Claims for Patent: 8,580,792

Summary for Patent: 8,580,792

Title:	Inhibitor compounds and cancer treatment methods
Abstract:	A synergistically effective combination of an anti-cancer agent and a therapeutic compound, such as an mTOR-Rictor complex inhibitor, a Serine 473 phosphorylation inhibitor, an AKT2 inhibitor, or a combination thereof, for use in the treatment of cancer, and methods and uses thereof. Also included are methods and uses of a thiosemicarbazone for treating a cancer in a mammal in need thereof characterized by over-expression of RAS, by an EGFR mutation, and/or by over-expression of AKT2.
Inventor(s):	Danter; Wayne R. (London, CA)
Assignee:	Critical Outcome Technologies Inc. (London, Ontario, CA)
Application Number:	13/363,558
Patent Claims:	1. A therapeutically effective composition for use in the treatment of cancer comprising an anti-cancer agent and a therapeutically effective amount of a compound comprising a compound of Formula I or IA: ##STR00086## a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, optical isomer, and/or combination thereof; wherein: R.sub.1 and R.sub.2 together form a substituted or unsubstituted polycyclic ring comprising at least two ring systems, said at least two ring systems comprising a first ring system bonded to C1 and a second ring system fused to the first ring system, wherein: the first ring system is a substituted or unsubstituted aromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or the first ring system is a substituted or unsubstituted heteroaromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or the first ring system is a substituted or unsubstituted saturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted unsaturated carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B: ##STR00087## wherein X.sub.1 to X.sub.6 are each independently selected from carbon or a heteroatom; or the first ring system is a substituted or unsubstituted unsaturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B: ##STR00088## wherein X.sub.1 to X.sub.6 are each independently selected from carbon or a heteroatom; or the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and R.sub.3 to R.sub.11 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; R.sub.12 is selected from H or a hydrocarbyl group; Y is selected from a heteroatom; Ring is selected from a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, wherein the nitrogen in the Ring is bonded to A; A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; and n is 0 or 1; wherein the composition produces a synergistic therapeutic effect as compared to sole administration of either the anti-cancer agent or the compound, wherein the cancer is selected from the group consisting of a cancer having over-expression of RAS, a cancer having an EGFR mutation, and a cancer having overexpression of AKT2. 2. The composition according to claim 1, wherein the compound is an mTOR-Rictor complex inhibitor. 3. The composition according to claim 1, wherein the anti-cancer agent is an mTOR-Raptor complex inhibitor. 4. The composition according to claim 1, wherein the anticancer agent is a cytotoxic agent. 5. The composition according to claim 4, wherein the synergistic effect is reduction or prevention of resistance to the cytotoxic agent. 6. The composition according to claim 1, wherein the anti-cancer agent is selected from the group consisting of cisplatin, rapamycin, tecrolimus, temsirolimus, paclitaxel, erlotinib, cetuximab, doxorubicin, and combinations thereof. 7. The composition according to claim 1, wherein the cancer is treatable by inhibition of mTOR. 8. The composition according to claim 1, wherein the amount of the anti-cancer agent is selected to lower overall toxicity as compared to administration of the anti-cancer agent alone in an amount sufficient to achieve substantially the same treatment effect on cancerous cells. 9. The composition according to claim 1, wherein the dose of at least one of the anti-cancer agent or the compound is selected to increase the overall treatment effect on cancerous cells as compared to administration of the anti-cancer agent alone in an amount producing substantially the same toxicity. 10. The composition according to claim 1, wherein the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group. 11. The composition according to claim 1, wherein n is 0. 12. The composition according to claim 1, wherein n is 1 and A is a substituted or unsubstituted heteroaromatic group. 13. The composition according to claim 12, wherein A is a pyridinyl group. 14. The composition according to claim 1, wherein Y is a nitrogen atom. 15. The composition according to claim 14, wherein R.sub.7 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted heteroaromatic group and R.sub.3 to R.sub.6 and R.sub.8 to R.sub.12 are each independently selected from H or a substituted or unsubstituted hydrocarbon group. 16. The composition according to claim 15, wherein R.sub.7 is the substituted or unsubstituted alkyl group or a substituted or unsubstituted pyridyl group and R.sub.3 to R.sub.6 and R.sub.8 to R.sub.12 are each H. 17. The composition of claim 1, wherein the compound is selected from: ##STR00089## a pharmaceutically-acceptable salt, hydrate, solvate and/or combination thereof. 18. The composition according to claim 17, wherein the compound of Formula I is: ##STR00090## pharmaceutically-acceptable salt, hydrate, solvate and/or combination thereof. 19. The composition according to claim 17, wherein the compound of Formula I is: ##STR00091## a pharmaceutically-acceptable salt, hydrate, solvate and/or combination thereof. 20. A pharmaceutically-acceptable oxalate or tartrate salt of a compound of Formula I or IA for use in the treatment of cancer: ##STR00092## and/or optical isomer thereof; wherein: R.sub.1 and R.sub.2 together form a substituted or unsubstituted polycyclic ring comprising at least two ring systems, said at least two ring systems comprising a first ring system bonded to C1 and a second ring system fused to the first ring system, wherein: the first ring system is a substituted or unsubstituted aromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or the first ring system is a substituted or unsubstituted heteroaromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or the first ring system is a substituted or unsubstituted saturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted unsaturated carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B: ##STR00093## wherein X.sub.1 to X.sub.6 are each independently selected from carbon or a heteroatom; or the first ring system is a substituted or unsubstituted unsaturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B: ##STR00094## wherein X.sub.1 to X.sub.6 are each independently selected from carbon or a heteroatom; or the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and R.sub.3 to R.sub.11 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; R.sub.12 is selected from H or a hydrocarbyl group; Y is selected from a heteroatom; Ring is selected from a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, wherein the nitrogen in the Ring is bonded to A; A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; and n is 0 or 1, wherein the cancer is selected from the group consisting of a cancer having over-expression of RAS, a cancer having an EGFR mutation, and a cancer having overexpression of AKT2. 21. The composition according to claim 1, wherein the anti-cancer agent is more than one anti-cancer agent. 22. The composition according to claim 1 further comprising gemcitabine. 23. The composition according to claim 6 further comprising gemcitabine. 24. The composition according to claim 1, wherein the cancer is characterized by a KRAS mutation. 25. The composition according to claim 24, wherein the cancer is selected from the group consisting of leukemia, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, multiple myeloma, endometrial cancer, and ovarian cancer. 26. The composition according to claim 25, wherein the cancer is colorectal cancer. 27. The composition according to claim 23, wherein the cancer is characterized by an EGFR mutation. 28. The composition according to claim 23, wherein the cancer is selected from the group consisting of lung cancer, glioblastoma, colon cancer, gastric cancer, renal cancer, prostate cancer, breast cancer, and ovarian cancer. 29. The composition according to claim 28, wherein the cancer is non-small cell lung cancer or small cell lung cancer. 30. The composition according to claim 23, wherein the cancer is characterized by over-expression of AKT2. 31. The composition according to claim 30, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, pancreatic cancer, glioma, glioblastoma, lung cancer, and prostate cancer.

Details for Patent 8,580,792

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2027-01-11
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2027-01-11