Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

Abstract

The widely used pentafluorosulfanyl group (SF 5 ) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium™). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1 H -benzo[ 1,4 ]diazepin-2( 3H )-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF 5 group, led to a loss of potency for potentiating GABA A receptor activation, most likely because of a lost ligand interaction with His102 in the GABA A receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.