Ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for treating skin diseases and conditions

Abstract

The present invention relates to method for treating skin diseases and skin conditions in a subject in need of such treatment, which comprises administering a therapeutically effective amount of a composition comprising ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or enantiomers thereof, pharmaceutical compositions containing them and their use as pharmaceuticals.

1 .- 11 . (canceled) 
     
     
         12 . A method for treating psoriasis comprising administering to a subject a therapeutically effective amount of a composition comprising a compound having a structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or optionally substituted C 1-3  alkyl; 
         R 2  is H or optionally substituted C 1-3  alkyl; 
         R 3  is H, optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; and 
         R is optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; or 
         a pharmaceutically acceptable salt thereof; and 
         one or more selected from the group consisting of pharmaceutically acceptable carriers, preservatives, auxiliary agents, stabilizing agents, thickening agents, coloring agents and perfumes. 
       
     
     
         13 . The method of claim  1 , wherein R 1  is C 1-3  alkyl. 
     
     
         14 . The method of claim  1 , wherein R 2  is C 1-3  alkyl. 
     
     
         15 . The method of claim  1 , wherein R 1  is methyl. 
     
     
         16 . The method of claim  1 , wherein R 2  is methyl. 
     
     
         17 . The method of claim  1 , wherein R 3  is H, phenyl or C 1-10  alkyl. 
     
     
         18 . The method of claim  1 , wherein R 3  is H. 
     
     
         19 . The method of claim  1 , wherein R is selected from the group consisting of methyl, iso-butyl, tert-butyl, iso-propyl, ethylphenyl, phenyl, 2-amino-1-phenylethyl, 2-(2-amino-3-methyl-butyrylamino)-2-methyl-prop-1-yl, 1-amino-2-methyl-prop-1-yl, 2-(2-amino-acetylamino)-2-methyl-prop-1-yl. Most preferred R groups are tert-butyl, iso-propyl. 
     
     
         20 . The method of claim  1 , wherein R 1  is H or C 1-3  alkyl; R 2  is H or C 1-3  alkyl; R 3  is H, C 1-10  alkyl, heterocycle or aryl; and R is C 1-10  alkyl, heterocycle or aryl. 
     
     
         21 . The method of claim  1 , wherein the compound having a structure of Formula II is selected from the group consisting of:
 iso-Butyric acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   2,2-Dimethyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   Acetic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   Benzoic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   3-Methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   3-Phenyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2-Amino-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2-(2-Amino-acetylamino)-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; and   2-Amino-3-phenyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester.   
     
     
         22 . The method according to claim  1 , wherein the pharmaceutically acceptable carriers are selected from the group consisting of glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides and dextrans. 
     
     
         23 . The method according to claim  1 , wherein the composition is formulated for topical skin application. 
     
     
         24 . The method according to  claim 23 , wherein the composition is formulated to enhance long duration of action. 
     
     
         25 . The method according to  claim 24 , wherein the composition is formulated with slow releasing pellets. 
     
     
         26 . The method according to claim  1 , wherein the composition is formulated as suspension, gel, solution, lotion, cream, ointment, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles, microparticles, nanoparticles, wet cloths, soaps, cleansing bars, dry cloths, facial cloths. 
     
     
         27 . The method according to  claim 23 , wherein the pharmaceutical composition is formulated as suspension, gel, solution, lotion, cream, ointment, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles, microparticles, nanoparticles, wet cloths, soaps, cleansing bars, dry cloths, facial cloths. 
     
     
         28 . The method according to  claim 23 , wherein the pharmaceutical compositions is further formulated as a solid, semi-solid or liquid. 
     
     
         29 . The method according to claim  1 , wherein the pharmaceutical compositions is further formulated for oral use, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.