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).
Claims7
A compound of Formula II, or a pharmaceutically acceptable salt thereof:
- E-A-Z′-L1-D (Formula II)
- wherein:
- D is represented by the following structural formula:
- R1 is F;
- R2 is methyl;
- -L1-Z′—* is —(C1-C4 alkylene)-O—CH2—NR8—*, —(C1-C4 alkylene)-NR8—*, or —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-O—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;
- E is C(═O)—(C1-C10 alkylene)-X3;
- and
- X3 is
- and
- A is a peptide comprising 2 to 4 amino acids, wherein A is substituted with one or more polyol, wherein polyol is —(C1-C6 alkylene)-X5—Y3, wherein:
- X5 is —NR12C(═O)— or —C(═O)NR12—;
- Y3 is C6 alkyl substituted with 5 OH groups;
- and
- R12 is —H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.
A compound of Formula III, or a pharmaceutically acceptable salt thereof:
- CBA-E′-A-Z′-L1-D (Formula III)
- wherein:
- D is represented by the following structural formula:
- R1 is F;
- R2 is methyl;
- -L1-Z′—* is —(C1-C4 alkylene)-O—CH2—NR8—*, —(C1-C4 alkylene)-NR8—*, or —(C1-C5 alkylene)-NR5C(═O)—(C1-C5 alkylene)-O—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;
- 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;
- and
- A is a peptide comprising 2 to 4 amino acids, wherein A is substituted with one or more polyol;
- and wherein polyol is —(C1-C6 alkylene)-X5—Y3, wherein:
- X5 is —NR12C(═O)— or —C(═O)NR12—;
- Y3 is C6 alkyl substituted with 5 OH groups;
- and
- R12 is —H, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl.
A compound represented by the following formula:
- or a pharmaceutically acceptable salt thereof.
A compound represented by the following formula:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.