Synthesis and anticonvulsant activity evaluation of 5-Phenyl-[1,2,4] triazolo[4,3-c]quinazolin-3-amines

Article abstract of DOI:10.1002/ardp.201200376

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h, which showed an ED₅₀ value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED₅₀ and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti-MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system-mediated mechanisms might be involved in its anticonvulsant activity. Copyright

Full text of DOI:10.1002/ardp.201200376

Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
119
Full Paper
Synthesis and Anticonvulsant Activity Evaluation
of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines
Yan Zheng1, Ming Bian1,2, Xian-Qing Deng1, Shi-Ben Wang1, and Zhe-Shan Quan1
1 College of Pharmacy, Yanbian University, Yanji City, Jilin, China
2 Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia University for Nationalities, Inner
Mongolia Autonomous Region, Tongliao, China
In the present study we describe the syntheses and anticonvulsant activity evaluation of 5-phenyl-
[1,2,4]triazolo[4,3-c]quinazolin-3-amine derivatives. Their anticonvulsant activity and neurotoxicity
were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The
majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of
these compounds, the most promising was compound 8h, which showed an ED50 value of 27.4 mg/kg
and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED50
and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti-MES efficacy, the
potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide
were also established, with the results suggesting that the GABAergic system-mediated mechanisms
might be involved in its anticonvulsant activity.
Keywords: Anticonvulsant / Maximal electroshock / Quinazoline / Synthesis / Triazolo
Received: October 3, 2012; Revised: November 6, 2012; Accepted: November 9, 2012
DOI 10.1002/ardp.201200376
Introduction
vulsant [18, 19]. Since the appearance of methaqualone
(a well known sedative-hypnotic containing the quinazolin-
4(3H)-one nucleus) in the early 1970s, more and more
researches are focused on the program that aims to develop
an anticonvulsant in 4(3H)-quinazolinones [20–25]. In fact,
these studies confirm that the quinazolin-4(3H)-one nucleus
possesses a pharmacophoric character for anticonvulsant
activities. Moreover, the 1,2,4-triazole nucleus and its deriva-
tives have received considerable attention owing to their
effective biological importance. And their biological import-
ance associated with anticonvulsant activity has been estab-
lished in our previous work [26–32].
Epilepsy, one of the most frequent neurological afflictions in
men characterized by excessive temporary neuronal dis-
charges resulting in uncontrolled convulsion, inflicts more
than 60 million people worldwide [1, 2]. Despite the develop-
ment of several new anticonvulsants, the treatment of epi-
lepsy remains still inadequate. It is roughly estimated that up
to 28–30% of patients are poorly treated with the available
antiepileptic drugs (AEDs) [3, 4]. Moreover, many AEDs have
serious side effects [5–10], and lifelong medication may be
required. Therefore, there is a continuing demand for new
anticonvulsant agents with more selectivity and lower
toxicity.
Based on the above mentioned facts and in continuation of
an ongoing program aiming at finding new lead structures
with potential anticonvulsant activities, we have incorpor-
ated five nitrogenous heterocyclic molecules (1,2,4-triazole,
tetrazole, 1,2,4-triazol-3-amine, 1,2,4-triazol-3(4H)-one, and 3-
methyl-1,2,4-triazole) into the 2-phenyl-4(3H)-quinazolinone
nucleus to get several new lead structures 6–10. Preliminary
anticonvulsant screening demonstrated that compound 8
possessed positive activity at the dose of 100 mg/kg, while
compounds 6, 7, 9, and 10 did not show the protection at the
same dose. As a consequence, a series of 5-phenyl-[1,2,4]-
triazolo[4,3-c]quinazolin-3-amine derivatives was designed
One of the most frequently encountered heterocycles in
medicinal chemistry is 4(3H)-quinazolinones, which have
diverse pharmacological activities like antitumor [11, 12],
antiinflammatory [13], antimicrobial activities [14, 15], and
CNS activities such as CNS depressant [16, 17] and anticon-
Correspondence: Zhe-Shan Quan, College of Pharmacy, Yanbian
University, No. 977, GongYuan Road, Yanji City, Jilin 133000, China.
E-mail: zsquan@ybu.edu.cn
Fax: þ86 433-2436020
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120
Y. Zheng et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
with substituted moieties possessing different electronic
environment on the benzene in the hope of developing potent
and safe new anticonvulsant compounds. The structures of
all target compounds were characterized. Anticonvulsant
activity and neurotoxicity were evaluated by the maximal
electroshock seizure (MES) test and the rotarod test, respect-
ively. The most active compound 8h was subjected to some
chemical-induced seizure models, including pentylenetetra-
zole (PTZ) and thiosemicarbazide (TSC) induced seizure tests.
Results and discussion
Chemistry
All the compounds were prepared as outlined in Schemes 1
and 2. Cyclization of 2-aminobenzamide with appropriate
benzaldehydes gave substituted 2-phenyl-2,3-dihydroquina-
zolin-4(1H)-ones (2), which were oxidized by KMnO4 to obtain
compounds 3. The compounds 3 underwent sulfurization in
the presence of Lawesson’s reagent to form 2-phenylquinazo-
line-4(3H)-thiones (4). Replacing the sulfur atom in com-
pounds 4 with the hydrazine group by treatment with
hydrazine hydrate produced the key intermediates 5.
Finally, intermediates 5 reacted with formic acid, NaNO2/
HCl, cyanogene bromide, carbonyl diimidazole, and acetic
anhydride to obtain compounds 6, 7, 8, 9, and 10, respect-
ively. Their chemical structures were characterized using IR,
1H-NMR, MS, and elemental analysis techniques. The detailed
physical and analytical data are listed in the Experimental
part.
Scheme 2. Synthetic route of target compounds.
anticonvulsant activity was assessed by the most adopted
animal model electroshock (MES) test. All the synthesized
compounds were administered intraperitoneally into mice
using doses of 30 and 100 mg/kg, and the observations were
taken at two different time intervals (0.5 and 4.0 h). The
results were presented in Table 1.
Pharmacology
Phase I evaluation of anticonvulsant activity
The pharmacological tests of all the target compounds were
performed according to the standard protocol given by the
epilepsy branch of the National Institute of Neurological
Disorders and Stroke (NINDS) and adopted by the
Antiepileptic Drug Development (ADD) program [33]. Their
In the preliminary anticonvulsant screening, several com-
pounds showed a certain degree of protection in the MES
screen which was indicative of the anticonvulsant ability of
these compounds. Nine compounds were active at a dose of
100 mg/kg after 0.5 h. These include compounds 8a–8e, 8h,
Scheme 1. Synthetic route of the key inter-
mediate compound 5.
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Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
Anticonvulsant Activity of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines
121
Table 1. Phase I evaluation of anticonvulsant activity in mice (i.p.).
N
N
N
N
N
N
N
N
N
N
N
OH
NH2
N
N
N
N
N
N
N
N
N
N
R
_
9
10
6
7
8a 8s
Compounds
R
MESa) (mg/kg) 0.5 h
MES (mg/kg) 4 h
100
30
100
30
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
6
-H
o-F
m-F
p-F
o-Cl
m-Cl
p-Cl
o-Br
m-Br
p-Br
o-CF3
m-CF3
p-CF3
m-NO2
p-CH3
o-OCH3
m-OCH3
p-OCH3
-H
2/3b)
2/3
3/3
1/3
2/3
0/3
0/3
3/3
1/3
0/3
1/3
0/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
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
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2/3
0/3
–
0/3
–
0/3
–
–
–
–
–
–
7
9
10
-H
-H
-H
–
–
–
a)
Maximal electroshock: Doses of 30, 100, and 300 mg/kg were administrated intraperitoneally in mice; the animals were examined
0.5 h after administration.
b)
The figures n1/n2: the animals protected/the animals tested.
The dash (–): The compound was not tested in mice at the dose of 30 mg/kg.
8i, 8k, and 8m. Among these, compounds 8c and 8h showed
protection against seizure at the dose 30 mg/kg after 0.5 h.
No compound showed activity at the dose of 100 mg/kg at 4 h
interval. In the series of 8a–8r, we can see that electron
withdrawing groups (8b–8n) were found to be uncertain
on the anticonvulsant activity, while electron releasing
groups (8o–8r) obviously decreased the anticonvulsant
activity when compared to compound 8a. Introduction of
the same halogen in different positions seems to have a differ-
ent effect on the activity. For the three F-substituted derivatives
(8b–8d), the potency order was m-F > o-F > p-F. Among the
three Cl-substituted derivatives (8e–8g), the potency order was
o-Cl > m-Cl ¼ p-Cl. For the three Br-substituted derivatives
(8h–8j), the potency order was o-Br > m-Br > p-Br.
sant screening, they 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 standard drug carbamazepine and valproate, are
reported in Table 2. 5-(3-Fluorophenyl)-[1,2,4]triazolo[4,3-c]-
quinazolin-3-amine (8c) and 5-(2-bromophenyl)-[1,2,4]triazolo-
[4,3-c]quinazolin-3-amine (8h) gave an ED50 of 44.8 and
27.4 mg/kg, and a protective index (PI) of 4.4 and 5.8, respect-
ively. Both of them showed weaker anticonvulsant activity
compared to the currently used AED carbamazepine but
better than valproate. Moreover, both compounds showed
a safer profile than valproate, and a comparable PI when
compared with carbamazepine.
Phase II evaluation of anticonvulsant activity
Because of the considerable anticonvulsant activity of com-
pounds 8c and 8h presented in the preliminary anticonvul-
Speculation upon mechanism
To speculate about the possible mechanism of anticonvulsant
action of the structures, compound 8h was tested against
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Y. Zheng et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
Table 2. Quantitative anticonvulsant data in mice (i.p.).
Compounds
ED50 mg/kg (MES)
TD50 mg/kg (rotarod)
PI (TD50/ED50)
8c
8h
44.8 (26.24–76.48)
27.4 (19.89–37.70)
9.8 (8.9–10.8)
182.6 (137.16–242.96)
157.8 (114.61–217.19)
44.0 (40.2–48.1)
4.1
5.8
4.5
1.6
Carbamazepine
Valproate
272 (247–338)
426 (369–450)
convulsions induced by chemical substances, including
PTZ and TSC. Compound 8h 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.
seizures, suggesting that the GABAergic system-mediated
mechanisms might be involved in its anticonvulsant activity.
In summary, the current study has demonstrated that
a series of 5-phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amine
derivatives were effective in the MES screens. The most prom-
ising was compound 8h, which showed an ED50 value of
27.4 mg/kg and a PI value of 5.8. These values were superior
to those provided by valproate (ED50 and PI values of 272 and
1.6, respectively) in the MES test in mice. As well as its anti-
MES efficacy, the potencies of compound 8h against seizures
induced by PTZ and TSC were also established, with the
results suggesting that the GABAergic system-mediated
mechanisms might be involved in its anticonvulsant activity.
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 8h inhibited the clonic
seizures and tonic seizures induced by PTZ at the rates of 20
and 90%, respectively, and also showed complete inhibition
of the death compared to the control (Table 3). These results
revealed that compound 8h possessed potent activity against
sc-PTZ. PTZ have been reported to produce seizures by inhib-
iting g-aminobutyric acid (GABA) neurotransmission [34, 35].
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 [36], while enhancement of GABAergic
neurotransmission is known to inhibit or attenuate seizures.
The findings of the present study suggest that the newly
synthesized compound 8h might inhibit or attenuate PTZ-
induced seizures in mice by enhancing GABAergic effects.
In the TSC-induced seizure model, the anticonvulsant
effect is similar to that of the sc-PTZ 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 8h showed inhi-
bition of clonic seizures at a rate of 30%, and absolute pro-
tection against the tonic seizures and death induced by TSC.
TSC are competitive inhibitors of the GABA synthesis enzyme
glutamate decarboxylase (GAD), and they inhibit the syn-
thesis of GABA, resulting in decreasing GABA levels in the
brain [37]. Compound 8h showed antagonism to TSC-induced
Experimental
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a
IRPrestige-21. 1H-NMR spectra were measured on an AV-300
(Bruker, Switzerland), and all chemical shifts were given in
ppm relative to tetramethysilane. Mass spectra were measured
on an HP1100LC (Agilent Technologies, USA). The ionization
technique used for recording mass spectra was atmospheric
pressure chemical ionization (APCI). Elemental analyses were
performed on a 204Q CHN (Perkin Elmer, USA). The chemicals
were purchased from Aldrich Chemical Corporation.
General procedure for the preparation of compounds 2 [38]
Compound 1 (1 g, 7.3 mmol) and appropriate benzaldehyde
(9.6 mmol) were dissolved in dichloromethane (25 mL) and
refluxed for 2–3 d. After completion of the reaction, excess
solvent was removed under reduced pressure. Then water was
added to the residue to get white crystal, which was further
filtered and washed with excess of water. The white crystal was
Table 3. Effects of compound 8h on chemical-induced seizures in mice (i.p.).
Chemical substances Compound Doses (mg/kg) Test time (h) Clonic seizures (%) Tonic seizures (%) Lethality (%)
Pentylenetetrazol
DMSO
Carbamazepine
8h
DMSO
Carbamazepine
8h
–
0.5
0.5
0.5
0.5
0.5
0.5
100
100
80
100
100
70
60
0
10
100
0
60
0
0
100
0
0
50
50
–
50
50
Thiosemicarbazide
0
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Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
Anticonvulsant Activity of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines
123
directly used in the next step without purification, whose yield
was above 98%.
bromide (0.24 g, 2.1 mmol) in dioxane (6 mL) was added drop-
wise to the mixture under ice-bath and the reaction temperature
was kept below 108C. After stirring for 12 h, the solvent was
removed under reduced pressure. The residue was recrystallized
from ethanol to get a pure product 8.
General procedure for the preparation of compounds 3 [39]
A mixture of 2 (6.7 mmol) and potassium permanganate (0.53 g,
3.3 mmol) in dimethyl formamide (20 mL) was refluxed for
2–3 h. The resulting suspension was filtered to remove the
insoluble solid and excess solvent of the filtrate was removed
under reduced pressure. Then water was added to the residue to
get a white precipitate with a yield range of 85–90%, which was
directly used in the next step without purification.
5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amine (8a)
Yield: 73%, m.p. 256–2578C. 1H-NMR (DMSO-d6): d 5.20 (s, 2H,
–NH2), 7.59–7.84 (m, 8H, Ar–H), 8.31 (d, 1H, J ¼ 7.4 Hz, Ar–H).
IR (KBr) cmꢀ1: 1510, 1610 (C N), 3086, 3114 (N–H). MS m/z 262
–
–
(MþH). Anal. calcd. for C15H11N5: C, 68.95; H, 4.24; N, 26.80.
Found: C, 68.95; H, 4.24; N, 26.80.
General procedure for the preparation of compounds 4 [40]
A mixture of 3 (8.5 mmol) and Lawesson’s reagent (2.1 g,
5 mmol) in toluene (20 mL) was refluxed for 2–3 h. After remov-
ing the solvent under reduced pressure, the crude product was
purified by silica gel column chromatography (V CH3OH/
CH2Cl2 ¼ 1:100) with a yield range of 30–56%.
5-(2-Fluorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-3-
amine (8b)
Yield: 76%, m.p. 250–2528C. 1H-NMR (DMSO-d6, CDCl3): d 5.14
(s, 2H, NH2), 7.30–7.42 (m, 2H, Ar–H), 7.64–7.75 (m, 4H, Ar–H),
7.82 (d, 1H, J ¼ 7.5 Hz, Ar–H), 8.35 (d, 1H, J ¼ 7.8 Hz, Ar–H). IR
(KBr) cmꢀ1: 1534, 1670 (C N), 3034, 3432 (N–H). MS m/z 280
–
–
(MþH). Anal. calcd. for C15H10FN5: C, 64.51; H, 3.61; N, 25.08.
General procedure for the preparation of compounds 5 [41]
To a solution of compounds 4 (6.3 mmol) in methanol, 80%
hydrazine hydrate (3.15 g, 50 mmol) was added and the mixture
was refluxed for 12 h. After completion of the reaction, the
major solvent was removed under reduced pressure. Waiting
for a moment, a precipitate formed, which was filtered and
washed by a small amount of methanol to obtain a pure product
with a yield range of 70–76%.
Found: C, 64.74; H, 3.89; N, 24.85.
5-(3-Fluorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-3-
amine (8c)
Yield: 71%, m.p. 270–2718C. 1H-NMR (DMSO-d6, CDCl3): d 5.18
(s, 2H, NH2), 7.37–7.42 (m, 1H, Ar–H), 7.52–7.73 (m, 5H, Ar–H),
7.82–7.87 (m, 1H, Ar–H), 8.42 (d, 1H, J ¼ 6.9 Hz, Ar–H). IR (KBr)
cmꢀ1: 1515, 1646 (C N), 3111, 3419 (N–H). MS m/z 280 (MþH).
–
–
Anal. calcd. for C15H10FN5: C, 64.51; H, 3.61; N, 25.08. Found: C,
64.70; H, 3.84; N, 24.88.
Procedure for the preparation of 5-phenyl-
[1,2,4]triazolo[4,3-c]quinazoline (6)
5-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
A mixture of compound 5 (R ¼ H) (0.45 g, 1.9 mmol) and formic
acid (30 mL) was heated at 1208C for 6 h. After removing the
excess formic acid under reduced pressure, the residue was
purified by silica gel column chromatography (V CH3OH/
CH2Cl2 ¼ 1:60) to get a white solid 6. Yield: 81%, m.p. 180–
1828C. 1H-NMR (CDCl3): d 7.59–7.63 (m, 3H, Ar–H), 7.74 (t, 1H,
J ¼ 7.5 Hz, Ar–H), 7.84–7.90 (m, 1H, Ar–H), 8.47 (s, 1H, triazole-H),
3-amine (8d)
Yield: 78%, m.p. 257–2588C. 1H-NMR (DMSO-d6): d 5.30 (s, 2H,
NH2), 7.41 (t, 2H, J ¼ 8.1 Hz, Ar–H), 7.64–7.75 (m, 2H, Ar–H),
7.80–7.84 (m, 3H, Ar–H), 8.32 (d, 1H, J ¼ 7.9 Hz, Ar–H). IR (KBr)
cmꢀ1: 1508, 1643 (C N), 3105, 3417 (N–H). MS m/z 280 (MþH).
–
–
Anal. calcd. for C15H10FN5: C, 64.51; H, 3.61; N, 25.08. Found: C,
64.66; H, 3.78; N, 24.89.
d 8.50–8.59 (m, 4H, Ar–H). IR (KBr) cmꢀ1: 1527, 1604 (C N).
–
–
MS m/z 247 (MþH). Anal. calcd. for C15H10N4: C, 73.16; H, 4.09;
N, 22.75. Found: C, 73.32; H, 4.27; N, 22.48.
5-(2-Chlorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8e)
Yield: 80%, m.p. 246–2488C. 1H-NMR (DMSO-d6, CDCl3): d 5.00
(s, 2H, NH2), 7.52–7.80 (m, 7H, Ar–H), 8.32 (d, 1H, J ¼ 8.0 Hz,
Procedure for the preparation of 5-phenyltetrazolo-
[1,5-c]quinazoline (7)
Ar–H). IR (KBr) cmꢀ1: 1532, 1662 (C N), 3025, 3426 (N-H). MS m/z
–
–
To a solution of compound 5 (R ¼ H) (0.5 g, 2.1 mmol) in 9 mL
30% HCl, 10% NaNO2 (0.15 g NaNO2 dissolved in 1.5 mL H2O)
solution was added dropwise below 58C. The mixture was stirred
for 12 h below 58C. The precipitate formed was filtered to get the
crude product, which was purified by silica gel column chroma-
tography (V CH3OH/CH2Cl2 ¼ 1:80) to get a white solid 7. Yield:
73%, m.p. 162–1638C. 1H-NMR (CDCl3): d 7.63–7.71 (m, 3H, Ar–H),
7.80–7.86 (m, 1H, Ar–H), 7.95–8.00 (m, 1H, Ar–H), 8.21(d, 1H,
296 (MþH). Anal. calcd. for C15H10ClN5: C, 60.92; H, 3.41; N, 23.68.
Found: C, 61.14; H, 3.50; N, 23.82.
5-(3-Chlorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8f)
Yield: 70%, m.p. 244–2468C. 1H-NMR (DMSO-d6, CDCl3): d 5.25
(s, 2H, NH2), 7.58–7.78 (m, 7H, Ar–H), 8.31 (d, 1H, J ¼ 7.4 Hz,
J ¼ 8.2 Hz, Ar–H), 8.64–8.73 (m, 3H, Ar–H). IR (KBr) cmꢀ1
:
Ar–H). IR (KBr) cmꢀ1: 1511, 1610 (C N), 3082, 3113 (N–H). MS m/z
–
–
–
1510, 1610 (C N). MS m/z 248 (MþH). Anal. calcd. for C14H9N5:
–
C, 68.01; H, 3.67; N, 28.32. Found: C, 67.86; H, 3.75; N, 28.53.
296 (MþH). Anal. calcd. for C15H10ClN5: C, 60.92; H, 3.41; N, 23.68.
Found: C, 61.11; H, 3.54; N, 23.79.
5-(4-Chlorophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8g)
Procedure for the preparation of compound 8
In a round-bottom flask, compound 5 (1.9 mmol) was dissolved
in dioxane (15 mL), then the solution was treated with Na2CO3
solution (0.21 g Na2CO3 dissolved in 6 mL H2O). Cyanogene
Yield: 78%, m.p. 266–2688C. 1H-NMR (DMSO-d6, CDCl3): d 5.17
(s, 2H, NH2), 7.52 (d, 2H, J ¼ 8.4 Hz, Ar–H), 7.56–7.65 (m, 2H,
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Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
Ar–H), 7.69 (d, 2H, J ¼ 8.4 Hz, Ar–H), 7.74–7.77 (m, 1H, Ar–H),
Ar–H), 8.39–8.65 (m, 3H, Ar–H). IR (KBr) cmꢀ1: 1534, 1667
8.33 (d, 1H, J ¼ 7.3 Hz, Ar–H). IR (KBr) cmꢀ1: 1492, 1643 (C N),
(C N), 3028, 3423 (N–H). MS m/z 307 (MþH). Anal. calcd. for
–
–
–
3093, 3410 (N–H). MS m/z 296 (MþH). Anal. calcd. for C15H10ClN5:
C, 60.92; H, 3.41; N, 23.68. Found: C, 61.11; H, 3.56; N, 23.87.
–
C15H10N6O2: C, 58.82; H, 3.29; N, 27.44. Found: C, 58.60; H,
3.33; N, 27.61.
5-(2-Bromophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
5-p-Tolyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amine (8o)
Yield: 75%, m.p. 250–2518C. 1H-NMR (DMSO-d6, CDCl3): d 2.41
(s, 3H, –CH3), 5.07 (s, 2H, NH2), 7.33 (d, 1H, J ¼ 8.2 Hz, Ar–H),
7.52 (d, 2H, J ¼ 9.0 Hz, Ar–H), 7.56–7.76 (m, 3H, Ar–H), 8.31
3-amine (8h)
Yield: 79%, m.p. 216–2188C. 1H-NMR (DMSO-d6, CDCl3): d 4.75
(s, 2H, NH2), 7.50 (t, 1H, J ¼ 7.5 Hz, Ar–H), 7.63–7.90 (m, 6H,
Ar–H), 8.49 (d, 1H, J ¼ 7.6 Hz, Ar–H). IR (KBr) cmꢀ1: 1529, 1668
(d, 1H, J ¼ 9.0 Hz, Ar–H). IR (KBr) cmꢀ1: 1534, 1671 (C N),
–
–
3037, 3432 (N–H). MS m/z 276 (MþH). Anal. calcd. for C16H13N5:
C, 69.80; H, 4.76; N, 25.44. Found: C, 69.99; H, 4.64; N, 25.32.
–
(C N), 3029, 3426 (N–H). MS m/z 340 (MþH). Anal. calcd. for
–
C15H10BrN5: C, 52.96; H, 2.96; N, 20.59. Found: C, 53.08; H,
3.11; N, 20.38.
5-(2-Methoxyphenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
5-(3-Bromophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8i)
3-amine (8p)
Yield: 72%, m.p. 230–2318C. 1H-NMR (DMSO-d6, CDCl3): d 3.79
(s, 3H, OCH3), 4.62 (s, 2H, NH2), 7.08–7.26 (m, 2H, Ar–H), 7.55–
7.72 (m, 4H, Ar–H), 7.90 (d, 1H, J ¼ 9.0 Hz, Ar–H), 8.50 (d, 1H,
Yield: 76%, m.p. 232–2348C. 1H-NMR (DMSO-d6): d 5.23 (s, 2H,
NH2), 7.45–7.89 (m, 7H, Ar–H), 8.32 (d, 1H, J ¼ 8.0 Hz, Ar–H).
J ¼ 8.2 Hz, Ar–H). IR (KBr) cmꢀ1: 1517, 1619 (C N), 3083, 3112
IR (KBr) cmꢀ1: 1531, 1669 (C N), 3039, 3433 (N–H). MS m/z 340
–
–
–
–
(N–H). MS m/z 292 (MþH). Anal. calcd. for C16H13N5O: C, 65.97; H,
(MþH). Anal. calcd. for C15H10BrN5: C, 52.96; H, 2.96; N, 20.59.
4.50; N, 24.04. Found: C, 66.18; H, 4.59; N, 23.87.
Found: C, 53.14; H, 3.08; N, 20.41.
5-(3-Methoxyphenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
5-(4-Bromophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8j)
3-amine (8q)
Yield: 73%, m.p. 238–2398C. 1H-NMR (DMSO-d6, CDCl3): d 3.82
(s, 3H, OCH3), 5.16 (s, 2H, NH2), 7.13–7.23 (m, 3H, Ar–H), 7.43–
7.69 (m, 3H, Ar–H), 7.76 (d, 1H, J ¼ 9.0 Hz, Ar–H), 8.31 (d, 1H,
Yield: 75%, m.p. 282–2848C. 1H-NMR (DMSO-d6, CDCl3): d 5.21
(s, 2H, NH2), 7.64–7.88 (m, 7H, Ar–H), 8.40 (d, 1H, J ¼ 7.3 Hz,
Ar–H). IR (KBr) cmꢀ1: 1513, 1642 (C N), 3113, 3418 (N–H). MS m/z
–
–
J ¼ 8.3 Hz, Ar–H). IR (KBr) cmꢀ1: 1539, 1670 (C N), 3039, 3433
–
–
340 (MþH). Anal. calcd. for C15H10BrN5: C, 52.96; H, 2.96; N, 20.59.
(N–H). MS m/z 292 (MþH). Anal. calcd. for C16H13N5O: C, 65.97; H,
Found: C, 53.17; H, 3.12; N, 20.40.
4.50; N, 24.04. Found: C, 66.14; H, 4.63; N, 23.82.
5-(2-(Trifluoromethyl)phenyl)-[1,2,4]triazolo-
[4,3-c]quinazolin-3-amine (8k)
5-(4-Methoxyphenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
Yield: 80%, m.p. 172–1748C. 1H-NMR (DMSO-d6, CDCl3): d 5.26
(s, 2H, NH2), 7.46–7.91 (m, 7H, Ar–H), 8.32 (d, 1H, J ¼ 7.6 Hz,
3-amine (8r)
Yield: 79%, m.p. 244–2458C. 1H-NMR (DMSO-d6,CDCl3): d 3.83
(s, 3H, OCH3), 5.02 (s, 2H, NH2), 7.01 (d, 2H, J ¼ 8.6 Hz, Ar–H),
7.54–7.58 (m, 4H, Ar–H), 7.75 (d, 1H, J ¼ 9.0 Hz, Ar–H), 8.33 (d,
Ar–H). IR (KBr) cmꢀ1: 1512, 1647 (C N), 3111, 3419 (N–H). MS m/z
–
–
330 (MþH). Anal. calcd. for C16H10F3N5: C, 58.36; H, 3.06; N, 21.27.
1H, J ¼ 8.6 Hz, Ar–H). IR (KBr) cmꢀ1: 1512, 1613 (C N), 3081,
–
–
3113 (N–H). MS m/z 292 (MþH). Anal. calcd. for C16H13N5O: C,
65.97; H, 4.50; N, 24.04. Found: C, 66.09; H, 4.41; N, 23.91.
Found: C, 58.59; H, 3.18; N, 21.04.
5-(3-(Trifluoromethyl)phenyl)-[1,2,4]triazolo-
[4,3-c]quinazolin-3-amine (8l)
Procedure for the preparation of 5-phenyl-
[1,2,4]triazolo[4,3-c]quinazolin-3-ol (9)
Yield: 73%, m.p. 174–1768C. 1H-NMR (DMSO-d6, CDCl3): d 5.34
(s, 2H, NH2), 7.68–8.05 (m, 7H, Ar–H), 8.44 (d, 1H, J ¼ 7.9 Hz,
To a tetrahydrofuran solution (8 mL) of compound 5 (R ¼ H)
(0.5 g, 2.1 mmol), carbonyl diimidazole (0.4 g, 2.5 mmol) was
added. The reaction mixture was heated at reflux for 8 h.
After removing the solvent under reduced pressure, the crude
product was purified by silica gel column chromatography (V
CH3OH/CH2Cl2 ¼ 1:20) to obtain a white solid. Yield: 44%, m.p.
248–2498C. 1H-NMR (CDCl3): d 7.49–7.56 (m, 4H, Ar–H), 7.78–7.87
(m, 2H, Ar–H), 8.28–8.36 (m, 3H, Ar–H), 11.99 (s, 1H, –OH). IR (KBr)
Ar–H). IR (KBr) cmꢀ1: 1530, 1668 (C N), 3029, 3427 (N–H). MS m/z
–
–
330 (MþH). Anal. calcd. for C16H10F3N5: C, 58.36; H, 3.06; N, 21.27.
Found: C, 58.62; H, 3.14; N, 21.07.
5-(4-(Trifluoromethyl)phenyl)-[1,2,4]triazolo-
[4,3-c]quinazolin-3-amine (8m)
1
Yield: 78%, m.p. 263–2668C. H-NMR (DMSO-d6, CDCl3): d 6.34 (s,
cmꢀ1: 1532, 1614 (C N). MS m/z 263 (MþH). Anal. calcd. for
–
2H, NH2), 7.65–7.85 (m, 4H, Ar–H), 7.98 (d, 1H, J ¼ 8.0 Hz, Ar–H),
–
C15H10N4O: C, 68.69; H, 3.84; N, 21.36. Found: C, 68.46; H,
3.95; N, 21.58.
8.25 (d, 1H, J ¼ 8.0 Hz, Ar–H), 8.78–8.82 (m, 2H, Ar–H). IR (KBr)
cmꢀ1: 1539, 1669 (C N), 3029, 3426 (N–H). MS m/z 330 (MþH).
–
–
Anal. calcd. for C16H10F3N5: C, 58.36; H, 3.06; N, 21.27. Found: C,
58.51; H, 3.21; N, 21.10.
Procedure for the preparation of 3-methyl-5-phenyl-
[1,2,4]triazolo[4,3-c]quinazoline (10)
A mixture of compound 5 (R ¼ H) (0.5 g, 2.1 mmol) and acetic
anhydride (5 mL) was heated at reflux for 4 h. After the com-
pletion of the reaction, the mixture was poured into 15 mL of
water, and then extracted with CH2Cl2. The CH2Cl2 layer was
5-(3-Nitrophenyl)-[1,2,4]triazolo[4,3-c]quinazolin-
3-amine (8n)
Yield: 71%, m.p. 238–2398C. 1H-NMR (DMSO-d6, CDCl3): d 5.37
(s, 2H, NH2), 7.67–7.86 (m, 4H, Ar–H), 8.17 (s, 1H, J ¼ 7.6 Hz,
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Arch. Pharm. Chem. Life Sci. 2013, 346, 119–126
Anticonvulsant Activity of 5-Phenyl-[1,2,4]triazolo[4,3-c]quinazolin-3-amines
125
dried over anhydrous MgSO4. Evaporation of the solvents gave a
crude product that was purified by silica gel column chroma-
tography (V CH3OH/CH2Cl2 ¼ 1:60) to get a white solid. Yield:
64%, m.p. 120–1228C. 1H-NMR (CDCl3): d 2.72 (s, 3H, ꢀCH3),
7.59–7.63 (m, 3H, Ar–H), 7.70 (t, 1H, J ¼ 7.5 Hz, Ar–H), 7.84
(t, 1H, J ¼ 7.5 Hz, Ar–H), 8.49–8.53 (m, 4H, Ar–H). IR (KBr)
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