Anthracycline Derivatives For Treating Tumor Diseases

A process for preparing compounds of the general formula (I), characterized in that an open-chain sugar compound of the general formula (II)

• in which R7 and R5 are the same and are each alkyl or alkylene having 2 to 3 carbon atoms;
• R9 and R10 are each an alkyl group having 1 to 3 carbon atoms;
• Y═[C(═O)], [C(═N)—OH] or [CH—OH], [CH—NR5R6] in both possible stereoisomeric arrangements, where R5 and R6 are either each a hydrogen atom or are one hydrogen atom and one trifluoroacetyl group (TFA);
• in which X═O, S or NR with R=hydrogen or a C1 to C4 alkyl group;
• R4 is an unbranched or branched alkyl or heteroalkyl chain having a chain length of 1 to 19 elements, where a maximum of 6 heteroatoms (O, N, S) in any combination are separated from one another by at least two carbon atoms, is converted by cleaving the diol and aldehyde protecting group to give a pyranose of the general formula (III)
• in which Y═[C(═O)], [C(═N)—OH] or [CH—OH], [CH—NR5R6] in both possible stereoisomeric arrangements, where R5 and R6 are either each a hydrogen atom or are one hydrogen atom and one trifluoroacetyl group (TFA);
• in which X═O, S or NR with R=hydrogen or a C1 to C4 alkyl group;
• R4 is an unbranched or branched alkyl or heteroalkyl chain having a chain length of 1 to 19 elements, where a maximum of 6 heteroatoms (O, N, S) in any combination are separated from one another by at least two carbon atoms, which is subsequently protected, preferably as O-trifluoroacetyl or O-para-nitrobenzoyl, forming compounds of the general formula (IIIa) or (IIIb)
• in which Y═[C(═O)], [C(═N)—OH] or [CH—OH], [CH—NR5R6] in both possible stereoisomeric arrangements, where R5 and R6 are either each a hydrogen atom or are one hydrogen atom and one trifluoroacetyl group (TFA);
• in which X═O, S or NR with R=hydrogen or a C1 to C4 alkyl group;
• R4 is an unbranched or branched alkyl or heteroalkyl chain having a chain length of 1 to 19 elements, where a maximum of 6 heteroatoms (O, N, S) in any combination are separated from one another by at least two carbon atoms, and these are subsequently glycosylated with a tetracyclic aglycone of the anthracycline (AA) structure type to give a compound of the general formula IIIc
• in which AA is a tetracyclic aglycone of the anthracycline structure type and X, Y, R3 and R4 are each as defined in formula I,
• but in the preferred embodiment the activated pyranoses of the general formula (IIIa) or (IIIb) are reacted in a glycosidation reaction with an anthraquinone-derived aglycone of the general formula (IV)
• in which R1 and R2 are each as defined in formula (I), wherein a reaction activation is effected, giving compounds of the general formula (Ia)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom or an NO2 group, R2 is a hydrogen atom, a hydroxyl or methoxy group, or an acyl or aroyl radical, R4 is defined as —(CH2—CH2—O)n— with n=1 to 6, and in which there is a hydrogen atom or a C1 to C4 alkyl group on the terminal oxygen atom of the chain.

A process for preparing compounds of the general formula (IV)

• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and R2 is hydrogen, characterized in that a tricyclic bromide of the general formula (VIII)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, is reacted with a synthon of the formula (IX)
• wherein the compound of the formula (IX) is deprotonated, and the subsequent alkylation leads to formation of an enantiomerically pure compound of the general formula (X)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, which is reacted with an organometallic reagent to give a compound of the general formula (XI)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and the keto group in the compound of the general formula (XI) is reduced in a hydride reduction to a hydroxyl group and then is ketalized to give a compound of the general formula (XII)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and subsequently the protecting group in the general formula (XII) is eliminated and the hydroxyl group released is oxidized by oxidation to give an aldehyde of the general formula (XIII)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and the compound of the general formula (XIII) thus obtained is converted by oxidative dealkylation to the anthraquinone derivative of the general formula XIV
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and subsequent detachment of the remaining protecting groups gives the hemiacetal of the general formula (XV)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group,
• the latter is cyclized to give the compound of the general formula (XVI)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, R12 and R13 are each a hydrogen atom, or are one hydrogen atom and one hydroxyl group in any combination, and the side chain hydroxyl group is oxidized to give a compound of the general formula (XVII)
• in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, R12 and R13 are each a hydrogen atom, or are one hydrogen atom and one hydroxyl group in any combination, and, provided that R12 and R13 are each a hydrogen atom, is then hydroxylated to give a compound of the general formula (IV) in which R1 is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO2 group, and R2 is hydrogen