Synthesis and anticonvulsant activity of 7-phenyl-6,7-dihydro-[1,2,4] triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.04.020

Herein, we described the syntheses and anticonvulsant activities of 7-(substituted-phenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1a-1o) and their derivatives. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock test (MES). The most promising compound 1i showed significant anticonvulsant activity in MES test with ED₅₀ value of 19.7 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard drugs. In addition, the potence of compound 1i against seizures induced by Pentylenetetrazole, Isoniazid, Thiosemicarbazide, 3-Mercaptopropionic acid, and Bicuculline in the chemical-induced seizure tests suggested that compound 1i displayed broad spectrum activity in several models, and it is likely to have several mechanisms of action including inhibiting voltage-gated ion channels and modulating GABAergic activity.

Full text of DOI:10.1016/j.ejmech.2011.04.020

European Journal of Medicinal Chemistry 46 (2011) 2955e2963
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and anticonvulsant activity of 7-phenyl-6,7-dihydro-[1,2,4]
triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives
,
a,
*
Xian-Qing Deng a, Li-Na Quan a, Ming-Xia Song a, Cheng-Xi Wei b , Zhe-Shan Quan
**
a College of Pharmacy, Yanbian University, No. 977, Park road, Yanji, Jilin 133002, China
b Institute of Neurosurgery, Inner Mongolia University for Nationalities, No. 1742, Holin River Street, Tongliao, Inner Mongolia Autonomous Region 028007, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we described the syntheses and anticonvulsant activities of 7-(substituted-phenyl)-6,7-dihydro-
[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1ae1o) and their derivatives. Most of the synthesized
compounds exhibited potent anticonvulsant activities in the maximal electroshock test (MES). The most
promising compound 1i showed significant anticonvulsant activity in MES test with ED50 value of
19.7 mg/kg. It displayed a wide margin of safety with protective index much higher than the standard
drugs. In addition, the potence of compound 1i against seizures induced by Pentylenetetrazole, Isoniazid,
Thiosemicarbazide, 3-Mercaptopropionic acid, and Bicuculline in the chemical-induced seizure tests
suggested that compound 1i displayed broad spectrum activity in several models, and it is likely to have
several mechanisms of action including inhibiting voltage-gated ion channels and modulating GABAergic
activity.
Received 1 February 2011
Received in revised form
6 April 2011
Accepted 7 April 2011
Available online 13 April 2011
Keywords:
Synthesis
Anticonvulsant
Triazolo[1,5-a]pyrimidin
Imidazo[1,2-a]pyrimidin
Pyrazolo[1,5-a]pyrimidin
Maximal electroshock
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
donors/acceptors. With respect to the compounds mentioned above,
obviously the hydrophobic site is the phenyl group and the substit-
Epilepsy, one of the most frequent neurological afflictions in men
characterized by excessive temporary neuronal discharges resulting
in uncontrolled convulsion, inflicts more than 60 million people
worldwide [1,2]. Although the current drugs provide adequate
seizure control in many patients, it is roughly estimated that up to
28e30% of patients are poorly treated with the available antiepi-
leptic drugs (AEDs) [3,4]. Moreover, many AEDs have serious side
effects [5e10], and lifelong medication may be required. Toxicity,
intolerance, and lack of efficacy are the limitations of the current
AEDs. All of these have stimulated intensive research on novel AEDs.
We previously described the synthesis and anticonvulsant activity
evaluation of some compounds containing triazole, the majority of
which exhibited potent activity in maximal electroshock test (MES)
and several chemical models such as Pentylenetetrazole- and Isoni-
azid-induced seizure tests (Fig. 1) [11e16]. From the currently used
AEDs, the major characteristics important in newly synthesized
compounds are the inclusion of a hydrophobic site and H-bond
uents on it, and the H-bond acceptor is the triazole.
As part of our continuous efforts to find better anticonvulsant
agents in this area, a series of 7-(substituted-phenyl)-6,7-dihydro-
[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1ae1o) were designed
and synthesized in this study, which also possessing the H-bond
acceptor e triazole and the hydrophobic site e phenyl group.
Compounds 2ae2c were synthesized by substituting the hydrogen
of the NH group in the compound 1a to identify whether the amide
group is of necessity for the anticonvulsant activity of this frame. For
further structureeactivity relationship (SAR) establishment, other
three series of compounds: 5-(substituted-phenyl)-5,6-dihy-
droimidazo[1,2-a]pyrimidin-7(8H)-ones (3ae3d), 7-(substituted-
phenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-ones (4ae4d),
and
7-(substituted-phenyl)-7,8-dihydrophenyl[d]imidazo[1,2-a]
pyrimidin-9(10H)-ones (5ae5d) were also prepared by replacing
the triazole in the compound 1 with imidazole, pyrazole, and phenyl
[d]imidazole. The structures of all target compounds were charac-
terized. Anticonvulsant activity and neurotoxicity were also evalu-
ated. For explaining the possible mechanism of action, the most
active compound 1i was tested in Pentylenetetrazole (PTZ), Isoni-
azid (ISO), Thiosemicarbazide (TSC), 3-Mercaptopropionic acid
(3-MP), and Bicuculline (BIC) induced seizure tests.
* Corresponding author. Tel./fax: þ86 433 2436004.
** Corresponding author. Tel.: þ86 475 8267818; fax: þ86 475 8267813.
E-mail addresses: weichengxi1224@yahoo.com.cn (C.-X. Wei), zsquan@ybu.edu.
cn (Z.-S. Quan).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.04.020

2956
X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
O
O
N
OR
OR
R
N
RO
NH
N
R-X
N
N
N
N
R
N
R
N
N
N
N
N
N
N
N
1a-1o
N
2a-2c
I
II
III
H
N
N
O
N
NH2
RO
S
RO
S
N
O
N
N
N
RO
N
N
N
N
N
NH2
NH
O
N
N
H
N
OCH3
N
IV
V
VI
R
R
Fig. 1. Structures of some compounds in containing triazole.
3a-3d
H
N
N
NH2
N
2. Chemistry
NH2
N
H
For the preparation of all compounds described in this paper,
appropriate substituted methyl cinnamates were used as starting
materials. All the compounds were prepared as outlined in Scheme 1.
Cyclization of methyl cinnamates with 1,2,4-triazol-3-amine gave
[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones 1ae1o under high
temperature conditions [17]. The syntheses of compounds 2ae2c,
which bear substituents in the N atom, were performed by treating 1a
with (CH3)2SO4, bromohexane, and benzyl chloride, respectively.
Cyclization of methyl cinnamates with 2-aminoimidazole hemisulfate
and K2CO3 in DMF led to 5-(substituted-phenyl)-5,6-dihydroimidazo
[1,2-a]pyrimidin-7(8H)-ones 3ae3d. Similarly, cyclization of methyl
cinnamates with 1H-pyrazol-5-amine or 1H-benzo[d]imidazol-2-
amine led to 7-(substituted-phenyl)-6,7-dihydropyrazolo[1,5-a]
pyrimidin-5(4H)-ones 4ae4d or 7-(substituted-phenyl)-7,8-dihy-
drophenyl[d]imidazo[1,2-a]pyrimidin-9(10H)-ones 5ae5d, respec-
O
O
NH
N
NH
N
N
N
R
R
4a-4d
5a-5d
Scheme 1. Synthetic route of target compounds.
(MES), the subcutaneous pentylenetetrazol (sc-PTZ), and the
kindling model e which are routinely used by most AED discovery
programs. Of these, the MES and sc-PTZ seizure models represent
the two animal seizure models most widely used in the search for
new AEDs [20,21]. In the present study we used the MES seizure
model for screening the anticonvulsant activity of target
compounds. Compounds 1ae1o were prepared to evaluate the
influence of the phenyl ring on anticonvulsant activity. Their
preliminary anticonvulsant activity were obtained and listed in
Table 1. After i.p. injection in mice using doses of 30, 100, and
300 mg/kg, the following observations can be made. All of the
compounds except 1h were active in the MES test indicating their
anticonvulsant properties. At the dose of 100 mg/kg, compounds
1a, 1b, 1e, 1f, 1i, 1j, and 1l showed complete protection, while 1g,
1m showed protection in 1/3 of the tested mice. Compounds 1b, 1e,
and 1i exhibited protection at 30 mg/kg in 1/3, 3/3, and 3/3,
respectively. None of the compounds showed protection in the 4 h
period.
Compounds 2ae2c, which have substitutes in the N atom of the
amide, were also evaluated for their anticonvulsant activity. All of
them showed protection in 1/3 of the tested mice at 100 mg/kg.
Decrease of their anticonvulsant activity was observed when
compared to 1a, which showed complete protection at 100 mg/kg.
These pharmacology data indicated that compounds containing
halogen in the ortho position (1b, 1e, 1i) possessed better anti-
convulsant activity than the others. What is more the amide in the
middle ring was also essential. Thus, with three substituents (o-F, o-
Cl, o-Br) and non-substituent reserved in the phenyl ring,
compounds 3ae3d, 4ae4d, and 5ae5d were prepared for struc-
tureeactivity relationships (SAR) studies. The anticonvulsant
activities of these compounds were shown in Table 1. For the 5-
(substituted-phenyl)-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-
ones (3ae3d), all the four compounds were active in the MES test.
tively. Their chemical structures were characterized using 1H NMR,13
C
NMR,MSandelementalanalysistechniques.Thedetailedphysicaland
analytical data are listed in Section 6.
3. Pharmacology
All the target compounds were screened for their anticonvul-
sant activity using the most adopted seizure model e the maximal
electroshock seizure (MES) test. Neurotoxicity was assessed by
rotarod test. The MES test and rotarod test were carried out by the
methods described in the Antiepileptic Drug Development Program
(ADD) of the National Institutes of Health following previously
described testing procedures (USA) [18,19]. All the compounds,
dissolved in DMSO, were evaluated for anticonvulsant activities
with KunMing mice in the 18e22 g weight range, which were
purchased from the Laboratory of Animal Research, College of
Pharmacy, Yanbian University. Some compounds possessed better
activity were quantified their anticonvulsant activity, and the best
one was tested in Pentylenetetrazole (PTZ), Isoniazid (ISO), Thio-
semicarbazide (TSC), 3-Mercaptopropionic acid (3-MP), and Bicu-
culline (BIC)-induced seizure tests.
4. Results and discussion
4.1. Phase I evaluation of anticonvulsant activity
As with any other class of drugs, the preclinical discovery and
development of a new chemical entity for the treatment of epilepsy
rely heavily on the use of predictable animal models. At present,
there are three models in vivo e the maximal electroshock seizure

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
2957
Table 1
Phase I evaluation of anticonvulsant activity in mice (i.p.).
O
O
N
O
N
O
O
NH
N
R
N
N
N
NH
NH
NH
R
N
N
N
N
N
R
R
R
R
N
N
4a-4d
3a-3d
5a-5d
2a-2c
1a-1o
Compds.
R
MESa (mg/kg)
0.5 h
Toxicity (mg/kg)
0.5 h
4 h
30
4 h
30
100
3/3
300
100
300
30
100
300
30
100
300
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
2-F
3-F
4-F
0/3
1/3
0/3
0/3
3/3
0/3
0/3
0/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
3/3
3/3
2/3
2/3
3/3
3/3
3/3
0/3
3/3
3/3
2/3
3/3
3/3
1/3
1/3
3/3
2/3
2/3
3/3
3/3
3/3
3/3
3/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
eb
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
0/3
0/3
e
1/3
1/3
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
0/3
0/3
e
0/3
0/3
e
3/3
0/3
0/3
3/3
3/3
1/3
0/3
3/3
3/3
0/3
3/3
1/3
0/3
0/3
1/3
1/3
1/3
3/3
3/3
1/3
2/3
3/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
e
e
e
e
2-Cl
3-Cl
4-Cl
2,4Cl
2-Br
3-Br
4-Br
3-CF3
4-CH3
2-OCH3
4-OCH3
CH3
C6H13
CH2C6H5
H
0/3
0/3
e
1/3
1/3
e
0/3
0/3
e
0/3
0/3
e
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
e
e
e
e
0/3
0/3
e
0/3
0/3
e
0/3
0/3
e
0/3
0/3
e
1j
1k
1l
1/3
e
3/3
e
0/3
e
0/3
e
1m
1n
1o
2a
2b
2c
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
0/3
0/3
e
0/3
1/3
e
0/3
0/3
e
0/3
0/3
e
2-F
2-Cl
2-Br
H
e
e
e
e
2/3
1/3
2/3
1/3
e
3/3
3/3
3/3
3/3
e
0/3
0/3
0/3
0/3
e
0/3
0/3
0/3
0/3
e
2-F
2-Cl
2-Br
H
2-F
2-Cl
2-Br
e
e
e
e
e
e
e
e
e
e
e
e
All positive reaction numbers are in bold italic.
a
Maximal electroshock test (number of animals protected/number of animals tested), the number of mice is three.
Not tested.
b
Compounds 3a and 3b showed complete protection at 100 mg/kg,
5(4H)-one (1i) was the most active and promising compound in
this work. It possessed strong anti-MES activity with ED50 of
19.7 mg/kg, which was close to currently used antiepileptic drugs
phenytoin and carbamazepine and better than that of phenobar-
bital and valproate. The neurotoxicity caused by it was minimal and
was markedly lower than all the drugs compared. It showed
a protective index of 34.8, which was many folds higher than the
current antiepileptic drugs having the PI values in the range of
1.6e6.9. Furthermore, compounds 1a, 1b, 1e, and 1f also showed
higher protective index than these current antiepileptic drugs.
while 3c, 3d showed protection in 1/3 and 2/3 of the tested mice,
respectively. No neurotoxicity was found except 3b. Compounds
4ae4d, which contained a pyrazole, showed complete protection at
the dose of 100 mg/kg, and compounds 4a and 4b exhibited
protection in 1/3 of the tested mice at 30 mg/kg. However, there
was no separation between the anticonvulsant dose and the
neurotoxic dose (100 mg/kg for both). When the triazole was
replaced by benzo[d]imidazole, all four compounds 5ae5d showed
no protection at 300 mg/kg.
4.2. Phase II evaluation of anticonvulsant activity
4.3. Structureeactivity relationships discussions
On the basis of the considerable anticonvulsant activity sug-
gested in phase I testing, compounds 1a, 1b, 1e, 1f, 1i, 1j, 1l, 3a, 3b,
and 4ae4d were subjected to phase II trials for quantification of
their anticonvulsant activity (indicated by ED50) and neurotoxicity
(indicated by TD50) in mice. Results of the quantitative test for
selected compounds, along with the data on the current antiepi-
leptic drugs, are shown in Table 2. Among the tested compounds,
7-(2-bromophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
Analyzing the activities of the synthesized compounds, the
following structureeactivity relationships (SAR) were obtained.
In the first group compounds (1ae1o), effects of different
substitutions at phenyl were observed. Introduction of halogen on
the phenyl ring changed (reduced or increased) the anticonvulsant
activity at different levels (compared with 1a). The bioevaluation
led to an understanding of the importance of the position of the
halogen at the phenyl. Compounds 1b, 1e, 1i, contained halogen in

2958
X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
Table 2
compared to the compounds with the triazole. Replacement of the
triazole ring by phenyl[d]imidazole (5ae5d) led to sharp
Quantitative anticonvulsant data in mice (i.p.).
a
Compds.
R
ED50 (mg/kg) (MES)
TD50 (mg/kg)
PIa
descending in activity, which might be due to steric hindrance to
binding by the additional phenyl group on the imidazole. Thus,
these data indicate that the frame with the triazole displayed the
best anticonvulsant activity and favorable PI, and this site may be
one of the active centers.
1a
1b
1e
1f
1i
1j
1l
3a
3b
4a
4b
4c
H
51.9(48.5e55.3)
31.7 (28.8e34.9)b
25.5 (23.6e27.5)
47.3 (43.0e52.0)
19.7 (17.9e21.7)
84.9 (77.2e93.4)
54.8 (49.8e60.3)
68.2 (62.0e75.0)
88.0 (80.0e96.8)
47.3 (43.0e52.0)
47.3 (43.0e52.0)
63.4 (57.6e69.7)
39.4 (35.8e43.4)
11.8 (9.7e14.1)
9.5 (8.1e10.4)
547.5(497.7e602.2)
456.4 (410.3e507.7)
464.8 (417.8e517.1)
528.1 (474.7e587.5)
684.7 (615.5e761.6)
591.7 (537.9e650.9)
158.4 (144.0e174.2)
458.3 (416.6e504.1)
387.2 (320.0e468.5)
118.3 (107.5e127.2)
118.3 (107.5e127.2)
94.7 (88.1e101.8)
132.0 (120.0e145.2)
76.1(69.1e83.7)
10.5
14.4
18.2
11.2
34.8
7.0
2.9
6.7
4.4
2.5
2.5
1.5
3.4
6.4
6.9
3.2
1.6
2-F
2-Cl
3-Cl
2-Br
3-Br
3-CF3
H
2-F
H
2-F
2-Cl
2-Br
e
4.4. Speculation of mechanism
In this study, the majority of synthesized compounds were
highly potent in the MES test, and the MES test is known to be
sensitive to sodium channel inhibitors (e.g. phenytoin, carbama-
zepine), which suggested that the tested compounds may inhibit
voltage-gated ion channels (particularly sodium channels). To
further investigate the effects of the anticonvulsant activity in
several different models and speculate about the possible mecha-
nism of anticonvulsant action, compound 1i was tested against
convulsions induced by chemical substances, including PTZ, ISO,
3-MP, TSC and BIC. Compound 1i was administered to mice at
50 mg/kg i.p., which was higher than its ED50 value and far below
its TD50 value. The reference drug carbamazepine was also
administered at 50 mg/kg i.p.
In the sc-PTZ model, carbamazepine inhibited the clonic
seizures, tonic seizures and death at the rates of 0%, 100%, and 100%,
respectively. While compound 1i inhibited the clonic seizures, tonic
seizures and lethality completely induced by sc-PTZ (Table 3),
which revealed that compound 1i possessed excellent activity
against sc-PTZ. Compound 1i, exhibiting high anticonvulsant
activity in the MES and sc-PTZ models which are most widely used
in the search for new AEDs, suggested that it really possesses a good
anticonvulsant profile. In the ISO model, carbamazepine inhibited
the clonic seizures, tonic seizures and death induced by ISO at the
rates of 50%, 100% and 100%, respectively. Compound 1i showed
inhibition of the clonic seizure, tonic seizures induced by ISO at the
rates of 0%, 100%, respectively and also showed partial inhibition of
the death compared to the control (Table 3). PTZ and ISO have been
4d
Carbamazepine
Phenytoin
Phenobarbital
Valproate
e
65.5 (52.5e72.9)
69 (62.8e72.9)
426 (369e450)
e
21.8 (21.8e25.5)
272 (247e338)
e
a
PI ¼ Protective (TD50/ED50).
The 95% confidence limits.
b
the ortho position, displayed better potency than 1a, while intro-
duction of halogen on the other position of the phenyl ring led to
weaker activity. Introduction of the strong electron-withdrawing
and lipophilic group eCF3 resulted in a similar activity to that of
1a, while its large neurotoxicity made it impossible to be a candi-
date. Three electron-donor derivatives containing p-CH3, o-OCH3,
and p-OCH3 were also prepared. However, these compounds
exhibited reduced anticonvulsant activities than the corresponding
halogen substituted derivatives. Introduction of the eCH3 was
found to show better activity than substitution with the -OCH3
group.
Compounds 2ae2c, prepared by replacing the hydrogen atom of
the amide in compound 1a with different substituents, exhibited
decreased activity when compared to the unsubstituted compound
1a. Thus, it is concluded that the amide group in this frame was
important for its anticonvulsant activity. The sizes of the substitu-
ents had no significant effects on their activity.
When the triazole ring was replaced by other heterocycles:
imidazole, pyrazole, and phenyl[d]imidazole, the anticonvulsant
activity was altered. The compounds containing the imidazole ring
(3ae3d) decreased the activity slightly compared to the
compounds 1ae1o bearing the triazole ring. Compounds contain-
ing the pyrazole ring (4ae4d) showed anticonvulsant activity
similar to compounds with the triazole. However, they showed
higher neurotoxicity, which led to a lower protective index (PI)
reported to produce seizures by inhibiting
g-aminobutyric acid
(GABA) neurotransmission [22,23]. GABA is the main inhibitory
neurotransmitter in the brain, and is widely implicated in epilepsy.
Inhibition of GABAergic neurotransmission or activity has been
shown to promote and facilitate seizures [24], while enhancement
of GABAergic neurotransmission is known to inhibit or attenuate
seizures. The findings of the present study suggest that the newly
synthesized compound 1i might inhibit or attenuate PTZ-induced
Table 3
Effects of compound 1i on chemical-induced seizures in mice.
Chemical substances
Pentylenetetrazol
Compound
Doses (mg/kg)
Test time (h)
Clonic seizures (%)
Tonic seizures (%)
Lethality (%)
DMSO
Carbamazepine
1i
e
0.5
0.5
0.5
100
100
0
60
0
0
60
0
0
50
50
Isoniazid
DMSO
Carbamazepine
1i
e
1
1
1
100
50
100
100
0
0
60
0
30
50
50
3-Mercaptopropionic acid
Thiosemicarbazide
Bicuculline
DMSO
Carbamazepine
1i
e
0.5
0.5
0.5
100
100
100
100
0
0
100
0
10
30
30
DMSO
Carbamazepine
1i
e
2.5
2.5
2.5
100
100
100
100
0
0
100
0
100
30
30
DMSO
Carbamazepine
1i
e
0.5
0.5
0.5
100
100
100
100
0
10
100
20
50
30
30

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
2959
seizures and ISO-induced seizures in mice by enhancing GABAergic
neurotransmission.
(Bruker, Switzerland), and all chemical shifts were given in parts
per million relative to tetramethysilane. Mass spectra were
measured on a HP1100LC (Agilent Technologies, USA). Elemental
analyses were performed on a 204Q CHN (Perkin Elmer, USA). The
chemicals were purchased from Aldrich Chemical Corporation.
In the 3-MP induced seizure model, carbamazepine inhibited
the clonic seizures, tonic seizures and death at the rates of 0%, 100%,
and 100%, respectively. In comparison, compound 1i showed the
anticonvulsant effect similar to that of carbamazepine in inhibiting
the clonic and tonic seizures, and inhibited the death largely
induced by 3-MP with the inhibition rate of 90% (Table 3). In the
TSC-induced seizure model, the anticonvulsant effect is similar to
that of the 3-MP induced seizure model. Compared with the control
group, carbamazepine showed inhibition of clonic and tonic
seizures and death at rates of 0%, 100%, and 100%, respectively.
Compound 1i showed inhibition of clonic and tonic seizures at rates
of 0% and 100%; however, there was no effect on death rates
induced by TSC (Table 3). 3-MP and TSC are competitive inhibitors
of the GABA synthesis enzyme glutamate decarboxylase (GAD), and
they inhibit the synthesis of GABA resulting in decrease of GABA
levels in the brain [25]. Compound 1i showed moderate antago-
nism to both 3-MP induced seizures and TSC-induced seizures,
suggesting that it might activate GAD or inhibit aminotransferase
(GABA-T) in the brain.
In the BIC induced seizure model, both carbamazepine and 1i
inhibited tonic seizures and death, but did not inhibit clonic
seizures. Carbamazepine showed inhibition of clonic and tonic
seizures and death at rates of 0%, 100%, and 80%, respectively.
Compound 1i showed inhibition of clonic and tonic seizures and
death at rates of 0%, 90%, and 50%, respectively (Table 3). BIC is
a competitive antagonist of GABAA receptor. BIC produces convul-
sions through its antagonism of the GABAA receptor [26]. As
compound 1i inhibited the seizures induced by BIC, it likely exerts
anticonvulsant activity at least partially through GABAA-mediated
mechanisms.
6.1.1. Synthesis of 7-(substituted-phenyl)-6,7-dihydro-[1,2,4]
triazolo[1,5-a]pyrimidin-5(4H)-one derivatives (1ae1o)
A
mixture of appropriate substituted methyl cinnamates
(6.2 mmol) and 1,2,4-triazol-3-amine (12.4 mmol, 1.04 g) was stir-
red for 16 h at 200 ꢀC. After cooling down, a yellow solid was
obtained, which was isolated and purified by silica gel column
chromatography with dichloromethane and methanol (50:1) to
give a white solid (1ae1o).
6.1.2. Synthesis of 7-(substituted-phenyl)-4-substituted-6,7-
dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one derivatives
(2ae2c)
KOH (6.4 mmol, 0.36 g) and 7-phenyl-6,7-dihydro-[1,2,4]tri-
azolo[1,5-a]pyrimidin-5(4H)-one (2.3 mmol, 0.5 g) were dissolved
in acetonitrile (40 mL). The reaction mixture was refluxed for 0.5 h,
then (CH3)2SO4 (for 2a) or bromohexane (for 2b) or benzyl chloride
(for 2c) (2.4 mmol) were added into the mixture accompanied with
some of benzyltriethylamine chloride (TEBA). The reaction mixture
was heated for 4e24 h at reflux temperature. Then the mixture was
poured into 100 mL of water. Aqueous layer was extracted with
dichloromethane (30 mL ꢁ 3). The combined layer of dichloro-
methane was dried by anhydrous MgSO4. The evaporation of the
solvent gave a crude product, which was purified by silica gel
column chromatography with dichloromethane and methanol
(80:1) to give a white solid.
6.1.3. Synthesis of 5-(substituted-phenyl)-5,6-dihydroimidazo[1,2-
a]pyrimidin-7(8H)-one derivatives (3ae3d)
5. Conclusion
To a solution of the appropriate substituted methyl cinnamates
(6.2 mmol) in DMF (20 mL) were added 2-aminoimidazole hemi-
sulfate (3.1 mmol, 0.82 g) and K2CO3 (0.86 g 6.2 mmol). The
mixture was refluxed for 6 h. After removing the solvent under
reduced pressure, the residue was purified by silica gel column
chromatography with dichloromethane and methanol (50:1) to
give a white solid (3ae3d).
In the present study we described the syntheses and anticon-
vulsant activity evaluation of 7-(substituted-phenyl)-6,7-dihydro-
[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones (1ae1o). In addition,
several series of derivatives were also synthesized and evaluated
for their anticonvulsant activity for SAR studies, which included
7-(substituted-phenyl)-4-substituted-6,7-dihydro-[1,2,4]triazolo
[1,5-a]pyrimidin-5(4H)-ones (2ae2c), 5-(substituted-phenyl)-
6.1.4. Synthesis of 7-(substituted-phenyl)-6,7-dihydropyrazolo[1,5-
a]pyrimidin-5(4H)-one derivatives (4ae4d)
5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-ones
(3ae3d),
7-
(substituted-phenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-
ones (4ae4d), and 7-(substituted-phenyl)-7,8-dihydrophenyl[d]
imidazo[1,2-a]pyrimidin-9(10H)-ones (5ae5d). Bioevaluation
demonstrated that the compounds possessing a triazole (1ae1o)
displayed the best anticonvulsant activity and favorable PI.
Compound 1i showed better anticonvulsant activity as compared to
the standard drugs in MES test. It also showed marked lower
neurotoxicity and therefore a higher protective index. In addition,
the potency of compound 1i against seizures induced by PTZ, ISO,
3-MP, TSC, and BIC in the chemical-induced seizure tests suggested
its broad spectrum activity in several models. It is likely to have
several mechanisms of action including inhibition of voltage-gated
ion channels and modulation of GABAergic activity.
A
mixture of appropriate substituted methyl cinnamates
(3.1 mmol) and 1H-pyrazol-5-amine (6.2 mmol, 0.51 g) was stir-
red for 16 h at 200 ꢀC. After cooling down, the mixture was iso-
lated and purified by silica gel column chromatography with
dichloromethane and methanol (50:1) to give a white solid
(4ae4d).
6.1.5. Synthesis of 7-(substituted-phenyl)-7,8-dihydrophenyl[d]
imidazo[1,2-a]pyrimidin-9(10H)-one derivatives (5ae5d)
To a solution of the appropriate substituted methyl cinnamates
(6.2 mmol) in DMF (5 mL) was added 1H-benzo[d]imidazol-2-
amine (6.2 mmol, 0.82 g). The reaction mixture was refluxed for
12 h. After removing the solvent under reduced pressure, the
residue was purified by silica gel column chromatography with
dichloromethane and methanol (50:1) to give a white solid
(5ae5d).
6. Experimental protocols
6.1. Chemistry
6.1.5.1. 7-Phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on IRPrestige-
21. 1H NMR and 13C NMR spectra were measured on an AV-300
one (1a). M.p. 214e216 ꢀC, yield ¼ 60%. 1H NMR (CDCl3, 300 MHz)
d
3.14 (dd, 1H, J1 ¼4.9 Hz, J2 ¼16.8 Hz, H-6), 3.39 (dd, 1H, J1 ¼7.2 Hz,
J2 ¼ 16.8 Hz, H-6), 5.63 (dd, 1H, J1 ¼4.9 Hz, J2 ¼ 7.2 Hz, H-7),

2960
X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
7.15e7.41 (m, 5H, AreH), 7.82 (s, 1H, H-2), 11.40 (s, 1H, H-4). 13C
7), 7.10 (d, 2H, J ¼ 8.4 Hz, AreH), 7.38 (d, 2H, J ¼ 8.4 Hz, AreH), 7.77
NMR (DMSO-d6)
d
39.0, 56.0, 126.4, 128.7, 129.4, 139.3, 150.5, 150.7,
(s,1H, H-2), 9.83 (s,1H, H-4). 13C NMR (DMSO-d6)
d 38.8, 55.4, 128.6,
167.6. IR (KBr, cmꢂ1): 1699 (C]O), 3191 (NH). MS m/z 215 (M þ 1).
Anal. Calcd. for C11H10N4O: C, 61.67; H, 4.71; N, 26.15. Found: C,
61.78; H, 4.79; N, 26.03.
129.3, 133.4, 138.1, 150.2, 150.7, 167.4. IR (KBr, cmꢂ1): 1701 (C]O),
3191 (NH). MS m/z 249 (M þ 1), 251 (M þ 3). Anal. Calcd. for
C11H9ClN4O: C, 53.13; H, 3.65; N, 22.53. Found: C, 53.19; H, 3.60; N,
22.46.
6.1.5.2. 7-(2-Fluorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (1b). M.p. 200e201 ꢀC, yield ¼ 70%. 1H NMR (CDCl3,
6.1.5.8. 7-(2,4-Dichlorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyr-
300 MHz)
d
3.15 (dd, 1H, J1 ¼4.1 Hz, J2 ¼ 16.9 Hz, H-6), 3.40 (dd, 1H,
imidin-5(4H)-one (1h). M.p. 267e268 ꢀC, yield ¼ 78%. 1H NMR
J1 ¼7.3 Hz, J2 ¼16.9 Hz, H-6), 5.90 (dd, 1H, J1 ¼4.1 Hz, J2 ¼ 7.3 Hz, H-
(CDCl3, 300 MHz)
d
3.15 (dd, 1H, J1 ¼4.6 Hz, J2 ¼16.8 Hz, H-6), 3.40
7), 7.11e7.36 (m, 4H, AreH), 7.82 (s, 1H, H-2), 10.73 (s, 1H, H-4). 13C
(dd, 1H, J1 ¼7.1 Hz, J2 ¼ 16.8 Hz, H-6), 6.00 (dd, 1H, J1 ¼4.6 Hz,
NMR (DMSO-d6)
d
37.4, 51.3, 116.5 (d, JCeF ¼ 84.0 Hz), 125.4 (d,
J2 ¼ 7.1 Hz, H-7), 6.55e7.80 (m, 3H, AreH), 8.75 (s, 1H, H-2). 13C
JCeF ¼ 12.0 Hz), 126.0 (d, JCeF ¼ 51.0 Hz), 128.5 (d, JCeF ¼ 12.0 Hz),
131.2 (d, JCeF ¼ 33.0 Hz), 150.7 (d, JCeF ¼ 45.0 Hz), 158.4, 161.6, 167.2.
IR (KBr, cmꢂ1): 1705 (C]O), 3190 (NH). MS m/z 233 (M þ 1). Anal.
Calcd. for C11H9FN4O: C, 56.89; H, 3.91; N, 24.13. Found: C, 56.97; H,
3.95; N, 24.05.
NMR (DMSO-d6) d 37.1, 53.4, 128.6, 129.4, 130.1, 133.0, 134.4, 135.3,
151.0, 151.3, 166.9. IR (KBr, cmꢂ1): 1703 (C]O), 3189 (NH). MS m/z
283 (M þ 1), 285 (M þ 3). Anal. Calcd. for C11H8Cl2N4O: C, 46.67;
H, 2.85; N, 19.79. Found: C, 46.83; H, 2.93; N, 19.70.
6.1.5.9. 7-(2-Bromophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
6.1.5.3. 7-(3-Fluorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (1i). M.p. 239e240 ꢀC, yield ¼ 66%. 1H NMR (CDCl3,
5(4H)-one (1c). M.p. 196e197 ꢀC, yield ¼ 68%. 1H NMR (CDCl3
300 MHz)
d
3.15 (dd, 1H, J1 ¼4.3 Hz, J2 ¼17.1 Hz, H-6), 4.43 (dd, 1H,
300 MHz)
d
3.11 (dd, 1H, J1 ¼4.6 Hz, J2 ¼ 16.8 Hz, H-6), 3.40 (dd, 1H,
J1 ¼7.7 Hz, J2 ¼ 17.1 Hz, H-6), 6.04 (dd, 1H, J1 ¼4.3 Hz, J2 ¼ 7.7 Hz, H-
7), 6.59 (d, 1H, J ¼ 7.4 Hz, AreH), 7.21e7.32 (m, 2H, AreH), 7.65 (d,
1H, J ¼ 7.6 Hz, AreH), 7.85 (s, 1H, H-2), 10.59 (s, 1H, H-4). 13C NMR
J1 ¼7.2 Hz, J2 ¼ 16.8 Hz, H-6), 5.63 (dd, 1H, J1 ¼4.6 Hz, J2 ¼ 7.2 Hz, H-
7), 6.95e7.41 (m, 4H, Ar -H), 7.82 (s, 1H, H-2), 10.79 (s, 1H, H-4). 13C
NMR (DMSO-d6)
d
38.3, 55.1, 113.5 (d, JCeF ¼ 90.0 Hz), 115.3 (d,
(DMSO-d6) d 37.5, 55.9, 121.9, 127.6, 129.0, 130.9, 134.0, 137.7, 151.0,
JCeF ¼ 84.0 Hz), 122.2, 131.1 (d, JCeF ¼ 33.0 Hz), 141.5 (d,
JCeF ¼ 21.0 Hz), 150.3 (d, JCeF ¼ 54.0 Hz), 160.7, 163.9, 167.0. IR (KBr,
cmꢂ1): 1708 (C]O), 3194 (NH). MS m/z 233 (M þ 1). Anal. Calcd. for
C11H9FN4O: C, 56.89; H, 3.91; N, 24.13. Found: C, 57.03; H, 3.98;
N, 24.07.
151.4, 166.9. IR (KBr, cmꢂ1): 1699 (C]O), 3192 (NH). MS m/z
293 (M þ 1). Anal. Calcd. for C11H9BrN4O: C, 45.07;
H, 3.09; N, 19.11. Found: C, 45.22; H, 3.16; N, 19.04.
6.1.5.10. 7-(3-Bromophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
midin-5(4H)-one (1j). M.p. 245e246 ꢀC, yield ¼ 70%. 1H NMR
6.1.5.4. 7-(4-Fluorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
(CDCl3, 300 MHz)
d
3.08 (dd, 1H, J1 ¼5.1 Hz, J2 ¼16.8 Hz, H-6),
5(4H)-one (1d). M.p. 210e212 ꢀC, yield ¼ 71%. 1H NMR (CDCl3
3.39 (dd, 1H, J1 ¼7.2 Hz, J2 ¼16.8 Hz, H-6), 5.59 (dd, 1H,
J1 ¼5.1 Hz, J2 ¼ 7.2 Hz, H-7), 7.06e7.52 (m, 4H, AreH), 7.78 (s, 1H,
300 MHz)
d
3.10 (dd, 1H, J1 ¼5.0 Hz, J2 ¼16.8 Hz, H-6), 3.40 (dd, 1H,
J1 ¼7.0 Hz, J2 ¼ 16.8 Hz, H-6), 5.61 (dd, 1H, J1 ¼5.0 Hz, J2 ¼ 7.0 Hz, H-
H-2), 10.22 (s, 1H, H-4). 13C NMR (DMSO-d6)
d 38.7, 55.4, 122.2,
7), 7.06e7.16 (m, 4H, AreH), 7.79 (s, 1H, H-2), 11.07 (s, 1H, H-4). 13C
125.8, 127.6, 129.7, 131.2, 131.6, 135.5, 150.8, 167.4. IR (KBr, cmꢂ1):
1704 (C]O), 3187 (NH). MS m/z 293 (M þ 1). Anal. Calcd. for
C11H9BrN4O: C, 45.07; H, 3.09; N, 19.11. Found: C, 45.21; H, 3.17;
N, 19.02.
NMR (DMSO-d6)
d
38.9, 55.4, 116.2 (d, JCeF ¼ 87.0 Hz), 128.9 (d,
JCeF ¼ 36.0 Hz), 135.3, 150.6 (d, JCeF ¼ 63.0 Hz), 160.7, 163.9, 167.5. IR
(KBr, cmꢂ1): 1703 (C]O), 3192 (NH). MS m/z 233 (M þ 1). Anal. Calcd.
for C11H9FN4O: C, 56.89; H, 3.91; N, 24.13. Found:
C, 57.09; H, 4.02; N, 24.00.
6.1.5.11. 7-(4-Bromophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
midin-5(4H)-one (1k). M.p. 235e236 ꢀC, yield ¼ 72%. 1H NMR
6.1.5.5. 7-(2-Chlorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
(CDCl3, 300 MHz)
d
3.09 (dd, 1H, J1 ¼4.9 Hz, J2 ¼ 17.0 Hz, H-6), 3.36
5(4H)-one (1e). M.p. 225e226 ꢀC, yield ¼ 62%. 1H NMR (CDCl3,
(dd, 1H, J1 ¼7.5 Hz, J2 ¼17.0 Hz, H-6), 5.58 (dd, 1H, J1 ¼4.9 Hz,
J2 ¼ 7.7 Hz, H-7), 7.04 (d, 2H, J ¼ 8.0 Hz, AreH), 7.53 (d, 2H,
J ¼ 8.0 Hz, AreH), 7.76 (s, 1H, H-2), 9.58 (s, 1H, H-4). 13C NMR
300 MHz)
d
3.16 (dd 1H, J1 ¼4.1 Hz, J2 ¼ 17.0 Hz, H-6), 3.43 (dd, 1H,
J1 ¼7.7 Hz, J2 ¼17.0 Hz, H-6), 5.63 (dd, 1H, J1 ¼4.1 Hz, J2 ¼ 7.7 Hz, H-
7), 7.15e7.41 (m, 4H, AreH), 7.85 (s, 1H, H-2). 13C NMR (DMSO-d6)
(DMSO-d6) d 38.7, 55.5, 122.0, 128.9, 132.3, 138.5, 150.5, 150.7, 167.4.
d
37.3, 53.7, 127.6, 128.4, 130.5, 130.7, 131.8, 136.2, 151.0, 151.1, 167.0.
IR (KBr, cmꢂ1): 1696 (C]O), 3194 (NH). MS m/z 293 (M þ 1). Anal.
Calcd. for C11H9BrN4O: C, 45.07; H, 3.09; N, 19.11. Found: C, 45.16;
H, 3.12; N, 19.08.
IR (KBr, cmꢂ1): 1703 (C]O), 3188 (NH). MS m/z 249 (M þ 1), 251
(M þ 3). Anal. Calcd. for C11H9ClN4O: C, 53.13; H, 3.65; N, 22.53.
Found: C, 53.27; H, 3.72; N, 22.46.
6.1.5.12. 7-(3-(Trifluoromethyl)phenyl)-6,7-dihydro-[1,2,4]triazolo
[1,5-a]pyrimidin-5(4H)-one (1l). M.p. 176e178 ꢀC, yield ¼ 80%. 1H
6.1.5.6. 7-(3-Chlorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (1f). M.p. 225e226 ꢀC, yield ¼ 69%. 1H NMR (CDCl3,
NMR (CDCl3, 300 MHz)
d
3.10 (dd, 1H, J1 ¼4.9 Hz, J2 ¼17.0 Hz, H-6),
300 MHz)
d
3.11 (dd 1H, J1 ¼5.0 Hz, J2 ¼ 16.9 Hz, H-6), 3.39 (dd, 1H,
3.41 (dd, 1H, J1 ¼7.5 Hz, J2 ¼ 17.0 Hz, H-6), 5.68 (dd, 1H, J1 ¼4.9 Hz,
J2 ¼ 7.7 Hz, H-7), 7.31e7.66 (m, 4H, AreH), 7.83 (s, 1H, H-2), 11.37 (s,
J1 ¼7.2 Hz, J2 ¼ 16.9 Hz, H-6), 5.60 (dd, 1H, J1 ¼5.0 Hz, J2 ¼ 7.2 Hz, H-
7), 7.03e7.36 (m, 4H, AreH), 7.66 (s, 1H, H-2), 10.47 (s, 1H, H-4). 13C
1H, H-4). 13C NMR (DMSO-d6)
d 38.7, 55.7, 123.8, 125.6, 129.4, 130.5,
NMR (DMSO-d6)
d
38.7, 55.5, 125.4, 126.8, 128.8, 131.0, 131.3, 133.9,
131.0, 140.4, 150.7, 150.8, 167.4. IR (KBr, cmꢂ1): 1701 (C]O), 3190
(NH). MS m/z 283 (M þ 1). Anal. Calcd. for C12H9F3N4O: C, 51.07;
H, 3.21; N, 19.85. Found: C, 51.22; H, 3.34; N, 19.77.
141.5, 150.8, 167.4. IR (KBr, cmꢂ1): 1700 (C]O), 3186 (NH). MS m/z
249 (M þ 1), 251 (M þ 3). Anal. Calcd. for C11H9ClN4O: C, 53.13; H,
3.65; N, 22.53. Found: C, 53.21; H, 3.76; N, 22.41.
6.1.5.13. 7-(4-Methylphenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
6.1.5.7. 7-(4-Chlorophenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
midin-5(4H)-one (1m). M.p. 206e207 ꢀC, yield ¼ 63%. 1H NMR
5(4H)-one (1g). M.p. 227e228 ꢀC, yield ¼ 71%. 1H NMR (CDCl3
(CDCl3, 300 MHz)
d
2.34 (s, 3H, eCH3), 3.11 (dd, 1H, J1 ¼5.3 Hz,
300 MHz)
d
3.14 (dd, 1H, J1 ¼4.5 Hz, J2 ¼16.8 Hz, H-6), 3.40 (dd, 1H,
J2 ¼ 16.8 Hz, H-6), 3.34 (dd, 1H, J1 ¼7.0 Hz, J2 ¼ 16.8 Hz, H-6), 5.57
J1 ¼7.2 Hz, J2 ¼ 16.8 Hz, H-6), 5.60 (dd, 1H, J1 ¼4.5 Hz, J2 ¼ 7.2 Hz, H-
(dd, 1H, J1 ¼5.3 Hz, J2 ¼ 7.0 Hz, H-7), 7.06 (d, 2H, J ¼ 8.0 Hz, AreH),

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
2961
7.20 (d, 2H, J ¼ 8.0 Hz, AreH), 7.79 (s, 1H, H-2), 11.28 (s, 1H, H-4). 13
C
AreH). 13C NMR (DMSO-d6)
d
39.1, 54.1, 115.4, 126.1, 126.4, 128.6,
NMR (DMSO-d6)
d
21.1, 39.0, 55.8, 126.3, 129.9, 136.3, 138.1, 150.4,
129.4, 140.0, 143.0, 167.3. IR (KBr, cmꢂ1): 1681 (C]O), 3194 (NH).
MS m/z 214 (M þ 1). Anal. Calcd. for C12H11N3O: C, 67.59; H, 5.20;
N, 19.71. Found: C, 67.73; H, 5.26; N, 19.77.
150.6, 167.6. IR (KBr, cmꢂ1): 1707 (C]O), 3194 (NH). MS m/z 229
(M þ 1). Anal. Calcd. for C12H12N4O: C, 63.15; H, 5.30; N, 24.55.
Found: C, 63.31; H, 5.37; N, 24.43.
6.1.5.20. 5-(2-Fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrimidin-
6.1.5.14. 7-(2-Methoxyphenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyr-
7(8H)-one (3b). M.p. 205e207 ꢀC, yield ¼ 31%. 1H NMR (CDCl3,
imidin-5(4H)-one (1n). M.p. 199e200 ꢀC, yield ¼ 65%. 1H NMR
300 MHz)
d
3.02 (dd, 1H, J1 ¼5.7 Hz, J2 ¼ 16.8 Hz, H-6), 3.21 (dd, 1H,
(CDCl3, 300 MHz)
d
3.09 (dd, 1H, J1 ¼3.4 Hz, J2 ¼ 17.0 Hz, H-6), 3.35
J1 ¼6.6 Hz, J2 ¼16.8 Hz, H-6), 5.66 (dd, 1H, J1 ¼5.7 Hz, J2 ¼ 6.6 Hz,
H-7), 6.53 (s, 1H, imidazoleeH), 6.84e7.16 (m, 3H, AreH), 7.26 (s,
1H, imidazoleeH), 7.32e7.37 (m, 1H, AreH). 13C NMR (DMSO-d6)
(dd, 1H, J1 ¼8.2 Hz, J2 ¼17.0 Hz, H-6), 3.83 (s, 3H, eOCH3), 5.85 (dd,
1H, J1 ¼3.4 Hz, J2 ¼ 8.2 Hz, H-7), 6.68e7.35(m, 4H, AreH), 7.80 (s,
1H, H-2), 10.93 (s, 1H, H-4). 13C NMR (DMSO-d6)
d
37.1, 52.7, 55.9,
d
37.5, 49.1, 115.4, 116.5 (d, JCeF ¼ 84.0 Hz), 125.5, 126.4, 127.1 (d,
112.1, 121.0, 126.9, 127.1, 130.3, 150.7, 150.8, 156.4, 167.6. IR (KBr,
cmꢂ1): 1688 (C]O), 3185 (NH). MS m/z 245 (M þ 1). Anal. Calcd. for
C12H12N4O2: C, 59.01; H, 4.95; N, 22.94. Found: C, 59.17; H, 4.84;
N, 22.85.
JCeF ¼ 54.0 Hz), 131.0 (d, JCeF ¼ 33.0 Hz), 143.2, 158.0, 161.2, 166.9. IR
(KBr, cmꢂ1): 1688 (C]O), 3197 (NH). MS m/z 232 (M þ 1). Anal.
Calcd. for C12H10FN3O: C, 62.33; H, 4.36; N, 18.17. Found: C, 62.51; H,
4.43; N, 18.08.
6.1.5.15. 7-(4-Methoxyphenyl)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyr-
6.1.5.21. 5-(2-Chlorophenyl)-5,6-dihydroimidazo[1,2-a]pyrimidin-
imidin-5(4H)-one (1o). M.p. 182e183 ꢀC, yield ¼ 65%. 1H NMR
7(8H)-one (3c). M.p. 233e234 ꢀC, yield ¼ 28%. 1H NMR (CDCl3,
(CDCl3, 300 MHz)
d
3.11 (dd, 1H, J1 ¼5.5 Hz, J2 ¼ 16.8 Hz, H-6), 3.33
300 MHz)
d
3.01 (dd, 1H, J1 ¼5.1 Hz, J2 ¼ 16.7 Hz, H-6), 3.26 (dd, 1H,
(dd, 1H, J1 ¼6.9 Hz, J2 ¼16.8 Hz, H-6), 3.80 (s, 3H, eOCH3), 5.55 (dd,
1H, J1 ¼5.5 Hz, J2 ¼ 6.9 Hz, H-7), 6.89 (d, 2H, J ¼ 8.7 Hz, AreH), 7.13
(d, 2H, J ¼ 8.7 Hz, AreH), 7.79 (s, 1H, H-2), 11.35 (s, 1H, H-4). 13C
J1 ¼6.9 Hz, J2 ¼ 16.7 Hz, H-6), 5.80 (dd, 1H, J1 ¼5.1 Hz, J2 ¼ 6.9 Hz,
H-7), 6.55 (s, 1H, imidazoleeH), 6.75 (d, 1H, J ¼ 7.5 Hz, AreH), 6.96
(s, 1H, imidazole-H), 7.23e7.47 (m, 3H, AreH). 13C NMR (DMSO-d6)
NMR (DMSO-d6)
d
39.0, 55.5, 55.6, 114.7, 127.8, 131.1, 150.3, 150.5,
d 37.1, 51.8, 115.6, 126.5, 126.7, 128.5, 130.5, 130.7, 131.5, 137.1, 143.2,
159.6, 167.7. IR (KBr, cmꢂ1): 1696 (C]O), 3192 (NH). MS m/z 245
(M þ 1). Anal. Calcd. for C12H12N4O2: C, 59.01; H, 4.95; N, 22.94.
Found: C, 59.23; H, 4.99; N, 22.81.
166.6. IR (KBr, cmꢂ1): 1688 (C]O), 3197 (NH). MS m/z 248 (M þ 1).
Anal. Calcd. for C12H10FN3O: C, 62.33; H, 4.36; N, 18.17. Found: C,
62.51; H, 4.43; N, 18.08.
6.1.5.16. 4-Methyl-7-phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyri-
6.1.5.22. 5-(2-Bromophenyl)-5,6-dihydroimidazo[1,2-a]pyrimidin-
midin-5(4H)-one(2a). M.p. 87e88 ꢀC, yield ¼86%. 1H NMR (CDCl3,
7(8H)-one (3d). M.p. 238e239 ꢀC, yield ¼ 35%. 1H NMR (CDCl3,
300 MHz)
d
3.17 (dd, 1H, J1 ¼5.2 Hz, J2 ¼ 16.7 Hz, H-6), 3.38 (dd,
300 MHz)
d
3.02 (dd, 1H, J1 ¼5.1 Hz, J2 ¼ 16.7 Hz, H-6), 3.26 (dd, 1H,
1H, J1 ¼7.0 Hz, J2 ¼16.7 Hz, H-6), 3.46 (s, 3H, NCH3), 5.57 (dd, 1H,
J1 ¼5.2 Hz, J2 ¼ 7.0 Hz, H-7), 7.08e7.38 (m, 5H, AreH), 7.73 (s, 1H,
J1 ¼7.0 Hz, J2 ¼ 16.7 Hz, H-6), 5.80 (dd, 1H, J1 ¼5.1 Hz, J2 ¼ 7.0 Hz, H-
7), 6.54 (s, 1H, imidazoleeH), 6.76 (d, 1H, J ¼ 7.6 Hz, AreH), 6.95 (s,
1H, imidazoleeH), 7.20e7.33 (m, 2H, AreH), 7.64 (d, 1H, J ¼ 7.6 Hz,
H-2). 13C NMR (DMSO-d6)
d 29.4, 39.0, 55.8, 126.6, 128.8, 129.4,
139.0, 150.5, 151.9, 166.2. IR (KBr, cmꢂ1): 1683 (C]O). MS m/z 229
(M þ 1). Anal. Calcd. for C12H12N4O: C, 63.15; H, 5.30; N, 24.55.
Found: C, 63.29; H, 5.26; N, 24.41.
AreH), 11.31 (s, 1H, NH). 13C NMR (DMSO-d6)
d 37.3, 54.0, 115.6,
121.8, 126.6, 126.8, 129.0, 130.8, 134.0, 138.6, 143.3, 166.5. IR (KBr,
cmꢂ1): 1684 (C]O), 3187 (NH). MS m/z 292 (M þ 1). Anal. Calcd. for
C12H10BrN3O: C, 49.34; H, 3.45; N, 14.38. Found: C, 49.52; H, 3.53;
N, 14.44.
6.1.5.17. 4-Hexyl-7-phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (2b). M.p. 92e94 ꢀC, yield ¼ 81%. 1H NMR (CDCl3,
300 MHz)
d
0.90 (t, 3H, J ¼ 6.8 Hz, CH3), 1.28e1.69 (m, 8H, (CH2)4),
6.1.5.23. 7-Phenyl-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-one
3.15 (dd, 1H, J1 ¼4.4 Hz, J2 ¼16.9 Hz, H-6), 3.38 (dd, 1H, J1 ¼7.1 Hz,
J2 ¼16.9 Hz, H-6), 3.99 (t, 2H, J ¼ 7.0 Hz, NCH3), 5.58 (dd, 1H,
J1 ¼4.4 Hz, J2 ¼ 7.1 Hz, H-7), 7.08e7.36 (m, 5H, AreH), 7.74 (s, 1H, H-
(4a). M.p. 187e189 ꢀC, yield ¼ 37%. 1H NMR (CDCl3, 300 MHz)
d
3.05 (dd,1H, J1 ¼3.8 Hz, J2 ¼ 16.5 Hz, H-6), 3.35 (dd,1H, J1 ¼7.0 Hz,
J2 ¼ 16.5 Hz, H-6), 5.67 (dd, 1H, J1 ¼3.8 Hz, J2 ¼ 7.0 Hz, H-7), 5.76 (d,
1H, J ¼ 1.6 Hz, pyrazoleeH), 7.45 (d, 1H, J ¼ 1.6 Hz, pyrazoleeH),
7.01e7.34 (m, 5H, AreH), 9.35 (s, 1H, NH). 13C NMR (DMSO-d6)
2). 13C NMR (DMSO-d6)
d 14.3, 22.4, 26.2, 27.6, 31.3, 39.1, 42.5, 55.6,
126.3, 128.7, 129.3, 138.9, 150.7, 151.4, 166.0. IR (KBr, cmꢂ1): 1678
(C]O). MS m/z 299 (M þ 1). Anal. Calcd. for C17H22N4O: C, 68.43; H,
7.43; N, 18.78. Found: C, 68.57; H, 7.49; N, 18.74.
d
40.8, 57.2, 89.8, 126.0, 128.3, 129.2, 139.9, 140.1, 140.6, 166.2. IR
(KBr, cmꢂ1): 1695 (C]O), 3182 (NH). MS m/z 214 (M þ 1). Anal.
Calcd. for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.76;
H, 5.25; N, 19.85.
6.1.5.18. 4-Benzyl-7-phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (2c). M.p. 79e80 ꢀC, yield ¼ 84%. 1H NMR (CDCl3,
300 MHz)
d
3.17 (dd, 1H, J1 ¼4.7 Hz, J2 ¼16.6 Hz, H-6), 3.41 (dd, 1H,
6.1.5.24. 7-(2-Fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-
J1 ¼7.0 Hz, J2 ¼16.6 Hz, H-6), 5.18 (s, 2H, NCH2), 5.56 (dd, 1H,
5(4H)-one (4b). M.p. 157e159 ꢀC, yield ¼ 39%. 1H NMR (CDCl3,
J1 ¼4.7 Hz, J2 ¼ 7.0 Hz, H-7), 6.94e7.45 (m, 10H, AreH), 7.74 (s, 1H,
300 MHz)
d
3.07 (dd, 1H, J1 ¼3.3 Hz, J2 ¼16.8 Hz, H-6), 3.35 (dd, 1H,
H-2). 13C NMR (DMSO-d6)
d
39.1, 45.8, 55.7, 126.5, 127.1, 127.9,
J1 ¼7.2 Hz, J2 ¼ 16.8 Hz, H-6), 5.79 (d, 1H, J ¼ 1.5 Hz, pyrazoleeH),
5.95 (dd, 1H, J1 ¼3.3 Hz, J2 ¼ 7.2 Hz, H-7), 6.46e7.30 (m, 4H, AreH),
7.46 (d, 1H, J ¼ 1.5 Hz, pyrazoleeH), 9.10 (s, 1H, NH). 13C NMR
128.1, 128.8, 129.3, 136.9, 138.7, 150.6, 151.5, 166.2. IR (KBr, cmꢂ1):
1699 (C]O), 3191 (NH). MS m/z 305 (M þ 1). Anal. Calcd. for
C18H16N4O: C, 71.04; H, 5.30; N, 18.41. Found: C, 71.16; H, 5.41; N,
18.32.
(DMSO-d6)
d
37.6, 52.5, 89.8, 116.4 (d, JCeF ¼ 84.0 Hz), 125.3, 127.2,
127.5, 131.7 (d, JCeF ¼ 33.0 Hz), 140.4 (d, JCeF ¼ 51.0 Hz), 157.9, 161.1,
165.8. IR (KBr, cmꢂ1): 1690 (C]O), 3201 (NH). MS m/z 232 (M þ 1).
Anal. Calcd. for C12H10FN3O: C, 62.33; H, 4.36; N, 18.17. Found:
C, 62.51; H, 4.42; N, 18.07.
6.1.5.19. 5-Phenyl-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-one
(3a). M.p. 210e211 ꢀC, yield ¼ 31%. 1H NMR (CDCl3, 300 MHz)
d
2.91 (dd, 1H, J1 ¼6.8 Hz, J2 ¼16.4 Hz, H-6), 3.12 (dd, 1H, J1 ¼6.1 Hz,
J2 ¼16.4 Hz, H-6), 5.38 (dd, 1H, J1 ¼6.8 Hz, J2 ¼ 6.1 Hz, H-7), 6.49 (s,
1H, imidazoleeH), 6.76 (s, 1H, imidazoleeH), 7.14e7.39 (m, 5H,
6.1.5.25. 7-(2-Chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-
5(4H)-one (4c). M.p. 188e189 ꢀC, yield ¼ 34%. 1H NMR (CDCl3,

2962
X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
300 MHz)
d
3.09 (dd, 1H, J1 ¼ 2.7 Hz, J2 ¼16.8 Hz, H-6), 3.38 (dd, 1H,
6.2. Pharmacology
J1 ¼7.5 Hz, J2 ¼ 16.8 Hz, H-6), 5.80 (d, 1H, J ¼ 1.8 Hz, pyrazoleeH),
6.06 (dd, 1H, J1 ¼2.7 Hz, J2 ¼ 7.5 Hz, H-7), 6.36e7.43 (m, 4H, AreH),
7.47 (d, 1H, J ¼ 1.8 Hz, pyrazoleeH), 9.17 (s, 1H, NH). 13C NMR
6.2.1. Anticonvulsant effects in the maximal electroshock seizure
(MES) test [27,28]
(DMSO-d6)
d
37.2, 55.2, 89.9, 126.8, 128.3, 130.4, 130.6, 131.2, 137.4,
The MES test was carried out by the methods described in the
ADD of the National Institutes of Health (USA) [18,19]. Seizures
were elicited with a 60 Hz alternating current of 50 mA intensity in
mice. The current was applied via corneal electrodes for 0.2 s.
Protection against the spread of MES-induced seizures was defined
as the abolition of the tonic maximal extension of the hind leg. At
0.5 h and 4 h after the administration of the compounds, the
activities were evaluated in MES test. In phase-I screening, each
compound was administered at the dose levels of 30, 100, and
300 mg/kg for evaluating the preliminary anticonvulsant activity.
For determination of the median effective dose (ED50) the median
toxic dose (TD50), the phase-II screening was prepared. Groups of
10 mice were given a range of intraperitoneal doses of the tested
compound until at least three points were established in the range
of 10e90% seizure protection or minimal observed neurotoxicity.
From the plot of this data, the respective ED50 and TD50 values, 95%
confidence intervals, slope of the regression line, and the standard
error of the slope were calculated by means of a computer program
written at National Institute of Neurological Disorders and Stroke
[18,19].
140.6, 140.8, 165.5. IR (KBr, cmꢂ1): 1694 (C]O), 3209 (NH). MS m/z
248 (M þ 1). Anal. Calcd. for C12H10ClN3O: C, 58.19; H, 4.07; N, 16.97.
Found: C, 58.31; H, 4.01; N, 16.85.
6.1.5.26. 7-(2-Bromophenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-
5(4H)-one (4d). M.p. 197e198 ꢀC, yield ¼ 33%. 1H NMR (CDCl3,
300 MHz)
d
3.12 (dd, 1H, J1 ¼2.2 Hz, J2 ¼ 16.8 Hz, H-6), 3.38 (dd, 1H,
J1 ¼7.7 Hz, J2 ¼ 16.8 Hz, H-6), 5.81 (d, 1H, J ¼ 1.8 Hz, pyrazoleeH),
6.04 (dd, 1H, J1 ¼ 2.2 Hz, J2 ¼ 7.7 Hz, H-7), 6.37 (d, 1H, J ¼ 5.5 Hz,
AreH), 7.16e7.26 (m, 2H, AreH), 7.48 (d, 1H, J ¼ 1.8 Hz,
pyrazoleeH), 7.60 (d, 1H, J ¼ 7.1 Hz, AreH), 9.65 (s, 1H, NH). 13C
NMR (DMSO-d6)
d 37.4, 57.4, 89.9, 121.4, 126.8, 128.9, 130.6, 133.9,
138.9, 140.6, 140.8, 165.5. IR (KBr, cmꢂ1): 1698 (C]O), 3205 (NH).
MS m/z 292 (M þ 1). Anal. Calcd. for C12H10BrN3O: C, 49.34; H, 3.45;
N, 14.38. Found: C, 49.52; H, 3.56; N, 14.27.
6.1.5.27. 7-Phenyl-7,8-dihydrophenyl[d]imidazo[1,2-a]pyrimidin-
9(10H)-one (5a). M.p. 282e283 ꢀC, yield ¼ 47%. 1H NMR (CDCl3,
300 MHz)
d
3.01 (dd, 1H, J1 ¼2.9 Hz, J2 ¼ 16.4 Hz, H-6), 3.42 (dd, 1H,
J1 ¼7.1 Hz, J2 ¼16.4 Hz, H-6), 5.80 (dd, 1H, J1 ¼ 2.9 Hz, J2 ¼ 7.1 Hz, H-
7), 5.76 (dd, 1H, J1 ¼2.9 Hz, J2 ¼ 7.1 Hz, H-7), 6.88e7.53 (m, 9H,
6.2.2. Neurotoxicity (NT) screening [18,19]
AreH). 13C NMR (DMSO-d6)
d
39.0, 52.4, 109.9, 118.0, 121.4, 122.2,
The neurotoxicity of the compounds was measured in mice
by the rotarod test. The mice were trained to stay on an accel-
erating rotarod of diameter 3.2 cm that rotates at 10 rpm.
Trained animals were given i.p. injection of the test compounds.
Neurotoxicity was indicated by the inability of the animal to
maintain equilibrium on the rod for at least 1 min in each of the
trials.
126.1, 128.7, 129.5, 132.8, 139.7, 142.4, 148.5, 167.7. IR (KBr, cmꢂ1):
1680 (C]O), 3190 (NH). MS m/z 264 (M þ 1). Anal. Calcd. for
C16H13N3O: C, 72.99; H, 4.98; N, 15.96. Found: C, 73.15; H, 4.89;
N, 15.87.
6.1.5.28. 7-(2-Fluorophenyl)-7,8-dihydroimidazo[1,2-a]pyrimidin-
9(10H)-one (5b). M.p. 269e270 ꢀC, yield ¼ 45%. 1H NMR (CDCl3,
300 MHz)
d
3.17 (dd, 1H, J1 ¼ 2.8 Hz, J2 ¼ 16.9 Hz, H-6), 3.42 (dd, 1H,
6.2.3. sc-PTZ-induced seizures [18,19]
J1 ¼7.6 Hz, J2 ¼16.9 Hz, H-6), 5.80 (dd, 1H, J1 ¼ 2.8 Hz, J2 ¼ 7.6 Hz, H-
7), 6.00 (dd, 1H, J1 ¼ 2.8 Hz, J2 ¼ 7.6 Hz, H-7), 6.70e7.79 (m, 8H,
At 0.5 h after the administration of the test compound, 85 mg/kg
PTZ dissolved in saline was administered sc. The animals (10 mice
in one group) placed in individual cages and observed for 0.5 h. The
numbers of clonic seizure (range from exaggerated twitches of the
limbs to violent shaking or vibrating of the stiffened extremities)
and tonic seizure (the extremities pull towards the body or rigidly
push away from it, usually maximal extension of the hind leg) as
well as the number of deaths were noted.
AreH). 13C NMR (DMSO-d6)
d 37.3, 55.4, 109.7, 116.7 (d,
JCeF ¼ 84.0 Hz), 118.0, 121.5, 122.3, 125.6, 126.4 (d, JCeF ¼ 54.0 Hz),
127.4, 131.1 (d, JCeF ¼ 33.0 Hz), 132.5, 142.4, 158.2, 161.5, 167.3. IR
(KBr, cmꢂ1): 1681 (C]O), 3194 (NH). MS m/z 282 (M þ 1). Anal.
Calcd. for C16H12FN3O: C, 68.32; H, 4.30; N, 14.94. Found: C, 68.48;
H, 4.41; N, 14.83.
6.1.5.29. 7-(2-Chlorophenyl)-7,8-dihydroimidazo[1,2-a]pyrimidin-
6.2.4. Isoniazid-induced seizures test [29]
9(10H)-one (5c). M.p. 272e273 ꢀC, yield ¼ 44%. 1H NMR (CDCl3,
At 0.5 h after the administration of the test compound, the
animals (10 mice in one group) were given in i.p. at dose of ISO
(250 mg/kg), a dose at which 100% of the animals showed
convulsive reactions. The mice were placed in individual cages and
observed for 1 h. The numbers of clonic and tonic seizures as well as
the number of deaths were noted.
300 MHz)
d
3.17 (dd, 1H, J1 ¼ 2.9 Hz, J2 ¼ 16.8 Hz, H-6), 3.42 (dd, 1H,
J1 ¼3.0 Hz, J2 ¼ 16.8 Hz, H-6), 5.80 (dd, 1H, J1 ¼2.9 Hz, J2 ¼ 3.0 Hz,
H-7), 6.11 (dd, 1H, J1 ¼ 2.9 Hz, J2 ¼ 3.0 Hz, H-7), 6.64e7.87 (m, 8H,
AreH). 13C NMR (DMSO-d6)
d 37.0, 50.2, 109.6, 118.1, 121.6, 122.4,
126.6, 128.6, 130.7, 130.9, 131.7, 132.4, 136.4, 142.4, 148.7, 167.0. IR
(KBr, cmꢂ1): 1682 (C]O), 3193 (NH). MS m/z 298 (M þ 1). Anal.
Calcd. for C16H12ClN3O: C, 64.54; H, 4.06; N, 14.11. Found: C, 64.61;
H, 4.13; N, 14.21.
6.2.5. 3-MP induced seizures test [30]
At 0.5 h after the administration of the test compound, 60 mg/kg
of 3-MP in saline solution was injected sc to mice (10 mice in one
group). The mice were placed in individual cages and observed for
0.5 h. The numbers of clonic and tonic seizures as well as the
number of deaths were noted.
6.1.5.30. 7-(2-Bromophenyl)-7,8-dihydroimidazo[1,2-a]pyrimidin-
9(10H)-one (5d). M.p. 280e281 ꢀC, yield ¼ 41%. 1H NMR (CDCl3,
300 MHz)
d
3.17 (dd, 1H, J1 ¼ 2.7 Hz, J2 ¼16.8 Hz, H-6), 3.47 (dd, 1H,
J1 ¼7.9 Hz, J2 ¼ 16.8 Hz, H-6), 5.80 (dd, 1H, J1 ¼ 2.7 Hz, J2 ¼ 7.9 Hz,
H-7), 6.09 (dd, 1H, J1 ¼ 2.9 Hz, J2 ¼ 3.0 Hz, H-7), 6.68e7.85 (m, 8H,
6.2.6. Thiosemicarbazide-induced seizures test [31]
AreH), 13.27 (s, 1H, NeH). 13C NMR (DMSO-d6)
d
37.1, 52.4, 109.6,
At 0.5 h after the administration of the test compound, the
animals (10 mice in one group) were given an i.p. dose of TSC
(50 mg/kg). The mice were placed in individual cages and observed
for 2.5 h. The number of clonic seizures, tonic seizures, and the
lethality were recorded.
118.1, 121.7, 121.9, 122.5, 126.7, 129.2, 131.0, 132.3, 134.2, 137.9, 142.4,
148.7, 167.0. IR (KBr, cmꢂ1): 1688 (C]O), 3195 (NH). MS m/z 342
(M þ 1). Anal. Calcd. for C16H12BrN3O: C, 56.16; H, 3.53; N, 12.28.
Found: C, 56.28; H, 3.44; N, 12.17.

X.-Q. Deng et al. / European Journal of Medicinal Chemistry 46 (2011) 2955e2963
2963
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Acknowledgment
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This work was supported by the National Natural Science
Foundation of China (No. 30860340).
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