Novel Soluble 1,4 Benzodiazepine Compounds and Stable Salts Thereof

Abstract

The present invention relates to novel chemical compounds, methods for their discovery, and their therapeutic use. In particular, the present invention provides benzodiazepine derivatives and related compounds and methods of using benzodiazepine derivatives and related compounds as therapeutic agents to treat a number of conditions associated with the faulty regulation of the processes of programmed cell death, autoimmunity, inflammation, hyperproliferation, and the like.

1 . A composition comprising the following formula: 
       
         
           
           
               
               
           
         
         including both R and S enantiomeric forms, racemic mixtures, and stable salt forms;
 wherein R 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
            2,3-Diethybenzyl, 3,4-diethybenzyl, 1-adamantyl, 2-adamantyl bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-7-yl, 2-phenoxybenzyl, 3-phenoxybenzyl, 4-phenoxybenzyl, benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl, 1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl, and 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 2  comprises the following; 
         
       
       
         
           
           
               
               
           
         
         1-Hydroxy-2,6-dioxo-piperidin-4-yl, 1-hydroxy-2,6-dioxo-1,2,3,6-tetrahydro-pyridin-4-yl, 1,6-Dihydroxy-2-oxo-1,2-dihydro-pyridin-4-yl, 1-hydroxy-6-oxo-1,2,3,6-tetrahydro-pyridin-4-yl, 1-hydroxy-2-oxo-piperidin-4-yl, N-hydroxy-benzamid-4-yl, N-hydroxybenzamid-3-yl, N-hydroxybenzamid-2-yl, N-hydroxyacetamidyl, N-hydroxypropionamid-3-yl, or N-hydroxybutanamid-4-yl; 
         wherein R 3  is comprises the following:
 Br, CF 3 , Cl 
 
       
       
         
           
           
               
               
           
         
         
            bromo, trifluoromethyl, chloro, cyclopropyl, isopropoxy, sulfamoyl alkylsulfonyl, amido, 2-thienyl, or 3-thienyl; 
           wherein R 4  comprises 
         
         Me, H 
       
       
         
           
           
               
               
           
         
         
           wherein R 5  is selected from the group consisting of 
         
         alkyl, alkoxy, 
       
       
         
           
           
               
               
           
         
         2-(2′-imidazolyl)phenyl, 3-(2′-imidazolyl)phenyl, 4-(2′-imidazolyl)phenyl, 2-(4′-imidazolyl)phenyl, 3-(4′-imidazolyl)phenyl, 4-(4′-imidazolyl)phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-imidazolyl, 4-imidazolyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 2-alkanoylaminophenyl, 3-alkanoylaminophenyl, 4-alkanoylaminophenyl, 2-alkylcarbonylaminophenyl, 3-alkylcarbonylaminophenyl, 4-alkylcarbonylaminophenyl, 4-(4-morpholinylcarbonylamino)phenyl, 3-(4-morpholinylcarbonylamino)phenyl, 2-(4-morpholinylcarbonylamino)phenyl, 4-(3-morpholin-4-ylpropionylamino)phenyl, 3-(3-morpholin-4-ylpropionylamino)phenyl, 2-(3-morpholin-4-ylpropionylamino)phenyl, 2-(2-morpholin-4-ylethoxycarbonylamino)phenyl, 3-(2-morpholin-4-ylethoxycarbonylamino)phenyl, 4-(2-morpholin-4-ylethoxycarbonylamino)phenyl, 2-[2-(2-hydroxyethoxy)ethoxycarbonylamino]phenyl, 3-[2-(2-hydroxyethoxy)ethoxycarbonylamino]phenyl, 4-[2-(2-hydroxyethoxy)ethoxycarbonylamino]phenyl, 2-[2-(2-methoxyethoxy)ethoxycarbonylamino]phenyl, 3-[2-(2-methoxyethoxy)ethoxycarbonylamino]phenyl, or 4-[2-(2-methoxyethoxy)ethoxycarbonylamino]phenyl; and
 wherein R 6  comprises: 
 
         H, Br, F, OMe, OBn 3,5-di F 
       
       
         
           
           
               
               
           
         
         biphenyl-2-ylmethyl, 3′-bromobiphenyl-2-ylmethyl, 3′-fluorobiphenyl-2-ylmethyl, 3′-methoxybiphenyl-2-ylmethyl, 3′-benzyloxybiphenyl-2-ylmethyl, 3′,5′-difluorobiphenyl-2-ylmethyl, 3′-benzo[1,3]dioxol-4-ylbiphenyl-2-ylmethyl, 3′-benzo[1,3]dioxol-5-ylbiphenyl-2-ylmethyl, 3′-isopropoxybiphenyl-2-ylmethyl, 3′-(N-tert-butylcarbonyl)biphenyl-2-ylmethyl, 3′-tert-butylcarbonylbiphenyl-2-ylmethyl, 3′-[2-(2-hydroxyethoxy)ethoxy]biphenyl-2-ylmethyl, 3′-[2-(2-methoxyethoxy)ethoxy]biphenyl-2-ylmethyl, or 3′-sulfamoylbiphenyl-2-methyl. 
       
     
     
         2 . The composition of  claim 1 , wherein said compound is a 1,4-benzodiazepine salt. 
     
     
         3 . The composition of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A pharmaceutical composition comprising a 1,4-benzodiazepine salt selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The pharmaceutical composition of  claim 4 , further comprising an agent for treating a disorder selected from the group consisting of an immune disorder, a hyperproliferative disorder, or a chronic inflammatory condition. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein said hyperproliferative disorder is a cancer. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said cancer is a tumor, a neoplasm, a lymphoma, or a leukemia. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein said chronic inflammatory disease is asthma. 
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein said chronic inflammatory disease is psoriasis. 
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein said immune disorder is graft versus host disease. 
     
     
         11 . The pharmaceutical composition of  claim 4 , wherein said pharmaceutical composition is prepared for administration orally, rectally, vaginally, pulmonarily, parenterally, topically or intranasally.