Claims for Patent: 10,221,140

Summary for Patent: 10,221,140

Title:	Asymmetric bisaminoquinolines and bisaminoquinolines with varied linkers as autophagy inhibitors for cancer and other therapy
Abstract:	The invention provides novel asymmetric and symmetric bisaminoquinolmes and related compounds, methods of treatment and syntheses. The novel compounds exhibit effective anticancer activity and are useful in the treatment of a variety of autophagy-related disorders.
Inventor(s):	Amaravadi; Ravi K. (Media, PA), Winkler; Jeffrey (Wynnewood, PA)
Assignee:	THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA (Philadelphia, PA)
Application Number:	15/502,330
Patent Claims:	1. A compound according to the chemical structure: ##STR00058## Wherein R.sup.1 and R.sup.1' are each independently H, F, Cl, Br, I, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted O--C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.7 acyl, optionally substituted --(NH)-acyl, or optionally substituted C.sub.2-C.sub.7 ester; R and R' are each independently H, a C.sub.1-C.sub.6 optionally substituted alkyl group, a C.sub.1-C.sub.7 optionally substituted acyl group, a C.sub.2-C.sub.7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R' is bonded); R'' is H, Cy.sup.1 or (C.dbd.O).sub.z-G, where Cy.sup.1 is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C.sub.1-C.sub.12 alkyl, alkene or alkynyl group (wherein optional substituents include a C.sub.1-C.sub.u alkyl, alkene or alkynyl group substituted by (N-R.sup.J)--(C.sub.1-C.sub.8 alkyl, alkene or alkynyl group).sub.z-(Cy.sup.2).sub.x, where R.sup.J is H or a C.sub.1-C.sub.8 alkyl, alkene or alkynyl group, z is 0, 1 or 2, x is 0 or 1 and Cy.sup.2 is an optionally substituted aryl or heteroaryl group); RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 are each independently H, F, Cl, Br, I, an optionally substituted C.sub.1-C.sub.12 alkyl, alkene, alkynyl or alkoxy group with the proviso that at least one of RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 is other than H; Each p in linker group L.sup.1A is independently 1-10; and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof. 2. A compound according to the chemical structure: ##STR00059## wherein R.sup.1 and R.sup.1' are each independently H, F, Cl, Br, I, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted O--C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.7 acyl, an optionally substituted --(NH)-acyl, or optionally substituted C.sub.2-C.sub.7 ester; R and R' are each independently H, a C.sub.1-C.sub.6 optionally substituted alkyl group, a C.sub.1-C.sub.7 optionally substituted acyl group, a C.sub.2-C.sub.7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R' is bonded); R'' is H, Cy.sup.1 or (C.dbd.O).sub.z-G, where Cy.sup.1 is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C.sub.1-C.sub.12 alkyl, alkene or alkynyl group (wherein optional substituents include a C.sub.1-C.sub.12 alkyl, alkene or alkynyl group substituted by (NR.sup.J)--(C.sub.1-C.sub.8 alkyl, alkene or alkynyl group).sub.z-(Cy.sup.2).sub.x, where R.sup.J is H or a C.sub.1-C.sub.8 alkyl; alkene or alkynyl group, z is 0, 1 or 2, x is 0 or 1 and Cy.sup.2 is an optionally substituted aryl or heteroaryl group); RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 are each independently H, F, Cl, Br, I, an optionally substituted C.sub.1-C.sub.12 alkyl, alkene, alkynyl or alkoxy group with the proviso that at least one of RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 is other than H; p and p' in linker L.sup.1B are each independently 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof. 3. A compound according to the chemical structure IC: ##STR00060## wherein R.sup.1 and R.sup.1' are each independently H, F, Cl Br, I, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted O--C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.7 acyl, an optionally substituted --(NH)-acyl, or optionally substituted C.sub.2-C.sub.7 ester; R and R' are each independently H, a C.sub.1-C.sub.6 optionally substituted alkyl group, a C.sub.1-C.sub.7 optionally substituted acyl group, a C.sub.2-C.sub.7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R' is bonded); R.sup.M is independently at each occurrence H, F, Cl, Br, I, an optionally substituted C.sub.01-C.sub.12 alkyl, alkene, alkynyl or alkoxy group, with the proviso that at least one RM substituent is other than H; Each p in linker group L.sup.1C is independently 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvatess and polymorphs thereof. 4. A compound of Formula ID: ##STR00061## wherein R.sup.1 and R.sup.1' are each independently H, F, Cl, Br, I, CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted O--C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.7 acyl, optionally substituted --(NH)-acyl, or optionally substituted C.sub.2-C.sub.7 ester; R and R' are each independently H, a C.sub.1-C.sub.6 optionally substituted alkyl group, a C.sub.1-C.sub.7 optionally substituted acyl group, a C.sub.2-C.sub.7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R' is bonded); R'' is H, Cy.sup.1 or (C.dbd.O).sub.z-G, where Cy.sup.1 is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C.sub.1-C.sub.12 alkyl, alkene or alkynyl group (wherein optional substituents include a C.sub.1-C.sub.12 alkyl, alkene or alkynyl group substituted by (N--R.sup.J)--(C.sub.1-C.sub.8 alkyl, alkene or alkynyl group).sub.z-(Cy.sup.2).sub.x, where R.sup.J is H or a C.sub.1-C.sub.8 alkyl, alkene or alkynyl group, z is 0, 1 or 2, x is 0 or 1 and Cy.sup.2 is an optionally substituted aryl or heteroaryl group); RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 are each independently H, F, Cl, Br, I, an optionally substituted C.sub.1-C.sub.12 alkyl, alkene, alkynyl or alkoxy group with the proviso that at least one of RM.sup.1, RM.sup.2, RM.sup.3 and RM.sup.4 is other than H; Linker group L.sup.1D is an optionally substituted alkylene group containing from 1-20 methylene groups; and the pharmaceutically acceptable salts, enantiomers, diastereomers, solvates and polymorphs thereof. 5. A compound of formula IE: ##STR00062## Wherein R.sup.1 and R.sup.1' are each independently H, halo (F, Cl, Br or I), CN, NO.sub.2, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted O--C.sub.1-C.sub.6 alkyl, optionally substituted --(NH)-acyl, optionally substituted C.sub.2-C.sub.7 acyl or optionally substituted C.sub.2-C.sub.7 ester (oxycarbonyl ester or carboxyester, preferably carboxyester); Each RM is independently H, F, Cl, Br, I, an optionally substituted C.sub.1-C.sub.12 alkyl, alkene, alkynyl or alkoxy group with the proviso that at least one RM is other than H; R and R' are each independently H, a C.sub.1-C.sub.6 optionally substituted alkyl group, a C.sub.1-C.sub.7 (preferably C.sub.2-C.sub.7) optionally substituted acyl group, a C.sub.2-C.sub.7 optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R' is bonded); Linker group L.sup.1E is a ##STR00063## group or a ##STR00064## group wherein at least one of the CH.sub.2 groups in L.sup.1E is optionally substituted with an optionally substituted C.sub.1-C.sub.6 alkyl group including a cyclic alkyl group, each of which alkyl groups is optionally substituted, or at least two methylene groups (preferably two adjacent methylene groups) are optionally substituted with alkylene groups to form an optionally substituted C.sub.3-C.sub.8 cycloalkyl group, or linker group L.sup.1E is a (poly)ethylene glycol group having from 1 to 20 ethylene glycol units, each (poly)ethylene glycol group being optionally substituted at one or both of its distal ends with an A group, or L is a linear group containing from 1 to 5 non-contiguous amine groups N--R'', each amine group being separated from an adjacent amine group by an alkylene group containing from 1, 2, 3, 4, 5, 6, 7, or 8 (preferably 2, 3, 4, 5 or 6) methylene groups or an ethylene glycol containing group having from 1 to 6 (preferably 2 to 6, 3 to 6 or 4, 5 or 6) ethylene glycol units; X is absent, (CH.sub.2).sub.jO, or N--R''; Y is absent, CH.sub.2, O, CH.sub.2O or N--R'' and Y' is absent CH.sub.2, O, OCH.sub.2 or N--R'', with the proviso that when one or more of X, Y, and Y' is present, each of X and Y, X and Y' or Y and Y', when present, forms a stable bond; R'' is H or an optionally substituted C.sub.1-C.sub.6 alkyl group or an amine protecting group; each j is independently 1, 2, 3, 4, 5 or 6; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 with the proviso that when n is 0, X is (CH.sub.2).sub.j where j is at least 1 and at least one CH.sub.2 group is optionally substituted, preferably with a C.sub.1-C.sub.3 alkyl group which itself is optionally substituted with one or two hydroxyl groups or one, two, or three halo groups; A is absent, C.dbd.O or (CH.sub.2).sub.j and A' is C.dbd.O or (CH.sub.2).sub.j wherein at least one CH.sub.2 group in A or A' is optionally substituted, preferably with a C.sub.1-C.sub.3 alkyl group which is itself optionally substituted; Z is O or N--R.sup.Z; R.sup.Z is H or an optionally substituted C.sub.1-C.sub.3 alkyl group, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof. 6. The compound according to claim 5 wherein at least two of RM are other than H. 7. The compound according to claim 5 wherein R.sup.1 and R.sup.1' are each independently H or a halo group. 8. The compound according to claim 5 wherein L is a C.sub.6-C.sub.20 alkylene group. 9. The compound according to claim 5 wherein L is a (poly)ethylene glycol group having from 1 to 20 ethylene glycol units optionally substituted at one or both distal ends of said (poly)ethylene glycol group with an A group. 10. A compound according to claim 5 wherein L is a linear group containing from 1 to 5 non-contiguous amine groups N--R'', each amine group being separated from an adjacent amine group by an alkylene group containing 1, 2, 3, 4, 5, 6, 7, or 8 methylene groups or an ethylene glycol containing group containing 1, 2, 3, 4, 5 or 6 ethylene glycol units. 11. A compound according to claim 5 wherein R.sup.1 and R.sup.1' are Cl, or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. 13. The composition according to claim 12 further comprising an effective amount of at least one additional anticancer agent. 14. The composition according to claim 13 wherein said anticancer agent is a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody or a mixture thereof. 15. The composition according to claim 13 wherein said anticancer agent is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461.364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd21:71, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIC 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR.sub.1 KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]- benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH.sub.2 acetate [C.sub.59H.sub.84N.sub.18Oi.sub.4-(C.sub.2H.sub.4O.sub.2).sub.X where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate; prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, sspegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib and mixtures thereof. 16. A method of inhibiting autophagy in a biological system in which inhibition of autophagy is desired, said method comprising exposing said biological system to an effective amount of at least one compound according to claim 1 hereof. 17. A method of inhibiting or treating cancer in a patient in need comprising administering to said patient an effective amount of at least one composition according to claim 12. 18. The method according to claim 17, wherein said cancer is metastatic, recurrent and/or drug resistant. 19. The method according to claim 17, wherein said cancer is a carcinoma, cancer of the esophagus, head, kidney, liver, lung, nasopharyngeal, neck, ovary, pancreas, prostate, and stomach; a leukemia, a malignant lymphoma, a malignant melanoma; myeloproliferative diseases; a sarcoma, a tumor of the central nervous system, a germ-line tumor, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma, or a mixed type of neoplasia. 20. The method according to claim 19, wherein said leukemia is acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia, said lymphoma is Burkitt's lymphoma, Non-Hodgkin's lymphoma or B-cell lymphoma, said sarcoma is Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma or synovial sarcoma, said tumor of the central nervous system is a glioma, astrocytoma, oligodendroglioma, ependymoma, gliobastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, or Schwannoma, said germ-line tumor is bowel cancer, breast cancer, prostate cancer, cervical cancer or uterine cancer, said lung cancer is small cell lung cancer, mixed small cell and non-small cell cancer, pleural mesothelioma, metastatic pleural mesothelioma, small cell lung cancer or non-small cell lung cancer, said mixed neoplasia is carcinosarcoma or Hodgkin's disease and said tumors of mixed origin is Wilms' tumor and teratocarcinomas, or said cancer is colon, head and neck or melanoma. 21. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 1 to said patient and wherein said disease state or condition is cancer or malaria. 22. The method according to claim 21, wherein said disease state or condition is malaria. 23. The method according to claim 21, wherein said disease state is cancer. 24. The compound Lyso-19, Lyso-20, Lyso-21, Lyso-23, Lyso-25, Lyso-26, Lyso-27, Lyso-28, Lyso-29, Lyso-30, Lyso-31, Lyso-32, Lyso-33, Lyso-36 or Lyso-37 of FIG. 12 hereof, or the compound Lys 40, Lys 41, Lys 86, Lys 87, Lys 90, Lys 91, Lys 94, Lys 95, Lys 96 or Lys 97 of FIG. 13 hereof, or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 2 in combination with a pharmaceutically acceptable carrier, additive or excipient. 26. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 24 in combination with a pharmaceutically acceptable carrier, additive or excipient. 27. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 2 to said patient and wherein said disease state or condition is cancer or malaria. 28. The method according to claim 27, wherein said disease state or condition is malaria. 29. The method according to claim 27, wherein said disease state is cancer. 30. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 3 to said patient and wherein said disease state or condition is cancer or malaria. 31. The method according to claim 30, wherein said disease state or condition is malaria. 32. The method according to claim 30, wherein said disease state is cancer. 33. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 21 to said patient and wherein said disease state or condition is cancer or malaria. 34. The method according to claim 33, wherein said disease state or condition is malaria. 35. The method according to claim 33, wherein said disease state is cancer. 36. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 4 to said patient and wherein said disease state or condition is cancer or malaria. 37. The method according to claim 36, wherein said disease state or condition is malaria. 38. The method according to claim 36, wherein said disease state is cancer. 39. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 5 to said patient and wherein said disease state or condition is cancer or malaria. 40. The method according to claim 39, wherein said disease state or condition is malaria. 41. The method according to claim 39, wherein said disease state is cancer. 42. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 7 to said patient and wherein said disease state or condition is cancer or malaria. 43. The method according to claim 42, wherein said disease state or condition is malaria. 44. The method according to claim 42, wherein said disease state is cancer. 45. A method of treating a disease state or condition in a patient in need wherein said disease state or condition responds favorably to inhibition of autophagy comprising administering to said patient an effective amount of a compound according to claim 24 to said patient and wherein said disease state or condition is cancer or malaria. 46. The method according to claim 45, wherein said disease state or condition is malaria. 47. The method according to claim 45, wherein said disease state is cancer. 48. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 3 in combination with a pharmaceutically acceptable carrier, additive or excipient. 49. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 4 in combination with a pharmaceutically acceptable carrier, additive or excipient. 50. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 5 in combination with a pharmaceutically acceptable carrier, additive or excipient.

Details for Patent 10,221,140

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2034-08-08
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	06/21/1989		2034-08-08
Merck Teknika Llc	N/A	bcg vaccine	For Injection	103050	06/21/1989		2034-08-08
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2034-08-08