Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group

Effects of the trifluoromethoxy substituent on physico-chemical properties of compounds, such as kinetic solubility, lipophilicity and microsomal clearance, was studied in a series of aliphatic derivatives. It was found that kinetic solubility of the CF₃O-containing compounds was comparable to that of analogs, i.e. compounds bearing CH₃O and CF₃ moieties. The CF₃O-substituted compounds had higher lipophilicity as compared to methoxy analogues, and nearly the same like CF₃-bearing compounds. Microsomal stability studies indicated that the trifluoromethoxy group typically decreased metabolic stability of the corresponding derivatives as compared to either CH₃O- or CF₃-substituted counterparts, except for N-alkoxy(sulfon)amide series.