Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents

Stereoisomers of general formula (I),

• in which
• R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group,
• or R1 and R2 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(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
• wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms,
• or NR8R9,
• wherein R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl, or (CO)—C1-C5-alkyl,
• R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
• R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
• R3 means a C1-C10-alkyl group that optionally is substituted by a group that is selected from 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group 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 and that optionally is substituted by one or more groups selected from (C1-C5)-alkyl groups (which optionally is substituted by 1-3 hydroxy groups or 1-3 COOR13 groups);
• (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, wherein this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more locations,
• R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, wherein
• R10 means any hydroxy protective group or a C1-C10-alkyl group,
• R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, (C2-C8)alkinylaryl groups,
• a monocyclic or bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups;
• a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group,
• wherein these groups are linked via any position to the tetrahydronaphthalene system and optionally are hydrogenated at one or more locations,
• R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or together with the carbon atom of the tetrahydronaphthalene system mean a (C3-C6)-cycloalkyl ring,
• provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
• or a pharmaceutically acceptable salt thereof.

Stereoisomers of general formula II,

• in which
• R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group,
• or R1 and R2 together mean a group that is —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH—,
• wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms,
• or NR8R9,
• wherein R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
• R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
• R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
• R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups;
• an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group 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 and that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally is substituted by 1-3 hydroxy groups or 1-3 COOR13 groups, wherein R13 means hydrogen or (C1-C5)-alkyl);
• (C1-C5)-alkoxy groups, halogen atoms, hydroxy groups, NR8R9 groups, exomethylene groups, or oxygen, wherein this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more locations,
• R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, wherein R10 means any hydroxy protective group or a C1-C10-alkyl group,
• R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, (C2-C8)alkinylaryl groups,
• a monocyclic or bicyclic heteroaryl group that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms or 1-2 exomethylene groups;
• a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group, or a (C2-C8)alkinylheteroaryl group, wherein these groups can be linked via any position to the tetrahydronaphthalene system and optionally is hydrogenated at one or more locations,
• R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (C1-C6)-cycloalkyl ring,
• provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen.