Claims
- 1. A method of treating a cancer selected from the group consisting of leukemia, colon cancer, lung cancer, prostate cancer and breast cancer in warm-blooded animals comprising administering to warm-blooded animals in need thereof a unsubstituted or pharmaceutically acceptable substituted camptothecin with a 7-ring member β-hydroxy lactone ring of the formula wherein R1 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms haloalkyl of 1 to 6 carbon atoms, alkoxy alkyl of 2 to 12 carbon atoms and alkylthioalkyl of 2 to 12 carbon atoms, Rp is hydrogen or an easily cleavable group, R18 and R19 are individually selected from the group consisting of hydrogen, halogen, OH and alkyl and alkoxy of 1 to 6 carbon atoms and its non-toxic, pharmaceutically acceptable salts.
- 2. The method of claim 1 wherein R1 ethyl.
- 3. The method of claim 1 wherein R18 and R19 are hydrogen.
- 4. The method of claim 2 wherein R18 and R19 are hydrogen.
- 5. The method of claim 1 wherein Rp is hydrogen.
- 6. The method of claim 2 wherein Rp is hydrogen.
- 7. The method of claim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione; 5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione; 10-(benzyloxy)-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 11-[(dimethylamino)methyl]-5ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5,10-dihydroxy-11-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(4morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 8-ethyl-8-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione; 9-chloro-5-ethyl-10-fluoro-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6dihydro-1(2H)-pyridinylmethyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(dimethylamino)methyl]-5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-([benzyl(methyl)amino]methyl)-9chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9chloro-5-ethyl-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(4-benzyl-1-piperazinyl)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(dimethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(diisobutylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-12-[(dimethylamino)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6-dihydro-1(2H)-pyridinylmethyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-12-(1-pyrrolidinylmethyl)-1,4,5,1 3-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(4-benzyl-1-piperazinyl)methyl]-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 10-(benzyloxy)-5-ethyl-9-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[2-b]quinolin-5-yl 2-aminoacetate; 5-ethyl-9,10-difluoro-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinolin-5-yl 3-aminopropanoate; 2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino1,2-b]quinoline-11,14-dione; 2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; (+)-5ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; (+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine; or a pharmaceutically acceptable salt of the latter.
- 8. The method of claim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione; 5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-10H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione; 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3 15-dione; 5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 9,11-dichloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(dimethylamino)methyl]5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(4-benzyl-1-piperazinyl)methyl]9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(diethylamino)methyl]-5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(diisobutylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-12-[(dimethylamino)methyl]5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10methyl-12[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-1,14-dione; 2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; (+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methylhexahydropyridine; or a pharmaceutically acceptable salt of the latter.
- 9. The method of claim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]-quinoline-3,15-dione; 5,12-diethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 8-ethyl-8-hydroxy-2,3,8,9,12,15-hexahydro-1H,13H-[1,4]dioxino[2,3-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13-dione; 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 7-ethyl-7-hydroxy-7,8,11,14-tetrahydro-9H,12H-[1,3]dioxolo[4,5-g]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-9,12-dione; 9-chloro-5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 10-chloro-5-ethyl-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5,12-diethyl-9-fluoro-5-hydroxy-10-methoxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-5-hydroxy-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9,10-difluoro-5-hydroxy-12-(1-pyrrolidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9-chloro-5-ethyl-5-hydroxy-10-methyl-12-(4-morpholinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 9chloro-5-ethyl-5-hydroxy-10methyl-12-[(4-methyl-1-piperazinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[(diethylamino)methyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methyl-12-[(4-methyl-1-piperidinyl)methyl]1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 12-[3,6-dihydro-1(2H)-pyridinylmethyl]5-ethyl-9-fluoro-5-hydroxy-10-methyl-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5-hydroxy-10-methoxy-12-(1-piperidinylmethyl)-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 2,9-diethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 9-ethyl-9-hydroxy-2-methyl-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 2-benzyl-9-ethyl-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]oxazino[5,6-f]-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; 2-benzyl-9-ethyl-5-fluoro-9-hydroxy-1,2,3,9,10,16-hexahydro-13H-[1,3]-oxazino[5,6-f]oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-11,14-dione; (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; (+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine; or a pharmaceutically acceptable salt of the latter.
- 10. The method of claim 1 wherein the compound is selected from the group consisting of5-ethyl-5-hydroxy-1,4,5,13-tetrahydro3H,15H-oxepino[3′,4′:6,7]indolizino[1,2b]-quinoline-3,15-dione; 5-ethyl-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-10-fluoro-5-hydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; 5-ethyl-9-fluoro-5,10-dihydroxy-1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]-indolizino[1,2-b]quinoline-3,15-dione; (+)-5-ethyl-9,10 difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione; (+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]4-methyl-hexahydropyridine; or a pharmaceutically acceptable salt of the latter.
- 11. The method of claim 1 wherein the camptothecin is (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinoline-3,15-dione or (+)-1-[9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H,3H-oxepino[3′,4′:6,7]indolizino[1,2-b]quinolin-12-ylmethyl]-4-methyl-hexahydropyridium chloride.
Priority Claims (5)
Number |
Date |
Country |
Kind |
9512670 |
Jun 1995 |
GB |
|
96 15774 |
Dec 1996 |
FR |
|
96 15775 |
Dec 1996 |
FR |
|
96 15945 |
Dec 1996 |
FR |
|
97 10785 |
Aug 1997 |
FR |
|
Parent Case Info
This application is a divisional of Ser. No. 09/332,520, filed Jun. 14, 1999, now U.S. Pat. No. 6,339,091, which is a continuation-in-part of Ser. No. 08/973,561, filed Dec. 2, 1997, now U.S. Pat. No. 5,981,542, which is a continuation-in-part of PCT/FR96/00980, filed Jun. 21, 1996, and said Ser. No. 09/332,520 is a continuation-in-part of PCT/FR97/02217, filed Dec. 5, 1997 and a continuation-in-part of PCT/FR97/02218, filed Dec. 5, 1997 and a continuation-in-part of PCT/FR98/01768, filed Aug. 7, 1998.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5162532 |
Comins et al. |
Nov 1992 |
A |
Continuation in Parts (5)
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Number |
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08/973561 |
Dec 1997 |
US |
Child |
09/332520 |
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US |
Parent |
PCT/FR96/00980 |
Jun 1996 |
US |
Child |
08/973561 |
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US |
Parent |
PCT/FR98/01768 |
Aug 1998 |
US |
Child |
09/332520 |
Jun 1999 |
US |
Parent |
PCT/FR97/02218 |
Dec 1997 |
US |
Child |
PCT/FR98/01768 |
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US |
Parent |
PCT/FR97/02217 |
Dec 1997 |
US |
Child |
PCT/FR97/02218 |
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US |