogously to Example 1, 246 mg (0.85 mmol) of 2-hydroxy-3-(thiochroman-4 yl)-2-(trifluoromethyl)propanal is reacted with 150 mg (0.85 mmol) of 5-amino-7 fluoroquinazoline to form the corresponding I1-[(7-fluoro-2-methylquinazolin-5 yl)imino]-3-(thiochroman-4-yl)-2-(trifluoromethyl)propan-2-ol. 70 mg of imine is taken up in 4 ml of dichloromethane and treated at -40oC with 1.56 ml (1.56 mmol) of a 1 M BBr 3 solution. It is allowed to heat over 60 minutes to 0 0 C, 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 EtOAc, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/i-PrOH 2-4%), 13 mg of the desired product is obtained as a mixture of two diastereomers. Mixture of the diastereomers: 1H-NMR (300 MHz, MeOD, selected signals): 6 = 1.20-1.36 (m, IH), 1.55-1.75 (m, IH), 1.95 (t, IH), 2.24 (m, IH), 2.37 (dd, IH), 2.74 (m, 3H1), 2.88-3.10 (m, 2H), 3.20 (dd, 1H), 5.48 (s, 1H), 6.68-6.80 (m, 2H), 6.90-7.04 (m, 21-H), 7.20-7.45 (m, I H), 9.40 9.55 (m, 1 H). Analogously, there can be produced with use of the amines described above, in WO 2005/034939 or in WO2003/082827: 68 5-A [9-Fl uoro-5-hydroxy-3 a-methyl -5 -(tri fluoromethy 1)-2,3,3 a,4,5.6 hexahydrobenzo[delchromen-6-yllamino I -isociuinol in-I (2H)-one 5- [ 9-Fluoro-5-hydroxy-3a-methyl-5-(tri fluoromethyl)-2,3,3a,4,5 ,6 hexahydrobenzojdelchromen-6-yllamino -2-methylphthalazin- I -one 6-[(7,8-Di fluoro-2-methylqu inazol in-5-yl)amino]-2-methyl-5-(tri fluoromethyl) 2,3,3 a,4,5,6-hexah yd robenzo [del th ioch romen -5-o I 6-[(Indazol-4-yl)aminol-2-methyl-5-(tri fluoromethyl)-2,3,3a,4,5.,6 hexahydrobenzo[delthiochromen-5-oI 6-[(8-Fluoro-2-methylquinazolin-5-yI)aminol-3a-methyI 5-(trifluoromethyl) 2,3,3a,4,5,6-h exah ydrobenzo [del ch romen -5-o I 6-[(8-Fluoro-2-methylciuinazolin-5-yl)aminoi-2-methyI 5-(trifluoromethyl) 2,3,3a,4,5 ,6-hexahydrobenzordelthiochromen-5-oI 9-Fluoro-6-f(isociuinol in-5-yb~amino]-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo [del chromen-5 -o I 4-1[9-Fluoro-5-hydroxy-5-(trifluoromethyl)-2,3,3a,4,5,6 hexahydrobenzordelchromen-6-yllaminol - I ,3-dihydroindol-2-one 4-f~ [5-Hydroxy-5-(trifluoromethyl)-2,3a,4,5,6-hexahydrobenzo[delthiochromefl 6-yiaminol- I ,3-dihydroindol-2-one 9-Fluoro-6-r( I -methylindazol-4-yl)amino]-5-(trifluoromethy)-2,3,3a,4,5,6 hexahydrobenzofdelchromen-5-ol 5-4 [9-Fluoro-5-hydroxy-5-(tri fluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[delchromen-6-ylaminol-2-methylisoquinolin- I -one 69 51[ [5-Hydroxy-2-methy I-5-(tri fl uoromethy)-2,3,3a,4,5,6 hexahydrobenzordelthiochromen-6-yllamino I -I -methylguinol in-2-one 5-1 [9-F Iuoro-5 -hyd roxy-5 -(tri fl uorometh y)-2,3aA5,6 hexahydrobenzo [del ch romen-6-yl jam inol~-2-methylphthalazin- I -one 5-1[ 9-Fluoro-5-hydroxy-5-(tri fluoromethyl)-2,3,3a,4,5,6 hexahydrobenzo[delchromen-6-yllaminol-isociuinolin- I (2H)-one 5-f r5-1-Iydroxy-3a-methyl-5-(tri fluoromethyl)-2,3,3a,4,5,6 hexahydrobenzordelth iochromen-6-yllamino l-2-methylphthalazin- I -one 6-[(2-Methylquinazolin-5-yl)aminol-3a-methyI 5-(trifluoromethyl)-2,3,3a,4,5 .6 hexahydrobenzordelth iochromen-5-oI

Claims (15)

1. Stereoisomers of general formula (1), I:7 R~Re Ra 3 OH HNII () in which R' and R 2 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Clo)-alkyl group, a (CI-Co 10 )-alkoxy group, a (CI-Clo)-alkylthio group, a (CI-Cs) perfluoroalkyl group, a cyano group, a nitro group or R' and R 2 together mean a group that is selected from the groups -O (CH2)n-O-, -O-(CH2)n-CH2-, -O-CH=CH - , -(CH2)n+2-, -NH-(CH2)n+1, N(C 1 -C 3 -alkyl)-(CH 2 )n+i, or -NH-N=CH-, whereby n= I or 2, and the terminal atoms are linked to directly adjacent ring-carbon atoms, or NR 8 R 9 , whereby R 8 and R 9 , independently of one another, can be hydrogen, CI-Cs-alkyl or (CO)-CI-Cs-alkyl, R 3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-Clo)-alkyl group, a (C 1 -C 0 lo)-alkoxy group, a (CI-Clo) alkylthio group, a (C 1 -Cs)-perfluoroalkyl group, or a cyano group, R 4 means a C 1 -CI0-alkyl group, a Cl-C 0 lo-alkyl group that is substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (CI-Cs)-alkoxy groups; an optionally substituted (C 3 -C)-cycloalkyl 71 group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C 1 -Cs) alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR'o groups, whereby R1 0 means (Ci-C 6 )-alkyl or benzyl), (CI-Cs) alkoxy groups, hydroxy groups, halogen atoms, (C 1 -C 3 )-exoalkylidene groups and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tricyclic system and optionally can be hydrogenated at one or more sites, R 5 means a (C 1 -Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group, a (C 3 -C 7 )-cycloalkyl group, a (C3-C7) cycloalkyl(CI-C8)alkyl group, a (C 3 -C 7 )-cycloalkyl(C 2 -Cs)alkenyl group, a heterocyclyl group, a heterocyclyl(C -C 8 )alkyl group, a heterocyclyl(C 2 C 8 )alkenyl group, an aryl group, an aryl(Ci-Cs)alkyl group, an aryl(C 2 Cs)alkenyl group, an aryl(C 2 -Cg)alkinyl group; a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more keto groups, (C 1 -Cs)-alkyl groups, (CI-Cs)-alkoxy groups, halogen atoms, or (C 1 -C 3 ) exoalkylidene groups and that contains one or more nitrogen atoms and/or oxygen atoms and/or sulfur atoms; a heteroaryl(CI-Cs)alkyl group or a heteroaryl(C 2 -Cs)alkenyl group, whereby these groups can be linked via any position to the amine of the tricyclic system and optionally can be hydrogenated at one or more sites, 72 6 7 R and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, or a (CI-Cs)alkyl group, which can be substituted with OR , SR', or NRR 9 , p means 1,2 or 3, and X means an oxygen atom, a sulfur atom, a C-1 2 group or an NR 9 group.

2. Stereoisomers of general formula (1) according to claim 1, in which R1 and R 2 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-Clo)-alkyl group, a (CI-Co 10 )-alkoxy group, a (CI-Clo)-alkylthio group, a (CI-Cs) perfluoroalkyl group, a cyano group, or a nitro group, or R 1 and R 2 together mean a group that is selected from the groups -0 (CH 2 )n-O-, -O-(CH 2 )n-Cl-1 2 -, -O-CH=CH - , or -(CH 2 )n+ 2 -, whereby n = 1 or 2, and the terminal atoms are linked to directly adjacent ring-carbon atoms, or NR 8R 9 , whereby R 8 and R 9 , independently of one another, can be hydrogen, CI-Cs-alkyl or (CO)-Ci-Cs-alkyl, R 3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-C 0 lo)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-C 0 lo) alkylthio group, a (CI-Cs)-perfluoroalkyl group, or a cyano group, R 4 means a Cl-C 10 -alkyl group; a C 1 -C 0 lo-alkyl group that is substituted by one or more groups selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (CI-Cs)-alkoxy groups; an optionally substituted phenyl group; a monocyclic or bicyclic heteroaryl group that optionally is substituted by I- 73 2 keto groups, 1-2 (Ci-Cs)-alkyl groups, 1-2 (CI-Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (CI-C 3 )-exoalkylidene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby these groups can be linked via any position to the amine of the tricyclic system and optionally can be hydrogenated at one or more sites, R 5 means a (C 1 -Cs)-alkyl group or an optionally partially or completely fluorinated (Ci-Cs)-alkyl group, an aryl group, an aryl(C 1 -Cg)alkyl group, an aryl(C 2 -C 8 )alkenyl group, a (C 3 -C 7 )cycloalkyl group, a (C 3 C 7 )cycloalkyl(CI-Cs)alkyl group, or a (C 3 -C 7 )cycloalkyl(C 2 -C 8 )alkenyl group, R 6 and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, or a methyl or ethyl group that should be substituted with OR 8 , SR 8 , or N(R9)2, p means 1,2 or 3, X means an oxygen atom, a sulfur atom, a CH 2 group or an NR 9 group.

3. Stereoisomers of general formula (I) according to claim 1, in which R and R 2 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-Cs)-alkyl group, a (C 1 -Cs)-alkoxy group, a (C 1 -Cs)-perfluoroalkyl group, a cyano group or a nitro group, R 3 means a hydrogen atom, a hydroxy group, a halogen atom, an optionally 74 substituted (CI-Clo)-alkyl group, or a (C 1 -Clo)-alkoxy group, R 4 means a (Ci-Ci0)-alkyl group, a (CI-Clo)-alkyl group that is substituted by 1-3 hydroxy groups or halogen atoms; a 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 that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (CI-Cs)-alkyl groups, 1-2 (C 1 -Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (CI-C 3 )-exoalkylidene groups, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites, R 5 means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group, 6 7 R and R 7 , independently of one another, mean a hydrogen atom, a halogen atom, a methyl or ethyl group, which should be substituted with OR 8, SR or N(R 9 ) 2 , whereby R 8 and R 9 , independently of one another, can be hydrogen, C 1 -Cs-alkyl or (CO)-C 1 -Cs-alkyl, p means 1, 2 or 3, and X means an oxygen atom, a sulfur atom, a CH 2 group or an NR 9 group.

4. Stereoisomers of general formula (1) according to claim 1, in which 75 R', R 2 and R 3 , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -Cio)-alkyl group, a (Ci-C 1 o)-alkoxy group, or a cyano group, R 4 means a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (Cl C 5 )-alkyl groups, 1-2 (C 1 -Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, 1-2 (C,-C 3 )-exoalkylidene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1 2 keto groups, whereby this group can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites, R 5 means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group, R 7 and R 8 , independently of one another, mean a hydrogen atom, a halogen atom, a methyl or ethyl group, p means I or 2, X means an oxygen atom or a sulfur atom.

5. Stereoisomers of general formula (1) according to claim 1, in which 1 2 3 R , R and R , independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (CI-Clo)-alkyl group, a (CI-Clo)-alkoxy group, or a cyano group, R 4 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, 76 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 that optionally is substituted by one or more groups selected from 1-2 keto groups, 1-2 (Ci-Cs)-alkyl groups, 1-2 (C 1 -Cs)-alkoxy groups, 1-3 hydroxy groups, 1-3 halogen atoms, or 1-2 (CI-C 3 )-exoalkylidene groups, whereby these groups can be linked via any position to the amine of the ring system and optionally can be hydrogenated at one or more sites, R s means a (CI-Cs)-alkyl group or an optionally partially or completely fluorinated (CI-Cs)-alkyl group, R 7 and R 8 , independently of one another, mean a hydrogen atom, a halogen atom, a methyl group or an ethyl group, p means I or 2, X means an oxygen atom or a sulfur atom.

6. Use of stereoisomers according to one of the preceding claims for the production of a pharmaceutical agent.

7. Use of the stereoisomers of claims 1-5 for the production of a pharmaceutical agent for the treatment of inflammatory diseases.

8. Pharmaceutical preparations that contain at least one stereoisomer according to claims 1-5 or mixtures thereof as well as pharmaceutically compatible vehicles. 77

9. Stereoisomers of general formula 1, according to one of claims 1-5, in the form of salts with physiologically compatible anions.

10. Process for the production of stereoisomers of general formula I, in which the radicals, unless otherwise mentioned, have the meanings defined in Claim 1, characterized in that either a) Stereoisomers of general formula (111) R R X-- CH)p R2 CH 2 R 3 (Ill) in which R', R 2 , R3, R , X and p have the meanings that are mentioned in claim 1, are converted by an optionally enantioselectively conducted En reaction with oQ-keto acids R 5 (CO)COOR o in the presence of optionally chiral Lewis acids into compounds of general formula (IV) 78 H )H R1X H OR R 2 Rs / O 0v R3 (IV) radical R 6 = H is introduced by hydrogenation and by reduction and reaction with amines of formula R 4 -NH 2 , whereby R 4 has the meaning that is indicated in claim I, the compounds of general formula (V) RR (V) in which R 2, R 2 , R 3 , R 4 , R, R, X and p have the meanings that are indicated in Claim 1, are produced and are then cyclized either without additional reagent or by adding inorganic or organic acids or Lewis acids at temperatures of-70 0 C to 80 0 C to form compounds of general formula 1, or b) compounds of general formula (VI) 79 R 7 X4( H) )P RCOR R (VI) that are produced according to methods that are known to one skilled in the art are converted by reduction of the double bond or by reaction with an R -containing cuprate reagent, in which R has the meanings indicated in claim 1, reduction of the ester and optionally oxidation into compounds of general formula (VII) iR17 0 R (VII) which then are reacted with a silicon compound of general formula CqF 2 q+i-Si(CH 3 ) 3 , whereby q can be 1, 2, 3 or 4, in the presence of a catalyst or with a metal organyl compound of formula R 5 A, in which R 5 has the meanings indicated in Claim 1, and A means magnesium-halogen or lithium, to form a compound of general formula (VIII) 80 1:7 ,X CHO H 2 R 5 R Rd R (VIll), which after oxidation and reaction with a compound of formula M-CN, whereby M can stand for sodium, potassium, copper or trimethylsilyl, is converted into a compound of general formula (X) 2 R CN R (x), which is converted after reduction into a compound of general formula (XI) R 1 7 iX4 C H2) H R R R 6 R R (xI) which can be reacted with an amine R 4 -NH 2 and cyclized analogously to process a), or 81 c) Compounds of general formula VIII X4 C H2), H 2 A S R:RS R (VIII) are reacted with alkenyl-metal organyl compounds RI 2 R' 3 (C)=C--A, whereby A means magnesium-halogen or lithium, and R 1 2 , R 13 mean hydrogen or CI-C 6 -alkyl, to generate compounds of general formula (XII) R7 R X C HAC)A M 2(xl , 21 R R (XII), which can be converted by oxidative cleavage of the double bond into compounds of general formula (X) that can be reacted analogously to variant b) to form compounds of general formula (I). I1. Process stage for the production of the stereoisomers of general formula I according to claim 10, wherein stereoisomers of general formula V 82 R' XR CH,), H RR V in which R', R 2 , R3, R 4 , R s , R 6 , R , X and p have the meanings that are defined in claim 1, are cyclized optionally with the addition of inorganic or organic acids or Lewis acids.

12. Compounds of general formula V according to Claim I 1I R R R 1 X'4 ( Ha)f. H R2 R" RR R3 V 1 2 3 4 6 6 in which R' , , R R , R 4 , R , R, R , X and p have the meanings that are defined in Claim 1.

13. Process stage for the production of compounds of general formula (1), according to Claim 10, wherein stereoisomers of general formula IV X * H ROR Rz A / 0 R) IV are reduced and are reacted with a corresponding amine of formula R 4 -NI-1 2 to form the imine of general formula (V).

14. Compounds of formula IV according to Claim 13, in which R', R2, R3, R s , X and p correspond to the meanings defined in Claim I. 83 FRY ( H 2 )P. 1 xx H R 1 OR R2 A 5 R3 IV

15. Compounds of formula 111 according to Claim 10, in which R , R R 3, R , X and p have the meanings that are defined in Claim 1. R' X-\ CH2}, Ra CH2 A 3 III

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.