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 compound of the formula (II) or a pharmaceutically acceptable salt thereof,
wherein
X is a S,—NH—, 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 carbocyclic, optionally substituted heterocyclic, or optionally substituted fused 2-, 3- or 4-ring heterocyclic; wherein when X is —NH—and R 1 is heterocyclic, the heterocyclic is substituted with at least one nitro;
provided that when X is a covalent bond, Y is ═NO—, —N(H)O—, or═N—;
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, 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, al kylcarbonyloxymethyl, 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, sugar, phosphosugar, 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, hydroxyearbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, lower alkoxycarbonyloxy, sugar, phosphosugar, 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, hydroxyl, R Q Y-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;
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, sugar, phosphosugar, 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 hylene (—CH 2 —) units of the linear alkylene group is optionally replaced with O, S or NH; and
R Q is optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted fused 2-, 3- or 4-ring heterocyclic.
2. The compound of claim 1 , 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.
3. The compound of claim 2 , wherein R 2 is selected from the group consisting of (tris(hydroxymethyl)methylamino)methyl, (bis(hydroxymethyl)methylamino)methyl, and (2-hydroxyethylamino)methyl.
4. The compound of claim 3 , 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.
5. The compound of claim 4 , wherein
R 3 is hydrogen; and
R 4 together with R 5 is methylenedioxy.
6. The compound of claim 4 , wherein each of R 3 , R 4 , and R 5 is hydrogen.
7. The compound of claim 1 , wherein R 1 is aromatic.
8. The compound of claim 7 , wherein X is a covalent bond.
9. The compound of claim 8 , wherein Y is ═NO— or —N(H)O—.
10. The compound of claim 9 , wherein n is 1 and each of R and R′ is independently methyl or hydrogen.
11. The compound of claim 10 , wherein R 1 is a substituted or unsubstituted carbocyclic.
12. The compound of claim 1 , wherein the substituted or unsubstituted carbocyclic is 9-fluorenyl.
13. The compound of claim 12 , wherein the 9-fluorenyl is substituted with at least one nitro group.
14. The compound of claim 13 , wherein R 1 is
15. A compound of claim 1 , wherein R 1 or R Q is
wherein R 20 is halo, alkyl, or substituted alkyl.
16. A compound of claim 1 , wherein R 1 Y-(T) n -X—C(O)O— is
17. The compound of claim 1 , wherein
R 2 is hydrogen;
R 3 is CH 2 NR 7 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, sugar, phosphosugar, 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.
18. The compound of claim 17 , 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.
19. The compound of claim 1 , 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, sugar, phosphosugar, 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.
20. The compound of claim 19 , wherein R 3 is hydrogen, R 4 is carbamoyloxy, and R 5 is hydrogen.
21. The compound of claim 19 , wherein R 2 is lower alkyl and R 4 is 4-(1-peridino)-1-piperidinocarbonyloxy.
22. The compound of claim 19 . wherein R 2 is hydrogen, and R 4 is 4-(1-piperidino)-1-piperidinocarbonyloxy.
23. The compound of claim 19 , wherein R 2 is hydrogen, R 3 is hydrogen and R 4 is tert-butyloxycarbonyloxy.
24. The compound of claim 1 , 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, lower alkoxycarbonyloxy, sugar, or phosphosugar;
R 5 is hydrogen; and
R 6 is hydrogen.
25. The compound of claim 24 , wherein R 2 is ethyl and R 4 is hydroxy.
26. The compound of claim 1 , wherein each of R 2 , R 4 , R 5 and R 6 is hydrogen and R 3 is amino or nitro.
27. The compound of claim 1 , 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, lower alkoxycarbonyloxy, sugar, or phosphosugar;
R 5 is hydrogen; and
R 6 is hydrogen.
28. The compound of claim 27 , wherein R 2 is t-butyldimethylsilyl and R 4 is hydroxy.
29. A composition comprising a compound according to claim 1 , together with a pharmaceutically acceptable excipient.
30. The compound of claim 1 , provided that when X is a covalent bond, R 1 is not fluorenyl or fluorenyl substituted with at least one nitro group.