Compositions and methods relating to novel compounds and targets 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 methods of using benzodiazepine derivatives as therapeutic agents to treat a number of conditions associated with the faulty regulation of the processes of programmed cell death, autoimmunity, inflammation, and hyperproliferation, and the like.

1 . A method of regulating hyperproliferating epithelium cells, comprising: 
 a) providing a sample with hyperproliferating epithelium cells, and a composition comprising a benzodiazepine compound; and    b) applying said composition to said sample.    
     
     
         2 . The method of  claim 1 , wherein applying of said composition to said sample decreases Erk½ activation within said sample.  
     
     
         3 . The method of  claim 1 , wherein said applying said composition to said sample inhibits keratinocyte proliferation within said sample.  
     
     
         4 . The method of  claim 1 , wherein said composition further comprises a topical corticosteroid.  
     
     
         5 . The method of  claim 4 , wherein said topical corticosteroid is selected from the group consisting of triamcinolone acetonide 0.1% cream and betamethasone dipropionate 0.05% cream.  
     
     
         6 . The method of  claim 1 , wherein said composition further comprises coal tar 2-10%.  
     
     
         7 . The method of  claim 1 , wherein said composition further comprises a vitamin D-3 analog.  
     
     
         8 . The method of  claim 7 , wherein said vitamin D-3 analog is calcipotriene.  
     
     
         9 . The method of  claim 1 , wherein said composition further comprises a keratolytic agent.  
     
     
         10 . The method of  claim 9 , wherein said keratolytic agent is anthralin 0.1-1%.  
     
     
         11 . The method of  claim 1 , wherein said composition further comprises a topical retinoid.  
     
     
         12 . The method of  claim 11 , wherein said topical retinoid is selected from the group consisting of tretinoin, and tazarotene.  
     
     
         13 . The method of  claim 1 , wherein said sample is a living subject.  
     
     
         14 . The method of  claim 13 , wherein said living subject is a human being suffering from epidermal hyperplasia.  
     
     
         15 . The method of  claim 14 , wherein said living subject has psoriasis.  
     
     
         16 . The method of  claim 1 , wherein said benzodiazepine compound is Bz-423.  
     
     
         17 . The method of  claim 1 , wherein said benzodiazepine compound comprises the following formula:  
       
         
           
           
               
               
           
         
         including both R and S enantiomeric foms and racemic mixtures;  
         wherein R1, R2, R3 and R4 are selected from the group consisting of: 
 hydrogen; CH 3 ; a linear or branched, saturated or unsaturated aliphatic chain having at least 1 carbon; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one hydroxy subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one thiol subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, wherein said aliphatic chain terminates with an aldehyde subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ketone subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; wherein said aliphatic chain terminates with a carboxylic acid subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amide subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one acyl group; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitrogen containing moiety; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amine subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ether subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one halogen subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitronium subgroup;  
 
         wherein R5 is selected from the group consisting of: OH; NO 2 ; OR′; wherein 
 R′ is selected from the group consisting of: 
 a linear or branched, saturated or unsaturated aliphatic chain having at least one carbon; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one hydroxyl subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one thiol subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, wherein said aliphatic chain terminates with an aldehyde subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ketone subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; wherein said aliphatic chain terminates with a carboxylic acid subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amide subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one acyl group; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitrogen containing moiety; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amine subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one halogen subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitronium subgroup; wherein R6 is selected from the group consisting of: Hyrdrogen; NO 2 ; Cl; F; Br; I; SR′; and NR 12 ; wherein R′ is defined as above in R5;  
 
 
         wherein R7 is selected from the group consisting of: 
 Hydrogen; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; and  
 
         wherein R8 is an aliphatic cyclic group larger than benzene; wherein said larger than benzene comprises any chemical group containing 7 or more non-hydrogen atoms.  
       
     
     
         18 . A pharmaceutical composition comprising: 
 a) a benzodiazepine compound that regulates epidermal hyperplasia; and    b) an agent selected from the following group: a topical corticosteroid, a keratolytic agent, a topical retinoid, a coal tar 2-10%, and a vitamin D-3 analog.    
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein said benzodiazepine compound is Bz-423.  
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein said benzodiazepine compound comprises the following formula:  
       
         
           
           
               
               
           
         
         including both R and S enantiomeric foms and racemic mixtures;  
         wherein R1, R2, R3 and R4 are selected from the group consisting of: 
 hydrogen; CH 3 ; a linear or branched, saturated or unsaturated aliphatic chain having at least 1 carbon; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one hydroxy subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one thiol subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, wherein said aliphatic chain terminates with an aldehyde subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ketone subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; wherein said aliphatic chain terminates with a carboxylic acid subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amide subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one acyl group; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitrogen containing moiety; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amine subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ether subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one halogen subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitronium subgroup;  
 
         wherein R5 is selected from the group consisting of: OH; NO 2 ; OR′; wherein 
 R′ is selected from the group consisting of: 
 a linear or branched, saturated or unsaturated aliphatic chain having at least one carbon; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one hydroxyl subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one thiol subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, wherein said aliphatic chain terminates with an aldehyde subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one ketone subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; wherein said aliphatic chain terminates with a carboxylic acid subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amide subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one acyl group; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitrogen containing moiety; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one amine subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one halogen subgroup; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons, and having at least one nitronium subgroup; wherein R6 is selected from the group consisting of: Hyrdrogen; NO 2 ; Cl; F; Br; I; SR′; and NR 12 ; wherein R′ is defined as above in R5;  
 
 
         wherein R7 is selected from the group consisting of: 
 Hydrogen; a linear or branched, saturated or unsaturated aliphatic chain having at least 2 carbons; and  
 
         wherein R8 is an aliphatic cyclic group larger than benzene; wherein said larger than benzene comprises any chemical group containing 7 or more non-hydrogen atoms.  
       
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein said pharmaceutical composition is used to treat an epidermal hyperplasia.  
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein said epidermal hyperplasia is caused by psoriasis.