Dimeric Quinacrine Derivatives As Autophagy Inhibitors For Cancer Therapy

Abstract

The invention provides dimeric quinacrine derivatives and related compounds and compositions, methods of treatment and syntheses. The novel compounds exhibit unexpected anticancer activity and are useful in the treatment of a variety of autophagy-related disorders.

1 . A compound of Formula I according to the chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′  and R 8′  are each independently H, halogen (F, Cl, Br or I) CN, NO 2 , OH, COOH, an optionally substituted C 1 -C 6  alkyl, an optionally substituted O—C 1 -C 6  alkyl, an optionally substituted C 1 -C 7  acyl, NR A R B  where R A  and R B  are each independently H, an optionally substituted C 1 -C 6  alky group or an optionally substituted —C 1 -C 7  acyl group, an optionally substituted C 2 -C 7  ester, —SO 2 NR A R B , where R A  and R B  are the same as above, —SO 3 R S  or SO 4 R, where R S  is H or an optionally substituted C 1 -C 6  alkyl; 
         R and R′ are each independently H, a C 1 -C 6  optionally substituted alkyl group, a C 1 -C 7  optionally substituted acyl group or a C 2 -C 7  optionally substituted carboxy ester group; and 
         L is a linker group which covalently links the two exocyclic amine groups at the 9 position of the acridine moiety to each other, 
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof. 
       
     
     
         2 . The compound according to  claim 1  according to the chemical structure IA: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 1′ , R 2′ , R 3′  and R 4′  are each independently H, halogen (F, Cl, Br or I) CN, NO 2 , OH, COOH, an optionally substituted C 1 -C 6  alkyl, optionally substituted O—C 1 -C 6  alkyl, optionally substituted C 1 -C 7  preferably C 2 -C 7  acyl, NR A R B  where R A  and R B  are each independently H or an optionally substituted C 1 -C 6  alky group, an optionally substituted C 1 -C 7  acyl or an optionally substituted C 2 -C 7  ester, —SO 2 NR A R B , where R A  and R B  are the same as above, —SO 3 R S  or SO 4 R S , where R S  is H or an optionally substituted C 1 -C 6  alkyl; R and R′ are each independently H, a C 1 -C 6  optionally substituted alkyl group, a C 1 -C 7  optionally substituted acyl group, a C 2 -C 7  optionally substituted carboxy ester group; 
         L is a linker group —(CH 2 Y) n —X—(Y′CH 2 ) n  or A-(CH 2 —CH 2 —Z) n -A′ wherein at least one of the CH 2  groups in L is optionally substituted; 
         X is absent, (CH 2 ) 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, an optionally substituted C 1 -C 12  alkyl group, Cy 1  or (C═O) z -G, where Cy 1  is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group, z is 0, 1, 2, 3, 4 or 5; 
         j is 1, 2, 3, 4 or 5; 
         Each n is independently an integer between 0-20, with the proviso that when each n is 0, X is (CH 2 ) j  where j is at least 1 and at least one CH 2  group is optionally substituted; 
         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; 
         Z is O or N—R Z ; and 
         R z  is H or an optionally substituted C 1 -C 3  alkyl group, 
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof. 
       
     
     
         3 . The compound according to  claim 1  wherein L is a group —(CH 2 Y) n —X—(Y′CH 2 ) n  or A-(CH 2 —CH 2 —Z) n -A′ wherein at least one of the CH2 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, an optionally substituted C 1 -C 12  alkyl group, Cy′ or (C═O) z -G, where Cy 1  is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group, wherein optional substituents include a C 1 -C 12  alkyl, alkene or alkynyl group substituted by (N—R J )—(C 1 -C 8  alkyl, alkene or alkynyl group) z -(Cy 2 ) x , where R J  is H or a C 1 -C 8  alkyl, alkene or alkynyl group, z is 0, 1, 2, 3, 4 or 5, x is 0 or 1 and Cy 2  is an optionally substituted aryl or heteroaryl group; 
 j is 1, 2, 3, 4 or 5; 
 Each n is independently an integer between 0-20, with the proviso that when each 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 ; and 
 R z  is H or an optionally substituted C 1 -C 3  alkyl group, 
 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof 
 
     
     
         4 . The compound according to  claim 1  wherein L is a —(CH 2 Y) n —X—(Y′CH 2 ) n — group, where X is N—R″, 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 or dialkyl amine group, wherein said amine group or said monoalkyl amine group is optionally substituted on the amine position with one or two 7-substituted-4-quinolinyl group or one or two optionally substituted 9-aminoacridinyl groups wherein the amine binds to the 4-position of the quinolinyl group or the 9-position of the optionally substituted acridinyl group(s), or one or both alkyl groups of said monoalkyl amine or dialkyl amine is itself further optionally substituted with at least one hydroxyl group, an 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) or one or two optionally substituted 9-aminoacridinyl groups, wherein the amine binds to the 4-position of the quinolinyl group or the 9-position of the acridinyl group and the 9-aminoacridinyl group is optionally substituted as broadly described for generic structure I above; and
 each n is independently an integer from 1 to 15, 
 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvent or polymorph thereof. 
 
     
     
         5 . The compound according to  claim 1  wherein L is a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where R″ is H, an optionally substituted C 1 -C 12  alkyl group, Cy or (C═O) z -G, where Cy 1  is an optionally substituted cycloalkyl, aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group; 
         z is 0, 1, 2, 3, 4 or 5; 
         and 
         p and q are each independently an integer between 1 and 15, with at least one of p or q preferably being at least 2; or 
         a pharmaceutically acceptable salt, enantiomers, diastereomers, solvents or polymorph thereof. 
       
     
     
         6 . The compound according to  claim 1 , wherein L is a moiety according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where each R″ is independently H, a C 1 -C 12  optionally substituted alkyl group, Cy 1  or (C═O) z -G, where Cy 1  is an optionally substituted C 5 -C 7  cycloalkyl or an optionally substituted aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group; 
         z is 0, 1, 2, 3, 4 or 5; and 
         p′ is an integer from 1-10, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 
         p″ and q′ are each independently an integer from 2-10, and preferably at least one of p′, p″ or q′ is different, or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 
       
     
     
         7 . The compound according to  claim 1  wherein L is a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         wherein each 
       
       
         
           
           
               
               
           
         
       
       is independently an optionally substituted fully or partially saturated 4-7 membered carbocyclic group optionally substituted with up to 5 hydroxyl or 5 halo groups, or an optionally substituted phenyl group;
 X L  is CR CYC R CYC , O or NR CYC    
 where R CYC  is H or a C 1 -C 12  optionally substituted alkyl group, Cy 1  or (C═O) z -G, where Cy 1  is an optionally substituted C 5 -C 7  cycloalkyl or an optionally substituted aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group; and 
 z is 0, 1, 2, 3, 4 or 5 or 
 a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 
 
     
     
         8 . The compound according to  claim 1  wherein L is a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         wherein D, E and F are each independently CH 2 , CH 2 CH 2 , O or NR with the proviso that O is not bonded to NR directly or through a single methylene group nor is NR bonded to another NR or X when X is NR CYC  directly or through a single methylene group and; 
         R is H or a C 1 -C 12  optionally substituted alkyl group; 
         X is CR CYC R CYC , O or NR CYC ; and 
         R CYC  is H or a C 1 -C 12  optionally substituted alkyl group, Cy 1  or (C═O) z -G, where Cy 1  is an optionally substituted C 5 -C 7  cycloalkyl or an optionally substituted aryl or heteroaryl group, G is H or an optionally substituted C 1 -C 12  alkyl, alkene or alkynyl group; and 
         z is 0, 1, 2, 3, 4 or 5, or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 
       
     
     
         9 . The compound according to  claim 1  wherein L is a group according to the chemical structure: 
       
         
           
           
               
               
           
         
         Where Z is CHR or O; 
         R is H or a C 1 -C 12  optionally substituted alkyl group; and 
         p and q are each independently an integer between 1 and 15 with at least one of p or q preferably being at least 2 where Z is O) or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. 
       
     
     
         10 . The compound according to  claim 1  wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′  and R 8′  are each independently H, halo (F, C, Br, I), CH 3 , CF 3 , OH, COOH, NH 2 , NO 2 , CN, C(O)CH 3 , OCH 3 , CH 2 OH, SO 2 NH 2  and SO 3 H. In certain preferred embodiments according to the present invention, R 1 , R 2 , R 3 , R 4  and R 1′ , R 2′ , R 3′ , R 4′ , are each independently H, F, Cl, CH 3 , CF 3 , OH, COOH, NH 2 , NO 2 , CN, C(O)CH 3 , OCH 3  and CH 2 OH. 
     
     
         11 . The compound according to  claim 1  wherein R 1 , R 2 , R 3 , R 4  and R 1′ , R 2′ , R 3′ , R 4′  are each independently H, F, C or OCH 3 . 
     
     
         12 . The compound according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4  and R 1′ , R 2′ , R 3′ , R 4′  are each independently H, F, C or OCH 3  and R 5 , R 6 , R 7 , R 8 , R 5′ , R 6′ , R 7′  and R 8′  are each H. 
     
     
         13 . The compound according to  claim 1 , wherein one of R 1  and R 2  and R 1′  and R 2′  is C and one of R 3  and R 4  and R 3  and R 4′  is OCH 3  and the remaining substituents on the acridine ring are hydrogen. 
     
     
         14 . The compound according to  claim 4  wherein R″ is H or CH 3  and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and
 Y and Y′ are absent or CH 2 . 
 
     
     
         15 . The compound according to  claim 1  or  2  which is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . A pharmaceutical composition comprising an effective amount of at least one compound according to  claim 1 , optionally in combination with an additional autophagy modulator compound and/or an additional bioactive agent, further in combination with a pharmaceutically acceptable carrier, additive and/or excipient. 
     
     
         17 . The pharmaceutical composition according to  claim 16  wherein said autophagy modulator is a bis-4-aminoiquinoline autophagy modulator as disclosed in PCT/US2012/35251 (WO/2012/149186) or PCT/US2015/044282 (WO2016/022956). 
     
     
         18 . The pharmaceutical composition according to  claim 16  or  17  wherein said additional bioactive agent is an anticancer agent 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, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimurnab, 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, tarnoxifen, 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 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, lonafamib, 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, raltinexed, 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-hydroxytarnoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-0-(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. 
     
     
         19 . The pharmaceutical composition according to  claim 15  or  16  wherein said additional bioactive agent is an anticancer agent selected from the group consisting of 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 Bc1-2 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. 
     
     
         20 . 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  or at least one composition according to  claim 16 . 
     
     
         21 .- 57 . (canceled)