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 
       
       
         
           
           
               
               
           
         
          group or 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 ) j  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 . The compound according to  claim 1 , wherein R 1  and R 1′  are each independently H, a halo group, a nitro group or a trifluoromethyl group. 
     
     
         3 . The compound according to  claim 1  wherein R and R′ are each independently H, a C 1 -C 3  alkyl group substituted with at least one hydroxyl group, alkoxy group, an amine, monoalkyl amine or dialkyl amine group, wherein said amine group or said monoalkyl amine group is optionally substituted on the amine position with a 7-substituted-4-quinolinyl group wherein the amine binds to the 4-position of the quinolinyl group and the 7 position of said quinolinyl group is substituted by R 1  or R1′ of  claim 1 , or one or both alkyl groups of said monoalkyl amine or dialkyl amine is itself further optionally substituted with at least one hydroxyl group, alkoxy group, an amine, a monoalkyl amine, a dialkyl amine wherein the amine or monoalkyl amine is optionally substituted on the amine position with one or two 7-substituted-quinolinyl group(s) wherein the amine binds to the 4-position of the quinolinyl group and the 7 position of said quinolinyl group is substituted by R 1  or R1′ of  claim 1 , and each of said alkoxy groups may be further substituted with an alkoxy group, preferably a methoxy group (thus forming a diether substituent). 
     
     
         4 . The compound according to  claim 1  wherein L is a 
       
         
           
           
               
               
           
         
       
       group, where X is N—R″; n is 1, 2, or 3; Y and Y′ are each independently absent or CH 2 ; and R″ is H or a C 1 -C 3  alkyl group which is optionally substituted with at least one hydroxyl group, an alkoxy group, an amine, monoalkyl amine, dialkyl amine group, wherein said amine group or said monoalkyl amine group is optionally substituted on the amine position with a 7-substituted-4-quinolinyl group wherein the amine binds to the 4-position of the quinolinyl group and the 7 position of said quinolinyl group is substituted by R 1  or R1′ of  claim 1 , or one or both alkyl groups of said monoalkyl amine or dialkyl amine is itself further optionally substituted with at least one hydroxyl group, alkoxy group, an amine, a monoalkyl amine or a dialkyl amine wherein the amine or monoalkyl amine is optionally substituted on the amine position with one or two 7-substituted-quinolinyl group(s) wherein the amine binds to the 4-position of the quinolinyl group and the 7 position of said quinolinyl group is substituted by R 1  or R1′ of  claim 1 , and each of said alkoxy group may be further substituted with a second alkoxy group, thus forming a diether substituent. 
     
     
         5 . A compound according to  claim 3  wherein said C 1 -C 3  alkyl group is substituted with an amine group which itself is substituted with one 7-substituted-4-quinolinyl group. 
     
     
         6 . The compound according to  claim 5  wherein said alkyl group is a C 2  alkyl group. 
     
     
         7 . The compound according to  claim 3  wherein said C 1 -C 3  alkyl group is substituted with an alkoxy group which itself is substituted with a second alkoxy group thus forming a diether group. 
     
     
         8 . The compound according to  claim 7  wherein said second alkoxy group is a methoxy group or an ethoxy group. 
     
     
         9 . A compound as depicted in Scheme 1 or Scheme 3-10 hereof. 
     
     
         10 . A compound of  claim 9  which is any one of compounds 28-40 of scheme 3 hereof. 
     
     
         11 . A compound of  claim 9  which is any one of compounds 41-46 of scheme 4 hereof. 
     
     
         12 . A compound of  claim 9  which is either of compounds 47-48 of scheme 5 hereof. 
     
     
         13 . A compound of  claim 9  which is either of compounds 49-50 of scheme 6 hereof. 
     
     
         14 . A compound of  claim 9  which is any one of compounds 51-58 of scheme 7 hereof. 
     
     
         15 . A compound of  claim 9  which is any one of compounds 63-70 of scheme 8 hereof. 
     
     
         16 . A compound of  claim 9  which is any one of compounds 71-78 of scheme 9 hereof. 
     
     
         17 . A compound of  claim 9  which is any one of compounds 79-82 of scheme 10 hereof. 
     
     
         18 . A compound according to  claim 9  which is compound 3 of scheme 1 hereof. 
     
     
         19 . A compound as depicted in  FIG. 14 ,  15  or  15 A hereof. 
     
     
         20 . The compound:
 N 1 -(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 2 -methylethane-1,2-diamine;   N 1 -(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)amino)ethyl)ethane-1,2-diamine;   N,N′-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(7-chloroquinolin-4-amine);   N′-(7-methoxyquinolin-4-yl)-N 2 -(2-((7-methoxyquinolin-4-yl)amino)ethyl)-N 2 -methylethane-1,2-diamine;   N,N-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(7-chloroquinolin-4-amine);   N 1 -(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 2 -methylethane-1,2-diamine trihydrochloride;   N 1 -(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)(methyl)amino)ethyl)-N 1 ,N 2 -dimethylethane-1,2-diamine;   N,N-((methylazanediyl)bis(ethane-2,1-diyl))bis(N-(7-chloroquinolin-4-yl)acetamide);   (S)—N 2 -(7-chloroquinolin-4-yl)-N—((S)-2-((7-chloroquinolin-4-yl)amino)propyl)-N-methylpropane-1,2-diamine;   2-(bis(2-((7-chloroquinolin-4-yl)amino)ethyl)amino)ethanol;   N 1 -(7-chloroquinolin-4-yl)-N 2 ,N 2 -bis(2-((7-chloroquinolin-4-yl)amino)ethyl)ethane-1,2-diamine, or   a pharmaceutically acceptable salt thereof.   
     
     
         21 . The compound according to  claim 1  which is N 1 -(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 2 -methylethane-1,2-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound according to  claim 1  which is N′-(7-chloroquinolin-4-yl)-N 2 -(2-((7-chloroquinolin-4-yl)amino)ethyl)-N 2 -methylethane-1,2-diamine trihydrochloride. 
     
     
         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 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         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, PIA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amnrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL 13-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, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methyl sulfonylpiperadinemethyl)-indolyl]-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 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, Ionafamib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SUI 1248, 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, fluoxylnesterone, 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-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD 121974, 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 inhibitor, 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)