Improved Synthesis of Anxiolytic, Anticonvulsant and Antinociceptive α2/α3-GABA(A)ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, as well as Neuropathic Pain

Guanguan Li; Lalit K Golani; Rajwana Jahan; Farjana Rashid; James M Cook

doi:10.1055/s-0037-1610211

Improved Synthesis of Anxiolytic, Anticonvulsant and Antinociceptive α2/α3-GABA(A)ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, as well as Neuropathic Pain

Synthesis (Stuttg). 2018 Oct;50(20):4124-4132. doi: 10.1055/s-0037-1610211.

Authors

Guanguan Li¹, Lalit K Golani¹, Rajwana Jahan¹, Farjana Rashid¹, James M Cook¹

Affiliation

¹ Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.

Abstract

An improved synthesis of the anxiolytic, anticonvulsant and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were executed in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of KRM-II-81, an alternative procedure was employed using the selective reducing reagent, potassium diisobutyl-t-butoxy aluminum hydride (PDBBA), to prepare the desired C(3)-aldehyde in the absence of [N(5)-C(6)] imine reduction in good yield on 20 gram scale.

Keywords: GABAAR; anxiety; benzodiazepines; epilepsy; imine; large scale; neuropathic pain; selective reduction.

Abstract

Grants and funding