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 - 154 . (canceled) 
   
   
       155 . A method of treating a disorder selected from the group consisting of an immune disorder, a hyperproliferative disorder, and a chronic inflammatory condition, comprising administering an effective amount of a benzodiazepine compound to a subject suffering from said immune disorder, said hyperproliferative disorder, or said chronic inflammatory condition. 
   
   
       156 . The method of  claim 155 , wherein said benzodiazepine comprises the following formula: 
     
       
         
         
             
             
         
       
     
     including a salt or ester thereof, or an enantiomer or a racemic mixture thereof;
 wherein R 1  is aliphatic or aryl; 
 wherein R 2  is aliphatic, aryl, —NH 2 , —NHC(═O)—R 5 , or a moiety that participates in hydrogen bonding; 
 wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, halo, amino, lower-alkyl-substituted-amino, acetylamino, hydroxyamino, an aliphatic group having 1-8 carbons and 1-20 hydrogens, aryl, and heterocyclic; 
 wherein R 5  is aryl, heterocyclic, —R 6 —NH—C(═O)—R 7  or —R 6 —C(═O)—NH—R 7 ; 
 wherein R 6  is an aliphatic linker of 1-6 carbons; and 
 wherein R 7  is aliphatic, aryl, or heterocyclic. 
 
   
   
       157 . The method of  claim 156 , wherein R 1  is a methyl. 
   
   
       158 . The method of  claim 156 , wherein R 2  is a substituted aryl. 
   
   
       159 . The method of  claim 156 , wherein the R 4  is a halogen. 
   
   
       160 . The method of  claim 159 , wherein the halogen is a chlorine. 
   
   
       161 . The method of  claim 156 , wherein R 3  is a hydroxyl. 
   
   
       162 . The method of  claim 155 , wherein said benzodiazepine comprises the following formula: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is aliphatic, aryl, —NH 2 , —NHC(═O)—R 5 , or a moiety that participates in hydrogen bonding. 
   
   
       163 . The method of  claim 155 , wherein said benzodiazepine comprises the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       164 . The method of  claim 155 , wherein the disorder is an immune disorder selected from the group consisting of graft versus host disease, rheumatoid arthritis, and systemic lupus erythematosus. 
   
   
       165 . The method of  claim 162 , wherein the disorder is an immune disorder selected from the group consisting of graft versus host disease, rheumatoid arthritis, and systemic lupus erythematosus. 
   
   
       166 . The method of  claim 163 , wherein the disorder is an immune disorder selected from the group consisting of graft versus host disease, rheumatoid arthritis, and systemic lupus erythematosus. 
   
   
       167 . The method of  claim 155 , wherein the disorder is a cancer. 
   
   
       168 . The method of  claim 162 , wherein the disorder is a cancer. 
   
   
       169 . The method of  claim 163 , wherein the disorder is a cancer. 
   
   
       170 . The method of  claim 167 , wherein the cancer is a tumor, a neoplasm, a lymphoma, or a leukemia. 
   
   
       171 . The method of  claim 168 , wherein the cancer is a tumor, a neoplasm, a lymphoma, or a leukemia. 
   
   
       172 . The method of  claim 169 , wherein the cancer is a tumor, a neoplasm, a lymphoma, or a leukemia. 
   
   
       173 . The method of  claim 155 , wherein the disorder is asthma. 
   
   
       174 . The method of  claim 162 , wherein the disorder is asthma. 
   
   
       175 . The method of  claim 163 , wherein the disorder is asthma. 
   
   
       176 . The method of  claim 155 , wherein the disorder is psoriasis. 
   
   
       177 . The method of  claim 162 , wherein the disorder is psoriasis. 
   
   
       178 . The method of  claim 164 , further comprising administering an additional agent for treating said immune disorder. 
   
   
       179 . The method of  claim 165 , further comprising administering an additional agent for treating said immune disorder. 
   
   
       180 . The method of  claim 166 , further comprising administering an additional agent for treating said immune disorder. 
   
   
       181 . The method of  claim 167 , further comprising administering an additional agent for treating said cancer. 
   
   
       182 . The method of  claim 168 , further comprising administering an additional agent for treating said cancer. 
   
   
       183 . The method of  claim 169 , further comprising administering an additional agent for treating said cancer. 
   
   
       184 . The method of  claim 176 , further comprising administering an additional agent for treating said psoriasis. 
   
   
       185 . The method of  claim 177 , further comprising administering an additional agent for treating said psoriasis. 
   
   
       186 . A method of treating an immune disorder, a hyperproliferative disorder, or a chronic inflammatory condition, comprising administering an effective amount of a benzodiazepine compound to a subject suffering from said immune disorder, said hyperproliferative disorder, or said chronic inflammatory condition; wherein said benzodiazepine compound is: 
     
       
         
         
             
             
         
       
     
     or a salt or ester thereof, or an enantiomer or a racemic mixture thereof.