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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Optimization of oxadiazole derivatives with a spirocyclic cyclohexane structure as novel GPR119 agonists
Kazuhito Harada1, Jun Mizukami1, Takashi Watanabe1
1Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Abstract:
We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.
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