Claims for Patent: 9,925,180
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Summary for Patent: 9,925,180
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: | 15/454,377 |
Patent Claims: | 1. A composition comprising an NQO1 substrate that is a DNQ analogue of Formula (I): ##STR00137## wherein R.sub.1 is alkyl; R.sub.3 is H; R.sub.2 and R.sub.4 are each
independently --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.5)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, alkenyl 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,
(cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, acylamino, arylamino, sulfonylamino, sulfinylamino, --COR.sup.x, --COOR.sup.x, --CONHR.sup.x, --NHCOR.sup.x, --NHCOOR.sup.x, --NHCONHR.sup.x, --N.sub.3, --CN, --NC, --NCO, --NO.sub.2, --SH,
-halo, alkoxycarbonyl, alkylaminocarbonyl, sulfonate, sulfonic acid, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, 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 or more hydroxy, amino, cyano, nitro, or halo groups; or a salt or
solvate thereof; in combination with a chemotherapeutic agent or an immunotherapeutic agent.
2. The composition according to claim 1 wherein the composition comprises a chemotherapeutic agent. 3. The composition according to claim 2 wherein the chemotherapeutic agent is selected from cisplatin, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, gefitinib, erlotinib, antibodies to EGFR, imatinib, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, epirubicin, idarubicin, mithramycin, deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide, 17.alpha.-Ethinylestradiol, Diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, cetuximab, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, Campath, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, tamoxifen, raloxifene, estrogen receptor binding agents, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, and methotrexate, or a combination thereof. 4. The composition according to claim 3 wherein the DNQ analogue of Formula (I) is compound 87 or compound 9-249: ##STR00138## 5. The composition according to claim 4 in combination with a pharmaceutically acceptable carrier. 6. The composition according to claim 5 wherein the composition comprises a cyclodextrin. 7. The composition according to claim 1 wherein R.sub.1 is (C.sub.1-C.sub.12)alkyl. 8. The composition according to claim 7 wherein R.sub.1 is methyl. 9. The composition according to claim 1 wherein R.sub.2 is (C.sub.1-C.sub.12)alkyl. 10. The composition according to claim 9 wherein R.sub.2 is methyl. 11. The composition according to claim 1 wherein R.sub.4 is (C.sub.1-C.sub.12)alkyl. 12. The composition according to claim 11 wherein R.sub.4 is branched or unbranched butyl. 13. The composition according to claim 1 wherein R.sub.1 is (C.sub.1-C.sub.12)alkyl, R.sub.2 is (C.sub.1-C.sub.12)alkyl, and R.sub.4 is branched or unbranched butyl. 14. The composition according to claim 13 wherein R.sub.1 is methyl, R.sub.2 is methyl, and R.sub.4 is branched or unbranched butyl. 15. The composition according to claim 14 in combination with a pharmaceutically acceptable carrier. 16. The composition according to claim 15 wherein the composition comprises a cyclodextrin. 17. A composition comprising compound 87: ##STR00139## in combination with a chemotherapeutic agent or an immunotherapeutic agent. 18. The composition according to claim 17 wherein the composition comprises a chemotherapeutic agent. 19. The composition according to claim 18 wherein the chemotherapeutic agent is selected from cisplatin, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, taxotere, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, gefitinib, erlotinib, imatinib, ara-C, adriamycin, cytoxan, gemcitabine, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, epirubicin, idarubicin, mithramycin, deoxycoformycin, Mitomycin-C, chlorotrianisene, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, cetuximab, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, melphalan, chlorambucil, busulfan, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, tamoxifen, raloxifene, gemcitabine, and navelbine, or a combination thereof. 20. The composition according to claim 19 in combination with a pharmaceutically acceptable carrier. 21. A composition comprising compound 9-249: ##STR00140## and a pharmaceutically acceptable carrier. 22. The composition according to claim 21 wherein the composition further comprises a chemotherapeutic agent or an immunotherapeutic agent. 23. The composition according to claim 22 wherein the composition comprises a chemotherapeutic agent and the chemotherapeutic agent is selected from cisplatin, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, taxotere, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, gefitinib, erlotinib, imatinib, ara-C, adriamycin, cytoxan, gemcitabine, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, epirubicin, idarubicin, mithramycin, deoxycoformycin, Mitomycin-C, chlorotrianisene, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, cetuximab, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, melphalan, chlorambucil, busulfan, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, tamoxifen, raloxifene, gemcitabine, and navelbine, or a combination thereof. |
Details for Patent 9,925,180
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Recordati Rare Diseases, Inc. | ELSPAR | asparaginase | For Injection | 101063 | 01/10/1978 | ⤷ Try a Trial | 2031-10-14 |
Genentech, Inc. | RITUXAN | rituximab | Injection | 103705 | 11/26/1997 | ⤷ Try a Trial | 2031-10-14 |
Genentech, Inc. | HERCEPTIN | trastuzumab | For Injection | 103792 | 09/25/1998 | ⤷ Try a Trial | 2031-10-14 |
Genentech, Inc. | HERCEPTIN | trastuzumab | For Injection | 103792 | 02/10/2017 | ⤷ Try a Trial | 2031-10-14 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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