The introduction of Mirogabalin besylate

Introduction

Mirogabalin besylate is a member of the gabapentinoid drug class, which includes gabapentin (Neurotin) and pregabalin (Lyrica). Daiichi Sankyo developed the drug, and it was first approved in Japan for the treatment of peripheral neuropathic pain (PNP), including diabetic PNP and postherpetic neuralgia. Mirogabalin was also clinically developed for treatment of fibromyalgia pain in the USA and the EU but was discontinued after it failed to meet primary end points in Phase III trials[1].

The analgesic properties of mirogabalin and related gabapentinoids derive from inhibiting calcium-mediated neurotransmitter release at voltage-gated calcium channels (VGCCs) within the dorsal horn. Gabapentinoids elicit their response by binding to the α2δ-1 subunit. Mirogabalin has a high affinity for the α2δ-1 and α2δ-2 subunits, which have been associated with analgesic effects (α2δ-1) and CNS side effects (α2δ-2). Mirogabalin has a remarkable dissociation half-life (>11 h at α2δ-1), which is substantially longer in duration than the half-life for pregabalin (∼1.5 h for both α2δ-1 and α2δ-2). This increase in half-life has been postulated to contribute to its potent, long-lasting analgesic effects while reducing side effects associated with gabapentinoids.

Metabolic

Mirogabalin administered orally was almost eliminated via urinary excretion[2]. A small part of the orally administered dose of mirogabalin was metabolised via glucuronidation at the amine and carboxylic acid moiety and oxidation as the primary metabolic pathway.

Synthesis method

The synthetic sequence above reflects a likely scalable route to mirogabalin as the besylate salt. Condensation of allyl alcohol (107) and butyraldehyde (108) provided acetal 109. Acid-mediated Claisen rearrangement through maleic acid (110) gave rise to aldehyde 111 upon exposure to warm DMA. Knoevenagel−Doebner condensation with malonic acid (112) afforded α,β- unsaturated acid 113, which was then treated with Ac2O under basic conditions to affect an intramolecular [2 + 2] cycloaddition reaction. This transformation, presumably through a ketene intermediate, delivered cyclobutanone 114 in 62% yield over the two-step sequence from 111. Horner−Wadsworth−Emmons olefination with phosphonate 115 delivered a mixture of E and Z alkenes, which underwent conjugate addition with nitromethane to arrive at nitroalkane 117. Reduction with Fe and subsequent chiral chromatographic separation of the resultant amine afforded optically pure 118. Acidic removal of the tert-butyl ester with 4 N HCl in dioxane, subjection to triethylamine, and finally treatment with a 1 M aqueous solution of phenyl sulfonic acid provided mirogabalin besylate in good yield across the two-step sequence.

References

[1] Andrew C. Flick. “Synthetic Approaches to the New Drugs Approved during 2019.” Journal of Medicinal Chemistry 64 7 (2021): 3604–3657.

[2] N. Yamamura. “Pharmacokinetics and metabolism of mirogabalin, a novel α2δ ligand, in rats and monkeys.” Xenobiotica 52 1 (2022): 54–64.