Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives.

Article abstract of DOI:10.1016/S0014-827X(01)01147-8

A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).

Full text of DOI:10.1016/S0014-827X(01)01147-8

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Il Farmaco 56 (2001) 821–826
Synthesis and anticonvulsant properties of
2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives
Alba Chimirri a,*, Angela De Sarro b, Giovambattista De Sarro c, Rosaria Gitto a,
a
Maria Zappala`
a Dipartimento Farmaco-Chimico, Uni6ersita` di Messina, 6iale Annunziata, 98168 Messina, Italy
b Cattedra di Chemioterapia, Istituto di Farmacologia, Facolta` di Medicina, Uni6ersita` di Messina, piazza XX Settembre, 98100 Messina, Italy
c Cattedra di Farmacologia, Dipartimento di Medicina Sperimentale e Clinica, Uni6ersita` di Catanzaro, 6ia T. Campanella,
88100 Catanzaro, Italy
Received 21 April 2001; accepted 9 June 2001
Abstract
A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties
evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at
C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-
a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13). © 2001 Elsevier Science
S.A. All rights reserved.
Keywords: 1H-Pyrrolo[1,2-a]benzimidazol-1-ones; Anticonvulsant agents
1. Introduction
Our structure–activity relationship studies investi-
gated the effect of the substituents on the pyrrolobenz-
imidazole system and the comparison of different
analogs allowed us to establish some structural require-
ments for anticonvulsant activity [3,5]. In addition it
was also demonstrated that some 1H-pyrrolo[1,2-
a]benzimidazol-1-ones possessed anticonvulsant effects
comparable to that of diphenylhydantoin [6].
In order to gain further insight into the structure–ac-
tivity relationships and to obtain more potent and less
toxic agents, we now report here the synthesis of new
2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-
one derivatives with different substituents on 2, 3a, 6
and 7 positions and the evaluation of anticonvulsant
activity in DBA/2 mice against sound-induced seizures.
Epilepsy is a brain function disorder characterized by
recurrent seizures that have a sudden onset. It was
assumed for many years that epilepsy could be treated
with just one drug, but it is now apparent that is not
the case as more than one mechanism may be responsi-
ble for the various types of seizures. Although most
seizures can be treated to some extent, 30% of all
patients suffering from epilepsy do not respond to any
current drug, either in monotherapy or in
combinations.
Drugs clinically active against epilepsy include
derivatives with common structural characteristics such
as a nitrogen heterocyclic system with a carbonyl group
and an aromatic or heteroaromatic nucleus linked to
the heterocyclic system.
As part of our program on the chemistry of hetero-
polycyclic systems as potential anticonvulsant agents,
we have previously described a series of 2,3,3a,4-te-
trahydro-1H-pyrrolo[1,2-a]benzimidazol-1-ones [1–5].
2. Experimental
2.1. Chemistry
Melting points were determined on a Kofler hot stage
apparatus and are uncorrected. Elemental analyses (C,
H, N) were carried out on a Carlo Erba Model 1106
* Corresponding author.
E-mail address: chimirri@pharma.unime.it (A. Chimirri).
0014-827X/01/$ - see front matter © 2001 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01147-8

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A. Chimirri et al. / Il Farmaco 56 (2001) 821–826
Elemental Analyzer and the results are within 90.4% of
the theoretical values. Merck silica gel 60 F254 plates
were used for analytical TLC; column chromatography
was performed on Merck silica gel 60 (70–230 mesh). 1H
NMR spectra were recorded in CDCl3 on a Varian
Gemini-300 spectrometer. Chemical shifts are expressed
in l (ppm) relative to TMS as internal standard and
coupling constants (J) in Hz. All exchangeable protons
were confirmed by addition of D2O. Mass spectra (MS)
were run on a Shimadzu GCMS QP 500 gas chromatog-
raphy-mass spectrometer. Compounds 8–10 and 13–15
were prepared according to a procedure previously
described [3].
2.1.2.3.
6-Fluoro-3a-phenyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (16). 1H NMR (l)
2.47–2.82 (m, 4H, CH2CH2), 4.66 (bs, 1H, NH), 6.25
(dd, 1H, J=1.9 and JHF=9.0 Hz, H-5), 6.50 (dd, 1H,
J=2.1 and JHF=9.5 Hz, H-7), 7.32–7.48 (m, 6H, H-8
and Ar).
2.1.2.4.
7-Fluoro-3a-phenyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (17). 1H NMR (l)
2.47–2.80 (m, 4H, CH2CH2), 4.35 (bs, 1H, NH), 6.56
(dd, 1H, J=2.3 and JHF=9.1 Hz, H-5), 6.64 (dd, 1H,
J=2.5 and JHF=10.6 Hz, H-6), 7.30 (dd, 1H, J=2.4
and JHF=8.25 Hz, H-8), 7.32–7.48 (m, 5H, Ar).
2.1.1. Synthesis of 4-fluoro-1,2-phenylenediamine (3)
To a mixture of 4-fluoro-2-nitroaniline (10 mmol) and
granulated tin, HCl 37% (10 ml) was added dropwise.
The reaction mixture was heated on a boiling water bath
for 1 h. The mixture was cooled, treated with a solution
of NaOH and extracted with CHCl3. The organic phase
was dried over Na2SO4, the solvent was evaporated and
the crude residue was used in subsequent reaction with-
out any further purification.
2.1.2.5.
2-Methyl-3a-phenyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (cis-18). Purified by
column chromatography using diethyl ether/light
petroleum (50:50) as eluant. 1H NMR (l) 1.23 (d,
J=6.9 Hz, 3H, CH3), 2.44 (dd, 1H, J=11.5 and
J=12.5 Hz, H-3), 2.70 (m, 1H, H-2) 3.02 (dd, 1H,
J=6.6 and J=11.5 Hz, H-3), 4.50 (bs, 1H, NH), 6.61
(d, 1H, J=7.5 Hz, H-5), 6.87 (t, 1H, J=7.5 Hz, H-7),
6.94 (t, 1H, J=7.5 Hz, H-6), 7.30–7.47 (m, 5H, Ar),
7.58 (d, 1H, J=7.5 Hz, H-8). MS, m/z: 264 (M+, 42),
263 (11), 196 (13), 195 (100), 193 (17), 187 (71), 159 (21),
104 (10), 77 (10).
2.1.2. General procedure for the synthesis of
2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]-
benzimidazol-1-ones 11, 12 and 16–25
A solution of 1,2-phenylenediamine derivative (1–3)
(10 mmol) in anhydrous toluene (50 ml) and 4-acylpro-
pionic acid (4–7) (10 mmol) was heated to reflux for 24
h with a Dean–Stark apparatus. The reaction mixture
was evaporated to dryness, and the oily residue was
recrystallized from suitable solvent or subjected to silica
gel column chromatography to afford the desired
product.
2.1.2.6.
2-Methyl-3a-phenyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (trans-18). Purified by
column chromatography using diethyl ether/light
petroleum (50:50) as eluant. 1H NMR (l) 1.11 (d,
J=7.6 Hz, 3H, CH3), 2.57 (dd, 1H, J=1.4 and J=12.6
Hz, H-3), 2.87 (m, 1H, H-2), 3.04 (dd, 1H, J=9.3 and
J=12.6 Hz, H-3), 4.47 (bs, 1H, NH), 6.59 (d, 1H,
J=7.6 Hz, H-5), 6.87 (t, J=7.5 Hz, 1H, H-7), 6.95 (t,
J=7.6 Hz, 1H, H-6), 7.28–7.46 (m, 5H, Ar), 7.58 (d,
J=7.5 Hz, 1H, H-8). MS, m/z: 264 (M+, 38), 263 (11),
196 (13), 195 (97), 194 (100), 193 (16), 187 (66), 159 (18),
104 (9.8), 77 (12).
2.1.2.1.
6-Fluoro-3a-methyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (11). Purified by
column chromatography using CHCl3/MeOH (95:5) as
1
eluant. H NMR (l) 1.50 (s, 3H, CH3), 2.34–2.82 (m,
4H, CH2CH2), 4.60 (bs, 1H, NH), 6.37 (dd, 1H, J=2.3
and JHF=9.1 Hz, H-5), 6.43 (dd, 1H, J=2.5 and
2.1.2.7. 6-Chloro-2-methyl-3a-phenyl-2,3,3a,4-tetrahy-
dro-1H-pyrrolo[1,2-a]benzimidazol-1-one
(cis-19).
J
HF=10.6 Hz, H-7), 7.29 (dd, 1H, JHF=5.0 and J=8.4
Purified by column chromatography using diethyl ether/
light petroleum (80:20) as eluant. H NMR (l) 1.21 (d,
1
Hz, H-8). MS, m/z: 268 (M+, 25), 267 (12), 214 (15), 213
(100), 212 (93), 211 (19), 191 (78), 149 (37), 110 (25), 109
(12), 108 (15), 104 (12), 90 (11), 89 (13), 83 (23), 82 (21),
77 (28), 76 (13), 65 (17), 63 (16), 57 (10), 55 (11), 51 (25).
3H, J=6.9 Hz, CH3), 2.44 (dd, 1H, J=11.7 and
J=12.3 Hz, H-3), 2.69 (m, 1H, H-2), 3.01 (dd, 1H,
J=6.7 and J=11.7 Hz, H-3), 4.70 (bs, 1H, NH), 6.57
(d, 1H, J=2.0 Hz, H-5), 6.80 (dd, 1H, J=2 and J=8.2
Hz, H-7), 7.31–7.43 (m, 5H, Ar), 7.45 (d, 1H, J=8.2
Hz, H-8). MS, m/z: 298 (M+, 31), 231 (33), 230 (44), 229
(100), 228 (90), 223 (17), 221 (61), 193 (24), 192 (11), 115
(10), 90 (14), 77 (18), 63 (18).
2.1.2.2.
7-Fluoro-3a-methyl-2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one (12). Purified by
column chromatography using CHCl3/MeOH (95:5) as
eluant. H NMR (l) 1.50 (s, 3H, CH3), 2.34–2.82 (m,
1
4H, CH2CH2), 4.24 (bs, 1H, NH), 6.56 (dd, 1H, J=2.3
and JHF=9.1 Hz, H-5), 6.64 (dd, 1H, J=2.5 and
2.1.2.8. 6-Chloro-2-methyl-3a-phenyl-2,3,3a,4-tetrahy-
JHF=10.6 Hz, H-6), 7.17 (dd, 1H, JHF=2.4 and J=
dro-1H-pyrrolo[1,2-a]benzimidazol-1-one
(trans-19).
8.25 Hz, H-8).
Purified by column chromatography using diethyl

A. Chimirri et al. / Il Farmaco 56 (2001) 821–826
823
1
1
ether/light petroleum (80:20) as eluant. H NMR (l)
eluant. H NMR (l) 2.34 (s,3H,CH3), 2.50–2.85 (m,
4H, CH2CH2), 4.47 (bs, 1H, NH), 6.50 (d, 1H, J=8.24
Hz, H-5), 6.89 (dd, 1H, J=2.0 and J=8.24 Hz, H-6),
7.20 and 7.30 (2d, 4H, J=8.1 Hz, Ar), 7.56 (d, 1H,
J=2.0 Hz, H-8).
1.11 (d, 3H, J=6.9 Hz, CH3), 2.56 (dd, 1H, J=1.4 and
J=12.6 Hz, H-3), 2.87 (m, 1H, H-2), 3.04 (dd, 1H,
J=9.4 and J=12.6 Hz, H-3), 4.55 (bs, 1H, NH), 6.55
(d, 1H, J=1.8 Hz, H-5), 6.82 (dd, 1H, J=1.8 and
J=8.2 Hz, H-7), 7.29–7.42 (m, 5H, Ar), 7.47 (d, 1H,
J=8.2 Hz, H-8).
2.1.2.14. 6-Fluoro-2,3,3a,4-tetrahydro-3a-(p-tolyl)-1H-
pyrrolo[1,2-a]benzimidazol-1-one (24). Purified by
column chromatography using CHCl3/MeOH (95:5) as
2.1.2.9. 7-Chloro-2-methyl-3a-phenyl-2,3,3a,4-tetrahy-
1
dro-1H-pyrrolo[1,2-a]benzimidazol-1-one
(cis-20).
eluant. H NMR (l) 2.34 (s, 3H, CH3), 2.50–2.80 (m,
Purified by column chromatography using diethyl
ether/light petroleum (80:20) as eluant. H NMR (l)
4H, CH2CH2), 4.58 (bs, 1H, NH), 6.31 (dd, 1H, J=2.4
and JHF=9.0 Hz, H-5), 6.50 (dd, 1H, J=2.5 and
1
1.22 (d, 3H, J=7.0 Hz, CH3), 2.43 (dd, 1H, J=11.5
and J=12.5 Hz, H-3), 2.69 (m, 1H, H-2), 3.02 (dd, 1H,
J=6.6 and J=11.5 Hz, H-3), 4.74 (bs, 1H, NH), 6.50
(d, 1H, J=8.2 Hz, H-5), 6.89 (dd, 1H, J=2 and
J=8.2 Hz, H-6), 7.31–7.47 (m, 5H, Ar), 7.56 (d, 1H,
J=2.0 Hz, H-8).
JHF=10.6 Hz, H-7), 7.20 and 7.28 (2d, 4H, J=8.1 Hz,
Ar), 7.44 (dd, 1H, JHF=5.03 and J=8.4 Hz, H-8).
MS, m/z: 282 (M+, 28), 281 (17), 228 (13), 227 (90),
226 (100), 225 (28), 224 (16), 191 (61), 149 (30), 116
(10), 115 (10), 110 (22), 108 (12), 91 (19), 89 (12), 83
(19), 65 (18), 63 (14).
2.1.2.10. 7-Chloro-2-methyl-3a-phenyl-2,3,3a,4-tetrahy-
2.1.2.15. 7-Fluoro-2,3,3a,4-tetrahydro-3a-(p-tolyl)-1H-
pyrrolo[1,2-a]benzimidazol-1-one (25). Purified by
column chromatography using CHCl3/MeOH (95:5) as
dro-1H-pyrrolo[1,2-a]benzimidazol-1-one
(trans-20).
Purified by column chromatography using diethyl
1
1
ether/light petroleum (80:20) as eluant. H NMR (l)
eluant. H NMR (l) 2.34 (s, 3H, CH3), 2.50–2.80 (m,
1.09 (d, 3H, J=7.5 Hz, CH3), 2.57 (dd, 1H, J=1.2 and
J=12.6 Hz, H-3), 2.87 (m, 1H, H-2), 3.03 (dd, 1H,
J=9.4 and J=12.6 Hz, H-3), 4.43 (bs, 1H, NH), 6.48
(d, 1H, J=8.2 Hz, H-5), 6.90 (dd, 1H, J=2.0 and
J=8.2 Hz, H-6), 7.29–7.41 (m, 5H, Ar), 7.56 (d, 1H,
J=2.0 Hz, H-8).
4H, CH2CH2), 4.35 (bs, 1H, NH), 6.56 (d, 1H, J=2.3
and JHF=9.1 Hz, H-5), 6.64 (dd, 1H, J=2.5 and
JHF=10.6 Hz, H-6), 7.30 (dd, 1H, J=2.4 and JHF=
8.25 Hz, H-8).
2.2. Lipophilicity measurements
2.1.2.11. 2,3,3a,4-Tetrahydro-3a-(p-tolyl)-1H-pyrrolo-
[1,2-a]benzimidazol-1-one (21). 1H NMR (l) 2.34 (s,
3H, CH3), 2.50–2.82 (m, 4H, CH2CH2), 4.52 (bs, 1H,
NH), 6.62 (dd, 1H, J=1.2 and J=7.6 Hz, H-5), 6.86
(dt, 1H, J=1.2 and J=7.6 Hz, H-7), 6.95 (dd, 1H,
J=1.2 and J=7.6 Hz, H-6), 7.20 and 7.33 (2d, 4H,
J=8.1 Hz, Ar), 7.57 (dd, 1H, J=1.2 and J=7.6 Hz,
H-8). MS, m/z: 264 (M+, 60), 263 (40), 210 (14), 209
(93), 208 (100), 207 (20), 206 (12), 173 (84), 131 (19), 92
(15), 91 (11), 65 (17).
The relative lipophilicity (Rm) of the compounds was
measured by reversed-phase high-performance thin-
layer chromatography (RP-HPTLC) according to the
method previously described [7]. Briefly, Whatman
KC18F plates were used as the non-polar stationary
phase. The plates were dried at 105 °C for 1 h before
use. The polar mobile phase was a 2:1 (v/v) mixture of
acetone and water. Each compound was dissolved in
CHCl3 (3 mg/ml), and 1 ml of solution was applied onto
the plate. The experiments were repeated five times with
a different disposition of the compounds on the plate.
The Rf values were expressed as the mean values of the
five determinations. The Rm values were calculated
from the experimental Rf values according to the for-
mula Rm=log[(1/Rf)−1]. Higher Rm values indicate
higher lipophilicity.
2.1.2.12. 6-Chloro-2,3,3a,4-tetrahydro-3a-(p-tolyl)-1H-
pyrrolo[1,2-a]benzimidazol-1-one (22). Purified by
column chromatography using CCl4/AcOEt (80:20) as
1
eluant. H NMR (l) 2.34 (s, 3H, CH3), 2.47–2.81 (m,
4H, CH2CH2), 4.60 (bs, 1H, NH), 6.56 (d, 1H, J=1.9
Hz, H-5), 6.79 (dd, 1H, J=1.9 and J=8.09 Hz, H-7),
7.19 and 7.30 (2d, 4H, J=8.1 Hz, Ar), 8.01 (d, 1H,
J=8.09 Hz, H-8). MS, m/z: 298 (M+, 46), 297 (26),
245 (33), 244 (38), 243 (100), 242 (79), 241 (13), 209
(22), 208 (15), 207 (78), 206 (10), 165 (19), 91 (12), 90
(12), 63 (15).
2.3. Pharmacology
2.3.1. Test of anticon6ulsant acti6ity against audiogenic
seizures in DBA/2 mice
All experiments were performed with DBA/2 mice
which are genetically susceptible to sound-induced
seizures [8]. DBA/2 mice (8–12 g; 22–25 days old) were
purchased from Charles River (Calco, Como, Italy).
Groups of 10 mice of either sex were exposed to
2.1.2.13. 7-Chloro-2,3,3a,4-tetrahydro-3a-(p-tolyl)-1H-
pyrrolo[1,2-a]benzimidazol-1-one (23). Purified by
column chromatography using CCl4/AcOEt (80:20) as

824
A. Chimirri et al. / Il Farmaco 56 (2001) 821–826
Scheme 1.
auditory stimulation 30 min following administration
of vehicle or each dose of drugs studied. The com-
pounds were given ip (0.1 ml/10 g of body weight of the
mouse) as a freshly prepared solution in 50% dimethyl
sulfoxide (DMSO) and 50% sterile saline (0.9% NaCl).
Individual mice were placed under a hemispheric Per-
spex dome (diameter 58 cm), and 60 s were allowed for
habituation and assessment of locomotor activity. Au-
ditory stimulation (12–16 kHz, 109 dB) was applied for
60 s or until tonic extension occurred, and induced a
sequential seizure response in control DBA/2 mice,
consisting of an early wild running phase, followed by
generalized myoclonus and tonic flexion and extension
sometimes followed by respiratory arrest. The control
and drug-treated mice were scored for latency to and
incidence of the different phases of the seizures [9]. The
experimental protocol and all the procedures involving
animals and their care were conducted in conformity
with the institutional guidelines and the European
Council Directive of laws and policies.
2.3.2. Statistical analysis
Statistical comparisons between groups of control
and drug-treated animals were made using Fisher’s
exact probability test (incidence of the seizure phases).
The ED50 values of each phase of audiogenic seizures
were determined for each dose of compound adminis-
tered, and dose–response curves were fitted using a
computer program by the method of Litchfield and
Wilcoxon [10].
Table 1
Physicochemical data for compounds 11, 12 and 16–25
3. Results and discussion
Comp.
Formula
M.p. (°C)
Solvent
Yield (%)
The synthesis of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-
a]benzimidazol-1-ones (8–25) was performed according
to the synthetic approach shown in Scheme 1, by
reacting the appropriate 1,2-phenylenediamine (1–3)
with 3-acylpropionic acids (4–7) in refluxing anhydrous
toluene. Derivatives 11, 12 and 16–25 are new com-
pounds, whereas the synthesis of 8–10 and 13–15 has
already been reported [3]. Physicochemical data of com-
pounds 11, 12 and 16–25 are reported in Table 1.
When a 4-substituted 1,2-phenylenediamine deriva-
tive (2 or 3) was employed as starting material two
series of isomeric derivatives, i.e. 6- or 7-substituted,
were isolated from the reaction mixture, with a clear
prevalence of the first. The regiospecificity may be
11
12
16
17
cis-18
trans-18
cis-19
trans-19
cis-20
trans-20
21
C
11H12FN2O 108–110
MeOH
MeOH
EtOH
EtOAc
MeOH
Et2O
69
12
71
16
35
29
28
21
16
11
78
44
10
61
9
C11H12FN2O 125–127
C16H13FN2O 168–170
C16H13FN2O 179–181
C17H16N2O
C17H16N2O
C17H15ClN2O 135–138
C17H15ClN2O 192–195
C17H15ClN2O 163–165
C17H15ClN2O 182–185
148–150
150–152
MeOH
Et2O
MeOH
EtOH
EtOH
MeOH
Et2O
C
17H16N2O
158–160
22
23
24
25
C17H15ClN2O 162–165
C17H15ClN2O 150–153
C17H15FN2O 128–130
C17H15FN2O 134–136
MeOH
Et2O

A. Chimirri et al. / Il Farmaco 56 (2001) 821–826
825
Table 2
Within 3a-methyl-substituted compounds (8, 9, and
11), the introduction of fluorine atom at C-6 position
on benzene fused ring (11) does not affect anticonvul-
sant properties of 6-unsubstituted one (8) whereas if
this position bears a chlorine atom (9) the potency
decreases.
Anticonvulsant activity against audiogenic seizures in DBA/2 mice
and relative lipophilicity (Rm)
Comp.
ED50 (mmol/kg) a (995% confidence limits)
Clonic phase
Tonic phase
Rm
A different trend was observed for 3a-phenylsubsti-
tuted derivatives (13, 14, and 16) among which the most
active was 6-chloro derivative 14. The anticonvulsant
effects were also generally increased by the introduction
of a methyl group at C-2 position (18 and 19). It is
interesting to note that also the stereochemistry influ-
ences the biological properties, the trans isomers being
more active than the corresponding cis ones.
Finally, the potency was strongly enhanced by the
presence of a p-tolyl moiety at C-3a (21, 22, and 24). In
particular, the combination of 6-chloro and p-tolyl
substituents afforded the most active derivative of our
series (22) which displayed an anticonvulsant potency
fivefold higher than that of unsubstituted compound
(13).
8
9
11
13
14
16
cis-18
trans-18
cis-19
trans-19
21
24.1 (12.7–45.5)
52.7 (33.3–83.2)
23.9 (14.9–38.5)
104 (78.4–138)
46.4 (26.8–80.5)
63.8 (45.5–89.7)
63.8 (45.1–90.2)
39.1 (22.7–67.5)
80.3 (47.9–134)
43.2 (27.9–66.9)
29.2 (17.2–49.3)
18.2 (7.02–47.2)
27.7 (17.5–44.1)
17.9 (8.34–38.6)
27.4 (12.0–62.3)
17.0 (9.19–31.6)
79.0 (59.5–105)
31.7 (18.3–54.9)
54.4 (37.5–78.8)
56.9 (40.9–89.2)
25.6 (15.5–45.5)
63.8 (45.1–90.2)
29.1 (15.0–56.4)
27.0 (15.6–46.7)
9.26 (2.35–36.5)
18.5 (12.5–27.5)
−0.357
−0.158
−0.288
−0.122
0.043
−0.065
−0.061
−0.061
0.131
0.122
−0.070
0.105
22
24
0.030
a All data were calculated according to the method of Litchfield
and Wilcoxon [10]. At least 32 animals were used to calculate each
ED50 value.
The relative lipophilicity (Rm) of the tested com-
pounds is summarized in Table 2. Although the most
active compound is also one of the most lipophilic
derivatives, a direct correlation between lipophilicity
and anticonvulsant activity cannot be pointed out. In
fact, compounds with similar Rm values (i.e. 16 and 18,
19 and 22) show different potency, thus suggesting the
importance of other parameters.
In conclusion, the synthesis and the evaluation of
anticonvulsant activity of new 2,3,3a,4-tetrahydro-1H-
pyrrolo[1,2-a]benzimidazol-1-one derivatives have been
reported. The obtained results demonstrate that the
presence of halogen atom at C-6 of the benzene-fused
ring and the p-tolyl group at C-3a position as well as
the stereochemical features of the system contribute to
the anticonvulsant activity.
explained on the basis of the proposed mechanism of
formation of these derivatives [3] which implies the
formation of an intermediate benzimidazole derivative
which successively undergoes cyclization controlled by
the electronic characteristics of the substituent present
on the benzimidazole moiety.
The structures of the 6- and 7-substituted isomers
1
were assigned on the basis of H NMR spectra, taking
into account the shielding effect that the 4-amino group
exerts on the proximal hydrogen at C-5. The resonance
pattern of this proton depends on the position of the
substituent, so the attribution is straightforward.
When 1 or 2 reacted with 3-benzoyl-2-methylpropi-
onic acid (7), owing to the presence of a chiral center in
the structure of g-ketoacid 7, the reaction furnished an
approximate 1:1 mixture of cis and trans isomers which
1
were identified on the basis of H NMR spectroscopy
assisted by NOE measurements: upon irradiation of the
C-2 methyl resonance it is possible to observe a weak
NOE effect for the aromatic protons of the C-3a-sub-
stituent only in cis derivatives.
Among 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzi-
midazol-1-ones reported in Table 1, only 6-substituted
derivatives were tested against audiogenic seizures in
DBA/2 mice because our previous studies had sug-
gested that 7-substituted ones did not show anticonvul-
sant effects. The employed audiogenic stimulation test
in DBA/2 mice has been considered an excellent animal
model for generalized epilepsy and for screening new
anticonvulsant drugs.
Acknowledgements
Financial support from the Italian Ministry of Uni-
versity and Scientific Technological Research
(MURST) and the Italian Council for Research (CNR,
Rome) is gratefully acknowledged.
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