CAMPTOTHECIN DERIVATIVES AS CHEMORADIOSENSITIZING AGENTS

• US 20080318873A1
• Filed: 07/29/2008
• Published: 12/25/2008
• Est. Priority Date: 10/21/2005
• Status: Active Grant

• Current Assignee: Sutter West Bay Hospitals
• Original Assignee: Catholic Healthcare West (CommonSpirit Health (Illinois)), California Pacific Medical Center (Sutter Health)
• Inventors: YANG, Li-Xi
• Granted Patent: US 8,563,537 B2
• Time in Patent Office: Days
• US Class Current: 514/23
• 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 method of sensitizing a subject'"'"'s tumor cells to radiation, which method comprises

a) administering to the subject in need thereof a camptothecin-based compound comprising one or more radiosensitizing electron-affinic groups and

b) exposing the tumor cells in the subject to a unit dose of radiation.

2. The method of claim 1, wherein at least one of the radiosensitizing electron-affinic groups is a nitro-substituted carbocyclic or a nitro-substituted heterocyclic moiety that is attached to the C5, C7, C9, C10, C11, C12 or C20 position of camptothecin.

3. The method of claim 2, wherein the carbocyclic or heterocyclic moiety at the C7, C9, C10, C11, C12 or C20 position of camptothecin is aromatic.

4. The method of claim 2, wherein the carbocyclic or heterocyclic moiety is (+)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid (TAPA).

5. The method of claim 2, wherein the carbocyclic or heterocyclic moiety is (−

)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid (TAPA).

6. The method of claim 2, wherein the carbocyclic or heterocyclic moiety is 2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-ethanoic acid (TNF-ethanoic acid).

7. The method of claim 1, wherein the camptothecin-based compound is selected from the group consisting of:

8. The method according to claim 1, where steps a) and b) are applied according to a treatment schedule effective to produce a synergistic anti-neoplastic effect.

58. The method of any one of claims 1, 9, 55 and 57, wherein the compound is administered parenterally.

59. The method of any one of claims 1, 9, 55 and 57, wherein the compound is administered intravenously.

60. The method of any one of claims 1, 9, 55 and 57, wherein the compound is administered intramuscularly.

61. The method of any one of claims 1, 9, 55 and 57, wherein the compound is administered orally.

62. The method of any one of claims 1, 9, 55 and 57, wherein the compound is administered in the form of a liposomal composition.

9. A method of sensitizing a subject'"'"'s tumor cells to radiation, which method comprises

a) administering to the subject a compound or a pharmaceutically acceptable salt thereof having

10. The method of claim 9, wherein W is R¹Y-L-C(O)—

.

11. The method according to claim 9 or 10, wherein R¹ is

phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino;

a fused, 2-, 3-, or 4-ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;

1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;

or

a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino.

12. The method according to claims 9 or 10, wherein R¹ is selected from the group consisting of O-quinone, semiquinone, fluorene, imidazole, triazole, pyridine, benzamide, nicotinamide, benzotriazine oxide, furan, thiophene, oxazole, or thiazole, where each of the aforementioned groups may be substituted or unsubstituted.

13. The method of claim 9, wherein R¹ is aromatic.

14. The method according to claim 9, wherein R¹ is substituted with at least one carbonyl, amido, trifluoromethyl, halogen, nitro, nitroso, sulfonyl, sulfinyl, phosphoryl, or oxo group.

15. The method according to claims 9 or 10, wherein R¹ is a nitro substituted imidazol-1-yl or 3-nitro-1,2,4-triazol-1-yl group having the following structure

16. The method according to claim 9, wherein each L is independently a bond or -(T)_n-X—

, wherein X is a O, S, —

NH—

, or a bond;

T is independently CRR′

;

n is an integer from 1 to 3, and each of R and R′

is independently selected from hydrogen, lower alkyl, and substituted lower alkyl.

17. The method of claim 16, wherein WO—

is selected from the group consisting of

18. The method according to claim 9 wherein steps a) and b) are applied according to a treatment schedule effective to produce a synergistic anti-neoplastic effect.

19-56. -56. (canceled)

57. A method of treating a neoplasm comprising:

a) administering to the subject a compound or a pharmaceutically acceptable salt thereof having