Benzodiazepine compositions for treating epidermal hyperplasia and related disorders

Abstract

The present invention provides, for example, pharmaceutical compositions comprising a benzodiazepine compound and an agent selected from the group consisting of a topical steroid, a keratolytic agent, a topical retinoid, a coal tar, and a vitamin D-3 analog. The pharmaceutical compositions are useful for treating medical disorders, such as epidermal hyperplasia.

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 Erk1/2 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′ 2 ; 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′ 2 ; 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.