Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase I inhibitors

Patent metadata

Field	Value
Publication number	US-9328073-B2
Application number	US-201214119673-A
Country	US
Kind code	B2
Filing date	May 24, 2012
Priority date	May 25, 2011
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

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.

First claim

What is claimed is:

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 acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, 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 acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO 2 H, SO 2 H, SO 3 H, PO 2 H, and PO 3 H, 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, hydroxy, amino, hydroxylamino, and hydrazino, 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 secondary or tertiary branched alkanol or cyclic alkanol or W is a ketone.

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 includes a branched alkyl.

4. The compound of claim 1 wherein W is CH 2 CH(OH)—R, where R is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted.

5. 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.

6. The compound of claim 1 wherein W is a ketoalkanol.

7. The compound of claim 1 wherein W further includes an amino group.

8. 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.

9. The compound of claim 1 wherein W is a hydroxy ketone.

10. The compound of claim 1 wherein W is a hydrogen bond forming group.

11. The compound of claim 1 wherein W is capable of forming one or more hydrogen bonds with residues in the DNA major groove.

12. The compound of claim 1 wherein W is capable of forming a hydrogen bond with Asn352 of a topoisomerase I.

13. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of hydrogen, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and SO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, 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.

14. The compound of claim 1 wherein R A represents four substituents each independently selected from the group consisting of, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.

15. The compound of claim 1 wherein R A represents two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle.

16. The compound of claim 1 wherein R D represents four substituents each independently selected from the group consisting of hydrogen, halo, and nitro, and hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and SO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, 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.

17. The compound of claim 1 wherein R D represents four substituents each independently selected from the group consisting of, halo, and nitro, and-hydroxy, amino, and thio, and acyl, sulfoxyl, and sulfonyl, and CO 2 H, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, carbaryl, carbarylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.

18. 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.

19. The compound of claim 1 wherein at least one of R A is nitro, or alkoxy or, methoxy.

20. The compound of claim 1 wherein at least two of R A are bismethoxy, or alkyleneoxy, or methyleneoxy.

21. The compound of claim 1 wherein at least one of R D is nitro, or alkoxy, or methoxy.

22. The compound of claim 1 wherein at least two of R D are bismethoxy, or alkylenedioxy, or methylenedioxy.

23. The compound of claim 1 wherein X and Y are taken together with the attached carbon to form carbonyl.

24. 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.

25. 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.

26. The compound of claim 1 , wherein said compound has the following formula:

wherein
R 1 is hydrogen or methoxy;
R 2 is hydrogen, methoxy, or nitro; and
W is selected from the group consisting of

27. The compound of claim 26 , wherein said compound is

wherein R 1 is hydrogen and R 2 is nitro.

Assignees

• Cushman Mark S
• Pommier Yves George
• Purdue Research Foundation

Inventors

• Cushman Mark S
• Pommier Yves George

Classifications

• C07D311/94

  condensed with rings other than six-membered or with ring systems containing such rings · CPC title

• C07D221/18 Primary

  Ring systems of four or more rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title