laninamivir octanoate

Laninamivir (L174000) prodrug; a novel long-acting neuraminidase inhibitor.

ChEBI: Laninamivir octanoate hydrate is a fatty acid ester.

Laninamivir octanote, a prodrug of a potent neuraminidase inhibitor (LANI), was approved and launched in 2010 in Japan for the treatment of influenza A and influenza B. This ester prodrug of a potent neuraminidase inhibitor was designed to permeate from the lung tissue to the plasma and then hydrolyze at such a rate to reveal the active form (laninamivir) as a long-acting therapeutic agent. Neuraminidase cleaves the glycosidic linkages of neuraminic acids which are responsible for binding new viruses to infected cells, thereby allowing viruses to release and infect other cells. Neuraminidase is essential for the replication of all influenza viruses. Like other neuraminidase inhibitors, laninamivir octanoate is a sialic acid analogue which is structurally similar to zanamivir, differing only by changing one of the hydroxy groups with a methyl ether substitution on the triol side chain. Laninamivir is administered via an inhalable formulation (20 mg, dry powder inhaler) and results from clinical trials of the drug have demonstrated that a single inhaled dose is as effective as a 5-day course of oseltamivir for treatment of influenza.

The synthesis of laninamivir octanoate began with the well-documented sugar intermediate 101. Alcohol 101 was alkylated with dimethyl sulfate in the presence of NaH in DMF to give methyl ether 102 in 80% yield. Acetonide 102 was then deprotected and subsequently acylated with Ac2O, AcOH, and H2SO4 (10:10:1, v/v) which resulted in oxazoline formation along with elimination of the methoxy functionality to furnish |á￡?|?-unsaturated ester 103. Exposure of oxazoline 103 to NaN3 in the presence of Dowex 50W/H+ produced the transamidoazide 104 in 70% yield over two steps. Azide 104 was then subjected to guanidine formation conditions utilizing N,N-bis(tertbutoxycarbonyl)-1H-pyrazole-1-carboxyamidine (106), which was prepared from pyrazole-1-carboxamidine (105) by consecutive protection of the amidine nitrogens, first by treatment with Boc anhydride and diisopropylethyl amine (DIEA) in DMF, and then subsequent treatment to Boc anhydride in the presence of NaH in THF to give 107 in 80% yield. The protected guanidine 107 was hydrolyzed under basic conditions to give the corresponding acid 108 in good yield. Acid 108 was esterified with diphenyl diazomethane in THF to provide 109 in 85% yield. Finally, the primary alcohol within diol 109 was selectively acylated with octanoyl chloride in the presence of TEA, followed by de-protection with TFA in CH2Cl2 to give laninamivir octanote (VIII) in 70% yield.