Synthesis and Anti‐Hyperalgesic Efficacy of MP‐103, a Non‐Racemic Enantiomeric Mixture of a New 1,4‐Diazabicyclo[4.3.0]nonan‐9‐one

Abstract With the aim to identify novel and improved drug candidates for the non‐opioid management of neuropathic pain, a few chiral fluorobenzenesulfonylamide derivatives of 1,4‐diazabicyclo[4.3.0]nonan‐9‐one, a rigid bicyclic analogue of piracetam, were prepared and characterized in animal models of chemotherapy‐induced neuropathic pain. The R ‐enantiomers of these novel compounds are generally more potent than their corresponding S ‐enantiomers. An oral dose of R ‐2‐fluorophenyl derivative 8a is better tolerated when compared to the R ‐3‐ fluorophenyl derivative 9a , (mouse Rota‐Rod test). Consequently, the enantiomeric 2‐fluorophenyl derivatives ( 8a and 8b ) are thoroughly investigated in an enlarged panel of inflammatory and neuropathic pain models, including several models of chemotherapy‐induced neuropathic pain. The R ‐enantiomer ( 8a ) is consistently more potent in its anti‐hypersensitivity profile than the S ‐enantiomer ( 8b ). Surprisingly, the non‐racemic enantiomeric mixture consisting of a 2‐to‐1, or better still, a 3‐to‐1 mixture of the R ‐enantiomer ( 8a ) over the S ‐enantiomer ( 8b ) is more potent than the R ‐enantiomer ( 8a ) alone or than their racemic mixture. These results are reminiscent of our previous report on MP‐101, a non‐racemic mixture of dimiracetam enantiomers. Although further investigations will be required to rationalize these findings at the pharmacokinetic or molecular level, racetam derivatives appear to be promising candidates for the management of persistent pain.