Demethylpenclomedine analogs and their use as anti-cancer agents

Abstract

This disclosure concerns novel demethylpenclomedine analogs. Also disclosed are pharmaceutical compositions and methods for using such compositions to treat hyperproliferative disorders. In one embodiment the analogs are represented by the formula

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, 
         wherein R is an optionally substituted lower alkyl group; 
         X is O or N(R 1 ) 
         G is one of —C(O)OR 2 ; —C(O)SR 2 ; —C(O)NR 3 R 4 ; 
         R 1  is hydrogen or optionally substituted aliphatic; 
         R 2  is optionally substituted aliphatic, optionally substituted aromatic, optionally substituted heterocyclic, optionally substituted heteroaromatic, optionally substituted aralkyl or combinations thereof; and 
         R 3  and R 4  independently are H, optionally substituted aliphatic, optionally substituted aromatic, optionally substituted heterocyclic, optionally substituted heteroaromatic, optionally substituted aralkyl or combinations thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein X is O. 
     
     
         3 . The compound of  claim 1 , wherein G is one of —C(O)OR 2  or —C(O)NR 3 R 4 . 
     
     
         4 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         8 . A method for treating a subject having a hyperproliferative disorder, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         9 . The method of  claim 8 , comprising administering from about 1 mg/m 2  to about 200 mg/m 2  to the subject per day. 
     
     
         10 . The method of  claim 8 , comprising administering from about 5 mg/m 2  to about 100 mg/m 2  to the subject per day. 
     
     
         11 . The method of  claim 8 , comprising administering from about 10 mg/m 2  to about 50 mg/m 2  to the subject per day. 
     
     
         12 . The method of  claim 8  wherein the hyperproliferative disorder comprises brain cancer, breast cancer, bladder cancer, bone cancer, cervical cancer, colon cancer, central nervous system cancer, esophageal cancer, gall bladder cancer, gastrointestinal cancer, head and neck cancer, Hodgkin's Disease, non-Hodgkin's lymphomas, laryngeal cancer, leukemia, lung cancer, melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, retinoblastoma, stomach cancer, testicular cancer, Wilms' tumor or a combination thereof. 
     
     
         13 . The method of  claim 8 , wherein the hyperproliferative disorder comprises a brain tumor. 
     
     
         14 . The method of  claim 8 , wherein the hyperproliferative disorder comprises at least one of metastatic breast cancer, lung cancer, sarcoma, colorectal cancer, lymphoma and leukemia to the brain. 
     
     
         15 . The method of  claim 8 , wherein the hyperproliferative disorder comprises metastatic breast cancer to the brain. 
     
     
         16 . The method of  claim 8 , wherein the hyperproliferative disorder comprises a glioblastoma. 
     
     
         17 . The method of  claim 8 , further comprising administering a second compound to the subject. 
     
     
         18 . The method of  claim 17 , wherein the second compound is selected from the microtubule binding agents, DNA intercalators, DNA alkylating agents, DNA cross-linkers, DNA synthesis inhibitors, DNA and/or RNA transcription inhibitors, enzyme inhibitors, gene regulators, enzymes, antibodies and angiogenesis inhibitors. 
     
     
         19 . The method of  claim 17 , wherein the second compound is selected from erotinib, gefitinib, temozolomide, paclitaxel, docetaxel, daunorubicin, cisplatin, carboplatin, oxaliplatin, colchicine, dolastatin 15, nocodazole podophyllotoan, rhizoxin, vinblastine, vindesine, vinorelbine (navelbine), the epothilones, the mitomycins, bleomycin, chlorambucil, carmustine, melphalan, mitoxantrone, 5-fluoro-5′-deoxyuridine, camptothecin, SFTI-1, topotecan, irinotecanetoposide, tenoposide, geldanamycin, methotrexate, adriamycin, actinomycin D, medroxyprogesterone, mifepristone, raloxifene, 5-azacytidine, 5-aza-2′-deoxycytidine, zebularine, tamoxifen, 4-hydroxytamoxifen, apigenin, rapamycin, angiostatin K1-3, L-asparaginase, staurosporine, genistein, fumagillin, endostatin, isophosphoramide mustard, thalidomide and analogs thereof.