Camptothecin derivatives as chemoradiosensitizing agents
View Patent ↗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.
1. A method of sensitizing tumor cells to radiation, which method comprises
a) administering to said cells a camptothecin-based compound comprising one or more radiosensitizing electron-affinic groups, wherein the electron-affinic groups are selected from the group consisting of (+)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid (TAPA), (−)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid (TAPA) and 2-(2,4,5,7-tetranito-9-flourenylidenaminooxy)-ethanoic acid (TNF-ethanoic acid).
2. A method for treating a cancer disorder in a subject having a tumor which method comprises administering to the subject a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
wherein
X is S, —NR—, or a covalent bond;
Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S, or a covalent bond;
T is independently CRR′;
each of R and R′ is independently selected from hydrogen, C 1-4 alkyl, and substituted C 1-4 alkyl;
n is an integer from 0 to 8;
R 1 is optionally substituted fluorenyl; wherein the optional substituent(s) are 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; provided that when X is a bond, Y is ═NO—, —N(H)O—, ═N— or S;
R 2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, 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, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower alkoxymethyl;
R 3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N—represent a cyclic amino-), CH 2 R 9 (where R 9 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), NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R 10 and R 11 taken together with —N—represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino or R 3 together with R 4 is furan, dihydrofuran or 1,4-oxazine-2-one;
R 4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-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, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R 4 together with R 3 is furan, dihydrofuran or 1,4-oxazine-2-one, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino;
R 6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino;
L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene (—CH 2 —) units of the linear alkylene group is optionally replaced with O, S or NH; and
R Q is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic.
3. The method of claim 2 , further comprising exposing the tumor in the subject to a unit dose of radiation.
4. The method of claim 2 , wherein X is a covalent bond and Y is ═NO— or —N(H)O—.
5. The method of claim 4 , wherein n is 1 and each of R and R′ is independently methyl or hydrogen.
6. The method of claim 5 , wherein R 1 , is substituted or unsubstituted 9-fluorenyl.
7. The method of claim 6 , wherein the 9-fluorenyl is substituted with at least one nitro group.
8. The method of claim 6 , wherein R 1 is
9. The method of claim 2 wherein the compound is selected from the group consisting of:
10. The method of claim 2 , wherein R 1 Y-(T) n , —X—C(O)O—is
11. The method according to claim 2 , wherein
R 2 is hydrogen;
R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono-or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N—represent a cyclic amino-), NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), or dialkylamino alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen or together with R 4 is methylenedioxy; and
R 6 is hydrogen.
12. The method of claim 11 , wherein R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is lower alkyl), R 4 is hydroxy, alkoxy, lower alkoxycarbonyloxy or alkylcarbonyloxy, and R 5 is hydrogen.
13. The method of claim 12 , wherein R 3 is CH 2 N(CH 3 ) 2 .
14. The method of claim 13 , wherein R 4 is hydroxy.
15. The method of claim 2 , wherein
R 2 is hydrogen, lower alkyl or halogenated lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkoxy, hydroxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen or together with R 4 is methylenedioxy; and
R 6 is hydrogen.
16. The method of claim 15 , wherein R 3 is hydrogen, R 4 is carbamoyloxy, and R 5 is hydrogen.
17. The method of claim 15 , wherein R 2 is lower alkyl and R 4 is 4-(1-piperidino) -1-piperidinocarbonyloxy.
18. The method of claim 17 , wherein R 2 is ethyl.
19. The method of claim 18 , wherein R 2 is hydrogen, and R 4 is 4-(1-piperidino)-1-piperidinocarbonyloxy.
20. The method of claim 15 , wherein R 2 is hydrogen, R 3 is hydrogen and R 4 is tert-butyloxycarbonyloxy.
21. The method of claim 2 , wherein
R 2 is lower alkyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkoxycarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
22. The method of claim 21 , wherein R 2 is ethyl and R 4 is hydroxy.
23. The method of claim 2 , wherein each of R 2 , R 4 , R 5 and R 6 is hydrogen and R 3 is amino or nitro.
24. The method of claim 23 , wherein R 3 is amino.
25. The method of claim 23 , wherein R 3 is nitro.
26. The method of claim 2 , wherein
R 2 is tri-lower alkylsilyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkoxycarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
27. The method of claim 26 , wherein R 2 is t-butyldimethylsilyl and R 4 is hydroxy.
28. The method of claim 2 wherein one of the R 2 , R 4 , or R 5 is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.
29. The method of claim 28 wherein R 2 is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.
30. The method of claim 29 , wherein
R 3 is hydrogen, dimethylamino, amino, or nitro;
R 4 is hydrogen, hydroxy, or 4-(1-piperidino)-1-piperidinocarbonyloxy; or
R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen; or
R 5 together with R 4 is methylenedioxy; and
R 6 is hydrogen.
31. The method of claim 30 , wherein
R 3 is hydrogen; and
R 4 together with R 5 is methylenedioxy, or
wherein each of R 3 , R 4 , and R 5 is hydrogen.
32. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered parenterally.
33. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered intravenously.
34. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered intramuscularly.
35. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered orally.
36. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered in the form of a liposomal composition.
37. The method of any one of claims 1 , 2 , and 28 , wherein the compound is administered in the form of a micelle.
38. A method of sensitizing tumor cells to radiation, which method comprises
a) administering to said cells a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
wherein
X is S, —NR—, or a covalent bond;
Y is ═NO—, —N(H)O—, ═N—, —NR—, O, S, or a covalent bond;
T is independently CRR 1 ;
each of R and R′ is independently selected from hydrogen, C 1-4 alkyl, and substituted C 1-4 alkyl;
n is an integer from 0 to 8;
R 1 is optionally substituted fluorenyl; wherein the optional substituent(s) are 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; provided that when X is a bond, Y is ═NO—, —N(H)O—, ═N— or S;
R 2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, 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, alkylcarbonyloxymethyl, benzoylmethyl, benzylcarbonyloxymethyl, lower alkyliminomethyl or lower alkoxymethyl;
R 3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N—represent a cyclic amino-), CH 2 R 9 (where R 9 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), NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), trialkylsilyl, dialkylamino alkyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino or R 3 together with R 4 is furan, dihydrofuran or 1,4-oxazine-2-one;
R 4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-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, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino, or R 4 together with R 3 is furan, dihydrofuran or 1,4-oxazine-2-one, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, 0 -quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino;
R 6 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, R Q Y-L-C(O)O—, cyano, nitro, amino, trialkylsilyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, O-quinone, substituted lower alkyl aminomethyl, or lower alkylcarbonylamino;
L is a bond or linear alkylene (1-8) group, optionally substituted with lower alkyl or substituted lower alkyl, wherein one or two methylene (—CH 2 —) units of the linear alkylene group is optionally replaced with O, S or NH; and
R Q is optionally substituted carbocyclic, heterocyclic, or fused 2-, 3- or 4-ring heterocyclic; and
b) exposing the tumor cells in the subject to a unit dose of radiation.
39. The method of claim 38 , wherein X is a covalent bond and Y is ═NO— or —N(H)O—.
40. The method of claim 39 , wherein n is 1 and each of R and R′ is independently methyl or hydrogen.
41. The method of claim 40 , wherein R 1 , is substituted or unsubstituted 9-fluorenyl.
42. The method of claim 41 , wherein the 9-fluorenyl is substituted with at least one nitro group.
43. The method of claim 41 , wherein R 1 is
44. The method of claim 38 wherein the compound is selected from the group consisting of:
45. The method of claim 38 , wherein R 1 Y—(T) n —X—C(O)O—is
46. The method according to claim 38 , wherein
R 2 is hydrogen;
R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono-or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N— represent a cyclic amino-), NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, or amino lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), or dialkylamino alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen or together with R 4 is methylenedioxy; and
R 6 is hydrogen.
47. The method of claim 46 , wherein R 3 is CH 2 NR 7 R 8 (where each of R 7 and R 8 is lower alkyl), R 4 is hydroxy, alkoxy, lower alkoxycarbonyloxy or alkylcarbonyloxy, and R 5 is hydrogen.
48. The method of claim 47 , wherein R 3 is CH 2 N(CH 3 ) 2 .
49. The method of claim 48 , wherein R 4 is hydroxy.
50. The method of claim 38 , wherein
R 2 is hydrogen, lower alkyl or halogenated lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is lower alkoxy, hydroxy, halogenated lower alkoxy, hydroxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen or together with R 4 is methylenedioxy; and
R 6 is hydrogen.
51. The method of claim 50 , wherein R 3 is hydrogen, R 4 is carbamoyloxy, and R 5 is hydrogen.
52. The method of claim 50 , wherein R 2 is lower alkyl and R 4 is 4-(1-piperidino)-1-piperidinocarbonyloxy.
53. The method of claim 52 , wherein R 2 is ethyl.
54. The method of claim 53 , wherein R 2 is hydrogen, and R 4 is 4-(1-piperidino)-1-piperidinocarbonyloxy.
55. The method of claim 50 , wherein R 2 is hydrogen, R 3 is hydrogen and R 4 is tert-butyloxycarbonyloxy.
56. The method of claim 38 , wherein
R 2 is lower alkyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkoxycarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
57. The method of claim 56 , wherein R 2 is ethyl and R 4 is hydroxy.
58. The method of claim 38 , wherein each of R 2 , R 4 , R 5 and R 6 is hydrogen and R 3 is amino or nitro.
59. The method of claim 58 , wherein R 3 is amino.
60. The method of claim 58 , wherein R 3 is nitro.
61. The method of claim 38 , wherein
R 2 is tri-lower alkylsilyl;
R 3 is hydrogen;
R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkoxycarbonyloxy;
R 5 is hydrogen; and
R 6 is hydrogen.
62. The method of claim 61 , wherein R 2 is t-butyldimethylsilyl and R 4 is hydroxy.
63. The method of claim 38 wherein one of the R 2 , R 4 , or R 5 is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.
64. The method of claim 63 wherein R 2 is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.
65. The method of claim 64 , wherein
R 3 is hydrogen, dimethylamino, amino, or nitro;
R 4 is hydrogen, hydroxy, or 4-(1-piperidino)-1-piperidinocarbonyloxy; or
R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen; or
R 5 together with R 4 is methylenedioxy; and
R 6 is hydrogen.
66. The method of claim 65 , wherein
R 3 is hydrogen; and
R 4 together with R 5 is methylenedioxy, or
wherein each of R 3 , R 4 , and R 5 is hydrogen.