Claims for Patent: 9,220,695

Summary for Patent: 9,220,695

Title:	Polyenolic zinc-binding agents (pezbins) actively promote inactivation of cancer stem cells and potentiate cytotoxic anti-tumor drug substances
Abstract:	The present invention provides a method of inhibiting the growth of or promoting differentiation and destruction of cancer stem cells (CSCs) comprising contacting the cancer stem cells with a compound having the structure: ##STR00001## or a pharmaceutically acceptable salt thereof.
Inventor(s):	Golub; Lorne M. (Smithtown, NY), Johnson; Francis (Setauket, NY), Botchkina; Galina I. (Stony Brook, NY), Ojima; Iwao (Port Jefferson, NY)
Assignee:	The Research Foundation for The State University of New York (Albany, NY)
Application Number:	14/408,748
Patent Claims:	1. A method of inhibiting the growth of or promoting differentiation of cancer stem cells (CSCs) comprising contacting the cancer stem cells with a compound having the structure: ##STR00033## wherein bond .alpha. and .beta. are each, independently, present or absent; X is CR.sub.5 or N; Y is CR.sub.10 or N; R.sub.1 is H, CF.sub.3, halogen, --NO.sub.2, --OCF.sub.3, OR.sub.12, --NHCOR.sub.12, --CONR.sub.12R.sub.13, --CSNR.sub.12R.sub.13, --C(.dbd.NH)NR.sub.12R.sub.13 --SR.sub.12, --SO.sub.2R.sub.13, --COR.sub.14, --CSR.sub.14, --C(.dbd.NR.sub.12)R.sub.14, --C(.dbd.NR.sub.12)NR.sub.13R.sub.14, --SOR.sub.12, --SONR.sub.12R.sub.13, --SO.sub.2NR.sub.12R.sub.13, --P(O)R.sub.12, --PH(.dbd.O)OR.sub.12 --P(.dbd.O)(OR.sub.12)(OR.sub.13), or --P(OR.sub.12)(OR.sub.13), wherein R.sub.12 and R.sub.13 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.14 is C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, --OR.sub.15, --NR.sub.16R.sub.17, or ##STR00034## wherein R.sub.15 is H, C.sub.3-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl; R.sub.16 and R.sub.17 are each, independently, H, C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.18, R.sub.19, R.sub.21, and R.sub.22 are each independently H, halogen, --NO.sub.2, --CN, --NR.sub.23R.sub.24, --SR.sub.23, --SO.sub.2R.sub.23, --CO.sub.2R.sub.23, --OR.sub.25, CF.sub.3, --SOR.sub.23, --POR.sub.23, --C(.dbd.S)R.sub.23, --C(.dbd.NH)R.sub.23, --C(.dbd.N)R.sub.23, --P(.dbd.O)(OR.sub.23)(OR.sub.24), --P(OR.sub.23)(OR.sub.24), --C(.dbd.S)R.sub.23, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.23, R.sub.24, and R.sub.25 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.20 is halogen, --NO.sub.2, --CN, --NR.sub.26R.sub.27, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.26 and R.sub.27 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently, H, halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --OR.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein when R.sub.1 is H, then R.sub.3, R.sub.4, R.sub.5, R.sub.8, R.sub.9, or R.sub.10, is halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. 2. A method of down-regulating cancer stem cell-relevant transcription factors comprising contacting the cancer stem cell with a compound having the structure: ##STR00035## wherein bond .alpha. and .beta. are each, independently, present or absent; X is CR.sub.5 or N; Y is CR.sub.10 or N; R.sub.1 is H, CF.sub.3, halogen, --NO.sub.2, --OCF.sub.3, --OR.sub.12, --NHCOR.sub.12, --CONR.sub.12R.sub.13, --CSNR.sub.12R.sub.13, --C(.dbd.NH)NR.sub.12R.sub.13 --SR.sub.12, --SO.sub.2R.sub.13, --COR.sub.14, --CSR.sub.14, --C(.dbd.NR.sub.12)R.sub.14, --C(.dbd.NR.sub.12)NR.sub.13R.sub.14, --SOR.sub.12, --SONR.sub.12R.sub.13, --SO.sub.2NR.sub.12R.sub.13, --P(O)R.sub.12, --PH(.dbd.O)OR.sub.12 --P(.dbd.O)(OR.sub.12)(OR.sub.13), or --P(OR.sub.12)(OR.sub.13), wherein R.sub.12 and R.sub.13 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.14 is C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, --OR.sub.15, --NR.sub.16R.sub.17, or ##STR00036## wherein R.sub.15 is H, C.sub.3-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl; R.sub.16 and R.sub.17 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.18, R.sub.19, R.sub.21, and R.sub.22 are each independently H, halogen, --NO.sub.2, --CN, --NR.sub.23R.sub.24, --SR.sub.23, --SO.sub.2R.sub.23, --CO.sub.2R.sub.23, --OR.sub.25, CF.sub.3, --SOR.sub.23, --POR.sub.23, --C(.dbd.S)R.sub.23, --C(.dbd.NH)R.sub.23, --C(.dbd.N)R.sub.23, --P(.dbd.O)(OR.sub.23)(OR.sub.24), --P(OR.sub.23)(OR.sub.24), --C(.dbd.S)R.sub.23, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.23, R.sub.24, and R.sub.25 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.20 is halogen, --NO.sub.2, --CN, --NR.sub.26R.sub.27, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.26 and R.sub.27 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently, H, halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --OR.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein when R.sub.1 is H, then R.sub.3, R.sub.4, R.sub.5, R.sub.8, R.sub.9, or R.sub.10, is halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. 3. The method of claim 1, further comprising contacting the cancer stem cell with a chemotherapeutic agent. 4. The method of claim 2, wherein the cancer stem cell-relevant transcription factor is CDX2, DLX2, EGR3, FOXP3, GLI2, HOXA2, HOXA7, HOXB3, HOXB8, HOXC10, HOXC9, HOXC6, HOXC4, HOXC5, IRX4, JUN, KLF2, NFATC1, NR2F2, PITX3, POU5F1, RUNX1, WT1, c-MYC, or SOX-2. 5. The method of claim 2, wherein the cancer stem cell-relevant transcription factor is each of CDX2, DLX2, EGR3, FOXP3, GLI2, HOXA2, HOXA7, HOXB3, HOXB8, HOXC10, HOXC9, HOXC6, HOXC4, HOXC5, IRX4, JUN, KLF2, NFATC1, NR2F2, PITX3, POU5F1, RUNX1, WT1, c-MYC, and SOX-2. 6. The method of claim 2, wherein the cancer stem cell-relevant transcription factors are at least five (5) transcription factors selected from the group consisting of CDX2, DLX2, EGR3, FOXP3, GLI2, HOXA2, HOXA7, HOXB3, HOXB8, HOXC10, HOXC9, HOXC6, HOXC4, HOXC5, IRX4, JUN, KLF2, NFATC1, NR2F2, PITX3, POU5F1, RUNX1, WT1, c-MYC, and SOX-2. 7. A method of inhibiting the growth of a tumor comprising cancer stem cells (CSCs) by contacting the tumor with a compound having the structure: ##STR00037## wherein bond .alpha. and .beta. are each, independently, present or absent; X is CR.sub.5 or N; Y is CR.sub.10 or N; R.sub.1 is H, CF.sub.3, halogen, --NO.sub.2, --OCF.sub.3, --OR.sub.12, --NHCOR.sub.12, --CONR.sub.12R.sub.13, --CSNR.sub.12R.sub.13, --C(.dbd.NH)NR.sub.12R.sub.13 --SR.sub.12, --SO.sub.2R.sub.13, --COR.sub.14, --CSR.sub.14, --C(.dbd.NR.sub.12)R.sub.14, --C(.dbd.NR.sub.12)NR.sub.13R.sub.14, --SOR.sub.12, --SONR.sub.12R.sub.13, --SO.sub.2NR.sub.12R.sub.13, --P(O)R.sub.12, --PH(.dbd.O)OR.sub.12 --P(.dbd.O)(OR.sub.12)(OR.sub.13), or --P(OR.sub.12)(OR.sub.13), wherein R.sub.12 and R.sub.13 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.14 is C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, --OR.sub.15, --NR.sub.16R.sub.17, or ##STR00038## wherein R.sub.15 is H, C.sub.3-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl; R.sub.16 and R.sub.17 are each, independently, H, C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.18, R.sub.19, R.sub.21, and R.sub.22 are each independently H, halogen, --NO.sub.2, --CN, --NR.sub.23R.sub.24, --SR.sub.23, --SO.sub.2R.sub.23, --CO.sub.2R.sub.23, --OR.sub.25, CF.sub.3, --SOR.sub.23, --POR.sub.23, --C(.dbd.S)R.sub.23, --C(.dbd.NH)R.sub.23, --C(.dbd.N)R.sub.23, --P(.dbd.O)(OR.sub.23)(OR.sub.24), --P(OR.sub.23)(OR.sub.24), --C(.dbd.S)R.sub.23, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.23, R.sub.24, and R.sub.25 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.20 is halogen, --NO.sub.2, --CN, --NR.sub.26R.sub.27, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.26 and R.sub.27 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently, H, halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --OR.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein when R.sub.1 is H, then R.sub.3, R.sub.4, R.sub.5, R.sub.8, R.sub.9, or R.sub.10, is halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. 8. The method of claim 7, wherein the compound inhibits the growth of cancer stem cells and/or promotes the differentiation of cancer stem cells. 9. The method of claim 7, further comprising contacting the tumor with a chemotherapeutic agent. 10. The method of claim 3, wherein the growth of cancer stem cells is not inhibited by, or the differentiation of cancer stem cells is not promoted by, or the cancer stem cell-relevant transcription factors are not inhibited by, the chemotherapeutic agent. 11. The method of claim 9, wherein the tumor is resistant to a chemotherapeutic agent due to the presence of cancer stem cells in the tumor. 12. The method of claim 7, wherein the compound has the structure ##STR00039## or a pharmaceutically acceptable salt thereof. 13. The method of claim 9, wherein the chemotherapeutic agent is SBT-1214. 14. The method of claim 3, wherein the chemotherapeutic agent is puromycin, 5-fluorocytidine, 2'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorocytidine, gemcitabine, cytarabine, cladribine, troxacitabine, abiraterone acetate, abraxane, adriamycin, afinitor, alimta, aloxi, amboclorin, aminolevulinic acid, anastrozole, aprepitant, aromasin, axitinib, azacitidine, bendamustine hydrochloride, bexarotene, bleomycin, bortezomib, cabazitaxel, capecitabine, cerubidine, clofarabine, clofarex, crizotinib, dacarbazine, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, dexrazoxane hydrochloride, docetaxel, doxil, deoxorubicin, ellence, epirubicin hydrochloride, eribulin mesylate, erlotinib hydrochloride, etoposide, evacet, everolimus, fludara, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, imatinib mesylate, imiquimod, irinotecan hydrochloride, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin calcium, leuprorelin, levulan, lomustine, lupron, matulane, methotrexate, mitomycin C, navelbine, nelarabine, nexavar, nilotinib, nolvadex, palonosetron hydrochloride, pazopanib hydrochloride, pemetrexed disodium, pralatrexate, prednisone, procarbazine hydrochloride, raloxifene hydrochloride, ruxolitinib phosphate, sorafenib tosylate, sunitinib malate, tamoxifen citrate, taxol, taxotere, temozolomide, temsirolimus, topotecan hydrochloride, toremifene, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, wellcovorin, xalkori, zevalin, zinecard, zoledronic acid, paclitaxel, anthracendione, cyclophosphamide, etoposide, LB100, cis-platin, or oxaliplatin. 15. The method of claim 7, wherein the cancer stem cells are colon cancer stem cells or prostate cancer stem cells. 16. A method of treating a patient suffering from cancer comprising administering to the patient a compound having the structure: ##STR00040## wherein bond .alpha. and .beta. are each, independently, present or absent; X is CR.sub.5 or N; Y is CR.sub.10 or N; R.sub.1 is H, CF.sub.3, halogen, --NO.sub.2, --OCF.sub.3, --OR.sub.12, --NHCOR.sub.12, --CONR.sub.12R.sub.13, --CSNR.sub.12R.sub.13, --C(.dbd.NH)NR.sub.12R.sub.13 --SR.sub.12, --SO.sub.2R.sub.13, --COR.sub.14, --CSR.sub.14, --C(.dbd.NR.sub.12)R.sub.14, --C(.dbd.NR.sub.12)NR.sub.13R.sub.14, --SOR.sub.12, --SONR.sub.12R.sub.13, --SO.sub.2NR.sub.12R.sub.13, --P(O)R.sub.12, --PH(.dbd.O)OR.sub.12 --P(.dbd.O)(OR.sub.12)(OR.sub.13), or --P(OR.sub.12)(OR.sub.13), wherein R.sub.12 and R.sub.13 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.14 is C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, --OR.sub.15, --NR.sub.16R.sub.17, or ##STR00041## wherein R.sub.15 is H, C.sub.3-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl; R.sub.16 and R.sub.17 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.18, R.sub.19, R.sub.21, and R.sub.22 are each independently H, halogen, --NO.sub.2, --CN, --NR.sub.23R.sub.24, --SR.sub.23, --SO.sub.2R.sub.23, --CO.sub.2R.sub.23, --OR.sub.25, CF.sub.3, --SOR.sub.23, --POR.sub.23, --C(.dbd.S)R.sub.23, --C(.dbd.NH)R.sub.23, --C(.dbd.N)R.sub.23, --P(.dbd.O)(OR.sub.23)(OR.sub.24) --P(OR.sub.23)(OR.sub.24), --C(.dbd.S)R.sub.23, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.23, R.sub.24, and R.sub.25 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.20 is halogen, --NO.sub.2, --CN, --NR.sub.26R.sub.27, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.26 and R.sub.27 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently, H, halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --OR.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein when R.sub.1 is H, then R.sub.3, R.sub.4, R.sub.5, R.sub.8, R.sub.9, or R.sub.10, is halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --NHR.sub.28R.sub.29.sup.+, --SR.sub.28, --SO.sub.2R.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, or --C(.dbd.O)-heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. 17. The method of claim 16, further comprising administering to the patient a chemotherapeutic agent. 18. The method of claim 16, wherein the compound has the structure: ##STR00042## wherein R.sub.14 is C.sub.2-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, --OR.sub.15, --NR.sub.16R.sub.17, or ##STR00043## wherein R.sub.15 is H, C.sub.3-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl; R.sub.16 and R.sub.17 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.18, R.sub.19, R.sub.21, and R.sub.22 are each independently H, halogen, --NO.sub.2, --CN, --NR.sub.23R.sub.24, --SR.sub.23, --SO.sub.2R.sub.23, --CO.sub.2R.sub.23, --OR.sub.25, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.23, R.sub.24, and R.sub.25 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.20 is halogen, --NO.sub.2, --CN, --NR.sub.26R.sub.27, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.26 and R.sub.27 are each, independently, H, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R.sub.2, R.sub.3, R.sub.4,R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently, H, halogen, --NO.sub.2, --CN, --NR.sub.28R.sub.29, --SR.sub.28, --SO.sub.2R.sub.28, --OR.sub.28, --CO.sub.2R.sub.28, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R.sub.28 and R.sub.29 are each, H, CF.sub.3, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and or a salt thereof. 19. The method of claim 17, wherein the compound has the structure ##STR00044## and the chemotherapeutic agent is SBT-1214. 20. The method of claim 17, wherein the compound has the structure ##STR00045## and the chemotherapeutic agent is puromycin, 5-fluorocytidine, 2'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorocytidine, gemcitabine, cytarabine, cladribine, troxacitabine, abiraterone acetate, abraxane, adriamycin, afinitor, alimta, aloxi, amboclorin, aminolevulinic acid, anastrozole, aprepitant, aromasin, axitinib, azacitidine, bendamustine hydrochloride, bexarotene, bleomycin, bortezomib, cabazitaxel, capecitabine, cerubidine, clofarabine, clofarex, crizotinib, dacarbazine, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, dexrazoxane hydrochloride, docetaxel, doxil, deoxorubicin, ellence, epirubicin hydrochloride, eribulin mesylate, erlotinib hydrochloride, etoposide, evacet, everolimus, fludara, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, imatinib mesylate, imiquimod, irinotecan hydrochloride, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin calcium, leuprorelin, levulan, lomustine, lupron, matulane, methotrexate, mitomycin C, navelbine, nelarabine, nexavar, nilotinib, nolvadex, palonosetron hydrochloride, pazopanib hydrochloride, pemetrexed disodium, pralatrexate, prednisone, procarbazine hydrochloride, raloxifene hydrochloride, ruxolitinib phosphate, sorafenib tosylate, sunitinib malate, tamoxifen citrate, taxol, taxotere, temozolomide, temsirolimus, topotecan hydrochloride, toremifene, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, wellcovorin, xalkori, zevalin, zinecard, zoledronic acid, paclitaxel, anthracendione, cyclophosphamide, etoposide, LB100, cis-platin, or oxaliplatin.

Details for Patent 9,220,695

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Acrotech Biopharma Llc	ZEVALIN	ibritumomab tiuxetan	Injection	125019	02/19/2002		2032-06-29