Camptothecin derivatives as chemoradiosensitizing agents

• US 7,875,602 B2
• Filed: 05/30/2006
• Issued: 01/25/2011
• Est. Priority Date: 10/21/2005
• Status: Active Grant

• Current Assignee: Sutter West Bay Hospitals
• Original Assignee: Catholic Healthcare West (CommonSpirit Health (Illinois)), Sutter West Bay Hospitals
• Inventors: Yang, Li-Xi
• Primary Examiner(s): Fetterolf; Brandon J
• Assistant Examiner(s): Stone; Christopher R
• Application Number:
  US11/444,150
• Publication Number:
  US 20070093432A1
• Time in Patent Office: 1,701 Days
• Field of Search: 514/183, 546/48
• US Class Current: 514/183
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings

Abstract

Camptothecin-based compounds are useful for treating a neoplasm in mammalian subjects by administering such compound to the subjects in combination with radiotherapy, i.e., the treatment of tumors with radioactive substances or radiation from a source external to the subject. Camptothecin-based compounds are modified by positioning at least one electron-affinic group around the camptothecin structure to enhance their value in combination with radiotherapy. New Camptothecin-based compounds are disclosed that are useful for treating cancer by administering the novel compounds alone or in combination with radiotherapy.

Claims

1. A compound of the formula (II) or a pharmaceutically acceptable salt thereof,

2. The compound of claim 1, wherein Y is ═

NO—

or —

N(H)O—

.

3. The compound of claim 2, wherein n is 1 and each of R and R′

is independently methyl or hydrogen.

4. The compound of claim 3, wherein R¹ is 9-fluorenyl optionally substituted with at least one nitro group.

5. The compound of claim 4 wherein the compound is selected from the group consisting of:

6. The compound of claim 4, wherein the 9-fluorenyl is substituted with at least one nitro group.

7. The compound of claim 6, wherein R¹ is

8. The compound of claim 7 wherein the compound is selected from the group consisting of:

9. A compound of claim 1, wherein R¹Y-(T)_n-X—

C(O)O—

is

10. The compound according to claim 1, wherein

R² is hydrogen;

R³ is CH₂NR⁷R⁸ (where each of R⁷ and R⁸ is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R⁷ and R⁸ taken together with —

N—

represent a cyclic amino-), NR¹⁰R¹¹ (where each of R¹⁰ and R¹¹ is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R¹⁰ and R¹¹ taken together with —

N—

represent a cyclic amino), or dialkylamino alkyl;

R⁴ is lower alkoxy, hydroxy, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, or R⁴ together with R⁵ is methylenedioxy;

R⁵ is hydrogen or together with R⁴ is methylenedioxy; and

R⁶ is hydrogen.

11. The compound of claim 10, wherein R³ is CH₂NR⁷R⁸ (where each of R⁷ and R⁸ is lower alkyl), R⁴ is hydroxy, alkoxy, lower alkoxycarbonyloxy or alkylcarbonyloxy, and R⁵ is hydrogen.

12. The compound of claim 11, wherein R³ is CH₂N(CH₃)₂.

13. The compound of claim 12, wherein R⁴ is hydroxy.

14. The compound of claim 1, wherein

R² is hydrogen, lower alkyl or halogenated lower alkyl;

R³ is hydrogen or lower alkyl;

R⁴ is lower alkoxy, hydroxy, halogenated lower alkoxy, hydroxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, or R⁴ together with R⁵ is methylenedioxy;

R⁵ is hydrogen or together with R⁴ is methylenedioxy; and

R⁶ is hydrogen.

15. The compound of claim 14, wherein R³ is hydrogen, R⁴ is carbamoyloxy, and R⁵ is hydrogen.

16. The compound of claim 14, wherein R² is lower alkyl and R⁴ is 4-(1-piperidino)-1-piperidinocarbonyloxy.

17. The compound of claim 16, wherein R² is ethyl.

18. The compound of claim 14, wherein R² is hydrogen, and R⁴ is 4-(1-piperidino)-1-piperidinocarbonyloxy.

19. The compound of claim 14, wherein R² is hydrogen, R³ is hydrogen and R⁴ is tert-butyloxycarbonyloxy.

20. The compound of claim 1, wherein

R² is lower alkyl;

R³ is hydrogen;

R⁴ is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, or phosphosugar;

R⁵ is hydrogen; and

R⁶ is hydrogen.

21. The compound of claim 20, wherein R² is ethyl and R⁴ is hydroxy.

22. The compound of claim 1, wherein each of R², R⁴, R⁵ and R⁶ is hydrogen and R³ is amino or nitro.

23. The compound of claim 22, wherein R³ is amino.

24. The compound of claim 22, wherein R³ is nitro.

25. The compound of claim 1, wherein

R² is tri-lower alkylsilyl;

R³ is hydrogen;

R⁴ is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, or phosphosugar;

R⁵ is hydrogen; and

R⁶ is hydrogen.

26. The compound of claim 25, wherein R² is t-butyldimethylsilyl and R⁴ is hydroxy.

27. A composition comprising a compound according to claim 1, together with a pharmaceutically acceptable excipient.

28. The compound of claim 1, wherein one of the R², R⁴, or R⁵ is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.

29. The compound of claim 28, wherein R² is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.

30. The compound of claim 29,

wherein

R³ is hydrogen, dimethylamino, amino, or nitro;

R⁴ is hydrogen, hydroxy, or 4-(1-piperidino)-1-piperidinocarbonyloxy;

or

R⁴ together with R⁵ is methylenedioxy;

R⁵ is hydrogen;

or

R⁵ together with R⁴ is methylenedioxy; and

R⁶ is hydrogen.

31. The compound of claim 30,

wherein

R³ is hydrogen;

and

R⁴ together with R⁵ is methylenedioxy.

32. The compound of claim 30, wherein each of R³, R⁴, and R⁵ is hydrogen.