Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4Hbenzo[f][1, 2,4]triazolo[4,3-a]azepine derivatives

Article abstract of DOI:10.1007/s00044-011-9771-5

A novel series of 8-alkoxy-5,6-dihydro-4Hbenzo[ f][1,2,4]triazolo[4,3-a] azepine derivatives were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The newly synthesized compounds were s

Full text of DOI:10.1007/s00044-011-9771-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2587–2594
DOI 10.1007/s00044-011-9771-5
ORIGINAL RESEARCH
Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives
•
Wen-Bin Zhang Rong-Bi Han Wei Zhang
•
•
•
Ri-Shan Jiang Feng-Yu Piao
Received: 22 March 2011 / Accepted: 27 July 2011 / Published online: 27 August 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of 8-alkoxy-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives were
Introduction
1
synthesized and characterized by IR, H NMR, 13C NMR,
It is reported that about 1% of the world’s population is
afflicted with Epilepsy. Nearly 2.4 million new cases
every year are being added to the reported figures (Sec-
retariats of WHO/IBE/ILAE 2009; Paswerk and Hoofd-
dorp, 2003). Although the current drugs provide adequate
seizure control in many patients, it is roughly estimated
that up to 28–30% of patients are poorly treated with the
available antiepileptic drugs (AEDs) (Yogeeswari et al.,
2005; Taylor et al., 2003). Therefore, continued search for
safer and more effective AEDs is urgently necessary. In
recent years, much efforts have been devoted to devel-
oping novel compounds as potential anticonvulsant agents
(Bialer and White, 2010; Perucca et al., 2007; Bialer
mass spectroscopy, and elemental analysis. The newly
synthesized compounds were screened for their anticon-
vulsant activities by the maximal electroshock (MES) test
and subcutaneous pentylenetetrazol (scPTZ) test, and their
neurotoxic effects were determined by the rotarod neuro-
toxicity test. Compound 8-pentyloxy-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3d) besides being
one of the most active compounds had the lowest toxicity.
In the anti-MES potency test, it showed median effective
dose (ED50) of 17.5 mg/kg, and had protective index (PI)
value of 6.5, which is slightly less than that of the prototype
drug carbamazepine (PI = 8.1). Its value of ED50 and PI in
the anti-scPTZ test were 21.2 and 5.4, respectively, the
latter value (PI) of which is much greater than that of the
prototype drug carbamazepine (ED50 [100, PI \0.72).
Possible structure–activity relationship has been discussed.
¨
et al., 2007; Loschera and Schmidtb, 2006; Guan et al.,
2009; Amnerkar and Bhusari, 2010; Stefan and Feuer-
stein, 2007; Pollard and French, 2006; Donner and Snead,
2006).
Benzazepine derivatives exhibit broad pharmacological
activity (Wei et al., 2009; Rivas et al., 2009; Bariwal
et al., 2008; Im et al., 2004). Triazole compounds have
wide variety of biological activities, the introduction of
triazole ring to some activated molecules may signifi-
cantly improve the biological activity of the parent
molecule because of the superposition of biological
activity (Sun et al., 2008 and 2009; Cui et al., 2005; Jin
et al., 2006; Hoelzemann et al., 2010). Previously, we
have reported some 1,3,4,5-tetrahydro-7-alkoxy-2H-1-
benzazepin-2-one derivatives as moderately active anti-
convulsant agents. In view of these and as a part of our
enduring studies in the area of anticonvulsant agents, it
was thought to be of beneficial interest to combine both
pharmacophoric groups (benzazepine nucleus and triazole
ring).
Keywords Benzotriazoloazepine ꢀ Synthesis ꢀ
Anticonvulsant activity
W.-B. Zhang ꢀ R.-B. Han ꢀ W. Zhang ꢀ R.-S. Jiang ꢀ
F.-Y. Piao (&)
Department of Chemistry, College of Science, Yanbian
University, Yanji 133002, Jilin Province,
People’s Republic of China
e-mail: fypiao4989@yahoo.com.cn
R.-B. Han
Key Laboratory of Natural Resources of Changbai Mountain &
Functional Molecules (Yanbian University),
Ministry of Education, Yanji 133002, Jilin Province,
People’s Republic of China
123

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Med Chem Res (2012) 21:2587–2594
We have synthesized a series of 8-alkoxy-2,4,5,6-tetra-
Table 1 Phase I anticonvulsant data in mice of compounds 3a–3o
(i.p.)
hydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azepin-1-one deriv-
atives and evaluated their anticonvulsant activity (Piao
et al., 2011). In order to obtain compounds with better
anticonvulsant activity, the following chemical structures
were designed, and their anticonvulsant activity prediction
using PASS software was performed. On the basis of
computer-based prediction of anticonvulsant activity by
PASS, the target compounds were synthesized through an
appropriate synthetic sequence, and their anticonvulsant
activity was evaluated by the maximal electroshock
(MES)t and subcutaneous pentylenetetrazol (scPTZ) tests,
while their neurotoxic effects were determined by the
rotarod neurotoxicity test.
Compounds
R
MESa
scPTZa
30b 100 300 30b 100
3a
3b
3c
3d
3e
3f
–CH3
0/3 1/5
1/5 5/5
5/5
–
0/5 0/5
0/5 0/5
2/5 5/5
–C3H7
–C4H9
5/5
5/5
5/5
5/5
5/5
5/5
–
–
–
–
–
–
–
–C5H11
–
5/5
4/5
–
–
–C6H13
–
–C7H15
–
3/5 5/5
0/5 5/5
0/5 0/5
0/5 5/5
0/5 5/5
2/5 5/5
0/5 5/5
1/5 5/5
0/5 5/5
0/5 0/5
3g
3h
3i
–PhCH2
–
–CH2C6H4(o–Cl)
–CH2C6H4(m–Cl)
–CH2C6H4(p–Cl)
–CH2C6H4(o–F)
–CH2C6H4(m–F)
–CH2C6H4(p–F)
–CH2C6H4(p–Br)
–
3/5 5/5
3/5 5/5
–
3j
–
3k
3l
5/5
–
–
Results and discussion
3/5 5/5
3/5 5/5
3/5 5/5
–
3m
3n
3o
–
Target compounds were prepared according to Scheme 1.
The starting material 7-hydroxy-4,5-dihydro-1H-benzo
[b]azepin-2(3H)-one previously synthesized using the
method described previously by the present authors’ group
(Wei et al., 2009) was reacted with appropriate alkyl halide
to produce the compounds 1a–1o (Ju and Rajender, 2004).
The said compounds then were reacted with phosphorus
pentasulfide in acetonitrile in the presence of triethylamine
under nitrogen, and the resulting compounds 2a–2o were
reacted further with methyl hydrazine carboxylate in
n-butanol to produce the target compounds 3a–3o.
–
–CH2C6H4(p–CH3) 3/5 5/5
–
All of the tested compounds were dissolved in DMSO
–, Not tested
a
The maximal electroshock test was induced after 30 min past
administration of the tested compounds
b
Doses are denoted in mg/kg
and 3i–3j were active at the dose of 100 mg/kg. The
remaining one compound 3a exhibited anti-MES effect
only under the high dose of 300 mg/kg. In the anti-scPTZ
test, nine compounds (3c, 3f–3g, and 3i–3n) exhibited
anticonvulsant effects at the dose of 100 mg/kg, while
compounds 3d and 3e showed such effect at the dose of
30 mg/kg. As a result of preliminary screening, compounds
3c–3g and 3i–3n were subjected to phase II trials for
quantification of their anticonvulsant activities [indicated
by MES, median effective dose (ED50) and scPTZ, ED50]
and neurotoxicities [indicated by median toxic dose (TD50)]
in mice (Table 2). On analyzing the activities of the syn-
thesized compounds, the following structure–activity rela-
tionships (SAR) were obtained.
Pharmacological tests of the 8-alkoxy-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3a–3o) were con-
ducted at the Epilepsy Branch of the National Institute of
Neurological Disorders and Stroke (NINDS) following the
protocol adopted by the Antiepileptic Drug Development
(ADD) program (Krall et al., 1978; Porter et al., 1984).
The results of preliminary (phase I) screening of com-
pounds 3a–3o are summarized in Table 1. All the synthe-
sized compounds exhibited anticonvulsant activities,
among which seven compounds 3c–3h and 3k possessed
anticonvulsant activities against MES-induced seizure at
the dose of 30 mg/kg, and then seven compounds 3b, 3l–3o,
Scheme 1 The synthesis route
of compounds 3a–3o. Reagents:
a RX, NaOH/C2H5OH,
80–92°C; b P2S5, (C2H5)3N/
CH3CN, 86–92°C, 5–7 h;
c H2NNHCOH/
HO
RO
RO
RO
a
b
c
N
N
H
N
N
H
O
O
N
H
S
N
1a-1o
2a-2o
3a-3o
(CH3)(CH2)3OH, 140–150°C,
40–48 h
R:
3a = -CH3
3e= n-C6H13
3i = CH2C6H4(m-Cl)
3j = CH2C6H4(p-Cl)
3k = CH2C6H4(o-F)
3l = CH2C6H4(m-F)
3m = CH2C6H4(p-F)
3n = CH2C6H4(p-Br)
3o = CH2C6H4(p-CH3)
3b = n-C3H7
3c = n-C4H9
3d = n-C5H11
3f = n-C7H15
3g = CH2C6H5
3h = CH2C6H4(o-Cl)
123

Med Chem Res (2012) 21:2587–2594
2589
Table 2 Phase II quantitative anticonvulsant data in mice (test drug administered i.p.)
Compounds
EDa50
TDb50
PIc
MES
scPTZ
Rotarod toxicity
MES
scPTZ
3b
73.3 (86.4–62.1)d
21.2 (24.4–18.4)d
17.5 (18.5–16.5)d
17.7 (21.2–14.8)d
19.7 (22.5–17.2)d
23.7 (27.1–20.1)d
20.5 (24.1–17.5)d
29.5 (35.5–24.5)d
27.4 (32.9–22.9)d
19.0 (22.8–15.8)d
27.4 (32.9–22.9)d
27.4 (32.9–22.9)d
27.0 (37.1–19.6)d
27.4 (32.9–22.9)d
21.8 (21.8–25.5)d
9.5 (8.1–10.4)d
[100
–
–
–
3c
36.7 (44.1–30.5)d
21.2 (25.5–17.5)d
24.6 (29.0–20.1)d
26.4 (31.7–22.0)d
78.9 (94.5–65.9)d
[100
73.3 (86.5–62.2)d
114.1 (137.2–94.9)d
84.2 (100.9–70.3)d
68.4 (78.0–60.0)d
78.9 (89.9–69.3)d
70.9 (81.8–61.5)d
119.8 (141.0–101.8)d
98.6 (112.0–86.8)d
84.9 (93.9–76.7)d
[100
97.4 (110.7–85.7)d
96.2 (112.0–82.6)d
82.9 (99.6–70.5)d
69.0 (62.8–72.9)d
65.5 (52.5–72.9)d
426 (369–450)d
71.6 (45.9–135)d
3.5
6.5
4.8
3.5
3.3
3.4
4.1
3.7
4.5
–
2.0
5.4
3.4
2.6
1.0
\0.7
1.5
1.4
2.4
–
3d
3e
3f
3g
3h
3i
80.7 (96.7–67.4)d
68.2 (81.3–57.3)d
35.4 (41.8–30.0)d
[100
3j
3k
3l
3m
47.3 (56.4–39.7)d
3.6
3.0
3.6
3.2
6.9
1.6
8.1
2.1
0.9
1.1
5.2
\0.2
2.9
\0.72
3n
[100
3o
90.1 (108.1–75.1)d
13.2 (8.8–15.9)d
[300
Phenobarbitale
Phenytoine
Valproatee
Carbame
272 (247–338)d
8.8 (5.5–14.1)d
149 (123–177)
[100
–, No activity at the corresponding dose
a
ED50 median effective dose required to assure anticonvulsant protection in 50% animals
TD50 median toxic dose eliciting minimal neurological toxicity in 50% animals
b
c
d
e
PI (TD50/ED50
)
95% confidence limits given in parentheses
Date from Ucar et al., (1998)
In general, owing to the enhancement of molecular
the most active compound was 3d, and its ED50 in the MES
and scMet tests were 17.5 and 21.2 mg/kg, respectively,
resulting in PIs of 6.5 and 5.4, respectively, which are
slightly less than that of the prototype drug carbamazepine
(PI = 8.1) in the anti-MES test, and much greater than the
PI in the anti-scPTZ test of carbamazepine (PI \0.72).
This may be because the hydrophilic-lipophilic property
of the compound 3d is relatively modest, which makes it
easy to vehicle and pass through the blood–brain barrier.
The scPTZ has been reported to produce seizures by
inhibiting c-aminobutyric acid (GABA) neurotransmission
(Hamilton and Russo, 1977; Bernasconi et al., 1988),
GABA is the main inhibitory neurotransmitter substance in
the brain, and is widely implicated in epilepsy. Inhibition
of GABA-ergic neurotransmission or activity has been
shown to promote and facilitate seizures (Arnoldi et al.,
1990), while enhancement of GABA-ergic neurotransmis-
sion is known to inhibit or attenuate seizures. The standard
anticonvulsant drugs used have also been shown to exert
their anticonvulsant action by enhancing GABA-ergic
neurotransmission and activity. The findings of the present
study tend to suggest that the derivatives in this study
hydrophobicity and electronic polarization, the anticonvul-
sant activity of an organic compound might be increased
remarkably after the introduction of a halogen atom. Par-
ticularly, the introduction of fluorine atoms may significantly
change the molecular electronic distribution, increase the
binding affinity of drug with receptor, and improve the bio-
logical activity of drug. The ortho-halogenated benzyloxy
substituted compounds may be more suitable for binding
with receptor in space. Among the 8-benzyloxy derivatives,
the anticonvulsant activity of compounds containing
substituted benzyloxy (o–F, o–Cl) was stronger than that of
the compound with non-substituted benzyloxy (3g) in the
anti-MES test, and the ED50 of 3i–3o (m–Cl p–Cl, m–F, and
p–F) was less than that of 3g in the anti-MES test.
Both experimental models of epilepsy showed that the
length of the alkyl chain appeared to have a direct impact on
anticonvulsant activity of the 8-alkyloxyl derivatives. From
compound 3a to 3f, as alkyl chain length increased, ED50
gradually increased with the compound 3d being the most
active. The trend reversed, however, when the alkyl chain
had more than five carbon atoms. Among these derivatives,
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Med Chem Res (2012) 21:2587–2594
General procedure for preparation of compounds 2a–2o
might have inhibited or attenuated PTZ-induced seizures in
mice by enhancing GABA-ergic neurotransmission.
It has been reported that the voltage-gated Na? ion
channel inhibit seizures by controlling neuronal excitability.
Conventional anti-epileptics generally inhibit sodium
currents (carbamazepine, phenobarbital, phenytoin, and
valproate) or enhance GABA-ergic inhibition (benzodiaze-
pines, phenobarbital, and valproate). The newly synthesized
compounds may evoke sodium channel blocker activity
(Piotr et al., 2005; Ha et al., 2002). Compounds (3d–3f)
showed strong anticonvulsant activities in both experimental
models of epilepsy, which may have a wide range of anti-
convulsant effects.
Acetonitrile (1.0 mL) and triethylamine (0.6 mL) were
placed in a three-necked round-bottomed flask, to which
P2S5 (0.4 g, 1.9 mmol) was added slowly in an ice bath and
stirred until dissolved. Then, the compounds 1a–1o
(1.7 mmol) were added while stirring. The mixture was
refluxed for 4–6 h in a nitrogen atmosphere. After
removing the solvent under reduced pressure, the residue
was dissolved in 60 mL of dichloromethane, washed with
water (60 9 3), and dried over anhydrous MgSO4. Evap-
oration of the solvents gave a crude product.
General procedure for preparation of compounds 3a–3o
Crude products 2a–2o (2 mmol) were reacted with methyl
hydrazine carboxylate (4 mmol) in n-butanol 10 mL under
nitrogen atmosphere for 40–48 h, the solvent was removed
under reduced pressure, and the residue dissolved with
ethy1 acetate, and washed with water 3 times. The ethy1
acetate layer was dried over anhydrous MgSO4, filtered,
and the solvent was concentrated, and then the residue was
purified by silica gel column chromatography (dichloro-
methane:Methanol = 35:1) to afford target compounds
3a–3o.
Conclusions
In summary, we synthesized a series of 8-alkoxy-5,6-dihy-
dro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives
and tested their anticonvulsant activities and neurotoxicities
using the MES test, scPTZ, and the rotarod tests after i.p.
injection. The target compounds synthesized by incorpo-
rating a triazole ring into the parent compounds at the first
and second positions of this compound, had significantly
increased anticonvulsant activity compared to the parent
compounds, and had improved anti-scPTZ activity com-
pared to the benzazepine triazolone derivatives (Piao et al.,
2011). Among them, 8-pentyloxy-5,6-dihydro-4H-benzo[f]
[1,2,4]triazolo[4,3-a]azepine (3d) was the most active and
had the lowest toxicity, with a MES ED50 of 17.5 mg/kg, and
a PI of 6.5, which PI is slightly less than that of carbamaz-
epine (PI = 8.1). Its scPTZ ED50 and PI were 21.2 mg/kg
and 5.4, respectively, with these PIs being much greater than
the PI of carbamazepine (ED50 [100, PI \0.72).
8-Methoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo
[4,3-a]azepine (3a)
Yield: 79%, mp 123.2–124.5°C; IR (KBr)/cm: 1619, 1506
(C=N, C=C), 1233 (C–O); 1H-NMR (300 MHz, MeOD) d:
2.25–2.36 (m, 2H, C5–H), 2.63 (t, J = 7.2 Hz, 2H, C6–H),
2.87 (t, J = 7.2 Hz, 2H, C4–H), 3.87 (s, 3H, O–CH3),
6.98–7.05 (m, 2H, Ar–H), 7.44 (d, J = 8.4 Hz, 1H, Ar–H),
8.74 (s, 1H, triazole CH); 1H NMR (300 MHz, DMSO-d6):
d 2.11–2.19 (m, 2H, C5–H), 2.42–2.60 (m, C6–H and
DMSO), 2.73 (t, J = 6.9 Hz, 2H, C4–H), 3.81 (s, 3H,
–OCH3), 6.96–7.09 (m, 2H, Ar–H), 7.44 (d, J = 8.7 Hz,
1H, Ar–H), 8.77 (s, 1H, triazole CH); 13C-NMR (75 MHz,
Materials and methods
Chemistry
0
MeOD) d: 20.8 (C4), 28.6 (C5), 29.6 (C6), 54.7 (C1 ),
112.81 (C9), 115.52 (C7), 123.72 (C10), 126.34 (C10a),
135.92 (C6a), 142.54 (C1), 154.05 (C3a), 160.12 (C8).
MS-APCI (positive ionization) m/z: 216 (M ? 1)?. Anal.
Calcd. for C12H13N3O: C, 66.96; H, 6.09; N, 19.52; found:
C, 66.76; H, 6.08; N, 19.81.
Melting points were determined on X-5 microscope melt-
ing point apparatus, which were uncorrected. The IR
spectra were recorded (in KBr) on a FT-IR (IRPRESTIGE-
21). 1H-NMR spectra were measured on an AV-300
(Bruker, Switzerland), and all the chemical shifts were
given in parts per million relative to tetramethylsilane.
Mass spectra were measured on a HP1100LC (Agilent
Technologies, USA). Combustion analyses (C, H, and N)
were performed on a PE-2400 (SHIMADZU). Microanal-
yses of C, N, and H were performed using a Heraeus CHN
rapid analyzer. The major chemicals were purchased from
Alderich Chemical Corporation. All other chemicals were
of analytic grade (Scheme 1).
8-Propyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo
[4,3-a]azepine (3b)
Yield: 55%, mp 96.0–97.3°C; IR (KBr)/cm: 1618, 1506
(C=N, C=C), 1263 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 0.99 (t, 3H, J = 7.2 Hz, –CH3), 1.70–1.80 (m, 2H, alkyl
0
C2 –H), 2.12–2.18 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
123

Med Chem Res (2012) 21:2587–2594
2591
DMSO), 2.73(t, 2H, J = 6.3 Hz, C4–H), 3.98 (t, 2H,
0
2.12–2.18 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
J = 6.3 Hz, alkyl C1 –H), 6.95–7.06 (m, 2H, Ar–H), 7.42(d,
1H, J = 8.4 Hz, Ar–H), 8.76 (s, 1H, triazole CH); 13C-
DMSO), 2.73 (t, 2H, J = 6.9 Hz, C4–H), 4.01 (t, 2H,
0
J = 6.0 Hz, alkyl C1 –H), 6.96–7.06 (m, 2H, Ar–H), 7.41
(d, 1H, J = 8.4 Hz, Ar–H), 8.76 (s, 1H, triazole CH); 13C-
0
NMR (75 MHz, DMSO-d6) d: 10.8 (C3 ), 21.4 (C4), 22.46
0
0
0
(C2 ), 28.7 (C5), 30.1 (C6), 69.8 (C1 ), 113.7 (C9), 116.7
(C7), 124.4 (C10), 127.1 (C10a), 136.0 (C6a), 143.1 (C1),
153.0 (C3a), 158.8 (C8); MS-APCI (positive ionization) m/z:
244 (M ? 1)?. Anal. Calcd. for C14H17N3O: C, 69.11; H,
7.04; N, 17.27. Found: C, 68.90; H, 7.03; N, 17.49.
NMR (75 MHz, DMSO-d6) d: 14.4 (C6 ), 21.4 (C4), 22.6
0
0
0
0
(C5 ), 25.6 (C3 ), 28.7 (C5), 29.1 (C2 ), 30.1 (C6), 31.4 (C4 ),
0
68.2 (C1 ), 113.6 (C9), 116.6 (C7), 124.4 (C10), 127.1
(C10a), 136.0 (C6a), 143.1 (C1), 153.0 (C3a), 158.8 (C8);
MS-APCI (positive ionization) m/z: 286 (M ? 1)?. Anal.
Calcd. for C17H23N3O: C, 71.55; H, 8.12; N, 14.72. Found:
C, 71.34; H, 8.11; N, 15.02.
8-Butyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo
[4,3-a]azepine (3c)
8-Heptyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-
a]azepine (3f)
Yield: 51%, mp 108.6–110.2°C; IR (KBr)/cm: 1616, 1504
(C=N, C=C),1261 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 0.94 (t, 3H, J = 7.5 Hz, –CH3), 1.38–1.51 (m, 2H, alkyl
Yield: 35%, mp 104.5–105.9°C; IR (KBr)/cm: 1616, 1504
(C=N, C=C), 1259 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 0.87 (t, 3H, J = 6.9 Hz, –CH3), 1.22–1.42 (m, 8H, alkyl
0
C3 –H), 1.66–1.76 (m, 2H, alkyl C2 –H), 2.10–2.20 (m, 2H,
0
C5–H), 2.47–2.56 (m, C6–H and DMSO), 2.73 (t, 2H,
0
J = 7.5 Hz, C4–H), 4.02 (t, 2H, J = 6.6 Hz, alkyl C1 –H),
0
C3 –H, C4 –H, C5 –H, and C6 ), 1.67–1.77 (m, 2H, alkyl
0
0
0
0
C2 –H), 2.12–2.20 (m, 2H, C5–H), 2.47–2.56 (m, C6–H,
6.95–7.06 (m, 2H, Ar–H), 7.42 (d, 1H, J = 8.4 Hz, Ar–H),
8.75 (s, 1H, triazole CH); 13C-NMR (75 MHz, DMSO-d6)
and DMSO), 2.73 (t, 2H, J = 7.2 Hz, C4–H), 4.00 (t, 2H,
J = 6.6 Hz, H-10), 6.94–7.05 (m, 2H, Ar–H), 7.41 (d, 1H,
J = 8.7 Hz, Ar–H), 8.76 (s, 1H, triazole CH); 13C-NMR
0
0
d: 14.1 (C4 ), 19.2 (C3 ), 21.4 (C4), 28.7 (C5), 30.1 (C6),
0
0
31.1 (C2 ), 68.0 (C1 ), 113.7 (C9), 116.7 (C7), 124.4 (C10),
127.1 (C10a), 136.0 (C6a), 143.1 (C1), 153.0 (C3a), 158.8
(C8); MS-APCI (positive ionization) m/z: 258 (M ? 1)?.
Anal. Calcd. for C15H19N3O: C, 70.01; H, 7.44; N, 16.33.
Found: C, 69.87; H, 7.43; N, 16.51.
0
0
(75 MHz, DMSO-d6) d: 14.4 (C7 ), 21.4 (C4), 22.5 (C6 ),
0
0
0
25.9 (C5 ), 28.7, (C5), 28.9 (C4 ), 29.1 (C3 ), 30.1 (C6), 31.7
0
0
(C2 ), 68.2 (C1 ), 113.7 (C9), 116.7 (C7), 124.4 (C10), 127.1
(C10a), 136.0 (C6a), 143.1 (C1), 153.0 (C3a), 158.8 (C8);
MS-APCI (positive ionization) m/z: 300 (M ? 1)?. Anal.
Calcd. for C18H25N3O: C, 72.21; H, 8.42; N, 14.03. Found:
C, 72.11; H, 8.40; N, 14.24.
8-Pentyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo
[4,3-a]azepine (3d)
Yield: 43%, mp 114.5–116.6°C; IR (KBr)/cm: 1616, 1504
(C=N, C=C), 1261 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 0.90 (t, 3H, J = 7.2 Hz, –CH3), 1.31–1.44 (m, 4H, alkyl
8-Benzyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-
a]azepine (3g)
0
0
0
C3 –H, and C4 –H), 1.70–1.76 (m, 2H, alkyl C2 –H),
2.12–2.18 (m, 2H, C5–H), 2.47–2.54 (m, C6–H, and DMSO),
2.73 (t, 2H, J = 7.5 Hz, C4–H), 4.01 (t, 2H, J = 6.6 Hz,
H-10), 6.95–7.06 (m, 2H, Ar–H), 7.41 (d, 1H, J = 8.7 Hz,
Ar–H), 8.75 (s, 1H, triazole CH); 13C-NMR (75 MHz,
Yield: 44%, mp 139.0–140.4°C; IR (KBr)/cm: 1601, 1506
(C=N, C=C), 1229 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.13–2.19 (m, 2H, C5–H), 2.47–2.56 (m, C6–H, and
DMSO), 2.74 (t, 2H, J = 7.2 Hz, C4–H), 5.16 (s, 2H, benzyl
CH2), 7.04–7.09 (m, 1H, Ar–H), 7.15–7.17 (m, 1H, Ar–H),
7.31–7.49 (m, 6H, Ar–H), 8.76 (s, 1H, triazole CH); 13C-
NMR (75 MHz, DMSO-d6) d: 21.5 (C4), 28.8 (C5), 30.2(C6),
70.1 (benzyl C), 114.0 (C9), 117.2 (C7), 124.5 (C10), 127.5
(C10), 128.2 (phenyl C2 and C6), 128.4 (phenyl C4), 129.06
(phenyl C3 and C5), 136.1 (C6a), 137.3 (phenyl C1), 143.1
(C1), 153.0 (C3a), 158.4 (C8); MS-APCI (positive ionization)
m/z: 292 (M ? 1)?. Anal. Calcd. for C18H17N3O: C, 74.20;
H, 5.88; N, 14.42. Found: C, 74.05; H, 5.86; N, 14.64.
0
0
0
DMSO-d6) d: 14.4 (C5 ), 21.4 (C4), 22.3 (C4 ), 28.1(C3 ), 28.7
0
0
(C5), 28.8 (C2 ), 30.1 (C6), 68.2 (C1 ), 113.6 (C9), 116.6 (C7),
124.4 (C10), 127.1 (C10a), 136.0 (C6a), 143.1 (C1), 153.0
(C3a), 158.8 (C8); MS-APCI (positive ionization) m/z: 272
(M?). Anal. Calcd. for C16H21N3O: C, 70.82; H, 7.80; N,
15.49. Found: C, 70.68; H, 7.79; N, 15.69.
8-Hexyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo
[4,3-a]azepine (3e)
8-(2-Chlorobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a][1]azepin (3h)
Yield: 40%, mp 112.3–113.8°C; IR (KBr)/cm: 1618, 1504
(C=N, C=C), 1260 (C–O); 1H-NMR (300 MHz, DMSO-d6)
0
d: 0.84–0.94 (m, 3H, –CH3), 1.23–1.43 (m, 6H, alkyl C3 –
Yield: 43%, mp 153.8–155.6°C. IR (KBr)/cm: 1607, 1506
(C=N, C=C), 1265 (C–O); 1H-NMR (300 MHz, DMSO-d6)
0
H, C4 –H, and C5 –H), 1.70–1.75 (m, 2H, alkyl C2 –H),
0
0
123

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Med Chem Res (2012) 21:2587–2594
d: 2.14–2.20 (m, 2H, C5–H), 2.42–2.62 (m, C6–H, and
DMSO), 2.60–2.75 (m, 2H, C4–H), 5.21 (s, 2H, benzyl
CH2), 7.06–7.20 (m, 2H, Ar–H), 7.40–7.64 (m, 5H, Ar–H),
8.77 (s, 1H, triazole CH); 13C-NMR (75 MHz, DMSO-d6)
d: 21.5 (C4), 28.7 (C5), 30.1 (C6), 67.7 (benzyl C), 114.0
(C9), 117.1 (C7), 124.6 (C10), 127.7 (C10a), 127.9 (phenyl
C5), 129.9 (phenyl C6), 130.5 (phenyl C3), 130.8 (phenyl
C4), 133.2 (phenyl C2), 134.5 (phenyl C1), 136.2 (C6a),
143.1 (C1), 153.0 (C3a), 158.2 (C-8); MS-APCI (positive
ionization) m/z: 326 (M ? 1)?. Anal. Calcd. for
C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C,
66.29; H, 4.94; N, 13.04.
d: 2.11–2.21 (m, 2H, C5–H), 2.47–2.56 (m, C6–H, and
DMSO), 2.74 (t, 2H, J = 7.2 Hz, C4–H), 5.20 (s, 2H.
benzyl CH2), 7.06–7.12 (m, 1H, Ar–H), 7.17–7.20 (m, 1H,
Ar–H), 7.23–7.31 (m, 2H, Ar–H), 7.40–7.48 (m, 2H, Ar–
H), 7.56–7.62 (m, 1H, Ar–H), 8.77 (s, 1H,triazole CH);
13C-NMR (75 MHz, DMSO-d6) d: 21.4 (C4), 28.7 (C5),
30.1 (C6), 64.4 (benzyl C), 113.9 (C9), 115.9 (d,
JC–F = 20.8 Hz, phenyl C3), 117.0(C7), 124.0 (d,
JC–F = 14.4 Hz, phenyl C1), 124.5 (C10), 125.1 (phenyl
C5), 127.6 (C10a), 131.0 (d, JC–F = 8.3 Hz, phenyl C4),
131.3 (phenyl C6), 136.2 (C6a), 143.1 (C1), 153.0 (C3a),
158.2 (C8), 160.9 (d, JC–F = 244.8 Hz, phenyl C2); MS-
APCI (positive ionization) m/z: 310 (M ? 1)?. Anal.
Calcd. for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58.
Found: C, 69.68; H, 5.20; N, 13.74.
8-(3-Chlorobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3i)
Yield: 44%, mp 113.2–117.7°C. IR (KBr)/cm: 1618, 1503
(C=N, C=C), 1261 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.10–2.25 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
DMSO), 2.74 (t, 2H, J = 7.2 Hz, C4–H), 5.18 (s, 2H,
benzyl CH2), 7.06–7.10 (m, 2H, Ar–H), 7.43–7.62 (m, 5H,
Ar–H), 8.77 (s, 1H, triazole CH); 13C-NMR (75 MHz,
DMSO-d6) d: 21.4 (C4), 28.7 (C5), 30.1 (C6), 69.0 (benzyl
C), 114.0 (C9), 117.2 (C7), 124.5 (C10), 126.7 (phenyl C-6),
127.6 (C10a), 127.8 (phenyl C2), 128.3 (phenyl C4), 130.9
(phenyl C5), 133.6 (phenyl C3), 136.1 (C6a), 139.8 (phenyl
C1), 143.1 (C1), 153.0 (C3a), 158.1 (C8); MS-APCI (posi-
tive ionization) m/z: 326 (M ? 1)?. Anal. Calcd. for
C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C,
66.29; H, 4.94; N, 13.04.
8-(3-Fluorobenzyloxy) -5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3l)
Yield: 38%, mp 120.1–121.3°C; IR (KBr)/cm: 1597, 1508
(C=N, C=C), 1260 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.13–2.19 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
DMSO), 2.74 (t, 2H, J = 7.2 Hz, C4–H), 5.19 (s, 2H,
benzyl CH2), 7.04–7.10 (m, 1H, Ar–H), 7.16–7.21 (m, 2H,
Ar–H), 7.29–7.34 (m, 2H, Ar–H), 7.43–7.48 (m, 2H, Ar–
H), 8.76 (s, 1H, triazole CH); 13C-NMR (75 MHz, DMSO-
d6) d: 21.4 (C4), 28.7 (C5), 30.1 (C6), 69.1 (benzyl C),
114.0 (C9), 114.8 (d, JC–F = 21.7 Hz, phenyl C2), 115.2 (d,
JC–F = 20.8 Hz, phenyl C4), 117.2 (C7), 124.0 (d,
JC–F = 2.2 Hz, phenyl C6), 124.5 (C10), 127.6 (C10a),
131.0 (d, JC–F = 8.3 Hz, phenyl C5), 136.1 (C6a), 140.2 (d,
JC–F = 7.4 Hz, phenyl C1), 143.1 (C1), 153.0 (C3a), 158.2
(C8), 162.7 (d, JC–F = 242.2 Hz, phenyl C3); MS-APCI
(positive ionization) m/z: 310 (M ? 1)?. Anal. Calcd. for
C18H16FN3O: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.81;
H, 5.19; N, 13.60.
8-(4-Chlorobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3j)
Yield: 39%, mp 166.6–168.2°C; IR (KBr)/cm: 1614, 1499
(C=N, C=C), 1261 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.10–2.22 (m, 2H, C5–H), 2.47–2.56 (m, C6–H, and
DMSO), 2.73–2.80 (m, 2H, C4–H), 5.16 (s, 2H, benzyl
CH2), 7.04–7.16 (m, 2H, Ar–H), 7.41–7.50 (m, 5H, Ar–H),
8.76 (s, 1H, triazole CH); 13C-NMR (75 MHz, DMSO-d6)
d: 21.5 (C4), 28.7 (C5), 30.1 (C6), 69.2 (benzyl C), 114.1
(C9), 117.2 (C7), 124.5 (C10), 127.6 (C10a), 129.0 (phenyl
C3 and C5), 130.0 (phenyl C2 and C6), 133.0 (phenyl C4),
136.1 (C6a), 136.3 (phenyl C1), 143.1 (C1), 153.0 (C3a),
158.2 (C8); MS-APCI (positive ionization) m/z: 326
(M ? 1)?. Anal. Calcd. for C18H16ClN3O: C, 66.36; H,
4.95; N, 12.90. Found: C, 66.23; H, 4.93; N, 12.92.
8-(4-Fluorobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3m)
Yield: 40%, mp 145.0–146.2°C; IR (KBr)/cm: 1604, 1506
(C=N, C=C), 1229 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.11–2.21 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
DMSO), 2.74 (t, 2H, J = 6.9 Hz, C6–H), 5.14 (s, 2H,
benzyl CH2), 7.04–7.16 (m, 1H, Ar–H), 7.14–7.16 (m, 1H,
Ar–H), 7.20–7.27 (m, 2H, Ar–H), 7.44 (d, 1H, J = 8.7 Hz,
Ar–H), 7.50–7.56 (m, 2H, Ar–H), 8.76 (s, 1H, triazole CH);
13C-NMR (75 MHz, DMSO-d6) d: 21.4 (C4), 28.7 (C5),
30.1 (C6), 69.3 (benzyl C), 114.0 (C9), 115.8 (d,
JC–F = 21.2 Hz, phenyl C3 and C5), 117.1 (C7), 124.5
(C10), 127.5 (C10a), 130.5 (d, JC–F = 8.4 Hz, phenyl C2
and C6), 133.4 (phenyl C1), 136.1 (C6a), 143.1 (C1), 153.0
(C3a), 158.3 (C8), 162.3 (d, JC–F = 242.2 Hz, phenyl C4);
8-(2-Fluorobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3k)
Yield: 40%, mp 140.0–141.8°C; IR (KBr)/cm: 1618, 1492
(C=N, C=C), 1263 (C–O); 1H-NMR (300 MHz, DMSO-d6)
123

Med Chem Res (2012) 21:2587–2594
2593
MS-APCI (positive ionization) m/z: 310 (M ? 1)?. Anal.
Calcd. for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58.
Found: C, 69.75; H, 5.17; N, 13.59.
i.p.) with anticonvulsant activity and neurotoxicity being
assessed at 30-min intervals after administration. Anti-
convulsant efficacy was measured in the MES and the
scPTZ tests. In the MES test, seizures were elicited with a
60 Hz, a.c. of 50 mA intensity in mice. The current was
applied via corneal electrodes for 0.2 s. Abolition of the
hind-limb tonic extensor component of the seizure indi-
cated protection against the spread of MES-induced sei-
zures. The scPTZ test involved subcutaneous injection of a
convulsant dose of pentylenetetrazol (85 mg/kg in mice).
Elevation of the pentylenetetrazol-induced seizure thresh-
old was indicated by the absence of clonic spasms for at
least 5-s duration over a 30-min period following admin-
istration of the test compound. Anticonvulsant drug-
induced neurologic deficit was detected in mice by using
the rotarod ataxia test.
8-(4-Bromobenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3n)
Yield: 33%, mp 150.1–151.8°C; IR (KBr)/cm: 1614, 1497
(C=N, C=C), 1260 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.13–2.18 (m, 2H, C5–H), 2.47–2.56 (m, C6–H and
DMSO), 2.74 (t, 2H, J = 7.2 Hz, C4–H), 5.15 (s, 2H,
benzyl CH2), 7.00–7.07 (m, 1H, Ar–H), 7.14–7.16 m, 1H,
Ar–H), 7.42–7.46 (m, 2H, Ar–H), 7.61 (d, 2H, J = 8.4 Hz,
Ar–H), 8.76 (s, 1H, trazolel CH); 13C-NMR (75 MHz,
DMSO-d6) d: 21.4 (C4), 28.7 (C5), 30.1 (C6), 69.2 (benzyl
C), 114.0 (C9), 117.2 (C7), 121.5 (phenyl C4), 124.5 (C10),
127.5 (C10a), 130.3 (phenyl C2 and C6), 131.9 (phenyl C3
and C5), 136.1 (C6a), 136.7 (phenyl C1), 143.1 (C1), 153.0
(C3a), 158.2 (C8); MS-APCI (positive ionization) m/z: 370
(M ? 1)?. Anal. Calcd. for C18H16BrN3O: C, 58.39; H,
4.36; N, 11.35. Found: C, 58.27; H, 4.35; N, 11.36.
Anticonvulsant activity was expressed in terms of the
ED50, and neurotoxicity was expressed as the TD50. For
determination of the ED50 and TD50 values, groups of 10
mice were given a range of i.p. doses of the tested com-
pounds until at least three points were established in the
range of 10–90% seizure protection or minimal observed
neurotoxicity (Krall et al., 1978; Porter et al., 1984). From
the plots of these data, the respective ED50, TD50 values
and 95% confidence intervals were calculated by means of
Trimmed Spearman–Karber method (Okada et al., 1989).
8-(4-Methylbenzyloxy)-5,6-dihydro-4H-
benzo[f][1,2,4]triazolo[4,3-a]azepine (3o)
Yield: 43%, mp 130.1–131.3°C; IR (KBr)/cm: 1608, 1504
(C=N, C=C), 1227 (C–O); 1H-NMR (300 MHz, DMSO-d6)
d: 2.10–2.22 (m, 2H, C5–H), 2.32 (s, 3H, –CH3), 2.47–2.56
(m, C6-H, and DMSO), 2.70–2.80 (m, 2H, C4–H), 5.11 (s,
2H, benzyl CH2), 7.00–7.25 (m, 4H, Ar–H), 7.30–7.50 (m,
3H, Ar–H), 8.76 (s, 1H, triazole CH); 13C-NMR (75 MHz,
DMSO-d6) d: 21.2 (CH3), 21.4 (C4), 28.7 (C5), 30.1 (C6),
69.9 (benzyl C), 114.0 (C9), 117.2 (C7), 124.4 (C10), 127.4
(C10a), 128.3 (phenyl C2 and C6), 129.5 (phenyl C3 and C5),
134.2 (phenyl C4), 136.1 (C6a), 137.7 (phenyl C1), 143.1
(C1), 153.0 (C3a), 158.4 (C8); MS-APCI (positive ioniza-
tion) m/z: 306 (M ? 1)?. Anal. Calcd. for C19H19N3O:
C,74.73; H, 6.27; N, 13.76. Found: C, 74.51; H, 6.26; N,
13.91.
Acknowledgments This study was supported by the National Nat-
ural Science Foundation of China (No. 30460151 and No. 30760290)
and Important Item Foundation of Ministry of Education People’s
Republic of China (No. 20070422029).
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