Substituted indeno [1,2-b]indole derivatives as novel inhibitors of protein kinase CK2 and their use as tumor therapeutic agents, cytostatics and diagnostic aids

A compound of structure I, structure IA or structure II:

• wherein:
• R represents
• a hydrogen atom or
• a straight or branched chain C1-C8-alkyl group or
• a C3-C8-cycloalkyl group or
• a straight or branched chain C2-C8-alkenyl group or
• a C3-C8-cycloalkenyl group or
• an aryl group or
• a heteroaryl group or
• an aryl-C1-C8-alkyl group or
• a heteroaryl-C1-C8-alkyl group,
• wherein R is optionally mono- or polysubstituted, identically or differently substituted by
• hydroxy groups or
• cyano groups or
• nitro groups or
• halogen atoms or
• carboxy groups or
• sulfonic acid groups or
• groups of formula COOR12 (alkoxycarbonyl group) or SO2OR13 (alkoxy sulfonic acid group), wherein each of R12, R13, which are identical or different, is a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group or a straight or branched C2-C8-alkenyl group, in each case optionally mono- or polysubstituted identically or differently substituted by hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups, or groups of the formulae NR14R15, CONR14R15, and CSNR14R15, SO2NR14R15, wherein each of R14, R15 which are identical or different, is a hydrogen atom or a straight or branched C1-C8-alkyl group or a C3-C8-cycloalkyl group, or R14, R15 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, or
• groups of the formulae CONR16R17 (carboxamide group), CSNR16R17 (thiocarboxamide group), and SO2NR16R17 (sulfonamide groups), wherein each of R16, R17 which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group or R16, R17 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, in each case optionally mono- or polysubstituted identically or differently substituted by hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups, or amino groups NR18R19, wherein each of R18R19 which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group or straight or branched chain C2-C8-alkenyl group or R18R19 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, or
• acyloxy groups OCOR20, wherein R20 is a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group, which in each case is optionally identically or differently substituted, mono- or polysubstituted by hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups, or groups of formulae COOR21, NR21R22, CONR21R22, CSNR21R22, and SO2NR21R22, wherein each of R21, R22, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R21, R22 together with the nitrogen to which they are attached form a nitrogen-containing heterocycle, or
• groups of formula OR23NR24R25 (aminoalkyloxy), wherein R23 is a straight or branched chain C1-C8-alkyl group, each of R24, R25, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R24, R25 together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocycle;
• each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, which are identical or different, are independently from each other
• a hydrogen atom or
• a straight or branched chain C1-C8-alkyl group or
• a C3-C8-cycloalkyl group or
• a straight or branched chain C2-C8-alkenyl group or
• a C3-C8-cycloalkenyl group or
• an aryl group or
• a straight or branched chain aryl-C1-C8-alkyl group or
• a heteroaryl group or
• a hydroxy group or
• a straight or branched chain C1-C8-alkoxy group or
• a C3-C8-cycloalkoxy group or
• a straight or branched chain C2-C8-alkenyloxy group or
• a C3-C8-cycloalkenyloxy group or
• a C1-C2-alkylenedioxy group, which forms one of the groups R1-R10 with an adjacent group R1-R10, or
• an acyloxy group OCOR26, wherein R26 is a straight or branched chain C1-C8-alkyl group or a straight or branched chain C2-C8-alkenyl group or a C3-C8-cycloalkyl group, or a straight or branched chain aryl-C1-C8-alkoxy group or
• an alkoxycarbonylalkyl group R27COOR28, wherein each of R27, R28, which are identical or different, is a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group, or a carboxy group, COOH, or
• a group of formulae CONR29R30 (carboxamide group), CSNR29R30 (thiocarboxamide group), and SO2NR29R30 (sulfonamide group), wherein each of R29, R30, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group or R29, R30 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, or
• an alkoxycarbonyl group COOR31, wherein R31 is a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group, or
• an amino group NR32R33, wherein each of R32, R33, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group, a straight or branched chain C2-C8-alkenyl group or R32, R33 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, or
• an aminoalkyloxy group of formula OR34NR35R36, wherein R34 is a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group, and each of R35, R36, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or C3-C8-cycloalkyl group, or R35, R36 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle,
• wherein each of the groups R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 is optionally mono- or polysubstituted, identically or differently independently from each other substituted by
• hydroxy groups or
• cyano groups or
• nitro groups or
• halogen atoms or
• carboxy groups or
• sulfonic acid groups or
• aryl group or
• heteroaryl group or
• groups of formulae COOR37, NR37R38, CONR37R38 (carboxamide group), CSNR37R38 (thiocarboxamide group), and SO2NR37R38 (sulfonamide group), wherein each of R37, R38 which are identical or different is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R37, R38 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, optionally mono- or poly-substituted identically or differently substituted by hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups or groups of formulae COOR39, NR39R40, CONR39R40, CSNR39R40, and SO2NR39R40, wherein each of R39, R40, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R39, R40 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle,
• wherein each of X, Y, Z, which are identical or different, are independently from each other
• an oxygen atom,
• an imino function NR41, wherein R41 is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group or a C3-C8-cycloalkenyl group or an aryl group or heteroaryl group, or
• an alkyloxyimino function NOR42, wherein R42 is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkenyl group or a C3-Crcycloalkenyl group, or
• an aryloxyimino function NOR43, wherein R43 is an aryl group or heteroaryl group,
• wherein NR41, NOR42 and NOR43, are each optionally mono- or polysubstituted, identically or differently independently from each other substituted by aryl groups, heteroaryl groups, hydroxy groups, cyano groups, nitro groups, halogen atoms or by groups of formulae COOR44, NR44R45 (amino group), CONR44R45 (carboxamide group), CSNR44R45 (thiocarboxamide group), and SO2NR44R45 (sulfonamide group), wherein each of R44, R45, which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group, or R44, R45 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle,
• wherein X—R11 in structure IA is
• a hydroxy group or
• an alkoxy group O—R11, wherein R11 is a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or a straight or branched chain C2-C8-alkylene group, which in each case is optionally mono- or polysubstituted by aryl groups, heteroaryl groups, hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups or groups of formulae COOR46, NR46R47, CONR46R47, CSNR46R47, and SO2NR46R47 wherein each of R46, R47 which are identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R46, R47 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, or
• an acyloxy group OCOR48, wherein R48 is a straight or branched chain C1-C8-alkyl group or a straight or branched chain C2-C8-alkenyl group or a C3-C8-cycloalkyl group or an aryl group or a heteroaryl group, which in each case optionally mono- or polysubstituted by aryl groups, heteroaryl groups, hydroxy groups, cyano groups, nitro groups, halogen atoms, carboxy groups or groups of formulae COOR49, NR49R50, CONR49R50, CSNR49R50, and SO2NR49R50, wherein each of R49, R50, which may be identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R49, R50 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle,
• wherein C2-C8-alkenyl groups independently from each other are defined as straight or branched chain hydrocarbon chains having at least one double bond up to the maximum number of conjugated double bonds, and
• wherein C3-C8-cycloalkenyl groups independently from each other are defined as cyclic hydrocarbons having at least one double bond up to the maximum number of conjugated double bonds, and
• wherein aryl groups independently from each other are defined as phenyl or naphthyl groups, which may be substituted with one or more identical or different substituents such as linear or branched chain C1-C8-alkyl groups, C3-C8-cycloalkylgroups, phenyl-C1-C8-alkyl group, naphthyl-C1-C8-alkyl group, C1-C2-alkylenedioxy group, hydroxy group, nitro group, cyano group, halogen atoms, linear or branched chain C1-C8-alkoxy groups, phenoxy group, linear or branched chain C1-C8-alkoxycarbonyl groups, carboxy group, groups of formulae OCR51NR52R53 (amino-C1-C8-alkoxy group), NR52R53 (thiocarboxamide group), CONR52R53 (carboxamide group), CSNR52R53 (thiocarboxamide group), and SO2NR52R53 (sulfonamide group), wherein R51 is a linear or branched chain C1-C8-alkyl group, and each of R52, R53, which are identical or different, is a hydrogen atom or a linear or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R52, R53 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle,
• wherein heteroaryl groups independently from each other are defined as aromatic mono- or bicyclic 5 to 12 membered ring systems containing 1-3 hetero atoms (O, N, S), which may be substituted with one or more identical or different substituents such as linear or branched chain C1-C8-alkyl groups, C3-C8-cycloalkyl groups, linear or branched chain C1-C8-alkylene groups, aryl groups, hydroxy groups, nitro groups, cyano groups, halogen atoms, linear or branched chain C1-C8-alkoxy groups, C3-C8-cycloalkoxy groups, phenoxy groups, groups of formulae OCR54NR55R56 (amino-C1-C8-alkoxy group), NR55R56 (amino group), CONR55R56 (carboxamide group), CSNR55R56 (thiocarboxamide group), and SO2NR55R56 (sulfonamide group), wherein R54 is a straight or branched chain C1-C8-alkyl group, and each of R55, R56, which may be identical or different, is a hydrogen atom or a straight or branched chain C1-C8-alkyl group or a C3-C8-cycloalkyl group or R55, R56 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocycle, and
• wherein nitrogen-containing heterocycle independently from each other are defined as a saturated 5-7 membered monocycle, which in addition to nitrogen further contains 1-3 heteroatoms,
• or a salt thereof with a pharmaceutically acceptable acid,
• or a mixture of isomers, or a pure isomer thereof, wherein isomers are optical isomers and geometric isomers with regard to double bonds.