Camptothecin derivatives
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).
1. A compound of Formula II, or a pharmaceutically acceptable salt thereof:
E-A-Z′-L 1 -D (Formula II)
wherein:
D is represented by the following structural formula:
R 1 is F;
R 2 is methyl;
-L 1 -Z′—* is —(C 1 -C 4 alkylene)-O—CH 2 —NR 8 —*, —(C 1 -C 4 alkylene)-NR 8 —*, or —(C 1 -C 5 alkylene)-NR 5 C(═O)—(C 1 -C 5 alkylene)-O—CH 2 —NR 8 —*, where * is the site covalently attached to A;
each R 5 is independently —H, methyl, or benzyl;
each R 8 is independently —H, methyl, or benzyl;
E is C(═O)—(C 1 -C 10 alkylene)-X 3 ; and
X 3 is
and
A is a peptide comprising 2 to 4 amino acids, wherein A is substituted with one or more polyol, wherein polyol is —(C 1 -C 6 alkylene)-X 5 —Y 3 , wherein:
X 5 is —NR 12 C(═O)— or —C(═O)NR 12 —;
Y 3 is C 6 alkyl substituted with 5 OH groups; and
R 12 is —H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or benzyl.
2. The compound of claim 1 , wherein polyol is
wherein R 12 is H or methyl.
3. The compound of claim 1 , wherein the compound is represented by the following formula:
or a pharmaceutically acceptable salt thereof.
4. A compound of Formula III, or a pharmaceutically acceptable salt thereof:
CBA-E′-A-Z′-L 1 -D (Formula III)
wherein:
D is represented by the following structural formula:
R 1 is F;
R 2 is methyl;
-L 1 -Z′—* is —(C 1 -C 4 alkylene)-O—CH 2 —NR 8 —*, —(C 1 -C 4 alkylene)-NR 8 —*, or —(C 1 -C 5 alkylene)-NR 5 C(═O)—(C 1 -C 5 alkylene)-O—CH 2 —NR 8 —*, where * is the site covalently attached to A;
each R 5 is independently —H, methyl, or benzyl;
each R 8 is independently —H, methyl, or benzyl;
E′ is C(═O)—(C 1 -C 10 alkylene)-X 6 —*; where * is the site covalently linked to CBA;
X 6 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 —(C 1 -C 6 alkylene)-X 5 —Y 3 , wherein:
X 5 is —NR 12 C(═O)— or —C(═O)NR 12 —;
Y 3 is C 6 alkyl substituted with 5 OH groups; and
R 12 is —H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or benzyl.
5. The compound of claim 4 , wherein polyol is
wherein R 12 is H or methyl.
6. A compound represented by the following formula:
or a pharmaceutically acceptable salt thereof.
7. A compound represented by the following formula:
or a pharmaceutically acceptable salt thereof.