Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase I inhibitors
The invention described herein pertains to substituted indenoisoquinoline compounds as described herein, wherein R A , R D , W, X and Y are defined herein, pharmaceutical compositions and formulations comprising the indenoisoquinoline compounds, their synthesis, and methods for their use in the treatment and/or prevention of cancer.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R A represents four substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and derivatives thereof, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, and derivatives thereof, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or R A represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
R D represents three substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and derivatives thereof, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, and derivatives thereof, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or R D represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
X and Y are each independently selected from the group consisting of hydrogen, and hydroxy, amino, hydroxylamino, and hydrazino, and derivatives thereof, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, and arylalkyl, each of which is optionally substituted; or X and Y are taken together with the attached carbon to form carbonyl, imino, oximino, hydrazono, and alkylidenyl, each of which is optionally substituted; and
W is a branched or cyclic alkanol, or W is a ketone, and wherein W includes a secondary or tertiary alcohol.
2. The compound of claim 1 wherein W is a polyhydroxyalkane, or a diol, or a carbohydrate, or a sugar alcohol, or a C 3 -C 6 sugar alcohol, or a C 4 -C 6 sugar alcohol, or a C 5 -C 6 sugar alcohol.
3. The compound of claim 1 wherein W is CH 2 CH(OH)—CH(OH)—R, where R is hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted.
4. The compound of claim 1 wherein W includes the following divalent radical
where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.
5. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of hydrogen, alkyl, halo, nitro, hydroxyl, alkoxy, amino, and thio, or R A represents at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
6. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of hydrogen and halo.
7. The compound of claim 1 wherein R D represents two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.
8. The compound of claim 1 wherein at least two of R D are bismethoxy or methylenedioxy.
9. The compound of claim 1 wherein X and Y are taken together with the attached carbon to form a carbonyl group.
10. The compound of claim 1 , wherein said compound is represented by the formula:
wherein
R 1 and R 2 are each independently hydrogen, halo, nitro, hydroxyl, or methoxy;
R 3 and R 4 are each independently hydrogen or methoxy, or R 3 and R 4 are taken together with the attached carbons to form an optionally substituted heterocycle; and
W is selected from the group consisting of
11. The compound of claim 10 , wherein said compound is represented by the formula
12. The compound of claim 10 , wherein R 1 is hydrogen and R 2 is halo.
13. The compound of claim 10 , wherein R 1 is hydrogen and R 2 is fluoro or chloro.
14. The compound of claim 10 , wherein both R 1 and R 2 are halo.
15. The compound of claim 10 , wherein both R 1 and R 2 are fluoro or chloro.
16. The compound of claim 10 , wherein W is
17. The compound of claim 10 , wherein W is
18. The compound of claim 1 , wherein said compound is
19. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof for treating cancer.
20. A method for treating cancer, the method comprising the step of administering to a patient in need of relief from the cancer a composition comprising a therapeutically effective amount of one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof.