Claims for Patent: 7,470,720

Summary for Patent: 7,470,720

Title:	Methods and compositions for use in treating cancer
Abstract:	The invention provides methods and compositions for use in treating diseases associated with excessive cellular proliferation, such as cancer.
Inventor(s):	Littlefield; Bruce A. (Andover, MA), Towle; Murray J. (Auburn, NH)
Assignee:	Eisai R&D Management Co., Ltd. (Tokyo, JP)
Application Number:	10/687,526
Patent Claims:	1. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the formula: ##STR00005## wherein A is a C.sub.1-6 saturated or C.sub.2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having between 1 and 10 substituents, inclusive, independently selected from cyano, halo, azido, oxo, and Q.sub.1; each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2R.sub.1, OSO.sub.2R.sub.1, NR.sub.2R.sub.1, NR.sub.2(CO)R.sub.1, NR.sub.2(CO)(CO)R.sub.1, NR.sub.4(CO)NR.sub.2R.sub.1, NR.sub.2(CO)OR.sub.1, (CO)OR.sub.1, O(CO)R.sub.1, (CO)NR.sub.2R.sub.1, and O(CO)NR.sub.2R.sub.1; each of R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 is independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl, C.sub.6-10 aryl, C.sub.6-10 haloaryl, C.sub.6-10 hydroxyaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 aryl, C.sub.6-10 haloaryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl, C.sub.2-9 heterocyclic radical, C.sub.2-9 heterocyclic radical-C.sub.1-6 alkyl, C.sub.2-9 heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl; each of D and D' is independently selected from R.sub.3 and OR.sub.3, wherein R.sub.3 is H, C.sub.1-3 alkyl, or C.sub.1-3 haloalkyl; n is 0 or 1; E is R.sub.5 or OR.sub.5; G is O, S, CH.sub.2, or NR.sub.6; each of J and J' is independently H, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; or J and J' taken together are .dbd.CH.sub.2 or --O-(straight or branched C.sub.1-5 alkylene)-O--; Q is C.sub.1-3 alkyl; T is ethylene or ethenylene, optionally substituted with (CO)OR.sub.7, where R.sub.7 is H or C.sub.1-6 alkyl; each of U and U' is independently H, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; or U and U' taken together are .dbd.CH.sub.2 or --O-(straight or branched C.sub.1-5 alkylene)-O--; X is H or C.sub.1-6 alkoxy; each of Y and Y' is independently H or C.sub.1-6 alkoxy; or Y and Y' taken together are .dbd.O, .dbd.CH.sub.2, or --O-(straight or branched C.sub.1-5 alkylene)-O--; and each of Z and Z' is independently H or C.sub.1-6 alkoxy; or Z and Z' taken together are .dbd.O, .dbd.CH.sub.2 or --O-(straight or branched C.sub.1-5 alkylene)-O--; or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1, wherein n is 0. 3. The pharmaceutical composition of claim 1, wherein each of D and D' is independently selected from R.sub.3, C.sub.1-3 alkoxy, and C.sub.1-3 haloalkyloxy. 4. The pharmaceutical composition of claim 1, wherein R.sub.5 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl, C.sub.6-10 aryl, C.sub.6-10 haloaryl, C.sub.6-10 hydroxyaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6-10 aryl-C.sub.1-6 alkyl, C.sub.1-6 alkyl-C.sub.6-10 is aryl, C.sub.6-10 haloaryl-C.sub.1-6 alkyl, C.sub.1-6, alkyl-C.sub.6-10 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 alkyl)-C.sub.1-3 alkyl, C.sub.2-9 heterocyclic radical, C.sub.2-9 heterocyclic radical-C.sub.1-6 alkyl, C.sub.2-9 heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl. 5. The pharmaceutical composition of claim 1, wherein A comprises a C.sub.1-6 saturated or C.sub.2-6 unsaturated hydrocarbon skeleton, said skeleton having at least one substituent selected from cyano, halo, azido, oxo, and Q.sub.1; each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, S0.sub.2R.sub.1, OSO.sub.2R.sub.1, NR.sub.2R.sub.1, NR.sub.2(CO)R.sub.1, and O(CO)NR.sub.2R.sub.1; n is 0; G is O; J and J' taken together are .dbd.CH.sub.2; Q is methyl; T is ethylene; U and U' taken together are .dbd.CH.sub.2; X is H; each of Y and Y' is H; and Z and Z' taken together are .dbd.O or .dbd.CH.sub.2. 6. The pharmaceutical composition of claim 1, wherein each Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2R.sub.1, OSO.sub.2R.sub.1, NH(CO)R.sub.1,NH(CO)(CO)R.sub.1 , and O(CO)NHR.sub.1; each R.sub.1 is independently selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6 aryl, C.sub.6 haloaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6 aryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 aryl, C.sub.6 haloaryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 haloaryl, (C.sub.1-3 alkoxy-C.sub.6 aryl)-C.sub.1-3 alkyl, C.sub.29 heterocyclic radical, C.sub.2-9heteroaryl, and C.sub.2-9 heteroaryl-C.sub.1-6 alkyl; one of D and D' is methyl or methoxy, and the other is H; n is 0; G is O; J and J' taken together are .dbd.CH.sub.2; Q is methyl; T is ethylene; U and U' taken together are .dbd.CH.sub.2; X is H; each of Y andY' is H; and Z and Z' taken together are .dbd.O. 7. The pharmaceutical composition of claim 5, wherein A has at least one substituent selected from hydroxyl, amino, azido, halo, and oxo. 8. The pharmaceutical composition of claim 7, wherein A comprises a saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl, amino and azido. 9. The pharmaceutical composition of claim 8, wherein A has at least two substituents independently selected from hydroxyl, amino, and azido. 10. The pharmaceutical composition of claim 8, wherein A has at least two substituents independently selected from hydroxyl and amino. 11. The pharmaceutical composition of claim 8, wherein A has at least one hydroxyl substituent and at least one amino substituent. 12. The pharmaceutical composition of claim 8, wherein A has at least two hydroxyl substituents. 13. The pharmaceutical composition of claim 8, wherein A comprises a C.sub.2-4 hydrocarbon skeleton. 14. The pharmaceutical composition of claim 8, wherein A comprises a C.sub.3 hydrocarbon skeleton. 15. The pharnmceutical composition of claim 13, wherein A has an (S)-hydroxyl on the carbon atom alpha to the carbon atom linking A to the ring containing G. 16. The pharmaceutical composition of claim 5, wherein A comprises a C.sub.1-6 saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl and cyano. 17. The pharmaceutical composition of claim 6, wherein Q.sub.1 is independently selected from OR.sub.1, SR.sub.1, SO.sub.2R.sub.1, and OSO.sub.2R.sub.1 where each R.sub.1 is independently selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6 aryl, C.sub.6 haloaryl, C.sub.1-3 alkoxy-C.sub.6 aryl, C.sub.6aryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 aryl, C.sub.6 haloaryl-C.sub.1-3 alkyl, C.sub.1-3 alkyl-C.sub.6 haloaryl, and (C.sub.1-3 alkoxy-C.sub.6 aryl)-C .sub.1-3 alkyl. 18. The pharmaceutical composition of claim 1, comprising a compound of the following structure ##STR00006## or a pharmaceutically acceptable salt thereof. 19. The pharmaceutical composition of claim 1, comprising a compound of the following structure ##STR00007## or a pharmaceutically acceptable salt thereof. 20. The pharmaceutical composition of claim 1, further comprising a pharmaceutically-acceptable carrier. 21. The pharmaceutical composition of claim 1, further comprising one or more other pharmaceutically-active agents. 22. The pharmaceutical composition of claim 21, wherein the one or more other pharmaceutically-active agents is selected from the group consisting of anti-tumor agents, immune-stimulating agents, interferons, cytokines, anti-MDR agents, and anti-angiogenesis agents. 23. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for administration by oral, topical, parenteral, intramuscular, or intravenous routes, or administration by injection or inhalation. 24. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a controlled-release formulation.