Camptothecin derivatives
AssigneeImmunoGen, Inc.
InventorsRavi V.J. Chari, Wayne C. Widdison, Wei Li, David P. Pleynet
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Abstract
Disclosed herein are novel cytotoxic compounds, and cytotoxic conjugates comprising these cytotoxic compounds and cell-binding agents. More specifically, this disclosure relates to novel camptothecin derivatives thereof, intermediates thereof, conjugates thereof, and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents (anticancer agents).
Claims22
A compound of Formula I, or a pharmaceutically acceptable salt, thereof:
- wherein:
- D is represented by the following structural formula:
- R1 is —F;
- R2 is -methyl;
- -L1-Z is —(C1-C4 alkylene)-OR6, or —(C1-C4 alkylene)-N(R6)2;
- or (ii) —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-OR6, —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-SR6, —(C1-C5 alkylene)-S—(C1-C5 alkylene)-SR6, or —(C1-C5 alkylene)-S—(C1-C5 alkylene)-SSR6;
- R5 is independently —H, methyl, or benzyl;
- and
- R6 is independently —H, methyl, or benzyl,
- with the proviso that -L1Z cannot be —CH2OH.
A compound of Formula II, or a pharmaceutically acceptable salt thereof:
- wherein:
- D is represented by the following structural formula:
- R1 is F;
- R2 is methyl;
- L1-Z′-* is (i) —(C1-C4 alkylene)-O—CH2—NR8—*, —(C1-C4 alkylene)-S—CH2—NR8—*, or —(C1-C4 alkylene)-NR8—*, or (ii) —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-O—CH2—NR8—*, —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-S—CH2—NR8—*, —(C1-C5 alkylene)-S—(C1-C5 alkylene)-S—CH2—NR8—*, or —(C1-C5 alkylene)-S—(C1-C5 alkylene)-SS—CH2—NR8—*, where * is the site covalently attached to A;
- each R5 is independently-H, methyl, or benzyl;
- each R8 is independently-H, methyl, or benzyl;
- A is a peptide comprising 2 to 10 amino acids;
- wherein A is optionally substituted with one or more polyol;
- and
- E is —C(═O)—(C1-C10 alkylene)-X3;
- and
- X3 is
A compound of Formula III, or a pharmaceutically acceptable salt thereof:
- wherein:
- D is represented by the following structural formula:
- R1 is F;
- R2 is methyl;
- -L1-Z′-* is (i) —(C1-C4 alkylene)-O—CH2—NR8—*, —(C1-C4 alkylene)-S—CH2—NR8—*, or —(C1-C4 alkylene)-NR8—*, or (ii) —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-O—CH2—NR8—*, —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-S—CH2—NR8—*, —(C1-C5 alkylene)-S—(C1-C5 alkylene)-S—CH2—NR8—*, or —(C1-C5 alkylene)-S—(C1-C5 alkylene)-SS—CH2—NR8—*, where * is the site covalently attached to A;
- each R5 is independently-H, methyl, or benzyl;
- each R8 is independently-H, methyl, or benzyl;
- A is a peptide comprising 2 to 10 amino acids;
- wherein A is optionally substituted with one or more polyol;
- E′ is —C(═O)—(C1-C10 alkylene)-X6-*;
- where * is the site covalently linked to CBA;
- X6 is
- and
- CBA is a cell binding agent.
Dependencies are inferred from the claim text.