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.

What is claimed is: 
     
         1 . A method for treating a skin disease or condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound 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 a pharmaceutically acceptable carrier, preservative, auxiliary agent, stabilizing agent, thickening agent, coloring agent and perfume; 
         wherein the skin disease or condition is sunburn, chronic sun damage, a discreet erythema, menopause-associated hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, telangiectasia of the face, or cutaneous hyperactivity with dilation of blood vessels of the skin. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is C 1-3  alkyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is C 1-3  alkyl. 
     
     
         4 . The method of  claim 1 , wherein R 1  is methyl. 
     
     
         5 . The method of  claim 1 , wherein R 2  is methyl. 
     
     
         6 . The method of  claim 1 , wherein R 3  is H, phenyl or C 1-10  alkyl. 
     
     
         7 . The method of  claim 1 , wherein R 3  is H. 
     
     
         8 . The method of  claim 1 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, sec-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, iso-hexyl, 3-methyl-butyl, 2-amino-N-isobutyl acetamide, iso-butyl, tert-butyl, iso-propyl, methylphenyl, 
       
         
           
           
               
               
           
         
       
       or phenyl, wherein the phenyl is optionally be substituted with C 1-6  alkyl, amino, halogen, —O(C 1-6  alkyl), —OC(O)(C 1-6  alkyl), —C(O)O(C 1-6  alkyl), —NHC(O)(C 1-6  alkyl), —C(O)NH(C 1-6  alkyl) or —S(C 1-6  alkyl). 
     
     
         9 . 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. 
     
     
         10 . 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.   
     
     
         11 . The method according to  claim 1 , wherein the pharmaceutically acceptable carrier is 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. 
     
     
         12 . The method according to  claim 1 , wherein the composition is formulated for topical skin application. 
     
     
         13 . The method according to  claim 12 , wherein the composition is formulated to enhance long duration of action. 
     
     
         14 . The method according to  claim 13 , wherein the composition is formulated with slow releasing pellets. 
     
     
         15 . The method according to  claim 1 , wherein the composition is formulated as a suspension, gel, solution, lotion, cream, ointment, foam, emulsion, microemulsion, milks, serum, aerosol, spray, dispersion, microcapsule, vesicle, microparticle, nanoparticle, wet cloth, soap, cleansing bar, dry cloth or facial cloth. 
     
     
         16 . The method according to  claim 1 , wherein the pharmaceutical composition is a solid, semi-solid or liquid. 
     
     
         17 . The method according to  claim 1 , wherein the pharmaceutical composition is formulated for oral use as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, syrup or elixir.