Etoposide analogs and methods of use thereof
AssigneeThe University of North Carolina at Chapel Hill
InventorsKuo-Hsiung Lee, Zhiyan Xiao, Kenneth F. Bastow
Life of this patent
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Abstract
Etoposide analogs such as 4′-O-demethyl-4β-[4″-(methyl-L-tyrosine-N-carbonyl)-anilino]-4-desoxy-podophyllotoxin (12) and 4′-O-demethyl-4β-[4″-(methyl-L-tryptophan-N-carbonyl)-anilino]-4-desoxypodophyllotoxin (13) are described, along with pharmaceutical formulations containing the same, methods of use thereof, and intermediates and methods of making the same.
Claims25
A compound according to Formula I:
- 42
- wherein:
- X is a linking group selected from the group consisting of —O—, —S—, —NH—, —CO—, —CH═N—, or CH2NH—;
- R1 is a covalent linkage between X and Y, or is loweralkyl, loweralkenyl, or phenyl, and when phenyl is unsubstituted or is substituted from one to four times with loweralkyl, hydroxy, alkoxyl, alkylogen, or alkylamino, alkyoxycarbonyl, amino, halogen, nitro, or nitrile;
- Y is —NHCO— or —CONH—;
- Z is —CHR2—(CH2)nR3, where n is 0 to 2 and R2 is —COOH, —NH2, —COOR31 where R31 is loweralkyl, COOCH2Ph, or —NHCOOCH2Ph;
- R3 is a lower alkyl, loweralkenyl or aryl, which may be unsubstituted or substituted one or more times with loweralkyl, loweralkenyl, or hydroxy, alkoxyl, alkylamino, thioalkyl, hydroxycarbonyl, guanidino, or amido;
- and
- D is selected from the group consisting of —CH2OC(═O)—;
- —CH2OC(═CH2)—;
- —CH2CH2C(═O)—;
- —CH2OC(═S)—;
- —CH2OCH2—;
- —CH2OCH(—OH)—;
- —CH2OCH(OCH3)—;
- —CH2CH2C(—NR12)— where R12 is loweralkyl;
- —C(═O)CH2C(O)—;
- —CH2OS(═O)(═O)OCH2—;
- and —CH2OS(═O)OCH2—;
- or a pharmaceutically acceptable salt thereof.
A method of treating a cancer, comprising administering to a subject in need thereof a treatment effective amount of a compound according to Formula I:
- 44
- wherein:
- X is a linking group selected from the group consisting of —O—, —S—, —NH—, —CO—, —CH═N═, or CH2NH—;
- R1 is a covalent linkage between X and Y, or is loweralkyl, loweralkenyl, or phenyl, and when phenyl is unsubstituted or is substituted from one to four times with loweralkyl, hydroxy, alkoxyl, alkylogen, or alkylamino, alkyoxycarbonyl, amino, halogen, nitro, or nitrile;
- Y is —NHCO— or —CONH—;
- Z is —CHR2—(CH2)nR3, where n is 0 to 2 and R2 is —COOH, —NH2, —COOR31 where R31 is loweralkyl, COOCH2Ph, or —NHCOOCH2Ph;
- R3 is a lower alkyl, loweralkenyl or aryl, , which may be unsubstituted or substituted one or more times with loweralkyl, loweralkenyl, or hydroxy, alkoxyl, alkylamino, thioalkyl, hydroxycarbonyl, guanidino, or amido;
- and
- D is selected from the group consisting of —CH2OC(═O)—;
- —CH2OC(═CH2)—;
- —CH2CH2C(═O)—;
- —CH2OC(═S)—;
- —CH2OCH2—;
- —CH2OCH(—OH)—;
- —CH2OCH3)—;
- —CH2CH2C(—NR12)—where R12 is loweralkyl;
- —C(═O)CH2C(O)—;
- —CH2OS(═O)(═O)OCH2—;
- and —CH2OS(═O)OCH2—;
- or a pharmaceutically acceptable salt thereof.
A compound having the formula:
- 46
- wherein:
- X is a linking group selected from the group consisting of —CH═N—, or —CH2NH—;
- and
- D is selected from the group consisting of —CH2OC(═CH2)—;
- —CH2CH2C(═O)—;
- —CH2OC(═S)—;
- —CH2CH2C(—NR12)— where R12 is loweralkyl;
- —C(═O)CH2C(O)—;
- and —CH2OS(═O)(═O)OCH2—.
Dependencies are inferred from the claim text.