ANTICONVULSANT ACTIVITY OF ENANTIOMERIC CINNAMAMIDE DERIVATIVES
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were used: R-2-aminopropan-1-ol for 1, S-2-aminopropan-1-ol for 2, R-2-
aminobutan-1-ol for 3, and S-2-aminobutan-1-ol for 4. Appropriate aminoalkanol
was dissolved in 5.5% solution of K2CO3. Then about 10 mL of toluene was
added and the solution of an equimolar amount of trans-cinnamoyl chloride
in toluene was added dropwise for about 20 min while the reaction mixture
was mixed on a magnetic stirrer. The precipitates of crude products were
obtained, filtered from the reaction mixtures, and washed with a 5% solution
of K2CO3 and distilled water. The obtained compounds were dried and
crystallized from a mixture of n-hexane/toluene (3/1 v/v).
Analytical Data for Compounds 1–4
R(–)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1). CAS:
1609486-23-8, white solid (yield 83%), mp 128–130 °C; [α]2D0 = À6.62 deg dmÀ1
cm3 gÀ1 (c = 0.02 gcmÀ3 in methanol); 1H-NMR (300 MHz, CDCl3, δ): 1.25 (d,
J. = 6.9 Hz, 3H; CH3), 2.93 (bs, 1H; OH), 3.58-3.64 (m, 1H; CHH-OH), 3.73-3.77
(m, 1H; CHH-OH), 4.17-4.24 (m, 1H; CH-(CH2OH)), 5.85 (bs, 1H; NH), 6.40
(d, J= 15.6 Hz, 1H; Ar-CH = CH); 7.25-7.50 (m, 5H; Ar-H), 7.63 (d, J= 15.6 Hz,
1H; Ar-CH = CH). ESI-MS (m/z): [M+H]+ calcd. for C12H16NO2, 206.11, found,
206.18. Anal. calcd. for C12H15NO2: C 70.22, H 7.37, N 6.82; found: C 70.09, H
7.40, N 6.79. Rf = 0.58 (CHCl3/CH3OH 9/1 v/v).
Fig. 1. Structures of enantiomeric antiepileptic drugs (a) levetiracetam, (b)
pregabalin, (c) eslicarbazepine acetate.
mainly to active derivative - S-licarbazepine and only partly to
inactive one - R-licarbazepine. Moreover, eslicarbazepine ace-
tate is not metabolized to carbamazepine-10,11-epoxide which
is responsible for adverse effects and induction of liver en-
zymes.9–11 The above examples show that stereochemistry
plays an important role in anticonvulsant and antiepileptic
activity.
We have previously reported some racemic and achiral trans-
cinnamoyl derivatives of aminoalkanols possessing anticonvul-
sant activity. One of the most active compounds among them, R,
S-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (Fig. 2),
N-trans-cinnamoyl derivative of R,S-2-aminopropan-1-ol, showed
ED50s of 86.6 and 60.9 mg/kg when tested in mice after intraper-
itoneal (i.p.) administration in maximal electroshock and 6-Hz
test, respectively.12,13
S(+)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (2). CAS:
1609486-24-9, white solid (yield 80%), mp 128–130 °C; [α]2D0 =6.85 degdmÀ1 cm3
gÀ1 (c = 0.02 gcmÀ3 in methanol); 1H-NMR (300 MHz, CDCl3, δ): 1.25
(d, J= 6.7 Hz, 3H; CH3). 2.55 (bs, 1H; OH), 3.61 (dd, J =6.2 Hz, J= 11.0 Hz, 1H;
CHH-OH), 3.75 (dd, J= 3.6 Hz, J= 10.9 Hz, 1H; CHH-OH), 4.18-4.26 (m, 1H;
CH-(CH2OH)), 5.89 (bs, 1H; NH), 6.41 (d, J =15.6Hz, 1H; Ar-CH =CH), 7.26-
7.37 (m, 3H; Ar-H), 7.46-7.50 (m, 2H; Ar-H), 7.63 (d, J= 15.6 Hz, 1H; Ar-C-
H = CH). ESI-MS (m/z): [M+ H]+ calcd. for C12H16NO2, 206.11, found, 206.12.
Anal. calcd. for C12H15NO2: C 70.22, H 7.37, N 6.82; found: C 70.12, H 7.41, N
6.86. Rf = 0.58 (CHCl3/CH3OH 9/1 v/v).
In the present article we report enantiomeric N-trans-cinnamoyl
derivatives of 2-aminopropan-1-ols and 2-aminobutan-1-ols. We
used crystallographic methods to evaluate the configuration of
2-aminopropan-1-ols derivatives. The compounds were tested for
anticonvulsant activity in various models of seizures in mice and
rats. We anticipated finding potential relationships between anti-
convulsant activity and configuration of the tested compounds.
R(+)-(2E)-N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide (3). CAS:
201005-58-5, white solid (yield 83%), mp 123–124 °C; [α]2D0 =36.53 degdmÀ1
cm3 gÀ1 (c = 0.02 gcmÀ3 in methanol); 1H-NMR (300 MHz, CDCl3, δ): 1.00
(t, J= 7.4 Hz, 3H; CH3), 1.50-1.72 (m, 2H; CH2), 2.68 (bs, 1H; OH), 3.63-3.70
(m, 1H, CHH-OH), 3.74-3.79 (m, 1H; CHH-OH), 3.97-4.06 (m, 1H; NH-CH),
5.88 (d, J = 7.2 Hz, 1H; NH), 6.43 (d, J= 15.6 Hz, 1H; Ar-CH = CH), 7.33-7.51
(m, 5H; Ar-H), 7.64 (d, J= 15.6 Hz, 1H; Ar-CH = CH). Anal. calcd. for
C13H17NO2 : C 71.21, H 7.81, N 6.39; found: C 71.08, H 7.79, N 6.35. Rf = 0.60
(CHCl3/CH3OH 9/1 v/v).
MATERIALS AND METHODS
Chemistry
S(–)-(2E)-N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide (4). CAS:
1359050-10-4, white solid (yield 80%), mp 123–124 °C; [α]
Reagents were manufactured by Alfa Aesar (Ward Hill, MA). Solvents
were commercially available materials of reagent grade. Melting points
(mp) are uncorrected and were determined using a Büchi (Germany)
SMP-20 apparatus. Specific rotation was measured on a Jasco (Tokyo,
Japan) P-2000 polarimeter. The 1H NMR spectra were obtained in CDCl3
by means of a Varian (Palo Alto, CA) Mercury-VX 300 NMR spectrometer
with TMS as internal standard. Results of 1H NMR are presented in the
following format: chemical shift δ in ppm, multiplicity, coupling constant J,
number of protons, protons’ position. Multiplicities are shown as the abbre-
viations: s (singlet), bs (broad singlet), d (doublet), dd (doublet of doublets),
t (triplet), m (multiplet). The LC-MS spectra were obtained on Waters (Mil-
ford, MA) ACQUITYTM TQD system with TQ detector (Waters). The
ACQUITY UPLC BEH C18 column was used (Waters). Elemental analyses
were performed on a Vario EI III elemental analyzer. Thin-layer chromatog-
raphy was carried out on precoated aluminum sheets (silica gel 60 F-254,
Merck, Darmstadt, Germany); spots were visualized by UV light.
20 = À35.79 deg dmÀ1 cm3 gÀ1 (c = 0.02 gcmÀ3 in methanol); 1H-NMR
D
(300 MHz, CDCl3, δ): 1.00 (t, J = 7.4 Hz, 3H; CH3), 1.50-1.72 (m, 2H; CH2),
2.68 (t, J = 5.6 Hz, 1H; OH), 3.64-3.71 (m, 1H; CHH-OH), 3.75-3.82 (m, 1H;
CHH-OH), 3.96-4.07 (m, 1H; NH-CH), 5.75 (d, J = 7.9 Hz, 1H; NH), 6.43 (d,
J = 15.6 Hz, 1H, Ar-CH = CH), 7.36-7.52 (m, 5H; Ar-H), 7.65 (d, J = 15.6 Hz,
1H; Ar-CH = CH). Anal. calcd. for C13H17NO2 : C 71.21, H 7.81, N 6.39; found:
C 71.28, H 7.88, N 6.27. Rf = 0.60 (CHCl3/CH3OH 9/1 v/v).
Crystallography
Crystals suitable for an X-ray structure analysis were obtained from
propyl acetate by slow evaporation of the solvent at room temperature.
The X-ray diffraction data for the crystals of compounds 1 and 2 were
collected on the Oxford Diffraction SuperNova four circle diffractometer
equipped with the Cu (1.54184 Å) Kα radiation source and graphite mono-
chromator. The crystals data, details of data collection, and structures re-
finement parameters are summarized in Table 1. The structures were
solved by direct methods using SIR-9714 and all nonhydrogen atoms were
refined anisotropically using weighted full-matrix least-squares on F2. Re-
finement and further calculations were carried out using SHELXL-97.15
The hydrogen atoms bonded to carbons were included in the structure
at idealized positions and were refined using a riding model with Uiso
(H) fixed at 1.2 Ueq of C and 1.5 Ueq for methyl groups. Hydrogen atoms
attached to oxygen and nitrogen atoms were found from the difference
Fourier map and refined without any restraints. For molecular graphics
ORTEP16 and MERCURY17 programs were used.
Synthesis of Compounds 1–4
Compounds 1–4 were obtained by means of a previously published
procedure of N-acylation.12,13 In the reactions, enantiomeric aminoalkanols
Fig. 2. Structure of R,S-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide.
Chirality DOI 10.1002/chir