C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes
View Patent ↗Taxanes having an ethyl ester or cyclopropyl ester substituent at C(10), a keto substituent at C(9), a hydroxy substituent at C(7), a thienyl substituent at C(3′) and a cyclobutyloxycarbamate or cyclopentyloxycarbamate substituent at C(3′), pharmaceutical compositions comprising such taxanes, methods of treatment and administration, and methods of preparation of medicaments comprising the taxanes.
1. A taxane having the structure (1):
wherein R 10a is ethyl or cyclopropyl; X 3 is thienyl; and X 10 is cyclobutyl or cyclopentyl.
2. The taxane of claim 1 , the taxane having a structure selected from (1AA), (1BB), (1CC), and (1DD):
3. A pharmaceutical composition comprising a taxane having the structure (1):
and at least one pharmaceutically acceptable carrier, wherein R 10a is ethyl or cyclopropyl; X 3 is thienyl; and X 10 is cyclobutyl or cyclopentyl.
4. The pharmaceutical composition of claim 3 wherein the taxane has the structure (1bb):
5. The pharmaceutical composition of claim 3 wherein the taxane has a structure selected from (1A), (1B), (1C), and (1D):
6. The pharmaceutical composition of claim 3 wherein the taxane has a structure selected from (1AA), (1BB), (1CC), and (1DD):
7. A method of inhibiting tumor growth in a mammal, said method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 1 .
8. The method of claim 7 wherein the taxane has a structure selected from (1AA), (1BB), (1CC), and (1DD):
9. The method of claim 7 wherein the tumor includes tumor cells exhibiting multidrug resistance.
10. The method of claim 9 wherein the multidrug resistant tumor cells overexpress a drug-efflux transporter.
11. The method of claim 10 wherein the drug-efflux transporter is an ATP-binding cassette transporter.
12. The method of claim 11 wherein the ATP-cassette transporter is P-glycoprotein, an MDR-associated protein, a breast cancer resistance protein, a multidrug resistance-associated protein, or a combination thereof.
13. The method of claim 7 wherein the tumor is resistant to paclitaxel.
14. The method of claim 7 wherein the tumor is resistant to docetaxel.
15. The method of claim 7 wherein the tumor is an epithelial cell carcinoma.
16. The method of claim 7 wherein the tumor is a brain glioblastoma, a breast carcinoma, a colon carcinoma, a kidney carcinoma, a liver carcinoma, a lung carcinoma, an ovarian carcinoma, a pancreatic carcinoma, a renal carcinoma, or a skin melanoma.
17. The method of claim 7 wherein the tumor is a colon carcinoma, a lung carcinoma, a pancreatic carcinoma, a renal carcinoma, or a skin melanoma.
18. The method of claim 7 wherein the tumor is a colon carcinoma, a lung carcinoma, a renal carcinoma, or a skin melanoma.
19. The method of claim 7 wherein the tumor is SNB-19 brain glioblastoma, HCT116 colon carcinoma, HT-29 colon carcinoma, DLD-1 colon carcinoma, A549 lung carcinoma, HOP-18 lung carcinoma, MSTO-211H mesothelioma, A375 melanoma, MALME-3 melanoma, SK-MEL-28 melanoma, OVCAR4 ovarian carcinoma, OVCAR5 ovarian carcinoma, PANC-1 pancreatic adenocarcinoma, BxPC-3pancreatic carcinoma, 786-0 renal carcinoma, or TK-10 renal carcinoma.
20. The method of claim 7 wherein the tumor is DLD-1 colon carcinoma, MSTO-211H mesothelioma, A375 melanoma, or 786-0renal carcinoma.