Claims for Patent: 8,575,164

Summary for Patent: 8,575,164

Title:	Combination cancer therapy
Abstract:	Methods and compositions for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially (a) a therapeutically effective amount of an anti-cancer agent and (b) an IGF1R inhibitor compound of Formula I, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. Suitable IGF1R inhibitor may be represented by Formula I: ##STR00001## wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, R.sup.1, and Q.sup.1 are defined herein.
Inventor(s):	Arnold; Lee D. (East Islip, NY), Ji; Qun-Sheng (Babylon, NY), Buck; Elizabeth (Farmingdale, NY), Haley; John D. (Farmingdale, NY), Mulvihill; Mark J. (Farmingdale, NY)
Assignee:	OSI Pharmaceuticals, LLC (Farmingdale, NY)
Application Number:	12/072,269
Patent Claims:	1. A method for treating cancer, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer or breast cancer, comprising administering to a patient simultaneously or sequentially: (i) a therapeutically or sub-therapeutically effective amount of an anti-cancer agent that inhibits serine phosphorylation of IRS1, or a pharmaceutically salt thereof; and (ii) a therapeutically or sub-therapeutically effective amount an IGF-1R inhibitor represented by the formula: ##STR00128## wherein: A is CH or N; X is CH or N; Y and Z are independently H, methyl, ethyl, or halogen; and R.sup.1 is cycloC.sub.3-10alkyl substituted by one or more independent G.sup.11 substituents; G.sup.11 is halo, oxo, --CF.sub.3, --OCF.sub.3, OR.sup.21, --NR.sup.21R.sup.31(R.sup.2a1).sub.j4, --C(O)R.sup.21, --CO.sub.2R.sup.21, --C(.dbd.O)NR.sup.21R.sup.31, --NO.sub.2, --CN, --S(O).sub.j4R.sup.21, --SO.sub.2NR.sup.21R.sup.31, NR.sup.21(C.dbd.O)R.sup.31, NR.sup.21C(.dbd.O)OR.sup.31, NR.sup.21C(.dbd.O)NR.sup.31R.sup.2a1, NR.sup.21S(O).sub.j4R.sup.31, --C(.dbd.S)OR.sup.21, --C(.dbd.O)SR.sup.21, --NR.sup.21C(.dbd.NR.sup.31)NR.sup.2a1R.sup.3a1, --NR.sup.21C(.dbd.NR.sup.31)OR.sup.2a1, --NR.sup.21C(.dbd.NR.sup.31)SR.sup.2a1, --OC(.dbd.O)OR.sup.21, --OC(.dbd.O)NR.sup.21R.sup.31, --OC(.dbd.O)SR.sup.21, --SC(.dbd.O)OR.sup.21, --SC(.dbd.O)NR.sup.21R.sup.31, --P(O)OR.sup.21OR.sup.31, C.sub.1-10alkylidene, C.sub.0-10alkylidene, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxyC.sub.1-10alkyl, C.sub.1-10alkoxyC.sub.2-10alkenyl, C.sub.1-10alkoxyC.sub.2-10alkynyl, C.sub.1-10alkylthioC.sub.1-10alkyl, C.sub.1-10alkylthioC.sub.2-10alkenyl, C.sub.1-10alkylthioC.sub.2-10alkynyl, cycloC.sub.3-8alkyl, cycloC.sub.3-8alkenyl, cycloC.sub.3-8alkylC.sub.1-10alkyl, cycloC.sub.3-8alkenylC.sub.1-10alkyl, cycloC.sub.3-8alkylC.sub.2-10alkenyl, cycloC.sub.3-8alkenylC.sub.2-10alkenyl, cycloC.sub.3-8alkylC.sub.2-10alkynyl, cycloC.sub.3-8alkenylC.sub.2-10alkynyl, heterocyclyl-C.sub.0-10alkyl, heterocyclyl-C.sub.2-10alkenyl, or heterocyclyl-C.sub.2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, --CF.sub.3, --OCF.sub.3, --OR.sup.2221, --NR.sup.2221R.sup.3331(R.sup.222a1).sub.j4a, --C(O)R.sup.2221--CO.sub.2R.sup.2221, --C(.dbd.O)NR.sup.2221R.sup.3331, --NO.sub.2, --CN, --S(O).sub.j4aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331, --NR.sup.2221C(.dbd.O)R.sup.3331, --NR.sup.2221C(.dbd.O)OR.sup.3331, --NR.sup.2221C(.dbd.O)NR.sup.3331R.sup.222a1, --NR.sup.2221S(O).sub.j4aR.sup.3331, --C(.dbd.S)OR.sup.2221, --C(.dbd.O)SR.sup.2221, --NR.sup.2221C(.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1, --NR.sup.2221C(.dbd.NR.sup.3331)OR.sup.222a1, --NR.sup.2221C(.dbd.NR.sup.3331)SR.sup.222a1, --C(.dbd.O)OR.sup.2221, --OC(.dbd.O)NR.sup.2221R.sup.3331, --OC(.dbd.O)SR.sup.2221, --SC(.dbd.O)OR.sup.2221, --P(O)OR.sup.2221OR.sup.3331, or --SC(.dbd.O)NR.sup.2221R.sup.3331 substituents; or G.sup.11 is aryl-C.sub.0-10alkyl, aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, hetaryl-C.sub.0-10alkyl, hetaryl-C.sub.2-10alkenyl, or hetaryl-C.sub.2-10alkynyl, any of which is optionally substituted with one or more independent halo, --CF.sub.3, --OCF.sub.3, --OR.sup.2221, --NR.sup.2221R.sup.3331(R.sup.222a1, R.sup.2221a1).sub.j5a, --C(O)R.sup.2221, --CO.sub.2R.sup.2221, --C(.dbd.O)NR.sup.2221R.sup.3331, --NO.sub.2, --CN, --S(O).sub.j5aR.sup.2221, --SO.sub.2NR.sup.2221R.sup.3331, --NR.sup.2221C(.dbd.O)R.sup.3331, --NR.sup.2221C(.dbd.O)OR.sup.3331, --NR.sup.2221C(.dbd.O)NR.sup.3331R.sup.222a1, --NR.sup.2221S(O).sub.j5aR.sup.3331, --C(.dbd.S)OR.sup.2221, --C(.dbd.O)SR.sup.2221, --NR.sup.2221C(.dbd.NR.sup.3331)NR.sup.222a1R.sup.333a1, --NR.sup.2221C(.dbd.NR.sup.3331)OR.sup.222a1, --NR.sup.2221C(.dbd.NR.sup.3331)SR.sup.222a1, --C(.dbd.O)OR.sup.2221, --OC(.dbd.O)NR.sup.2221R.sup.3331, --OC(.dbd.O)SR.sup.2221, --SC(.dbd.O)OR.sup.2221, --P(O)OR.sup.2221OR.sup.3331, or --SC(.dbd.O)NR.sup.2221R.sup.3331 substituents; R.sup.21, R.sup.2a1.sub., R.sup.31, R.sup.3a1, R.sup.2221, R.sup.222a1, R.sup.3331, and R.sup.333a1 are each independently C.sub.0-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxyC.sub.2-10alkenyl, C.sub.1-10alkoxyC.sub.2-10alkynyl, C.sub.1-10alkylthioC.sub.1-10alkyl, C.sub.1-10alkylthioC.sub.2-10alkenyl, C.sub.1-10alkylthioC.sub.2-10alkynyl, cycloC.sub.3-8alkyl, cycloC.sub.3-8alkenyl, cycloC.sub.3-8alkylC.sub.1-10alkyl, cycloC.sub.3-8alkenylC.sub.1-10alkyl, cycloC.sub.3-8alkylC.sub.2-10alkenyl, cycloC.sub.3-8alkenylC.sub.2-10alkenyl, cycloC.sub.3-8alkylC.sub.2-10alkynyl, cycloC.sub.3-8alkenylC.sub.2-10alkynyl, heterocyclyl-C.sub.0-10alkyl, heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, hetaryl-C.sub.0-10alkyl, hetaryl-C.sub.2-10alkenyl, or hetaryl-C.sub.2-10alkynyl, any of which is optionally substituted by one or more independent G.sup.111 substituents; or in the case of --NR.sup.21R.sup.31(R.sup.2a1).sub.j4 or --NR.sup.2221R.sup.3331(R.sup.222a1).sub.j4a or --NR.sup.2221R.sup.3331(R.sup.222a1).sub.j5a, then R.sup.2221 and R.sup.3331 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted by one or more independent G.sup.1111 substituents and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R.sup.2221 and R.sup.3331 are attached; each G.sup.111 is independently C.sub.0-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxyC.sub.1-10alkyl, C.sub.1-10alkoxyC.sub.2-10alkenyl, C.sub.1-10alkoxyC.sub.2-10alkynyl, C.sub.1-10alkylthioC.sub.1-10alkyl, C.sub.1-10alkylthioC.sub.2-10alkenyl, C.sub.1-10alkylthioC.sub.2-10alkynyl, cycloC.sub.3-8alkyl, cycloC.sub.3-8alkenyl, cycloC.sub.3-8alkylC.sub.1-10alkyl, cycloC.sub.3-8alkenylC.sub.1-10alkyl, cycloC.sub.3-8alkylC.sub.2-10alkenyl, cycloC.sub.3-8alkenylC.sub.2-10alkenyl, cycloC.sub.3-8alkylC.sub.2-10alkynyl, cycloC.sub.3-8alkenylC.sub.2-10alkynyl, heterocyclyl-C.sub.0-10alkyl, heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, hetaryl-C.sub.0-10alkyl, hetaryl-C.sub.2-10alkenyl, or hetaryl-C.sub.2-10alkynyl, any of which is optionally substituted with one or more independent halo, --CF.sub.3, --OCF.sub.3, --OR.sup.77, --NR.sup.77R.sup.87, --C(O)R.sup.77, --CO.sub.2R.sup.77, --CONR.sup.77R.sup.87, --NO.sub.2, --CN, --S(O).sub.j5aR.sup.77, --SO.sub.2NR.sup.77R.sup.87, --NR.sup.77C(.dbd.O)R.sup.87, --NR.sup.77C(.dbd.O)OR.sup.87, --NR.sup.77C(.dbd.O)NR.sup.78R.sup.87, --NR.sup.77S(O).sub.j5aR.sup.87, --C(.dbd.S)OR.sup.77, --C(.dbd.O)SR.sup.77, --NR.sup.77C(.dbd.NR.sup.87)NR.sup.78R.sup.88, --NR.sup.77C(.dbd.NR.sup.87)OR.sup.78, --NR.sup.77C(.dbd.NR.sup.87)SR.sup.78, --OC(.dbd.O)OR.sup.77, --OC(.dbd.O)NR.sup.77R.sup.87, --OC(.dbd.O)SR.sup.77, --SC(.dbd.O)OR.sup.77, --P(O)OR.sup.77OR.sup.87, or --SC(.dbd.O)NR.sup.77R.sup.87 substituents; or in the case of --NR.sup.78R.sup.88, R.sup.78 and R.sup.88 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C.sub.1-10alkoxy, --SO.sub.2NR.sup.778R.sup.888, or --NR.sup.778R.sup.888 substituents, and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R.sup.78 and R.sup.88 are attached; R.sup.77, R.sup.78, R.sup.87, R'', R.sup.778, and R.sup.888 are each independently C.sub.0-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.1-10alkoxyC.sub.1-10alkyl, C.sub.1-10alkoxyC.sub.2-10alkenyl, C.sub.1-10alkoxyC.sub.2-10alkynyl, C.sub.1-10alkylthioC.sub.1-10alkyl, C.sub.1-10alkylthioC.sub.2-10alkenyl, C.sub.1-10alkylthioC.sub.2-10alkynyl, cycloC.sub.3-8alkyl, cycloC.sub.3-8alkenyl, cycloC.sub.3-8alkylC.sub.1-10alkyl, cycloC.sub.3-8alkenylC.sub.1-10alkyl, cycloC.sub.3-8alkylC.sub.2-10alkenyl, cycloC.sub.3-8alkenylC.sub.2-10alkenyl, cycloC.sub.3-8alkylC.sub.2-10alkynyl, cycloC.sub.3-8alkenylC.sub.2-10alkynyl, heterocyclyl-C.sub.0-10alkyl, heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl, C.sub.1-10alkylcarbonyl, C.sub.2-10alkenylcarbonyl, C.sub.2-10alkynylcarbonyl, C.sub.1-10alkoxycarbonyl, C.sub.1-10alkoxycarbonylC.sub.1-10alkyl, monoC.sub.1-6alkylaminocarbonyl, diC.sub.1-6alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or C.sub.1-10alkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C.sub.1-10alkoxy, --SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), or --N(C.sub.0-4alkyl)(C.sub.0-4alkyl) substituents; or R.sup.77, R.sup.78, R.sup.87, R.sup.88, R.sup.778, and R.sup.888 are each independently aryl-C.sub.0-10alkyl, aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, hetaryl-C.sub.0-10alkyl, hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, mono(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, mono(aryl)aminoC.sub.1-6alkyl, di(aryl)aminoC.sub.1-6alkyl, or --N(C.sub.1-6alkyl)-C.sub.1-6alkykaryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, --O(C.sub.0-4alkyl), C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl, --COOH, C.sub.1-4alkoxycarbonyl, --CON(C.sub.0-4alkyl)(C.sub.0-10alkyl), --SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), or --N(C.sub.0-4alkyl)(C.sub.0-4alkyl) substituents; j4, j4a, and j5a are each independently 0, 1, or 2. 2. The method of claim 1, wherein the cancer comprises non-small cell lung cancer. 3. The method of claim 1, wherein the IGFR inhibitor comprises cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-m- ethyl-cyclobutanol, or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein the IGFR inhibitor comprises cis-3-[4-Amino-5-(8-fluoro-2-phenyl-quinolin-7-yl)-imidazo[5,1f][1,2,4]tr- iazin-7-yl]-1-methyl-cyclobutanol, or a pharmaceutically acceptable salt thereof. 5. The method of claim 3, wherein the anti-cancer agent comprises erlotinib, cetuximab, gefitinib, or a pharmaceutically acceptable salt thereof. 6. The method of claim 3, wherein the anti-cancer agent comprises erlotinib or a pharmaceutically acceptable salt thereof. 7. The method of claim 6, wherein the cancer comprises non-small cell lung cancer. 8. The method of claim 1, wherein the anticancer agent is selected from Ras inhibitors, Raf inhibitors, MEK inhibitors, or PKC inhibitors. 9. The method of claim 1, wherein the anti-cancer agent is a MEK inhibitor. 10. The method of claim 1, wherein the anti-cancer agent is an MEK inhibitor, or a pharmaceutically acceptable salt thereof, and the IGFR inhibitor is cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-m- ethyl-cyclobutanol, or a pharmaceutically acceptable salt thereof. 11. The method of claim 1, wherein the anti-cancer agent is a Raf protein kinase family inhibitor. 12. The method of claim 1, wherein the anti-cancer agent is sorafenib. 13. The method of claim 1, wherein the anti-cancer agent is a Raf protein kinase family inhibitor, or a pharmaceutically acceptable salt thereof, and the IGFR inhibitor is cis-3-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-m- ethyl-cyclobutanol, or a pharmaceutically acceptable salt thereof. 14. The method of claim 1, wherein the anti-cancer agent is ZD-6474, IMC-1121b, CDP-791, imatinib, sunitinib malate, PTK-787, lapatinib, sirolimus, temsirolimus, everolimus, CP-751871, RAV-12, IMC-A12, 19D12, PS-1145, or orbortezomib.

Details for Patent 8,575,164

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2025-12-19
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2025-12-19