Novel bisaminoquinoline compounds, pharmaceutical compositions prepared therefrom and their use

Abstract

The present invention relates to novel bisaminoquinoline compounds, pharmaceutical compositions comprising these novel compounds and methods for inhibiting autophagy in biological systems. Methods of treating cancer in patients in need using compounds and/or compositions according to the present invention alone or in combination with at least one additional anticancer agent represent additional aspects of the invention. Methods of treating disease states and/or conditions in which inhibition of autophagy plays a favorable treatment role including rheumatoid arthritis, malaria, antiphospholipid antibody syndrome, lupus, chronic urticaria and Sjogren's disease, with compounds according to the present invention represent additional aspects of the invention.

1 . A compound according to the chemical structure I 
       
         
           
           
               
               
           
         
         Wherein R 1  and R 1′  are each independently H, halo (F, Cl, Br or I), CN, NO 2 , optionally substituted C 1 -C 6  alkyl (when substituted, preferably substituted with 1 or 2 hydroxyl groups or 3-5 fluoro groups), optionally substituted O—C 1 -C 6  alkyl (preferably, OCH 3 ), optionally substituted C 2 -C 7  acyl (preferably acetyl) or optionally substituted C 2 -C 7  ester (oxycarbonyl ester or carboxyester, preferably carboxyester); 
         R and R′ are each independently H, a C 1 -C 6  optionally substituted alkyl group, a C 1 -C 7  (preferably C 2 -C 7 ) optionally substituted acyl group, a C 2 -C 7  optionally substituted carboxy ester group (which forms a urethane group with the nitrogen atom to which R or R′ is bonded); 
         L is a CH 2 Y n XY′CH 2  n  group or a ACH 2 —CH 2 —Z n -A′ group wherein either A or A′ may be bonded to either of the two amine groups in compound I and wherein at least one of the CH 2  groups in L is optionally substituted with a C 1 -C 3  alkyl group which itself is optionally substituted with one or two hydroxyl groups; 
         X is absent, (CH 2 ) j  O, S or N—R″; 
         Y is absent, CH 2 , O, CH 2 O or N—R″ and Y′ is absent CH 2 , O, OCH 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 1 -C 6  (preferably C 1 -C 3 ) alkyl group; 
         j is 1, 2 or 3 (preferably 1 or 2); 
         n is 0, 1, 2, 3 or 4, with the proviso that when n is 0, X is (CH 2 ) j  where j is at least 1 and at least one CH 2  group is optionally substituted with a C 1 -C 3  alkyl group which itself is optionally substituted with one or two hydroxyl groups; 
         A is absent or (CH 2 ) and A′ is (CH 2 ) j  wherein at least one CH 2  group in A or A′ is optionally substituted with a C 1 -C 3  alkyl group which is itself optionally substituted with one or two hydroxyl groups; 
         Z is O or N—R Z ; 
         R Z  is H or an optionally substituted C 1 -C 3  alkyl group, 
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 
       
     
     
         2 .- 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising an effective amount of at least one compound according to  claim 1  in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in combination with at least one additional anticancer agent. 
     
     
         24 . 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. 
     
     
         25 . A method of inhibiting or treating cancer in a patient in need comprising administering to said patient an effective amount of at least one compound according to  claim 1 , optionally in combination with at least one additional anticancer agent. 
     
     
         26 . The method according to  claim 25  wherein said cancer is metastatic. 
     
     
         27 . The method according to  claim 26  wherein said cancer is a drug-resistant cancer. 
     
     
         28 . A method of reducing the likelihood that cancer will occur in a patient or that a cancer will metastasize in a patient comprising administering at least one compound according to  claim 1 , optionally in combination with at least one additional anticancer agent. 
     
     
         29 . The method according to  claim 25  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, a mixed type of neoplasia, 
     
     
         30 . The method according to  claim 29  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 
     
     
         31 . The method according to  claim 29  wherein said lymphoma is Burkitt's lymphoma, Non-Hodgkin's lymphoma or B-cell lymphoma. 
     
     
         32 . The method according to  claim 29  wherein said sarcoma is Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma or synovial sarcoma. 
     
     
         33 . The method according to  claim 29  wherein 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. 
     
     
         34 . The method according to  claim 29  wherein said germ-line tumor is bowel cancer, breast cancer, prostate cancer, cervical cancer or uterine cancer. 
     
     
         35 . The method according to  claim 29  wherein 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. 
     
     
         36 . The method according to  claim 29  wherein said mixed neoplasia is carcinosarcoma and Hodgkin's disease and said tumors of mixed origin is Wilms' tumor and teratocarcinomas. 
     
     
         37 . The method according to  claim 29  wherein said cancer is ovarian, breast, colon, head and neck, medulloblastoma or B-cell lymphoma, 
     
     
         38 . The method according to  claim 29  wherein said cancer is melanoma or non-small cell lung cancer. 
     
     
         39 . The method according to  claim 25  wherein said additional 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, GSK461364, 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, azd2171, batabulin, of atunmumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 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, tamnoxifen, 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(But) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH 2  acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) 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, arnsacrine, 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. 
     
     
         40 . The method according to  claim 25  wherein said additional 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. 
     
     
         41 . 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. 
     
     
         42 . The method according to  claim 41  wherein said disease state or condition is rheumatoid arthritis, malaria, antiphospholipid antibody syndrome, lupus, chronic urticaria or Sjogren's disease. 
     
     
         43 . The method according to  claim 42  wherein said disease state is malaria. 
     
     
         44 .- 63 . (canceled)