Anthracycline Derivatives For Treating Tumor Diseases

Abstract

The invention relates to anthracycline derivative compounds for treating tumor diseases, and related methods, compositions, and kits.

1 . A compound of the formula (IX) 
       
         
           
           
               
               
           
         
       
     
     
         2 . A compound of the general formula (X) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         3 . A compound of the general formula (XI) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         4 . A compound of the general formula (XII) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         5 . A compound of the general formula (XIII) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         6 . A compound of the general formula (XIV) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         7 . A compound of the general formula (XV) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group. 
       
     
     
         8 . 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 R 7  and R 5  are the same and are each alkyl or alkylene having 2 to 3 carbon atoms; R 9  and R 10  are each an alkyl group having 1 to 3 carbon atoms; Y═[C(═O)], [C(═N)—OH] or [CH—OH], [CH—NR 5 R 6 ] in both possible stereoisomeric arrangements, where R 5  and R 6  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 C 1  to C 4  alkyl group; R 4  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—NR 5 R 6 ] in both possible stereoisomeric arrangements, where R 5  and R 6  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 C 1  to C 4  alkyl group; R 4  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, R 3  and R 4  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 R 1  and R 2  are each as defined in formula (I), wherein a reaction activation is effected, giving compounds of the general formula (Ia) 
       
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom or an NO 2  group, R 2  is a hydrogen atom, a hydroxyl or methoxy group, or an acyl or aroyl radical, R 4  is defined as —(CH 2 —CH 2 —O) n — with n=1 to 6, and in which there is a hydrogen atom or a C 1  to C 4  alkyl group on the terminal oxygen atom of the chain. 
       
     
     
         9 . The process as claimed in  claim 8 , characterized in that compounds of the general formula (II) are prepared by coupling a C2 unit of the general formula (V) 
       
         
           
           
               
               
           
         
         in which R 7  and R 8  are each as defined in formula (II) to a protected derivative of L-threose (enantiomerically pure C4 unit) of the general formula (VI) 
       
       
         
           
           
               
               
           
         
         in which X, R 9 , R 10  are each as defined in formula (II) and Z=hydrogen, or at least or more than one, preferably one or two, methyl, fluorine, chlorine, bromine or nitro groups, and the resulting addition product of the general formula (VII) 
       
       
         
           
           
               
               
           
         
         in which R 7 , R 8 , R 9 , R 10  are each as defined in formula (II), and Z=hydrogen, or at least or more than one, preferably one or two, methyl, fluorine, chlorine, bromine or nitro groups, and Y═CH—OH, is oxidized by oxidation to the ketone [Y═C(═O)] of the general formula (VII) and then the nitrogen is introduced, preferably via an oxime [Y═C(═N)—OH] of the general formula (VII), in which the protecting group on X is subsequently detached and R 4  as defined in formula (I) is introduced, wherein the introduction of an unbranched or branched alkyl or heteroalkyl chain on X is effected by substitution, preferably with the aid of a non-nucleophilic base, wherein the alkyl or heteroalkyl chain to be introduced is activated with a leaving group beforehand and the resultant oxime [Y═C(═N)—OH] of the general formula (II) is subsequently reduced with a metal hydride, forming amines [Y═CH—NH 2 ] of the general formula (II), which are subsequently protected, forming a sugar compound of the general formula (II) [Y═CH—NR 5 R 6 ] in which R 5 /R 6  are different and are each as defined in formula (I). 
       
     
     
         10 . A process for preparing compounds of the general formula (IV) 
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, and R 2  is hydrogen, characterized in that a tricyclic bromide of the general formula (VIII) 
       
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  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 R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, which is reacted with an organometallic reagent to give a compound of the general formula (XI) 
       
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  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 R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  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 R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  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 R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, and subsequent detachment of the remaining protecting groups gives the hemiacetal of the general formula (XV) 
       
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, 
         the latter is cyclized to give the compound of the general formula (XVI) 
       
       
         
           
           
               
               
           
         
         in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, R 12  and R 13  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 R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, R 12  and R 13  are each a hydrogen atom, or are one hydrogen atom and one hydroxyl group in any combination, and, provided that R 12  and R 13  are each a hydrogen atom, is then hydroxylated to give a compound of the general formula (IV) in which R 1  is a hydrogen atom, a hydroxyl or methoxy group, a halogen atom, especially a fluorine, chlorine or bromine atom, or an NO 2  group, and R 2  is hydrogen