Claims for Patent: 10,285,986

Summary for Patent: 10,285,986

Title:	Compounds and anti-tumor NQO1 substrates
Abstract:	Compositions comprising Formula (I) can be selectively lethal toward a variety of different cancer cell types. The compositions are useful for the management, treatment, control, or adjunct treatment of diseases, where the selective lethality is beneficial in chemotherapeutic therapy.
Inventor(s):	Hergenrother; Paul J. (Champaign, IL), Boothman; David A. (Dallas, TX), Bair; Joseph S. (Albany, CA), Palchaudhuri; Rahul (Cambridge, MA), Parkinson; Elizabeth I. (Champaign, IL)
Assignee:	The Board of Trustees of the University of Illinois (Urbana, IL) The Board of Regents of the University of Texas System (Austin, TX)
Application Number:	15/933,671
Patent Claims:	1. A method of treating cancer in a mammal comprising administering to a mammal in need of cancer treatment an effective anticancer amount of a compound of Formula (I): ##STR00139## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are each independently --H or --X--R; each X is independently a direct bond or a bridging group, wherein the bridging group is --O--, --S--, --NH--, --C(.dbd.O)--, --O--C(.dbd.O)--, --C(.dbd.O)--O--, --O--C(.dbd.O)--O--, or a linker of the formula --W-A-W--, wherein each W is independently --N(R')C(.dbd.O)--, --C(.dbd.O)N(R')--, --OC(.dbd.O)--, --C(.dbd.O)O--, --O--, --S--, --S(O)--, --S(O).sub.2--, --N(R')--, --C(.dbd.O)--, --(CH.sub.2).sub.n-- where n is 1-10, or a direct bond, wherein each R' is independently H, (C.sub.1-C.sub.6)alkyl, or a nitrogen protecting group; and each A is independently (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.16)alkenyl, (C.sub.2-C.sub.16)alkynyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.10)aryl, --(OCH.sub.2--CH.sub.2).sub.n-- where n is 1 to about 20, --C(O)NH(CH.sub.2).sub.n--wherein n is 1 to about 6, --OP(O)(OH)O--, --OP(O)(OH)O(CH.sub.2).sub.n-- wherein n is 1 to about 6, or (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.16)alkenyl, (C.sub.2-C.sub.16)alkynyl, or --(OCH.sub.2--CH.sub.2).sub.n-- interrupted between two carbons, or between a carbon and an oxygen, with a cycloalkyl, heterocycle, or aryl group; each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (cycloalkyl)heteroalkyl, (heterocycloalkyl)heteroalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, hydrogen, hydroxy, hydroxyalkyl, alkoxy, (alkoxy)alkyl, alkenyloxy, alkynyloxy, (cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, --COR.sup.x, --COOR.sup.x, --CONHR.sup.x, --NHCOR.sub.x, --NHCOOR.sup.x, --NHCONHR.sup.x, --N.sub.3, --CN, --NC, --NCO, --NO.sub.2, --SH,-halo, alkoxycarbonyl, alkylaminocarbonyl, sulfonate, sulfonic acid, alkyl sulfonyl, alkylsulfinyl, aryl sulfonyl, arylsulfinyl, aminosulfonyl, R.sup.xS(O)R.sup.y--, R.sup.xS(O).sub.2R.sup.y--, R.sup.xC(O)N(R.sup.x)R.sup.y--, R.sup.xSO.sub.2N(R.sup.x)R.sup.y--, R.sup.xN(R.sup.x)C(O)R.sup.y--, R.sup.xN(R.sup.x)SO.sub.2R.sup.y--, R.sup.xN(R.sup.x)C(O)N(R.sup.x)R.sup.y--, carboxaldehyde, acyl, acyloxy, --OPO.sub.3H.sub.2, --OPO.sub.3Z.sub.2 where Z is an inorganic cation, or saccharide; where each R.sup.x is independently H, OH, alkyl or aryl, and each R.sup.y is independently a group W; wherein any alkyl or aryl can be optionally substituted with one to four hydroxy, amino, cyano, nitro, or halo groups; or a salt or solvate thereof; provided that the compound is not deoxynyboquinone (DNQ); wherein the cancer is thereby treated, cell of the cancer are killed, or the cancer is inhibited from growing. 2. The method of claim 1 wherein the cancer is characterized by tumor cells with elevated NAD(P)H quinone oxidoreductase (NQO1) levels. 3. The method of claim 2 wherein the cancer is breast cancer, lung cancer, pancreatic cancer, or prostate cancer. 4. The method of claim 1 wherein R.sub.1 is a (C.sub.1-20)alkyl group. 5. The method of claim 1 wherein R.sub.2 is a (C.sub.1-20)alkyl group. 6. The method of claim 1 wherein R.sub.3 is H. 7. The method of claim 1 wherein R.sub.4 is a straight chain or branched (C.sub.1-20)alkyl group. 8. The method of claim 1 wherein R.sub.1 is methyl, R.sub.2 is methyl, or R.sub.1 and R.sub.2 are both methyl. 9. The method of claim 1 further comprising administering a chemotherapeutic agent or an immunotherapeutic agent. 10. The method of claim 9 wherein the chemotherapeutic agent is selected from altretamine, aminoglutethimide, amsacrine, anastrozole, ara-C, L-Asparaginase, avastin, bexxar, bleomycin, busulfan, campath, camptostar, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chlormethine, chlorotrianisene, cisplatin, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, deoxycoformycin, diethylstilbestrol, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, antibodies to EGFR, epirubicin, epothilones, erlotinib, estramustine, estrogen receptor binding agents, 17.alpha.-ethinylestradiol, etoposide, exemestane, farnesyl-protein transferase inhibitors, floxuridine, fludarabine phosphate, 5-fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib, gemcitabine, goserelin, hexamethylmelamine, hydroxyprogesterone, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, letrozole, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrolacetate, melphalan, 6-mercaptopurine, methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin, Mitomycin-C, mitotane, mitoxantrone, nitrosurea, paclitaxel, pentostatine, pipobroman, plicomycin, porfimer, prednisolone, prednisone, procarbazine, raloxifene, reloxafine, rituximab, SCH 66336, streptozocin, tamoxifen, taxotere, temozolomide, teniposide, testolactone, testosterone, 6-thioguanine, thiotepa, topotecan, toremifene, transplatinum, trastuzumab, triamcinolone, triethylenemelamine, triethylenethiophosphoramine, trisenox, velcade, vinblastine, vincristine, vindesine, vinorelbine, and uracil mustard. 11. The method of claim 1 wherein: R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is 2-methyl-propyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is butyl; R.sub.1 is methyl; R.sub.3 is hydrogen; R.sub.2 is propyl; and R.sub.4 is butyl; R.sub.1 and R.sub.4 are methyl; R.sub.2 is propyl and R.sub.3 is hydrogen; R.sub.1 is propyl; R.sub.2 and R.sub.4 are methyl and R.sub.3 is hydrogen; R.sub.1 and R.sub.2 are ethyl; R.sub.3 is hydrogen; and R.sub.4 is methyl; R.sub.1 is propyl; R.sub.2 is methyl; R.sub.3 is hydrogen; and R.sub.4 is butyl; R.sub.1 and R.sub.2 are propyl; R.sub.3 is hydrogen; and R.sub.4 is butyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is C.sub.12alkyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is tert-butyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is hydroxypropyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is 3,3-dimethylbutyl[-CH.sub.2CH.sub.2C(CH.sub.3).sub.2CH.sub.3]; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is 3-methybutyl[-CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.3]; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is propyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is n-pentyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is n-hexyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is isopropyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is cyclooctyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is cyclopropyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is methylcyclopropyl; R.sub.1 and R.sub.2 are methyl; R.sub.3 is hydrogen; and R.sub.4 is ethylcyclopropyl; R.sub.2 and R.sub.4 are methyl; R.sub.3 is hydrogen; and R.sub.1 is C.sub.12alkyl; R.sub.1 and R.sub.4 are methyl; R.sub.3 is hydrogen; and R.sub.2 is C.sub.12alkyl; R.sub.2 is --CH.sub.2OPO.sub.3Na.sub.2; R.sub.1 and R.sub.4 are methyl; and R.sub.3 is hydrogen; R.sub.2 and R.sub.4 are methyl; R.sub.1 is --CH.sub.2OPO.sub.3Na.sub.2; and R.sub.3 is hydrogen; R.sub.1 and R.sub.2 are methyl; R.sub.4 is --CH.sub.2OPO.sub.3Na.sub.2; and R.sub.3 is hydrogen; R.sub.1 and R.sub.2 are methyl; R.sub.4 is --CH.sub.2CH.sub.2OPO.sub.3Na.sub.2; and R.sub.3 is hydrogen; R.sub.2 is --CH.sub.2OH; R.sub.1 and R.sub.4 are methyl; and R.sub.3 is hydrogen; R.sub.2 and R.sub.4 are methyl; R.sub.1 is --CH.sub.2OH; and R.sub.3 is hydrogen; R.sub.1 and R.sub.2 are methyl; R.sub.4 is --CH.sub.2OH; and R.sub.3 is hydrogen; or R.sub.1 and R.sub.2 are methyl; R.sub.4 is --CH.sub.2CH.sub.2OH; and R.sub.3 is hydrogen; wherein the cancer is characterized by tumor cells with elevated NAD(P)H quinone oxidoreductase (NQO1) levels. 12. The method of claim 11 wherein the cancer is breast cancer, lung cancer, pancreatic cancer, or prostate cancer. 13. The method of claim 12 wherein the lung cancer is Non-Small-Cell Lung Carcinoma. 14. The method of claim 11 further comprising administering a chemotherapeutic agent or an immunotherapeutic agent. 15. The method of claim 14 wherein the chemotherapeutic agent is selected from altretamine, aminoglutethimide, amsacrine, anastrozole, ara-C, L-Asparaginase, avastin, bexxar, bleomycin, busulfan, campath, camptostar, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chlormethine, chlorotrianisene, cisplatin, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, deoxycoformycin, diethylstilbestrol, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, antibodies to EGFR, epirubicin, epothilones, erlotinib, estramustine, estrogen receptor binding agents, 17.alpha.-ethinylestradiol, etoposide, exemestane, farnesyl-protein transferase inhibitors, floxuridine, fludarabine phosphate, 5-fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib, gemcitabine, goserelin, hexamethylmelamine, hydroxyprogesterone, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, letrozole, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrolacetate, melphalan, 6-mercaptopurine, methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin, Mitomycin-C, mitotane, mitoxantrone, nitrosurea, paclitaxel, pentostatine, pipobroman, plicomycin, porfimer, prednisolone, prednisone, procarbazine, raloxifene, reloxafine, rituximab, SCH 66336, streptozocin, tamoxifen, taxotere, temozolomide, teniposide, testolactone, testosterone, 6-thioguanine, thiotepa, topotecan, toremifene, transplatinum, trastuzumab, triamcinolone, triethylenemelamine, triethylenethiophosphoramine, trisenox, velcade, vinblastine, vincristine, vindesine, vinorelbine, and uracil mustard. 16. A method of treating cancer in a mammal comprising administering to a mammal in need of cancer treatment an effective anticancer amount of the compound IB-DNQ: ##STR00140## wherein the cancer is thereby treated, cells of the cancer are killed, or the cancer is inhibited from growing. 17. The method of claim 16 wherein the cancer is characterized by tumor cells with elevated NAD(P)H quinone oxidoreductase (NQO1) levels. 18. The method of claim 17 wherein the cancer is breast cancer, lung cancer, pancreatic cancer, or prostate cancer. 19. The method of claim 17 further comprising administering a chemotherapeutic agent or an immunotherapeutic agent. 20. The method of claim 19 wherein the chemotherapeutic agent is selected from altretamine, aminoglutethimide, amsacrine, anastrozole, ara-C, L-Asparaginase, avastin, bexxar, bleomycin, busulfan, campath, camptostar, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chlormethine, chlorotrianisene, cisplatin, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, deoxycoformycin, diethylstilbestrol, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, antibodies to EGFR, epirubicin, epothilones, erlotinib, estramustine, estrogen receptor binding agents, 17.alpha.-ethinylestradiol, etoposide, exemestane, farnesyl-protein transferase inhibitors, floxuridine, fludarabine phosphate, 5-fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib, gemcitabine, goserelin, hexamethylmelamine, hydroxyprogesterone, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, letrozole, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrolacetate, melphalan, 6-mercaptopurine, methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin, Mitomycin-C, mitotane, mitoxantrone, nitrosurea, paclitaxel, pentostatine, pipobroman, plicomycin, porfimer, prednisolone, prednisone, procarbazine, raloxifene, reloxafine, rituximab, SCH 66336, streptozocin, tamoxifen, taxotere, temozolomide, teniposide, testolactone, testosterone, 6-thioguanine, thiotepa, topotecan, toremifene, transplatinum, trastuzumab, triamcinolone, triethylenemelamine, triethylenethiophosphoramine, trisenox, velcade, vinblastine, vincristine, vindesine, vinorelbine, and uracil mustard. 21. A method of treating cancer in a mammal comprising administering to a mammal in need of cancer treatment an effective anticancer amount of the compound IP-DNQ: ##STR00141## wherein the cancer is thereby treated, cells of the cancer are killed, or the cancer is inhibited from growing. 22. The method of claim 21 wherein the cancer is characterized by tumor cells with elevated NAD(P)H quinone oxidoreductase (NQO1) levels. 23. The method of claim 22 wherein the cancer is breast cancer, lung cancer, pancreatic cancer, or prostate cancer. 24. The method of claim 22 further comprising administering a chemotherapeutic agent or an immunotherapeutic agent. 25. The method of claim 24 wherein the chemotherapeutic agent is selected from altretamine, aminoglutethimide, amsacrine, anastrozole, ara-C, L-Asparaginase, avastin, bexxar, bleomycin, busulfan, campath, camptostar, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chlormethine, chlorotrianisene, cisplatin, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, deoxycoformycin, diethylstilbestrol, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, antibodies to EGFR, epirubicin, epothilones, erlotinib, estramustine, estrogen receptor binding agents, 17.alpha.-ethinylestradiol, etoposide, exemestane, farnesyl-protein transferase inhibitors, floxuridine, fludarabine phosphate, 5-fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib, gemcitabine, goserelin, hexamethylmelamine, hydroxyprogesterone, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, letrozole, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrolacetate, melphalan, 6-mercaptopurine, methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin, Mitomycin-C, mitotane, mitoxantrone, nitrosurea, paclitaxel, pentostatine, pipobroman, plicomycin, porfimer, prednisolone, prednisone, procarbazine, raloxifene, reloxafine, rituximab, SCH 66336, streptozocin, tamoxifen, taxotere, temozolomide, teniposide, testolactone, testosterone, 6-thioguanine, thiotepa, topotecan, toremifene, transplatinum, trastuzumab, triamcinolone, triethylenemelamine, triethylenethiophosphoramine, trisenox, velcade, vinblastine, vincristine, vindesine, vinorelbine, and uracil mustard.

Details for Patent 10,285,986

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2031-10-14
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2031-10-14
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Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2031-10-14
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2031-10-14
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2031-10-14