Uses
Eslicarbazepine acetate, (BIA 2-093), is a promising antiepileptic drug structurally related to Carbamazepine and Oxcarbazepine. Neuroprotective & Neuroresearch product.
Clinical Use
Eslicarbazepine acetate is a prodrug of eslicarbazepine (licarbazepine)
which is a metabolite of oxcarbazepine. Eslicarbazepine
acetate was recently approved in Europe for the
treatment of adjunctive therapy for partial-onset of seizures,
with or without secondary generalizations, in adults with epilepsy.
9 The mechanism of its action is the inhibition of voltage
gated sodium channels in the brain, making brain cells less
prone to excitability. The drug was discovered and developed
by Bial, a small privately held Portuguese pharmaceutical company,
and is marketed in Europe by Eisai Pharmaceutical Co.
Synthesis
A
number of racemic syntheses have been reported that require
separation using chiral auxiliaries along with several asymmetric reduction methods starting with the commercially available
(Bosche Scientific, LLC) oxcarbazepine 48. The scheme highlights
two asymmetric approaches, asymmetric reduction of ketone
48 followed by esterification or asymmetric
hydrogenation of vinyl acetate 50 to give the acetate directly.
Thus asymmetric reduction of oxcarbazepine 48 was accomplished
using Ru(Cl2)(p-cymene)2 as the catalyst, (S,S)-TsDAEN
with formic acid as the stoichiometric reductant in a mixed solvent
system at reflux followed by cooling to 80°C. Addition of
MTBE, followed by a slow cooling to room temperature afforded
the crystals of alcohol 49, which were collected by filtration and
dried to obtain a 95% isolated yield in 97.8% ee. Several experiments
were described in the patent varying (1) catalyst loading,
(2) equivalents of formic acid, (3) pH of the reaction, (4) reaction
time and (5) the use of a phase transfer catalyst. Employment of
the phase transfer catalyst gave 90% yield and >99.9% ee of the
product with less than 2 ppm residual ruthenium content. Alcohol
49 was then converted to eslicarbazepine acetate IX by
reacting with acetic anhydride in the presence of DMAP and pyridine
in refluxing dichloromethane. After aqueous work-up, the
crude product was crystallized from isopropanol to give the desired
product eslicarbazepine acetate (IX) in 90% yield with
99.96% purity with undetectable amount of R isomer. In the second
approach, the acetate intermediate 50 was formed first in
88% yield which was then reduced via catalytic hydrogenation in
the presence of the preformed catalyst 51 to give eslicarbazepine
acetate (IX) in 94% ee. No yield was given for the formation of
the product using this route.
Drug interactions
Potentially hazardous interactions with other drugs Antidepressants: anticonvulsant effect possibly
antagonised by MAOIs, SSRIs and TADs; avoid
with St John’s wort.Antiepileptics: avoid concomitant use with
carbamazepine, oxcarbazepine; concentration
reduced by phenytoin and concentration of
phenytoin increased.Antimalarials: anticonvulsant effect antagonised by
mefloquineAntipsychotics: antagonism of anticonvulsant effectOestrogens and progestogens: reduced contraceptive
effect.Orlistat: possibly increased risk of convulsions.Ulipristal: possibly reduces contraceptive effect -
avoid
Metabolism
Eslicarbazepine acetate is rapidly and extensively
biotransformed to its major active metabolite
eslicarbazepine by hydrolytic first-pass metabolism.
Minor metabolites in plasma are R-licarbazepine and
oxcarbazepine, which were shown to be active, and the
glucuronic acid conjugates of eslicarbazepine acetate,
eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate and its metabolites are mainly
excreted in the urine unchanged.
