Isocarbostyril alkaloid derivatives having anti-proliferative and anti-migratory activities

A compound having the structural formula I or II, stereoisomers, tautomers, racemates, or a pharmaceutically acceptable salt and/or solvate thereof,

• wherein
• R1 is hydrogen or a group selected from hydroxyl, alkyl, aryl, alkoxy, aryloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylaminothiocarbonyloxy, arylaminothiocarbonyloxy, alkylcarbonyloxy, arylcarbonyloxy, Het1carbonyloxy, Het2-carbonyloxy, cycloalkylcarbonyloxy, aralkyl, cycloalkyl, Het1, Het2, alkenyl, alkynyl, alkylamino, arylamino, alkylaminoalkyl, alkylcarbonyl, alkylcarbonylamino, amino, cycloalkyloxy, alkylthio, arylthio, formylamino, Het1alkyl, Het2alkyl, Het1oxy, Het2oxy, or saccharyl, each group being optionally substituted with one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano, nitro, amino, aminoalkyl, alkylamino, alkenylamino, arylamino, Het1amino, Het2-amino, alkylaminosulfonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, arylcarbonyl, arylcarbonylamino, aryloxy, haloaryl, Het1alkyl, Het2alkyl, or hydroxyalkyl,
• R2 is oxo or a group selected from hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, amino, alkylamino, arylamino, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylaminothiocarbonyloxy, arylaminothiocarbonyloxy, alkenylcarbonyloxy, Het1amino, Het2-amino, Het1carbonyloxy, Het2-carbonyloxy, cycloalkylcarbonyloxy, alkoxy, alkenyloxy, alkynyloxy, alkylaminoalkyl, alkylcarbonyl, alkylcarbonylamino, cycloalkyloxy, alkylthio, formylamino, Het1oxy, Het2oxy, Het1alkyloxy, Het2alkyloxy, aryloxy, or saccharyl, each group being optionally substituted with one or more substituents independently selected from halogen, thiol, alkyl, haloalkyl, alkoxy, acyl, carboxyamino, acylamino, acetamido, haloalkoxy, alkylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano nitro, amino, aminoalkyl, alkylamino, alkenylamino, alkylamido, arylamino, Het1amino, Het2-amino, alkylaminosulfonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, arylcarbonyl, arylcarbonylamino, aryloxy, haloaryl, Het1alkyl, Het2alkyl, hydroxyalkyl, or phosphatyl,
• R3 is a group selected from hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, amino, alkylamino, arylamino, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylaminothiocarbonyloxy, arylaminothiocarbonyloxy, Het1amino, Het2-amino, Het1 carbonyloxy, Het2-carbonyloxy, cycloalkylcarbonyloxy, alkoxy, aryloxy, alkenyloxy, alkynyloxy, alkylaminoalkyl, alkylcarbonyl, alkylcarbonylamino, cycloalkyloxy, alkylthio, formylamino, Het1oxy, Het2oxy, Het1alkyloxy, Het2alkyloxy, or saccharyl, each group being optionally substituted with one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano nitro, aminoalkyl, alkylamino, alkenylamino, arylamino, Het1amino, Het2-amino, alkylaminosulfonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, arylcarbonyl, arylcarbonylamino, aryloxy, haloaryl, Het1alkyl, Het2alkyl, or hydroxyalkyl,
• R4 is a group selected from hydroxyl, alkylcarbonyloxy, alkoxy, aryloxy, sulfato, arylalkyloxy, arylcarbonyloxy, amino, alkylamino, arylamino, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylaminothiocarbonyloxy, arylaminothiocarbonyloxy, Het1amino, Het2-amino, Het1 carbonyloxy, Het2-carbonyloxy, cycloalkylcarbonyloxy, alkenyloxy, alkynyloxy, alkylaminoalkyl, alkylcarbonyl, alkylcarbonylamino, cycloalkyloxy, alkylthio, formylamino, Het1oxy, Het2oxy, Het1alkyloxy, Het2alkyloxy, alkyloxycarbonylalkyl, carboxyalkyl, alkylaminoalkyl, or saccharyl, each group being optionally substituted with one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano, nitro, amino, aminoalkyl, alkylamino, alkenylamino, arylamino, Het1amino, Het2-amino, alkylaminosulfonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, arylcarbonyl, arylcarbonylamino, aryloxy, haloaryl, Het1alkyl, Het2alkyl, or hydroxyalkyl,
• or wherein R3 and R4 together with the carbon atoms to which they are attached form a dioxolane ring, said ring being optionally substituted with one or two substituents selected from alkyl or aryl,
• R5 is hydrogen or a group selected from alkyl, alkyloxycarbonylalkyl, aryloxycarbonylalkyl, aryl, aralkyl, alkenyl, alkynyl, alkylaminoalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyl, Het1alkyl, Het2alkyl, alkyloxycarbonyl, aminocarbonyl, halo alkylcarbonylaminocarbonyl, alkylcarbonylaminocarbonyl, or cycloalkylalkyl, each group being optionally substituted with one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano, nitro, amino, aminoalkyl, alkylamino, alkenylamino, arylamino, Het1amino, Het2-amino, alkylaminosulfonyl, alkylcarbonylamino, alkyloxyaminoalkenyl, alkyloxycarbonyl, alkylsulfonyl, alkylsulfonylamino, alkylthio, arylcarbonyl, arylcarbonylamino, aryloxy, haloaryl, Het1alkyl, Het2alkyl, or hydroxyalkyl,
• R6 is hydrogen, oxo or thioxo,
• R7 is hydrogen, hydroxyl or a group selected from alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, alkylcarbonyloxy, arylcarbonyloxy, arylcarbonylalkyloxy, carboxyalkyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylaminothiocarbonyloxy, arylaminothiocarbonyloxy, alkyloxycarbonylalkyloxy, aryloxycarbonylalkyloxy, hydroxycarbonylalkyloxy, Het1carbonyloxy, Het2-carbonyloxy, aryloxy, sulfato, Het1oxy, Het2oxy, alkylaminoalkyloxy, cycloalkyloxy, cycloalkylalkyloxy, Het1alkyloxy, Het2alkyloxy, amino, alkylamino, alkenylamino, alkylcarbonylamino, arylcarbonylamino, formylamino, arylamino, cycloalkylamino, Het1amino, Het2-amino, alkylsulfonylamino, phosphatyl, thiol, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkenylcarbonyloxy, —O—R8—O—R9, or saccharyl, wherein
• R8 is alkylene or alkenylene and R9 is selected from hydrogen, alkyl, aryl, Het1, Het2, or cycloalkyl;
• each group being optionally substituted with one or more substituents independently selected from halogen, thiol, alkyl, haloalkyl, alkoxy, acyl, carboxyamino, acylamino, acetamido, haloalkoxy, alkylcarbonyl, arylcarbonyl, aryl, aralkyl, Het1, Het2, cycloalkyl, carboxyl, oxo, cyano, nitro, amino, aminoalkyl, alkylamino, arylamino, alkylamido, Het1amino, Het2-amino, or phosphatyl,
• and wherein the dotted line represents an optional double bond,
• with the proviso that:
• when R1 is hydrogen, R2 and R4 are hydroxyl, R5 is hydrogen or methyl, and R6 is an oxo, then R7 is not hydroxyl when R3 is hydroxyl, when R1 is hydrogen, R2 and R4 are hydroxyl, R5 is hydrogen or methyl, R6 is an oxo and the dotted line represents a double bond, then R7 is not hydroxyl or methoxy when R3 is hydroxyl or methoxy,
• when R1, R2, R4 are acetoxy, R5 is hydrogen, R6 is an oxo, and R7 is hydroxyl, methoxy, or acetoxy, then R3 is not hydroxyl or acetoxy,
• when R1 is hydrogen, R3 and R4 together with the carbon atoms to which they are attached form 2,2-dimethyl-1,3-dioxolane, R5 is hydrogen, 4-methoxybenzyl, or methyl, and R6 is an oxo, then R7 is not hydrogen or hydroxyl when R2 is hydroxyl, methoxy, ethoxy, acetoxy or benzyloxy, and R7 is not acetoxy when R2 is acetoxy, and R7 is not methoxy when R2 is hydroxyl, methoxy, or acetoxy,
• when R2, R3, and R4 are acetoxy, R5 is hydrogen, R6 is an oxo, and R1 is hydrogen, benzoyloxy, or acetoxy, then R7 is not hydrogen, hydroxyl, acetoxy, or methoxy,
• when R2, R3, and R4 are hydroxyl, R5 is hydrogen or 4-methoxybenzyl, R6 is an oxo, and R7 is hydrogen, methoxy or hydroxyl, then R1 is not tetrahydropyranyloxy, benzoyloxy, benzyloxy, or 1-O-3-hydroxybutyryl,
• when R1 is hydrogen, R3 and R4 are acetoxy, R5 is hydrogen, R6 is an oxo, and R7 is methoxy or acetoxy, then R2 is not benzoyloxy or acetoxy,
• when R1 is hydrogen, R3 and R4 are methoxy, R5 is methyl, R6 is an oxo, and R7 is methoxy, then R2 is not methoxy,
• when R2, R3, and R4 are acetoxy, R5 is hydrogen, R6 is an oxo, and R7 is acetoxy, then R1 is not hydrogen,
• when R2, R3, and R4 are hydroxyl, R5 is hydrogen, R6 is an oxo, and R7 is hydroxyl or methoxy, then R1 is not benzoyloxy,
• when R1 is hydroxyl, R3 and R4 together with the carbon atoms to which they are attached form 2,2-dimethyl-1,3-dioxolane, R5 is hydrogen or 4-methoxybenzyl, and R6 is an oxo, then R7 is not hydrogen, hydroxyl, methoxy, or acetoxy when R2 is hydroxyl or acetoxy,
• when R1 is hydroxyl or hydrogen, R2, R3, and R4 are hydroxyl, R5 is hydrogen, R6 is an oxo, then R7 is not hydrogen, hydroxyl, methoxy, or benzyloxy,
• when R1 is hydrogen, R2, R3, and R4 are benzoyloxy, R5 is hydrogen, or benzoyl or benzoyloxy, R6 is an oxo, then R7 is not hydrogen or methoxy,
• when R1 is hydrogen, R2 and R3 and R4 are benzoyloxy, R6 is an oxo, and R7 is methoxy, then R3 is not methoxy,
• when R1, R2, R3, and R4 are benzoyloxy, R5 is hydrogen or benzoyl, and R6 is an oxo, then R7 is not hydrogen,
• when R1 is acetyloxy, R2, R3, and R4 are benzoyloxy, R5 is hydrogen, R6 is an oxo, then R7 is not hydrogen,
• when R1, R2, R3 and R4 are hydroxyl or acetyloxy, R5 is hydrogen, R6 is oxo, R7 is not phosphatyl,
• when R1 is hydrogen, R2, R3, and R4 are acetoxy, R5 is hydrogen, R6 is an oxo, then R7 is not hydrogen, and
• when R6 is hydrogen, R7 is not hydrogen.