Inhibitors of melanocyte tyrosinase as topical skin lighteners

Abstract

Methods and formulations are provided to reduce pigmentation in skin, using an array of compounds selected from benzimidazoles, phenylthioureas, phenyltiols, phenylamines, bi- and multicyclic phenols, thiopheneamines, and benzothiamides. The compounds preferably inhibit pigment systhesis in melanocytes through the tyrosinase pathway. The methods can be used for lightening skin, and for treating uneven skin complexions which result from hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, and lentigo. The compounds can be used medically or cosmetically.

1 . A method for protecting skin from ultraviolet rays and photoaging comprising administering to a human in need of ultraviolet ray absorption for protection from ultraviolet rays or photoaging, an effective amount of at least one compound defined by the structure.  
       
         
           
           
               
               
           
         
       
       and R10 is methyl, ethyl or propyl, or a pharmaceutically acceptable salt or ester thereof.  
     
     
         2 . The method of  claim 1  wherein R 10  is methyl.  
     
     
         3 . The method of  claim 1  wherein R 10  is ethyl.  
     
     
         4 . The method of  claim 1  wherein R 10  is propyl.  
     
     
         5 . The method of  claim 1  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         6 . The method of  claim 1  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         7 . The method of  claim 1  wherein the compound is an antioxidant.  
     
     
         8 . The method of  claim 1  wherein the administration is through a topical formulation.  
     
     
         9 . The method of  claim 1  wherein the method further lightens skin pigmentation.  
     
     
         10 . A method of inhibiting or preventing pigment production in a mammal comprising administering to the mammal an effective amount of a compound defined by the structure below, or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       and R 10  is methyl, ethyl or propyl.  
     
     
         11 . The method of  claim 10  wherein the compound has an IC 50  against mammalian tyrosinase activity of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanoctyic cells of greater than 500 uM.  
     
     
         12 . The method of  claim 10  wherein the compound has an IC 50  against melanin production in mammalian melanocytic cells of less than or equal to 300 uM, and an IC 50  of cytotoxicity in mammalian melanocytic cells of greater than 500 uM.  
     
     
         13 . The method of  claim 10  wherein the compound absorbs ultraviolet radiation.  
     
     
         14 . The method of  claim 10  wherein the compound is an antioxidant.  
     
     
         15 . The method of  claim 10  wherein the mammal is a human.  
     
     
         16 . The method of  claim 10  wherein the administration is through a topical formulation or an occlusive patch.  
     
     
         17 . The method of  claim 10  wherein the method is for lightening skin pigmentation  
     
     
         18 . The method of  claim 10  wherein the method is for treating hyperpigmentation-related medical conditions.  
     
     
         19 . The method of  claim 10  wherein R 10  is methyl.  
     
     
         20 . The method of  claim 10  wherein R 10  is ethyl.  
     
     
         21 . The method of  claim 10  wherein R 10  is propyl.  
     
     
         22 . A method of inhibiting tyrosine hydroxylase comprising administering an effective amount of a compound defined by the structure below or a pharmaceutically acceptable salt or ester thereof:  
       
         
           
           
               
               
           
         
       
       and R 10  is methyl, ethyl or propyl.  
     
     
         23 . The method of  claim 12  wherein the hyperpigmentation-related medical condition is melasma, age spots, freckles, ochronosis, postinflammatory hyperpigmentation, or lentigo.  
     
     
         24 . The method of  claim 22  wherein R 10  is methyl.  
     
     
         25 . The method of  claim 23  wherein R 10  is ethyl.  
     
     
         26 . The method of  claim 24  wherein R 10  is propyl.