Fulvene and fulvalene analogs and their use in treating cancers

Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are fulvene and/or fulvalene analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, as well as numerous inflammatory, degenerative and vascular diseases, including various ocular diseases. Representative fulvene and/or fulvalene analogs include fulvene and fulvalene analogues of various dyes, hormones, sugars, peptides, oligonucleotides, amino acids, nucleotides, nucleosides, and polyols. The compounds are believed to function, at least, by inhibiting Nox or ROS. In some embodiments, the Nox is one that is selectively expressed in cancer cells over normal cells, or one that is expressed in higher amounts in cancer cells over normal cells. Thus, the compounds are novel therapeutic agents for a variety of cancers and other diseases.

1 . A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a composition comprising a fulvene or fulvalene-containing therapeutic agent in an amount sufficient to inhibit a therapeutically significant amount of NOX or ROS expression, such that the growth of the tumor is at least partially inhibited. 
     
     
         2 . The method of  claim 1  wherein the mammal is a human. 
     
     
         3 . The method of  claim 1  wherein the cancer is selected from a group consisting of hemangioma, melanoma, rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, colon carcinoma, chronic lymphocytic carcinoma, hairy cell leukemia, osophogeal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma. 
     
     
         4 . The method of  claim 1 , wherein the cancer is a metastasized cancer. 
     
     
         5 . The method of  claim 1  wherein the human is immunosuppressed by reason of having undergone anti-cancer therapy prior to administration of the composition. 
     
     
         6 . The method of  claim 1 , wherein the cancer is manifested in the form of a solid tumor having cells that express one or more NOX enzymes at concentrations higher than those expressed in a non-cancer cell. 
     
     
         7 . The method of  claim 6 , wherein the tumor is a tumor of epithelial tissue, lymphoid tissue, connective tissue, bone, or the central nervous system. 
     
     
         8 . The method of  claim 1 , wherein the compounds are administered parenterally, orally, or directly into the tumor. 
     
     
         9 . The method of  claim 1 , wherein the compounds are administered via an implanted device. 
     
     
         10 . The method of  claim 1 , wherein the administration is provided using a sustained release formulation. 
     
     
         11 . The method of  claim 1 , wherein compound has one of the following formulas: 
       
         
           
           
               
               
           
         
         wherein: 
         X is O, S, NH or CH 2 , 
         x and y are integers of from 0 to 3, 
         G is selected from the group consisting of C 1-6  alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O) R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6  alkyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl. 
       
     
     
         12 . The method of  claim 1 , wherein the compound has one of the following formulas: 
       
         
           
           
               
               
           
         
         with the proviso that at least one of R is other than H. 
       
     
     
         13 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method for treating an ocular disorder, comprising administering to a mammal a fulvene or fulvalene-containing compound in an amount sufficient to treat the ocular disorder. 
     
     
         15 . The method of  claim 14 , wherein the amount of the fulvene or fulvalene-containing compound is sufficient to inhibit a therapeutically significant amount of NADPH oxidase. 
     
     
         16 . The method of  claim 14 , wherein the mammal is a human. 
     
     
         17 . The method of  claim 14 , wherein the ocular disorder is selected from the group consisting of wet or dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, cataract, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, ocular allergy, and dry eye. 
     
     
         18 . The method of  claim 14 , wherein the compound is administered by topical administration in the form of eye drops or other suitable topical formulations for direct administration to the eye. 
     
     
         19 . The method of  claim 14 , wherein the compound is administered by subconjunctival injection, periocular injection, or intravitreal injection. 
     
     
         20 . The method of  claim 14 , wherein the compound is administered by surgical implant. 
     
     
         21 . The method of  claim 14 , wherein the compound is administered by systemic administration or by iontophoresis. 
     
     
         22 . The method of  claim 14 , wherein the administration is provided using a sustained release formulation. 
     
     
         23 . The method of  claim 14 , wherein compound has one of the following formulae: 
       
         
           
           
               
               
           
         
         wherein: 
         X is O, S, NH or CH 2 , 
         x and y are integers of from 0 to 3, 
         G is selected from the group consisting of C 1-6  alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O) R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6  alkyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl. 
       
     
     
         24 . The method of  claim 14 , wherein the compound has one of the following formulae: 
       
         
           
           
               
               
           
         
         with the proviso that at least one of R is other than H. 
       
     
     
         25 . The method of  claim 14 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . A compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         wherein: 
         X is O, S, NH or CH 2 , 
         x and y are integers of from 0 to 3, 
         G is selected from the group consisting of C 1-6  alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O) R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6  alkyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl. 
       
     
     
         27 . A compound of any of the following formulae: 
       
         
           
           
               
               
           
         
         with the proviso that at least one of R is other than H. 
       
     
     
         28 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . A compound of the formulae: 
       
         
           
           
               
               
           
         
         wherein R′ is selected from the group consisting of H, C 1-6  straight chain, branched, or cyclic alkyl, aryl, arylalkyl, or alkylaryl.