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US 8,575,188 B2Granted
Camptothecin derivatives
AssigneeThreshold Pharmaceuticals, Inc.
InventorsXiaohong Cai, Jian-Xin Duan, Mark Matteucci, Yeyu Cao, Hailong Jiao
Life of this patent
Estimating the term…
Abstract
Various 14-nitro, 14-amino, and 14-substituted amino camptothecin derivatives are useful in the treatment of cancer and other hyperproliferative diseases. 14-Nitro camptothecin derivatives are conveniently prepared by reacting a camptothecin derivative with fuming nitric acid, optionally employing acetic anhydride as a solvent.
Claims17
A compound of Formula I:
- wherein
- u is 0 or 1;
- R1a, R1b, and R1c independently are H, halogen, hydroxyl, nitrile, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted C1-C6 alkoxy group, or R1a and R1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R1b and R1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle;
- R2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl group;
- or R2 and R1a together with the carbon atoms to which they are attached form a 5-7 membered substituted cycloalkyl ring;
- X is nitro or —NR3R4;
- each R3 and R4 are independently H, substituted or unsubstituted C1-C6 alkyl, —CO2R5, or —COR6;
- R5 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R6 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- or a carboxyl ester or a pharmaceutically acceptable salt thereof, provided however that the compound is not 14-nitro-20-acetoxycamptothecin.
7 more elements
A compound prepared by the process comprising contacting a compound of Formula IX:
- wherein
- u is 0 or 1;
- R1a, R1b, and R1c each independently are H, halogen, hydroxyl, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkoxy group, or R1a and R1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R1b and R1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle;
- and
- R2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl group;
- or R2 and R1a together with the carbon atoms to which they are bonded form a 5-7 membered substituted cycloalkyl ring;
- or
- a carboxyl ester or salt thereof
- with fuming nitric acid, provided however that the compound prepared excludes 14-nitro-20-acetoxycamptothecin.
6 more elements
A method of synthesis comprising contacting a compound of Formula IX:
- wherein
- u is 0 or 1;
- R1a, R1b, and R1c independently are H, halogen, hydroxyl, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkoxy group, or R1a and R1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R1b and R1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle;
- and
- R2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl group;
- or R2 and R1a together with the carbon atoms to which they are bonded form a 5-7 membered substituted cycloalkyl ring;
- or
- a carboxyl ester or a salt thereof
- with fuming nitric acid to provide a compound of Formula IXA:
6 more elements
Dependencies are inferred from the claim text.