| 摘要 |
The present invention relates to new functionalized morpholinyl anthracycline derivatives which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds, or the pharmaceutical compositions containing them. The invention also relates to the use of these derivatives in the preparation of conjugates. The morpholinyl anthracycline derivatives are of the formula Ant-L-W-Z-RM (I) wherein RM is null or a reactive moiety; Z is null or a peptidic, non peptidic or hybrid - peptidic and non peptidic - linker; W is null or a self-immolative system, comprising one or more self-immolative groups; L is null or a conditionally-cleavable moiety; Ant is an anthracycline moiety selected from the formulas (II), (III), (IV) and (V), wherein the wavy line indicates the attachment to the conditionally-cleavable moiety L, or to the self-immolative system W, or to the linker Z, or to the reactive moiety RM; provided that at least one of L, W, Z and RM is not null; R1 is halogen or NR4R5; R2 is OR6, NR7R8 or an optionally substituted group selected from straight or branched C1C4alkyl-, NR7R8-C1C4alkyl- and R60-C1C4alkyl-; R4 and R5 are independently hydrogen, a monosubstituted-benzyl, a disubstituted-benzyl, or an optionally substituted group selected from straight or branched C1-C6alkyl, NR7R8-C1-C6alkyl-, R60-C1-C6alkyl-, R7R8N-C1-C6alkylcarbonyl-, R60-C1-C6alkylcarbonyl-, R7R8N-C1-C6alkoxycarbonyl- and R60-C1-C6alkoxycarbonyl-; or R4 and R5, taken together with the nitrogen atom to which they are bound, form a heterocyclyl substituted with R4', wherein R4' is hydrogen or a group selected from straight or branched C1-C6alkyl and NR7R8-C1-C6alkyl-; R15 is null or an optionally substituted bivalent group selected from -NR7-C1-C6alkyl*, -O-C1-C6alkyl*, -NR7-C1-C6alkylcarbonyl*, -O-C1-C6alkylcarbonyl*, -NR7-C1-C6alkoxycarbonyl* and -O-C1-C6alkoxycarbonyl*, wherein * indicates the point of attachment to -NH-Ant; R6, R7 and R8 are independently hydrogen or an optionally substituted straight or branched C1-C6alkyl; or a pharmaceutically acceptable salt thereof. |
