Camptothecin derivatives as chemoradiosensitizing agents

• US 20070093432A1
• Filed: 05/30/2006
• Published: 04/26/2007
• Est. Priority Date: 10/21/2005
• Status: Active Grant

• Current Assignee: Catholic Healthcare West (CommonSpirit Health (Illinois)), 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 7,875,602 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.

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 formula (I)

wherein W is alkyl-(O)—

, or R¹Y-L-C(O), provided that when W is alkyl-C(O)—

, at least one of R², R³, R⁴, R⁵, or R⁶ is nitro;

L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene (—

CH₂—

) units of the linear alkylene group is optionally replaced with O, S or NH;

Y is ═

NO—

, —

N(H)O—

, ═

N—

, —

NR—

, O, S, or a bond;

R is H, alkyl, or substituted alkyl;

R¹ is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic;

R² is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, O-quinone, substituted lower alkyl aminomethyl, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, optionally substituted lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower alkoxymethyl;

R³ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkoxycarbonyloxy, sugar, phosphosugar, O-quinone, substituted lower alkyl aminomethyl, 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-), CH₂R⁹ (where R⁹ is lower alkoxy, cyano, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), 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), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino or R³ together with R⁴ is furan, dihydrofuran or 1,4-oxazine-2-one; and

R⁴ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R⁴ together with R³ is furan, dihydrofuran or 1,4-oxazine-2-one, or R⁴ together with R⁵ is methylenedioxy;

R⁵ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R⁵ together with R⁴ is methylenedioxy;

R⁶ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino; and

R^Q is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; and

b) exposing said subject to a unit dose of radiation.

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

20. The compound of claim 19 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.

21. The compound of claim 20 wherein R² is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.

22. The compound of claim 21

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.

23. The compound of claim 22

wherein

R³ is hydrogen;

and

R⁴ together with R⁵ is methylenedioxy.

24. The compound of claim 22 wherein each of R³, R⁴, and R⁵ is hydrogen.

25. The compound of claim 19, wherein R¹ is aromatic.

26. The compound of claim 25, wherein X is a covalent bond.

27. The compound of claim 26, wherein Y is ═

NO—

or —

N(H)O—

.

28. The compound of claim 27, wherein n is 1 and each of R and R′

is independently methyl or hydrogen.

29. The compound of claim 28, wherein R¹ is a substituted or unsubstituted cabocyclic.

30. The compound of claim 29, wherein the substituted or unsubstituted cabocyclic is 9-fluorenyl.

31. The compound of claim 30 wherein the compound is selected from the group consisting of:

32. The compound of claim 30, wherein the 9-fluorenyl is substituted with at least one nitro group.

33. The compound of claim 32, wherein R¹ is

34. The compound of claim 33 wherein the compound is selected from the group consisting of:

35. A compound of claim 19, wherein R¹ or R^Q is

36. A compound of claim 19, wherein R¹Y-(T)_n-X—

C(O)O—

is

37. The compound according to any claim 19, 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.

38. The compound of claim 37, 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.

39. The compound of claim 38, wherein R³ is CH₂N(CH₃)₂.

40. The compound of claim 39, wherein R⁴ is hydroxy.

41. The compound of claim 19, 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.

42. The compound of claim 41, wherein R³ is hydrogen, R⁴ is carbamoyloxy, and R⁵ is hydrogen.

43. The compound of claim 41, wherein R² is lower alkyl and R⁴ is 4-(1-piperidino)-1-piperidinocarbonyloxy.

44. The compound of claim 43, wherein R² is ethyl.

45. The compound of claim 44, wherein R² is hydrogen, and R⁴ is 4-(1-piperidino)-1-piperidinocarbonyloxy.

46. The compound of claim 41, wherein R² is hydrogen, R³ is hydrogen and R⁴ is tert-butyloxycarbonyloxy.

47. The compound of claim 19, 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.

48. The compound of claim 47, wherein R² is ethyl and R⁴ is hydroxy.

49. The compound of claim 19, wherein each of R², R⁴, R⁵ and R⁶ is hydrogen and R³ is amino or nitro.

50. The compound of claim 49, wherein R³ is amino.

51. The compound of claim 49, wherein R³ is nitro.

52. The compound of claim 19, 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.

53. The compound of claim 52, wherein R² is t-butyldimethylsilyl and R⁴ is hydroxy.

54. A composition comprising a compound according to claim 19, together with a pharmaceutically acceptable excipient.

55. A method for treating a cancer disorder in a subject having a tumor which method comprises administering to the subject a composition of claim 54.

56. A method of claim 55, further comprising exposing the tumor in the subject to a unit dose of radiation.

57. A method of treating a neoplasm comprising:

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

wherein W is alkylC(O)—

, or R¹Y-L-(O)—

, provided that when W is alkylC(O)—

, at least one of R², R³, R⁴, R⁵, or R⁶ is nitro;

L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene (—

CH₂—

) units of the linear alkylene group is optionally replaced with O, S or NH;

Y is ═

NO—

, —

N(H)O—

, ═

N—

, —

NR—

, O, S, or a bond;

R is H, alkyl, or substituted alkyl;

R¹ is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic;

R² is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkoxycarbonyloxy, sugar, phosphosugar, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxy methyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, or lower alkoxymethyl;

R³ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkoxycarbonyloxy, sugar, phosphosugar, 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-), CH₂R⁹ (where R⁹ is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, or mono- or di-lower alkylamino lower alkylthio), 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), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and

R⁴ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

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

R⁵ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, or lower alkylcarbonylamino;

R⁶ is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R^QY-L-C(O)O—

, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, or lower alkylcarbonylamino; and

R^Q is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; and

b) exposing said subject to a unit dose of radiation.