BAX agonist, compositions, and methods related thereto
The disclosure relates to BAX activators and therapeutic uses relates thereto. In certain embodiments, the disclosure relates to methods of treating or preventing cancer, such as lung cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein or pharmaceutically acceptable salt to a subject in need thereof.
1. A compound of Formula IB,
or salt thereof wherein,
Z is O, S, CH 2 , or NH;
W is hydroxy, amino, alkylamino, dialkylamino, aryl, or heterocyclyl wherein W is optionally substituted with one or more R 11 ;
R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are optionally substituted with one or more, the same or different R 10 ;
R 2 is nitro or amino wherein R 2 is optionally substituted with one or more, the same or different R 10 ;
R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different R 11 ;
R 11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different R 12 ; and
R 12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2. The compound claim 1 , wherein R 2 is nitro.
3. The compound of claim 1 , selected from the group:
4-{2-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-morpholine;
1-{2-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-piperazine;
2-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethanol;
2-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethylamine;
4-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-piperidine;
1-(4-Fluoro-benzenesulfonyl)-4-{2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-piperazine;
1-(4-{2-[2-(2-Nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-piperazin-1-yl)-ethanone;
1-Cyclopropanesulfonyl-4-{2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-piperazine; and
1-Methanesulfonyl-4-{2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethyl}-piperazine
or salts thereof.
4. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4 , further comprising a second therapeutic agent.
6. A method of treating breast cancer comprising administering a pharmaceutical composition of claim 4 to a subject diagnosed with, exhibiting symptoms of, or at risk of cancer.
7. The method of claim 6 , wherein the pharmaceutical compositions is administered in combination with a second chemotherapeutic agent.
8. The method of claim 7 , wherein the second chemotherapeutic agent is gefitinib, erlotinib, docetaxel, cis-platin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin, vincristine, vinblastine, vindesine, vinorelbine taxol, taxotere, etoposide, teniposide, amsacrine, topotecan, camptothecin bortezomib, anegrilide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol anastrozole, letrozole, vorazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, bevacizumab, combretastatin, thalidomide, and/or lenalidomide or combinations thereof.