Novel phosphinic and phosphonic acid analogues of the anticonvulsant valproic acid

Article abstract of DOI:10.1016/S0960-894X(00)00512-6

1-Propylbutylphosphinic acid 2, (1-propylbutyl)methylphosphinic acid 3 and 1-propylbutylphosphonic acid 4 have been synthesized as bioisosteres of the corresponding carboxylic acid valproate 1, which is a potent anticonvulsant. The novel phosphinic and phosphonic acids were tested for their anticonvulsant activity and were found to be inactive. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00512-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2547±2548
Novel Phosphinic and Phosphonic Acid Analogues of the
Anticonvulsant Valproic Acid
Jan Kehler,a,* Henrik I. Hansenb and Connie Sanchezc
aDepartment of Medicinal Chemistry, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
bDepartment of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark
cDepartment of Neuropharmacology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
Received 7 April 2000; revised 28 August 2000; accepted 6 September 2000
AbstractÐ1-Propylbutylphosphinic acid 2, (1-propylbutyl)methylphosphinic acid 3 and 1-propylbutylphosphonic acid 4 have been
synthesized as bioisosteres of the corresponding carboxylic acid valproate 1, which is a potent anticonvulsant. The novel phosphinic
and phosphonic acids were tested for their anticonvulsant activity and were found to be inactive. # 2000 Elsevier Science Ltd. All
rights reserved.
Valproic acid (VPA) 1 (Fig. 1) is currently one of the
most widely used ®rst-choice agents for the treatment
of epilepsy, especially for the treatment of generalized
seizures.1 Recently, VPA has also been used as an
e€ective antimanic agent,2 as a mood stabilizer,3 in
migraine prophylaxis,4 and with potential use in the
treatment of Alzheimer patients.5 Although VPA has
been in use for more than 20 years, its mechanism of
action is still unresolved. However, VPA has been shown
to moderately elevate the levels of the major inhibitory
neurotransmitter g-aminobutyric acid (GABA) in the
brain, presumably by inhibiting GABA-transaminase
and succinic semialdehyde dehydrogenase, and, hence
the catabolism of GABA.6
Furthermore, VPA inhibits cyclooxygenase7 and in¯u-
ences the brain energy metabolism.8 VPA is extensively
metabolized by a variety of conjugation and oxidative
processes and several of its metabolites are potent
anticonvulsants.1 Hundreds of analogues of VPA have
been synthesized and evaluated as anticonvulsants, but
the majority of the studies have concentrated on struc-
ture±activity studies in the carbon skeleton.1 Only two
analogues have been prepared in which the carboxylic
acid moiety has been isosterically replaced with another
acidic moiety, tetrazole9 and 1,2,4-oxadiazolidine-3,5-
dione,10 respectively, and both compounds were equi-
potent with VPA in anticonvulsant studies. Phos-
phinic11 and phosphonic acids12 have attracted
considerable attention in medicinal chemistry in recent
years due to their ability to function as e€ective bio-
isosteres for the carboxylic acid group. As part of our
ongoing research in the medicinal chemistry related to
epilepsy,13 we have recently reported the syntheses of
phosphorus based analogues of GABA.14 Here we wish
to report the syntheses and anticonvulsant properties of
novel phosphinic and phosphonic acid analogues 2±4 of
VPA.
The phosphinic acid 2 and phosphonic acid 4 were syn-
thesized from valproic acid (Scheme 1) by conversion to
the N-hydroxy thiopyridone ester, a convenient pre-
cursor of the carbon radical, which can be trapped by
yellow phosphorus and subsequently oxidized to the
phosphinic acid 2 at 0 ꢀC.15 The phosphinic acid was
separated from 25% contaminating phosphonic acid by
fractional crystallization of their anilinium salts from
Figure 1. Structures of valproic acid 1 and the phosphinic acid 2,
methylphosphinic acid 3 and phosphonic acid 4 analogues.
*Corresponding author. Tel.: +45-36442425 ext. 3232; fax: +45-
36301385; e-mail: jke@lundbeck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00512-6

2548
J. Kehler et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2547±2548
are not substrates for the presumed carboxylic acid
transporter responsible for transporting VPA over the
blood±brain±barrier, thus preventing the access of 2±4
to the CNS.
References and Notes
Scheme 1. Syntheses of the valproate analogues phosphinic acid 2,
and phosphonic acid 4. HO-spy is N-hydroxythiopyridone.
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Scheme 2. Syntheses of the valproate analogue methylphosphinic acid 3.
acetonitrile. Further oxidation of 2 by re¯uxing 30%
H2O2 for 12 h gave the phosphonic acid 4 in high
yield.15
The methylphosphinic acid 3 was synthesized by a
recently developed methodology16 (Scheme 2). Silyl
Abramov addition of ethyl methylphosphinate 614b to
4-heptanone catalyzed by hexamethydisilazane and
subsequent removal of the trimethylsilyl group with
triethylamine trihydro¯uoride gave the a-hydroxyphos-
phinate 7 in good yield. Compound 7 was deoxygenated
using a modi®ed Barton deoxygenation procedure,17 i.e.,
activation of the tertiary alcohol by methyl oxalyl chloride
and dimethylaminopyridine (DMAP) followed by
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hydride to give methylphosphinate 8 in good yield.
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The crystalline sodium salts of the VPA analogues 2±4
were tested for their anticonvulsant activity in amygdala
kindled rats.19 None of the novel compounds displayed
any anticonvulsant activity. Apparently, 2±4 are not
substrates for the enzymes or receptor(s) which mediate
the anticonvulsant activity of VPA, or alternatively 2±4
19. Racine, R. J. Electroencephalogr. Clin. Neurophysiol. 1972,
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