Uses
Laninamivir (L174000) prodrug; a novel long-acting neuraminidase inhibitor.
Definition
ChEBI: Laninamivir octanoate hydrate is a fatty acid ester.
Clinical Use
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.
Synthesis
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.
