Therapeutic applications of pro-apoptotic benzodiazepines

Abstract

Benzodiazepine compounds, and methods for using those compounds are provided. Some of the benzodiazepine compounds include 1,4-benzodiazepine-2-one and 1,4-benzodiazepine-2,5-dione compounds of the following structures: wherein R 1 , R 2 , R 3 and R 4 are as defined. The invention also includes enantiomers, pharmaceutically acceptable salts, prodrugs or derivatives of the benzodiazepine compounds. Any one or more of these benzodiazepine compounds can be used to treat a variety of dysregulatory disorders related to cellular death. Such disorders include autoimmune disorders, inflammatory conditions, hyperproliferative conditions, viral infections, and atherosclerosis. In addition, the above compounds can be used to prepare medicaments to treat the above-described dysregulatory disorders. The benzodiazepines can also be used in drug screening assays and other diagnostic methods.

1 - 129 . (canceled)  
     
     
         130 . A method of treating cancer, comprising administering to a subject an effective amount of a benzodiazepine compound having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         131 . The method of  claim 130 , further comprising co-administering one or more additional agents to the subject.  
     
     
         132 . The method of  claim 131 , wherein the additional agent is a chemotherapeutic agent or radiation.  
     
     
         133 . The method of  claim 130 , wherein the compound is administered orally, parenterally, topically or intranasally.  
     
     
         134 . The method of  claim 130 , wherein said cancer comprises neuroblastoma cells.  
     
     
         135 . The method of  claim 136 , wherein said treating comprises inhibiting the growth rate of said neuroblastoma cells.  
     
     
         136 . A method of treating graft-versus-host-disease, comprising administering to a subject an effective amount of a benzodiazepine compound having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         137 . The method of  claim 136 , further comprising co-administering one or more additional agents to the subject.  
     
     
         138 . The method of  claim 137 , wherein said one or more additional agents is selected from the group consisting of immunosuppressive agents, antimetabolite and/or chemotherapeutic agents, antibody and/or Ig agents, immunomodulating agents, and photoactive agents.  
     
     
         139 . The method of  claim 138 , wherein said immunosuppressive/cytotoxic agents are selected from the group consisting of methylprednisolone, prednisone, cyclosporin, sirolimus, tacrolimus, and mycophenolate mofetil.  
     
     
         140 . The method of  claim 138 , wherein said antimetabolite and/or chemotherapeutic agents are selected from the group consisting of methotrexate, and azathioprine.  
     
     
         141 . The method of  claim 138 , wherein said antibody and/or Ig agents is selected from the group consisting of antithymocyte globulin, IVIG, alemtuzumab and muromonab-CD3.  
     
     
         142 . The method of  claim 138 , wherein said immunomodulating agents comprise thalidomide.  
     
     
         143 . The method of  claim 138 , wherein said photoactive agents comprise methoxsalen.  
     
     
         144 . The method of  claim 138 , wherein the compound is administered orally, parenterally, topically or intranasally.  
     
     
         145 . A method of treating rheumatoid arthritis, comprising administering to a subject an effective amount of a benzodiazepine compound having the structure:  
       
         
           
           
               
               
           
         
       
     
     
         146 . The method of  claim 145 , further comprising co-administering one or more additional agents to the subject.  
     
     
         147 . The method of  claim 145 , wherein said one or more additional agents is selected from the group consisting of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, disease-modifying agents, immunomodulators, glucocorticoids, and interleukin-1 receptor inhibitors.  
     
     
         148 . The method of  claim 147 , wherein said nonsteroidal anti-inflammatory drugs comprise ibuprofen.  
     
     
         149 . The method of  claim 147 , wherein said cyclooxygenase-2 (COX-2) inhibitors comprise celecoxib.  
     
     
         150 . The method of  claim 147 , wherein said disease-modifying agents are selected from the group consisting of methotrexate, leflunomide, azathioprine, sulfasalazine, infliximab, adalimumab, and etanercept.  
     
     
         151 . The method of  claim 147 , wherein said immunomodulators comprise abatacept.  
     
     
         152 . The method of  claim 147 , wherein said glucocorticoids comprise prednisone.  
     
     
         153 . The method of  claim 147 , wherein said interleukin-1 receptor inhibitors anakinra.  
     
     
         154 . The method of  claim 145 , wherein the compound is administered orally, parenterally, topically or intranasally.