10′-fluorinated
A 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt is disclosed, as are methods of its preparation and use. A disclosed 10′-fluoro-vinca alkaloid compound has better cytotoxic potency against leukemia and cancer cell lines, and is about 8-times more cytotoxic to a multiple drug resistant cancer cell line than is a parental 10′-unsubstituted vinca alkaloid.
1. A 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt that corresponds in structure to a compound shown in Tables A or B below:
TABLE A
R 1
R 2
R 3
10′-Fluoro- vinblastine
—CH 3
10′-Fluoro- vincristine
10′-Fluoro- vindesine
—CH 3
—OH
1-Desmethyl- 10′-fluoro- vinblastine
—H
TABLE B
n
R 1
R 2
R 3
10′-Fluoro- vinorelbine
1
—CH 3
10′-Fluoro- anhydro- vinblastine
2
—CH 3
10′-Fluoro- anhydro- vincristine
2
10′-Fluoro- anhydro- vindesine
2
—CH 3
—OH.
2. The 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt according to claim 1 , wherein said compound corresponds in structure to a compound shown in Table A.
3. The 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt according to claim 1 , wherein said compound corresponds in structure to a compound shown in Table B.
4. The 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt according to claim 1 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovinblastine.
5. The 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt according to claim 1 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluoroanhydrovinblastine.
6. The 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt according to claim 1 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovincristine.
7. A pharmaceutical composition that comprises a microtubule formation-inhibiting or mitosis-inhibiting amount of a 10′-fluoro-vinca alkaloid compound of claim 1 or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable carrier.
8. The pharmaceutical composition according to claim 7 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table A.
9. The pharmaceutical composition according to claim 7 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table B.
10. The pharmaceutical composition according to claim 7 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovinblastine.
11. The pharmaceutical composition according to claim 7 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluoroanhydrovinblastine.
12. The pharmaceutical composition according to claim 7 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovincristine.
13. The pharmaceutical composition according to claim 7 , wherein said composition is adapted for parenteral administration.
14. A method of treating a mammal with a colon cancer or leukemia that comprises administering a pharmaceutical composition according to claim 7 to the mammal.
15. The method of treatment according to claim 14 , wherein said pharmaceutical composition is administered to said mammal a plurality of times.
16. The method of treatment according to claim 14 , wherein said treatment is administered parenterally.
17. The method of treatment according to claim 16 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Tables A or B below:
TABLE A
R 1
R 2
R 3
10′-Fluoro- vinblastine
—CH 3
10′-Fluoro- vincristine
10′-Fluoro- vindesine
—CH 3
—OH
1-Desmethyl- 10′-fluoro- vinblastine
—H
TABLE B
n
R 1
R 2
R 3
10′-Fluoro- vinorelbine
1
—CH 3
10′-Fluoro- anhydro- vinblastine
2
—CH 3
10′-Fluoro- anhydro- vincristine
2
10′-Fluoro- anhydro- vindesine
2
—CH 3
—OH.
18. The method of treatment according to claim 17 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table A.
19. The method of treatment according to claim 17 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table B.
20. The method of treatment according to claim 17 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovinblastine.
21. The method of treatment according to claim 17 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluoroanhydrovinblastine.
22. The method of treatment according to claim 17 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovincristine.
23. In a method of treating a mammal with cancer, lymphoma or leukemia that comprises administering a pharmaceutical composition containing an effective amount of a microtubule formation-inhibiting or mitosis-inhibiting amount of a vinca alkaloid, the improvement that comprises replacing said effective amount of a vinca alkaloid with an effective amount of a 10′-fluoro-vinca alkaloid compound that corresponds in structure to a compound shown in Tables A or B below:
TABLE A
R 1
R 2
R 3
10′-Fluoro- vinblastine
—CH 3
10′-Fluoro- vincristine
10′-Fluoro- vindesine
—CH 3
—OH
1-Desmethyl- 10′-fluoro- vinblastine
—H
TABLE B
n
R 1
R 2
R 3
10′-Fluoro- vinorelbine
1
—CH 3
10′-Fluoro- anhydro- vinblastine
2
—CH 3
10′-Fluoro- anhydro- vincristine
2
10′-Fluoro- anhydro- vindesine
2
—CH 3
—OH.
24. The method of treatment according to claim 23 , wherein said pharmaceutical composition is administered to said mammal a plurality of times.
25. The method of treatment according to claim 23 , wherein said treatment is administered parenterally.
26. The method of treatment according to claim 23 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table A.
27. The method of treatment according to claim 23 , wherein said 10′-fluoro-vinca alkaloid compound corresponds in structure to a compound shown in Table B.
28. The method of treatment according to claim 23 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovinblastine.
29. The method of treatment according to claim 23 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluoroanhydrovinblastine.
30. The method of treatment according to claim 23 , wherein said 10′-fluoro-vinca alkaloid compound is 10′-fluorovincristine.