Prodrugs of CC-1065 analogs
AssigneeImmunoGen, Inc.
InventorsRobert Yongxin Zhao, Ravi V.J. Chari
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Abstract
Prodrugs of analogs of the anti-tumor antibiotic CC-1065 having a cleavable protective group such as a piperazino carbamate, a 4-piperidino-piperidino carbamate or a phosphate, in which the protecting group confers enhanced water solubility and stability upon the prodrug, and in which the prodrug also has a moiety, such as a disulfide, that can conjugate to a cell binding reagent such as an antibody. The therapeutic use of such prodrug conjugates is also described; such prodrugs of cytotoxic agents have therapeutic use because they can deliver cytotoxic prodrugs to a specific cell population for enzymatic conversion to cytoxic drugs in a targeted fashion.
Claims28
A prodrug comprising an analog of CC-1065 in which the phenolic group of the alkylating portion of the molecule is protected and wherein said prodrug further comprises a linker capable of conjugating said prodrug to a cell binding agent.
A prodrug comprising an analog of a seco-cyclopropabenzindole-containing cytotoxic drug selected from the group consisting of analogs formed from a first subunit of formula (I) covalently linked to a second subunit of the formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) via an amide bond from the secondary amino group of the pyrrole moiety of the first subunit to the C-2 carboxyl of the second subunit,
- wherein the formula (I) is as follows:
- 3
- wherein the formulae (II)-(IX) are as follows:
- 4 5
- wherein R represents a moiety that enables linkage of said prodrug to a cell binding agent;
- wherein R1-R6 are each independently hydrogen, C1-C3 linear alkyl, methoxy, hydroxyl, primary amino, secondary amino, tertiary amino, or amido;
- and wherein R7 is an enzyme-cleavable protecting group.
Dependencies are inferred from the claim text.