Esters of 4,5-disubstituted-oxy-2-methyl-3,6-dioxo-cyclohexa-1,4-dienyl alkyl acids and preparation thereof

Abstract

Esters of 4,5-disubstituted-oxy-2-methyl-3,6-dioxo-cyclohexa-1,4-dienyl alkyl acids were prepared chemically and/or enzymatically. Depending upon the ester, improved melanocyte cytotoxicity was achieved. Improved cytotoxicity characteristics are consistent with ester analogs being more physiologically compatible and less irritating to skin than their corresponding acids.

1 . A process for preparing an ester comprising:
 a) reacting an acid, anhydride, or acid derivative of formula 2   
       
         
           
           
               
               
           
         
         
           wherein X is —OH, —SH, —F, —Cl, —Br, —I, or —OR 3 ; and R and R 1  are each independently a C 1 -C 4  alkyl; and n is 2-18; and 
           wherein R 3  is C 1 -C 6 -alkyl or substituted C 1 -C 6 -alkyl. 
         
       
       with an alcohol of formula 3: 
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , and R 6  are each an aliphatic hydrocarbons containing from about 6 to about 22 carbons 
       
       in the presence of an organic solvent to form at least on ester; and
 b) isolating said at least one ester. 
 
     
     
         2 . The process according to  claim 1 , wherein the solvent is diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, benzene, toluene, xylene, hexane, heptane, cyclohexane, or limonene, dichloromethane, dichloroethane, dibromoethane, tetrachloroethylene, chlorobenzene, acetonitrile, dimethyl formamide, dimethyl sulfoxide, or mixtures thereof. 
     
     
         3 . The process according to  claim 1 , wherein the reacting occurs at a temperature of between about −100° C. and a boiling point of the solvent. 
     
     
         4 . The process according to  claim 3 , wherein the temperature is between about 0° C. and about 60° C. 
     
     
         5 . The process according to  claim 4 , wherein the temperature is between about 20° C. and about 50° C. 
     
     
         6 . The method according to  claim 1 , wherein step a) further comprises being in the presence of an enzyme. 
     
     
         7 . The method according to  claim 6 , wherein, the enzyme is a protease, a lipase, or an esterase. 
     
     
         8 . A method for treating a skin condition comprising applying an effective amount of a composition, comprising an ester and a dermatologically acceptable carrier, wherein the ester is represented by the general formula 1: 
       
         
           
           
               
               
           
         
         wherein R and R 1  are each independently a C 1 -C 4  alkyl, R 2  is a C 6 -C 22  alkyl, C 6 -C 22  alkenyl, C 6 -C 20  dienyl, C 6 -C 22  trienyl, C 8 -C 22  tetraenyl or a mixture thereof, and n is 2-18. 
       
     
     
         9 . The method according to  claim 8 , wherein said skin condition is selected from the group consisting of skin roughness, skin wrinkles, photodamaged skin, skin hyperpigmentation, skin irritation, and skin inflammatory reaction.