Solenopsin and derivatives, therapeutic compositions, and methods related thereto

Abstract

This disclosure relates to solenopsin derivatives, pharmaceutical compositions, and therapeutic uses related thereto. In certain embodiments, the disclosure relates to compounds of the following formula: or salts, esters or prodrugs thereof as described herein.

1 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or salts, esters, or prodrugs thereof wherein: 
         R 1  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1  is optionally substituted with one or more, the same or different R 10 ; 
         R 2  is a long chain alkyl, hydrocarbon, or hydrophobic group, wherein R 2  is optionally substituted with one or more, the same or different R 10 ; 
         R 3  and R 4  are at each occurrence independently selected from hydrogen or hydroxy; 
         R 5 , R 6 , and R 7  are at each occurrence independently selected from hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 , R 6 , and R 7  are optionally substituted with one or more, the same or different R 10 ; 
         R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, 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 ; and 
         R 11  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 of  claim 1 , wherein R 2  is a hydrocarbon chain comprising between 10 and 23 carbons. 
     
     
         3 . The compound of  claim 1 , wherein R 3  or R 4  is hydrogen and the other is hydroxy. 
     
     
         4 . The compound of  claim 3 , wherein R 2  is a hydrocarbon chain comprising between 9 and 23 carbons. 
     
     
         5 . The compound of  claim 1 , wherein R 5  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 6  and R 7  are at each occurrence independently selected from hydrogen or alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 6  or R 7  are hydrogen and the other is alkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 6  and R 7  are hydrogen. 
     
     
         9 . The compound of  claim 1  selected from:
 2,4-dimethyl-6-nonadecylpiperidine; 
 2-methyl-6-nonadecylpiperidine; 
 2-methyl-6-pentadecylpiperidine; and 
 2-decyl-6-methylpiperidine. 
 
     
     
         10 . The compound of  claim 1  selected from 1-(piperidin-2-yl)decan-1-ol and 1-(6-methylpiperidin-2-yl)decan-1-ol. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claims 1 - 10  and a pharmaceutically acceptable excipient. 
     
     
         12 . A method of treating or preventing cancer comprising administering an effective amount of a pharmaceutical composition of  claim 11  to a subject in need thereof. 
     
     
         13 . The method of  claim 12 , wherein the subject diagnosed with, exhibiting symptoms of, or at risk of actinic keratosis, psoriasis, squamous cell carcinoma or basal cell carcinoma. 
     
     
         14 . The method of  claim 12 , wherein the cancer is venous ulcers, angiogenic disorders of the skin, a hematological malignancy, a leukemia, lymphoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia, acute monocytic leukemia (AMOL), Hodgkin's lymphomas, non-Hodgkin's lymphomas, Burkitt lymphoma, B-cell lymphoma, multiple myelomacervical, ovarian cancer, colon cancer, breast cancer, gastric cancer, lung cancer, melanoma, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, head cancer, neck cancer, and renal cancer. 
     
     
         15 . The method of  claim 12  wherein the compound is administered in combination with a second anti-cancer agent. 
     
     
         16 . The method of  claim 15 , wherein the second anti-cancer 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, anagrelide, 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.