10219-07-5Relevant academic research and scientific papers
N-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist's Toolbox
Schiesser, Stefan,Chepliaka, Hanna,Kollback, Johanna,Quennesson, Thibaut,Czechtizky, Werngard,Cox, Rhona J.
, p. 13076 - 13089 (2020)
Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-Trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-Trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-Trifluoromethyl amines are prone to hydrolysis, whereas N-Trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-Trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-Trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-Tert-butyl azoles. Consequently, we suggest that N-Trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.
