Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives

Article abstract of DOI:10.1002/ardp.201100326

The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED₅₀ value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4h displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system. The anticonvulsant activities of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n) were evaluated. Most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. 6-(4-Chlorophenyl)-[1, 2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED₅₀ value of 23.7 mg/kg and PI value of 10.8. Copyright

Full text of DOI:10.1002/ardp.201100326

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
1
Full Paper
Synthesis and Anticonvulsant Activities of Some
Triazolothiadiazole Derivatives
Xian-Qing Deng1, Zheng-Qi Dong2, Ming-Xia Song1, Bing Shu1, Shi-Ben Wang1,
and Zhe-Shan Quan1
1 College of Pharmacy, Yanbian University, Yanji, Jilin, China
2 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical
College, Beijing, China
The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a–4x) and their partially dehydrogenated products
5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a–5n). The bioevaluation
demonstrated that most compounds in the series of 4a–4x exhibited potent anticonvulsant
activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable
ED50 value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against
seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-
induced seizure tests suggested that compound 4h displayed broad-spectrum activity in several
models, and it may exert its anticonvulsant activity through affecting the GABAergic system.
Keywords: Anticonvulsant / Maximal electroshock / Pentylenetetrazole / Synthesis / Triazolothiadiazole
Received: September 18, 2011; Revised: February 20, 2012; Accepted: February 21, 2012
DOI 10.1002/ardp.201100326
Introduction
Moreover, the chemistry of 1,2,4-triazoles and their fused
heterocyclic derivatives has received considerable attention
owing to their synthetic and biological importance. In our
previous study, a series of triazolothiadiazines (Fig. 1, I) were
found to possess good anticonvulsant activity [19]. Among
these compounds, 6-(4-chlorophenyl)-7H-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazine was the most promising one with an
ED50 value of 40.9 mg/kg and a PI value of 6.5 in the maximal
electroshock test (MES).
Epilepsy, one of the most frequent neurological afflictions in
men characterized by excessive temporary neuronal discharges
resulting in uncontrolled convulsion, inflicts more than 2
million Americans and 60 million people worldwide [1, 2].
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) [3, 4]. Moreover, many AEDs have serious side
effects [5–10], and lifelong medication may be required.
Toxicity, intolerance, and lack of efficacy are the limitations
of the current AEDs. Therefore, the continued search for safer
and more effective new AEDs is necessary.
Based on the above results and in continuation of our
efforts directed toward the search for new heterocyclic com-
pounds with anticonvulsant activities, a series of triazolo-
thiadiazole derivatives (Fig. 1, II) were designed and
synthesized in this study. Compounds II, the ring contraction
analogues of compounds I through removal of a CH2 in the
compounds I, were anticipated to possess a better anticon-
vulsant activity. For further structure–activity relationship
(SAR) establishment, another series of compounds 5a–5n, the
dehydrogenated products of compounds II, were also pre-
pared. The structures of all the target compounds were
characterized. Anticonvulsant activity and neurotoxicity
were also evaluated. For explaining the possible mechanism
of action, the most active compound 4h was tested in pentyl-
The 1,2,4-triazole nucleus has been incorporated into a wide
variety of therapeutically important agents, such as antimi-
crobial [11–13], antiviral agents [14], anti-HIV [15, 16], anticon-
vulsant [15, 16], and enzyme inhibition activities [17, 18].
Correspondence: Dr. Zhe-Shan Quan, College of Pharmacy, Yanbian
University, No. 977, Park road, Yanji, Jilin 133002, China.
E-mail: zsquan@ybu.edu.cn
Fax: þ86 433 2436020
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2
X.-Q. Deng et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
test. Their preliminary anticonvulsant activities were
obtained and are listed in Tables 1 and 2.
The initial anticonvulsant evaluation of 4a–4x indicated
that all the compounds in this series were effective in i.p. MES
screens except 4q and 4r, indicative of their ability to prevent
seizure spread. At the dose of 100 mg/kg, compounds 4a–4h,
4k, and 4u–4x showed complete protection, while 4j, 4l–4m,
4o–4p, and 4t showed protection in 1/3 or 2/3 of the tested
mice. Compounds 4a, 4d, 4g, and 4v exhibited protection in
1/3 of the tested mice at 30 mg/kg. And compounds 4c, 4h,
and 4w exhibited protection in 2/3 of the tested mice at
30 mg/kg. For the series of 5a–5n, only 5a, 5b, 5d, 5f, 5g,
and 5j displayed poor anticonvulsant activity at the dose of
300 mg/kg.
Figure 1. Structures of compounds I and II.
enetetrazole (PTZ), 3-mercaptopropionic acid (3-MP), and
bicuculline (BIC) induced seizure tests.
Results and discussion
In the neurotoxicity screen, compounds 4i, 4l, 4n–4s, and
5a–5n did not show any neurotoxicity in the maximum dose
administered (300 mg/kg). Compounds 4v–4x revealed neuro-
toxicity at the dose of 100 mg/kg. The rest of the compounds
(majority) exhibited certain neurotoxicity at the dose of
300 mg/kg.
Chemistry
Target compounds were prepared according to Scheme 1. The
key intermediate, 4-amino-4H-1,2,4-triazole-3-thiol (3) was
prepared from thiocarbonohydrazide according to the
literature [20]. The resulting 3 was further treated with
fatty acids or aromatic acids in polyphosphoric acid (PPA),
or aromatic aldehydes in DMF to obtain 6-substituted-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a–4x)
and 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazole derivatives (5a–5n), respectively. Structures of these
compounds were confirmed by IR, MS, 1H NMR, and
elementary analysis.
On the basis of the considerable anticonvulsant activity
suggested in phase I testing, compounds 4c, 4h, and 4w were
subjected to phase II trials for the 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 of the standard
drugs carbamazepine and valproate, are shown in Table 3.
The tested compounds showed a higher protective index (PI)
than both standard drugs although their ED50 values were
bigger than that of carbamazepine. Among the tested com-
pounds, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zole (4h) gave an ED50 value of 23.7 mg/kg and a TD50 value of
254.6 mg/kg, which resulted in a higher PI value that was
TD50/ED50 ¼ 10.8, when compared to carbamazepine (4.5)
and valproate (1.6).
Pharmacological evaluations
MES screening
The anticonvulsant activity and neurotoxicity of the synthes-
ized compounds were evaluated following the standard
procedures proposed by the NIH anticonvulsant drug devel-
opment (ADD) program. The initial evaluation (phase I)
included the maximal electroshock seizure (MES) and neuro-
toxicity (TOX).
In the present study, we have synthesized a series of tri-
azolothiadiazole derivatives 4a–4x, and part of their dehy-
drogenated products 5a–5n. The results of bioevaluation led
to an understanding of the SAR of these compounds. In the
first series (4a–4x), compounds 4a–4k, whose phenyl ring was
The compounds 4a–4x and 5a–5n were administrated
intraperitoneally (i.p.) into the mice using doses of 30, 100,
and 300 mg/kg and the observations were taken at the time
interval of 0.5 h. Neurotoxicity was measured by the rotarod
Scheme 1. The synthesis route of the target
compounds.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
Anticonvulsant Activities of Some Triazolothiadiazole Derivatives
3
Table 1. Phase I anticonvulsant screening of the compounds 4a–4x
Compounds
R
MESa) (mg/kg)
TOX (mg/kg)
100
300
100
30
300
30
c)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
H
2-F
3-F
4-F
2,6-2F
2-Cl
3-Cl
–
–
–
–
–
–
–
–
3/3b)
3/3
3/3
3/3
3/3
3/3
3/3
3/3
0/3
2/3
3/3
1/3
2/3
0/3
1/3
1/3
0/3
0/3
0/3
1/3
3/3
3/3
3/3
3/3
1/3
0/3
2/3
1/3
0/3
0/3
1/3
2/3
–
–
0/3
–
–
–
–
–
–
–
–
–
0/3
1/3
2/3
0/3
1/3
2/3
2/3
1/3
1/3
2/3
1/3
2/3
0/3
1/3
1/3
0/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
2/3
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
1/3
2/3
2/3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4-Cl
2,4-2Cl
2-Br
4-Br
2/3
3/3
–
2-NO2
3-NO2
4-NO2
2-OCH3
3-OCH3
4-OCH3
–C2H5
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
2/3
3/3
1/3
2/3
2/3
0/3
0/3
1/3
3/3
–
–
–
–
–
0/3
0/3
4t
4u
4v
4w
4x
–
–
–
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.
The figures n1/n2: the animals protected/the animals tested.
The dash (–): not tested.
b)
c)
substituted with F, Cl, or Br, exhibited more potent anticon-
vulsant activity than those substituted with NO2 and
methoxyl (4l–4q). Compounds 4r–4x were triazolothiadiazole
molecules substituted by alkyl chain. The length of the alkyl
chain appeared to have a direct impact on the anticonvulsant
activity of these derivatives. From compounds 4r–4w, as alkyl
chain length increased, the anti-MES activity gradually
increased with the compound 4w (with the n-heptyl substi-
tuted group) being the most active. The trend reversed, how-
ever, when the alkyl chain had more than seven carbon
atoms. Obviously, in this study the activity curve of the alkyl
chain substituded derivatives is bell-shaped with a maximum
activity peak. It was noteworthy that the dehydrogenation of
thiadiazole in the series 4a–4x caused a significant reduction
or the complete loss of activity (e.g., compounds 5a–5n). It
seems that the conjugation and planar construction of the
triazolothiadiazole play a fundamental role in anticonvul-
sant activity.
Chemical-induced seizure models
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, car-
bamazepine), which suggested that the tested compounds
may inhibit voltage-gated ion channels (particularly sodium
channels). To further investigate the effects of the anti-
convulsant activity in several different models and speculate
about the possible mechanism of anticonvulsant action,
compound 4h was tested against convulsions induced
by chemical substances, including PTZ, 3-MP, and BIC.
Compound 4h was administered to mice at 30 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 30 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 4h inhibited the
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4
X.-Q. Deng et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
Table 2. Phase I anticonvulsant screening of the compounds 5a–5n
Compounds
R
MESa) (mg/kg)
100
TOX (mg/kg)
300
30
300
100
30
c)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
H
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
2-OCH3
3-OCH3
4-OCH3
4-CH3
2/3
1/3
0/3
2/3
0/3
1/3
1/3
0/3
0/3
1/3
0/3
0/3
0/3
0/3
0/3b)
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
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
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.
The figures n1/n2: the animals protected/the animals tested.
The dash (–): not tested.
b)
c)
clonic seizures, tonic seizures and lethality induced by sc-PTZ
at the rates of 90%, 100%, and 100%, respectively (Table 4),
which revealed that compound 4h possessed excellent
activity against sc-PTZ at the low dose of 30 mg/kg.
Compound 4h exhibited high anticonvulsant activity in
the MES and sc-PTZ model which are most widely used in
the search for new AEDs, which suggested that it really
possesses a good anticonvulsant profile. PTZ has been
reported to produce seizures by inhibiting g-aminobutyric
acid (GABA) neurotransmission [21, 22]. GABA is the main
inhibitory neurotransmitter in the brain, and is widely impli-
cated in epilepsy. Inhibition of GABAergic neurotransmission
or activity has been shown to promote and facilitate seizures
[23], while enhancement of GABAergic neurotransmission is
known to inhibit or attenuate seizures. The findings of the
present study suggest that the newly synthesized compound
4h might inhibit or attenuate PTZ-induced seizures in mice
by enhancing GABAergic neurotransmission.
In the 3-MP induced seizure model, both carbamazepine
and 4h inhibited the tonic seizures completely, which revealed
their strong antagonistic activity against 3-MP induced seizure
(Table 4). 3-MP is the competitive inhibitor of the GABA
synthesis enzyme glutamate decarboxylase (GAD), and it inhib-
its the synthesis of GABA resulting in the decrease of GABA
level in the brain [24]. Compound 4h showed antagonism to 3-
MP 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
4h inhibited tonic seizures completely. Carbamazepine showed
inhibition of clonic and tonic seizures and death at rates of 0,
100, and 80%, respectively. Compound 4h showed inhibition of
clonic and tonic seizures and death at rates of 50, 100, and 90%,
respectively (Table 4). BIC is a competitive antagonist of GABAA
receptor. BIC produces convulsions through its antagonism
of the GABAA receptor [25]. As compound 4h inhibited the
seizures induced by BIC, it likely exerts anticonvulsant activity
at least partially through GABAA-mediated mechanisms.
The results of the above chemical-induced seizure models
revealed that compound 4h is a broad-spectrum anticonvul-
sant and that it likely exerts its anticonvulsant activity
through affecting the GABAergic system.
Table 3. Phase II quantitative anticonvulsant data in mice
a)
b)
TD50
Compd.
ED50
PI
(TD50/ED50
)
4c
4h
4w
38.0 (33.0–43.9) 264.1 (288.9–304.6)
23.7 (20.5–27.3) 254.6 (218.8–296.3)
24.6 (21.5–28.1) 122.2 (105.0–142.2)
6.9
10.8
5.0
Carbamazepine 9.8 (8.9–10.8)
272.4 (247–338)
44.0 (40.2–48.1)
426.1 (369–450)
4.5
1.6
Valproate
a)
The dose measured in mg/kg.
Minimal neurotoxicity was determined by the rotarod test
30 min after the tested compounds were administrated.
b)
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
Anticonvulsant Activities of Some Triazolothiadiazole Derivatives
5
Table 4. Effects of compound 4h on chemically induced seizures in mice
Chemical substances
Pentylenetetrazol
3-Mercaptopropionic acid
Bicuculline
Compound
Doses
(mg/kg)
Test time
(h)
Clonic seizures
(%)
Tonic seizures
(%)
Lethality
(%)
DMSO
Carbamazepine
4h
DMSO
Carbamazepine
4h
DMSO
Carbamazepine
4h
–
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
100
100
10
100
100
100
100
100
50
100
0
0
100
0
0
100
0
0
100
0
0
100
0
0
100
20
10
30
30
–
30
30
–
30
30
1,2,4-triazole-3-thiol (3) (4 mmol) was added portionwise. The
reaction mixture was heated at 100–1408C for 4–8 h with stir-
ring, then cooled, and poured into ice-cold 10% aqueous sodium
carbonate. The solid product was collected, washed with water,
and dried to give compounds 4a–4x which were purified by silica
gel column chromatography.
Conclusions
In summary, the present studies revealed that a number of
triazolothiadiazole derivatives were effective in the MES
screens. Especially compound 4h showed the most activity
in these compounds and it possessed higher safety than the
marketed drugs carbamazepine and valproate with an ED50
value of 23.7 mg/kg and a PI (TD50/ED50) of 10.8. In addition,
compound 4h demonstrated antagonistic activity against
seizures induced by PTZ, 3-MP, and BIC. These results
suggested that compound 4h is a broad-spectrum anti-
convulsant and it likely exerts its anticonvulsant activity
through GABA-mediated mechanisms, such as affecting
GABAergic neurotransmission or the agonizing GABAA
receptor in the brain.
General procedure for preparation of compounds 5a–5n
An equimolecular mixture of compound 3 (3 mmol) and aro-
matic aldehydes (3 mmol), dry DMF (5 mL) and a catalytic
amount of triethyl benzyl ammonium chloride (10 mg) was
taken in to a round flask. The mixture was refluxed for about
5–8 h. After cooling, the mixture was poured into ice-water with
stirring. The precipitate was filtered, washed with water, dried,
and recrystallized from ethanol.
6-Phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4a
Mp 178–1808C; yield 48%. 1H NMR (CDCl3, 300 MHz), d 7.53–7.91
(m, 5H, Ar–H), 8.98 (s, 1H, triazole-H), IR (KBr) cmꢀ1: 1610–1580
Experimental
–
(N C). MS m/z 203 (MþH). Anal. Calcd. for C H N S: C, 53.45;
–
H, 2.99; N, 27.70. Found: C, 53.19; H, 2.76; N, 27.96.
9
6 4
Chemistry
Melting points were determined in open capillary tubes and were
uncorrected. IR spectra were recorded (in KBr) on IRPrestige-21.
1H NMR spectra were measured on an AV-300 (Bruker,
Switzerland), and all chemical shifts were given in ppm relative
to tetramethylsilane. Mass spectra were measured on an AXIMA
CFR Plus MALDI-TOF (Shimadzu, Japan). Elemental analyses were
performed on a 204Q CHN (Perkin Elmer, USA). The chemicals
were purchased from Aldrich Chemical Corporation.
6-(2-Fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4b
Mp 140–1428C; yield 55%. 1H NMR (CDCl3, 300 MHz), d 7.23–7.39
(m, 2H, Ar–H), 7.35–7.64 (m, 1H, Ar–H), 8.12–8.18 (m, 1H, Ar–H),
9.01 (s, 1H, triazole-H). IR (KBr) cmꢀ1: 1612–1581 (N C). MS m/z
–
–
221 (MþH). Anal. Calcd. for C9H5FN4S: C, 49.08; H, 2.29; N, 25.44.
Found: C, 49.25; H, 2.13; N, 25.67.
6-(3-Fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4c
The synthesis of 4-amino-4H-1,2,4-triazole-3-thiol 3
Thiocarbonohydrazide (2) 1.06 g (0.01 mol) and 20 mL formic
acids were refluxed for 40 min. After removing the excess formic
acid under reduced pressure, the residual mixture was purified
by silica gel column chromatography (dichloromethane/
methanol ¼ 60:1) to afford compound 3. Mp 155–1578C,
yield ¼ 37%. 1H NMR (CDCl3 300 MHz) d 5.68 (s, 2H, NH2), 8.45
(s, 1H, CH), 13.64 (s, 1H, SH); MS m/z 117 (MþH).
Mp 138–1408C; yield 59%. 1H NMR (CDCl3, 300 MHz), d 7.27–7.35
(m, 2H, Ar–H), 7.51–7.59 (m, 2H, Ar–H), 9.01 (s, 1H, triazole-H).
IR (KBr) cmꢀ1: 1608–1576 (N C). MS m/z 221 (MþH). Anal. Calcd.
–
–
for C9H5FN4S: C, 49.08; H, 2.29; N, 25.44. Found: C, 49.29; H, 2.08;
N, 25.62.
6-(4-Fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4d
Mp 198–2008C; yield 60%. 1H NMR (CDCl3, 300 MHz), d 7.25
(d, 2H, J ¼ 8.4 Hz, Ar–H), 7.90 (d, 2H, J ¼ 8.4 Hz, Ar–H), 8.96
General procedure for preparation of compounds 4a–4x
A mixture of aromatic acids or fatty acid (8 mmol) and PPA
(10 mL) was heated to 808C with stirring, then 4-amino-4H-
(s, 1H, triazole-H). IR (KBr) cmꢀ1: 1604–1577 (N C). MS m/z 221
–
–
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

6
X.-Q. Deng et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
(MþH). Anal. Calcd. for C9H5FN4S: C, 49.08; H, 2.29; N, 25.44.
6-(2-Nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4l
Mp 148–1508C; yield 61%. 1H NMR(CDCl3, 300 MHz), d 7.82–7.85
(m, 2H, Ar–H), 8.12–8.17 (m, 2H, Ar–H), 8.98 (s, 1H, triazole-H).
Found: C, 49.33; H, 2.07; N, 25.70.
IR (KBr) cmꢀ1: 1592–1579 (N C). MS m/z 248 (MþH). Anal. Calcd.
–
6-(2,6-Difluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4e
–
for C9H5N5O2S: C, 43.72; H, 2.04; N, 28.33. Found: C, 43.57;
H, 2.12; N, 28.17.
Mp 148–1508C; yield 60%. 1H NMR (CDCl3, 300 MHz), d 7.14–7.19
(m, 2H, Ar–H), 7.55–7.65 (m, 1H, Ar–H), 9.05 (s, 1H, triazole-H).
IR (KBr) cmꢀ1: 1622–1584 (N C). MS m/z 239 (MþH). Anal. Calcd.
6-(3-Nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
–
–
for C10H7FN4S: C, 51.27; H, 3.01; N, 23.92. Found: C, 51.45; H, 3.16;
N, 23.64.
4m
Mp 194–1968C; yield 62%. 1H NMR (CDCl3, 300 MHz), d 7.78–7.84
(m, 1H, Ar–H), 8.83–8.87 (m, 1H, Ar–H), 8.46–8.49 (m, 1H, Ar–H),
8.77 (s, 1H, Ar–H), 9.03 (s, 1H, triazole-H). IR (KBr) cmꢀ1: 1581–
6-(2-Chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4f
–
1574 (N C). MS m/z 248 (MþH). Anal. Calcd. for C H N O S: C,
–
43.72; H, 2.04; N, 28.33. Found: C, 43.50; H, 2.16; N, 28.11.
9
5 5 2
Mp 146–1498C; yield 49%. 1H NMR (CDCl3, 300 MHz), d 7.27–
7.61(m, 3H, Ar–H), 8.00–8.03 (m, 1H, Ar–H), 9.01 (s, 1H, triazole-
H). IR (KBr) cmꢀ1: 1589–1572 (N C). MS m/z 237 (MþH). Anal.
–
–
Calcd. for C9H5ClN4S: C, 45.67; H, 2.13; N, 23.67. Found: C, 45.84;
H, 2.02; N, 23.88.
6-(4-Nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4n
Mp 188–1908C; yield 64%. 1H NMR (CDCl3, 300 MHz), d 8.11
(d, 2H, J ¼ 8.9 Hz, Ar–H), 8.44 (d, 2H, J ¼ 8.9 Hz, Ar–H), 9.04
(s, 1H, triazole-H). IR (KBr) cmꢀ1: 1584–1569 (N C). MS m/z 248
–
6-(3-Chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4g
–
(MþH). Anal. Calcd. for C9H5N5O2S: C, 43.72; H, 2.04; N, 28.33.
Found: C, 43.56; H, 2.08; N, 28.20.
Mp 136–1388C; yield 48%. 1H NMR (CDCl3, 300 MHz), d 7.43–7.51
(m, 2H, Ar–H), 7.76 (s, 1H, Ar–H), 7.92–8.10 (m, 1H, Ar–H), 9.04
(s, 1H, triazole-H) IR (KBr) cmꢀ1: 1571–1569 (N C). MS m/z 237
–
–
(MþH). Anal. Calcd. for C9H5ClN4S: C, 45.67; H, 2.13; N, 23.67.
Found: C, 45.90; H, 2.05; N, 23.93.
6-(2-Methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4o
Mp 198–2018C; yield 45%. 1H NMR (CDCl3, 300 MHz), d 4.06 (s, 3H,
–OCH3), 7.07–7.17 (m, 2H, Ar–H), 7.53–7.59 (m, 1H, Ar–H), 8.20–
8.23 (m, 1H, Ar–H), 8.93 (s, 1H, triazole-H). IR (KBr) cmꢀ1: 1631–
6-(4-Chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4h
–
1575 (N C). MS m/z 233 (MþH). Anal. Calcd. for C10H8N4OS:
–
C, 51.71; H, 3.47; N, 24.12. Found: C, 51.97; H, 3.30; N, 23.89.
Mp 198–2018C; yield 48%. 1H NMR (CDCl3, 300 MHz), d 7.54
(d, 2H, J ¼ 6.6 Hz, Ar–H), 7.83 (d, 2H, J ¼ 6.6 Hz, Ar–H), 8.97
(s, 1H, triazole-H). IR (KBr) cmꢀ1: 1581–1574 (N C). MS m/z 237
–
–
(MþH). Anal. Calcd. for C9H5ClN4S: C, 45.67; H, 2.13; N, 23.67.
Found: C, 45.95; H, 2.06; N, 23.90.
6-(3-Methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4p
Mp 138–1408C; yield 56%. 1H NMR (CDCl3, 300 MHz), d 3.97 (s, 3H,
–OCH3), 7.12–7.16 (m, 1H, Ar–H), 7.41–7.49 (m, 3H, Ar–H), 8.95
(s, 1H, triazole-H). IR (KBr) cmꢀ1: 1628–1573 (N C). MS m/z 233
6-(2,4-Dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4i
–
–
(MþH). Anal. Calcd. for C10H8N4OS: C, 51.71; H, 3.47; N, 24.12.
Found: C, 51.88; H, 3.25; N, 23.86.
Mp 212–2148C; yield 60%. 1H NMR (CDCl3, 300 MHz), d 7.53–7.91
(m, 2H, Ar–H), 8.06–8.10 (m, 1H, Ar–H), 9.03 (s, 1H, triazole-H).
IR (KBr) cmꢀ1: 1594–1586 (N C). MS m/z 271 (MþH). Anal. Calcd.
–
–
for C9H4Cl2N4S: C, 39.87; H, 1.49; N, 20.66. Found: C, 39.63;
H, 1.35; N, 20.89.
6-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4q
Mp 180–1828C; yield 57%. 1H NMR (CDCl3, 300 MHz), d 3.91 (s, 3H,
–OCH3), 7.03 (d, 2H, J ¼ 8.5 Hz, Ar–H), 7.81 (d, 2H, J ¼ 8.5 Hz,
Ar–H), 8.91 (s, 1H, triazole-H). IR (KBr) cmꢀ1: 1634–1564 (N C). MS
–
6-(2-Bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4j
–
m/z 233 (MþH). Anal. Calcd. for C10H8N4OS: C, 51.71; H, 3.47;
N, 24.12. Found: C, 51.89; H, 3.51; N, 23.85.
Mp 158–1608C; yield 48%. 1H NMR (CDCl3, 300 MHz), d 7.43–7.55
(m, 2H, Ar–H), 7.77–7.88 (m, 2H, Ar–H), 9.01 (s, 1H, triazole-H).
IR (KBr) cmꢀ1: 1586–1570 (N C). MS m/z 281 (MþH). Anal. Calcd.
–
–
for C9H5BrN4S: C, 38.45; H, 1.79; N, 19.93. Found: C, 38.74;
H, 1.83; N, 19.98.
6-Ethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4r
Mp 80–828C; yield 75%. 1H NMR (CDCl3, 300 MHz), d 1.46 (t, 3H,
J ¼ 7.5 Hz, –CH3), 3.06 (q, 2H, J ¼ 7.5 Hz, –CH2–), 8.87 (s, 1H,
triazole-H). IR (KBr) cmꢀ1: 1628–1526 (N C). MS m/z 155 (MþH).
–
–
Anal. Calcd. for C5H6N4S: C, 38.95; H, 3.92; N, 36.34. Found: C,
39.17; H, 3.76; N, 36.59.
6-(4-Bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
4k
Mp 200–2038C; yield 43%. 1H NMR (CDCl3, 300 MHz), d 7.70
(d, 2H, J ¼ 6.6 Hz, Ar–H), 7.76 (d, 2H, J ¼ 6.6 Hz, Ar–H), 8.96
6-Propyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4s
Mp 43–448C; yield 78%. 1H NMR (CDCl3, 300 MHz), d 1.08 (t, 3H,
J ¼ 7.4 Hz, –CH3), 1.82–1.94 (m, 2H, –CH2–), 2.98 (q, 2H,
(s, 1H, triazole-H). IR (KBr) cmꢀ1: 1582–1569 (N C). MS m/z 281
–
–
(MþH). Anal. Calcd. for C9H5BrN4S: C, 38.45; H, 1.79; N, 19.93.
Found: C, 38.70; H, 1.91; N, 20.04.
J ¼ 7.5 Hz, –CH2–), 8.86 (s, 1H, triazole-H). IR (KBr) cmꢀ1
:
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
Anticonvulsant Activities of Some Triazolothiadiazole Derivatives
7
–
1624–1529 (N C). MS m/z 169 (MþH). Anal. Calcd. for C H N S: C,
–
42.84; H, 4.79; N, 33.31. Found: C, 42.56; H, 4.87; N, 33.58.
6
8 4
6-(3-Fluorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5c
Mp 164–1668C; yield 83%. 1H NMR (CDCl3, 300 MHz), d 7.34–7.39
(m, 1H, Ar–H), 7.67–7.75 (m, 2H, Ar–H), 8.05–8.09 (m, 1H, Ar–H),
8.06 (s, 1H, S–CH), 10.52 (s, 1H, triazole-H), 11.22 (s, 1H, NH).
6-Butyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4t
Mp 78–808C; yield 86%. 1H NMR (CDCl3, 300 MHz), d 0.98 (t, 3H,
J ¼ 7.0 Hz, –CH3), 1.44–1.53 (m, 2H, –CH2–), 1.76–1.86 (m, 2H,
–CH2–), 2.99 (t, 2H, J ¼ 7.6 Hz, –CH2–), 8.84 (s, 1H, triazole-H).
IR (KBr) cmꢀ1: 1600–1558 (N C) MS m/z 223 (MþH). Anal. Calcd.
–
–
for C9H7FN4S: C, 48.64; H, 3.17; N, 25.21. Found: C, 48.90; H, 3.12;
N, 25.07.
IR (KBr) cmꢀ1: 1622–1530 (N C). MS m/z 183 (MþH). Anal. Calcd.
–
–
for C7H10N4S: C, 46.13; H, 5.53; N, 30.74. Found: C, 45.89; H, 5.41;
N, 30.97.
6-(4-Fluorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5d
Mp 172–1748C; yield 81%. 1H NMR (CDCl3, 300 MHz), d 7.18
(d, 2H, J ¼ 8.6 Hz, Ar–H), 7.68 (d, 2H, J ¼ 8.6 Hz, Ar–H), 8.07
(s, 1H, S–CH), 10.39 (s, 1H, triazole-H), 11.39 (s, 1H, NH).
6-Pentyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4u
Mp 58–608C; yield 69%. 1H NMR (CDCl3, 300 MHz), d 0.93 (t, 3H,
J ¼ 6.7 Hz, –CH3), 1.36–1.44 (m, 4H, –CH2–CH2–), 1.79–1.88
(m, 2H, –CH2–), 3.00 (t, 2H, J ¼ 7.6 Hz, –CH2–), 8.86 (s, 1H,
–
IR (KBr) cmꢀ1: 1599–1555 (N C). MS m/z 223 (MþH). Anal.
–
–
Calcd. for C9H7FN4S: C, 48.64; H, 3.17; N, 25.21. Found: C,
48.81; H, 3.21; N, 25.13.
triazole-H). IR (KBr) cmꢀ1
: 1621–1533 (N C). MS m/z 197
–
(MþH). Anal. Calcd. for C8H12N4S: C, 48.96; H, 6.16; N, 28.55.
Found: C, 49.21; H, 6.04; N, 28.48.
6-(2-Chlorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
6-Hexyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4v
[1,3,4]thiadiazole 5e
Mp 44–468C; yield 66%. 1H NMR (CDCl3, 300 MHz), d 0.88 (t, 3H,
J ¼ 6.8 Hz, –CH3), 1.29–1.45 (m, 6H, –(CH2)3–), 1.79–1.86 (m, 2H,
–CH2–), 2.98 (t, 2H, J ¼ 7.6 Hz, –CH2–), 8.83 (s, 1H, triazole-H).
Mp 190–1928C; yield 65%. 1H NMR (CDCl3, 300 MHz), d 7.34–7.41
(m, 1H, Ar–H), 7.46–7.48 (m, 2H, Ar–H), 8.09–8.13 (m, 1H, Ar–H),
8.16 (s, 1H, S–CH), 10.82 (s, 1H, triazole-H), 10.95 (s, 1H, NH).
IR (KBr) cmꢀ1: 1619–1535 (N C). MS m/z 211 (MþH). Anal. Calcd.
–
–
IR (KBr) cmꢀ1: 1593–1547 (N C). MS m/z 239 (MþH). Anal. Calcd.
–
–
for C9H7ClN4S: C, 45.29; H, 2.96; N, 23.47. Found: C, 45.53; H, 3.07;
N, 23.32.
for C9H14N4S: C, 51.40; H, 6.71; N, 26.64. Found: C, 51.27; H, 6.90;
N, 26.83.
6-Heptyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4w
6-(3-Chlorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
Mp 50–528C; yield 65%. 1H NMR (CDCl3, 300 MHz), d 0.88 (t, 3H,
J ¼ 6.8 Hz, –CH3), 1.26–1.45 (m, 8H, –(CH2)4–), 1.76–1.86 (m, 2H,
–CH2–), 2.98 (t, 2H, J ¼ 7.6 Hz, –CH2–), 8.85 (s, 1H, triazole-H).
[1,3,4]thiadiazole 5f
Mp 156–1588C; yield 65%. 1H NMR (CDCl3, 300 MHz), d 7.50–7.53
(m, 1H, Ar–H), 7.58–7.60 (m, 1H, Ar–H), 7.69–7.73 (m, 1H, Ar–H),
7.88–7.90 (m, 1H, Ar–H), 8.01 (s, 1H, S–CH), 10.52 (s, 1H, triazole-
IR (KBr) cmꢀ1: 1618–1539 (N C). MS m/z 225 (MþH). Anal. Calcd.
–
–
for C10H16N4S: C, 53.54; H, 7.19; N, 24.98. Found: C, 53.76; H, 7.14;
N, 24.73.
H), 11.21 (s, 1H, NH). IR (KBr) cmꢀ1: 1594–1544 (N C). MS m/z 239
–
–
(MþH). Anal. Calcd. for C9H7ClN4S: C, 45.29; H, 2.96; N, 23.47.
Found: C, 45.46; H, 3.11; N, 23.25.
6-Octyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 4x
Mp 48–508C; yield 70%. 1H NMR (CDCl3, 300 MHz), d 0.85–0.90
(t, 3H, J ¼ 6.9 Hz, –CH3), 1.28–1.44 (m, 10H, –(CH2)5–), 1.79–1.84
(m, 2H, –CH2–), 2.98 (t, 2H, J ¼ 7.6 Hz, –CH2–), 8.84 (s, 1H,
–
6-(4-Chlorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5g
Mp 204–2068C; yield 61%. 1H NMR (CDCl3, 300 MHz), d 7.46
(d, 2H, J ¼ 8.5 Hz, Ar–H), 7.81 (d, 2H, J ¼ 8.5 Hz, Ar–H), 8.06
(s, 1H, S–CH), 10.51 (s, 1H, triazole-H), 11.61 (s, 1H, NH).
triazole-H). IR (KBr) cmꢀ1
: 1616–1541 (N C). MS m/z 239
–
(MþH). Anal. Calcd. for C11H18N4S: C, 55.43; H, 7.61; N, 23.51.
Found: C, 55.69; H, 7.74; N, 23.28.
IR (KBr) cmꢀ1: 1593–1545 (N C). MS m/z 239 (MþH). Anal.
–
–
Calcd. for C9H7ClN4S: C, 45.29; H, 2.96; N, 23.47. Found: C,
45.60; H, 3.02; N, 23.21.
5,6-Dihydro-6-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
5a
Mp 156–1588C; yield 74%. 1H NMR (CDCl3, 300 MHz), d 7.46–7.56
(m, 3H, Ar–H), 7.85–7.88 (m, 2H, Ar–H), 8.09 (s, 1H, S–CH), 10.36
(s, 1H, triazole-H), 11.52 (s, 1H, NH). IR (KBr) cmꢀ1: 1597–1553
6-(2-Bromophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5h
Mp 178–1808C; yield 66%. 1H NMR (CDCl3, 300 MHz), d 7.32–7.44
(m, 2H, Ar–H), 7.65–7.69 (m, 1H, Ar–H), 8.10–8.14 (m, 1H, Ar–H),
8.15 (s, 1H, S–CH), 10.91 (s, 1H, triazole-H), 11.20 (s, 1H, NH).
–
(N C). MS m/z 205 (MþH). Anal. Calcd. for C H N S: C, 52.92; H,
–
3.95; N, 27.43. Found: C, 53.24; H, 4.08; N, 27.21.
9
8 4
IR (KBr) cmꢀ1: 1594–1549 (N C). MS m/z 283 (MþH). Anal. Calcd.
–
–
for C9H7BrN4S: C, 38.18; H, 2.49; N, 19.79. Found: C, 37.94;
H, 2.55; N, 19.97.
6-(2-Fluorophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5b
Mp 168–1708C; yield 79%. 1H NMR (CDCl3, 300 MHz), d 7.20–7.29
(m, 2H, Ar–H), 7.33–7.43 (m, 1H, Ar–H), 8.07–8.10 (m, 1H, Ar–H),
8.12 (s, 1H, S–CH), 10.54 (s, 1H, triazole-H), 11.69 (s, 1H, NH).
6-(3-Bromophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5i
IR (KBr) cmꢀ1: 1603–1554 (N C). MS m/z 223 (MþH). Anal. Calcd.
–
–
for C9H7FN4S: C, 48.64; H, 3.17; N, 25.21. Found: C, 48.88; H, 3.04;
N, 25.02.
Mp 170–1728C; yield 68%. 1H NMR (CDCl3, 300 MHz), d 7.34–7.39
(m, 1H, Ar–H), 7.65–7.74 (m, 1H, Ar–H), 7.76–8.18 (m, 2H, Ar–H),
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

8
X.-Q. Deng et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–9
8.25 (s, 1H, S–CH), 10.53 (s, 1H, triazole-H), 11.04 (s, 1H, NH). IR
(KBr) cmꢀ1: 1594–1548 (N C). MS m/z 283 (MþH). Anal. Calcd.
levels of 30, 100, and 300 mg/kg for evaluating preliminarily the
anticonvulsant activity and neurotoxicity at 30 min interval after
administration. In the MES test, 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. The protection against
the spread of MES-induced seizures was defined as the abolition
of the hind limb tonic extension spasm. Anticonvulsant drug-
induced neurologic deficit was detected in mice by using the
rotarod test.
For determination of the median effective dose (ED50) and the
median toxic dose (TD50), the phase-II screening was prepared
(see Table 3). Groups of 10 mice were given a range of intra-
peritoneal doses of the tested compound until at least three
points were established in the range of 10–90% seizure protec-
tion or minimal observed neurotoxicity. From these data, the
respective ED50, TD50 values, and 95% confidence intervals were
calculated by probit analysis.
In chemically induced seizures (see Table 4), mice were given
doses of convulsant drugs that could induce seizures at least 97%
of animals. The doses used were: PTZ, 85 mg/kg; 3-mercaptopro-
pionic acid, 40 mg/kg; and BIC, 5.4 mg/kg. The test compounds
and standard AEDs were administered i.p. in a volume of
30 mg/kg to groups of 10 mice 30 min before injection of PTZ
(s.c.), 3-mercaptopropionic acid (i.p.) and BIC (s.c.). The mice
were placed in individual cages and observed for 30 min, the
number of clonic seizures, tonic seizures, and the lethality
were recorded [28, 29].
–
–
for C9H7BrN4S: C, 38.18; H, 2.49; N, 19.79. Found: C, 37.99; H,
2.61; N, 18.02.
6-(4-Bromophenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5j
Mp 200–2038C; yield 79%. 1H NMR (CDCl3, 300 MHz), d 7.63
(d, 2H, J ¼ 8.1 Hz, Ar–H), 7.73 (d, 2H, J ¼ 8.1 Hz, Ar–H), 8.25
(s, 1H, S–CH), 10.51 (s, 1H, triazole-H), 10.63 (s, 1H, NH).
IR (KBr) cmꢀ1: 1695–1544 (N C). MS m/z 283 (MþH). Anal.
–
–
Calcd. for C9H7BrN4S: C, 38.18; H, 2.49; N, 19.79. Found: C,
37.87; H, 2.63; N, 18.10.
5,6-Dihydro-6-(2-methoxyphenyl)-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5k
Mp 204–2068C; yield 72%. 1H NMR (CDCl3, 300 MHz), d 3.93 (s, 3H,
–OCH3), 6.96–7.07 (m, 2H, Ar–H), 7.48–8.05 (m, 2H, Ar–H), 8.58
(s, 1H, S–CH), 10.44 (s, 1H, triazole-H), 10.51 (s, 1H, NH). IR (KBr)
cmꢀ1: 1604–1551 (N C). MS m/z 235 (MþH). Anal. Calcd. for
–
–
C10H10N4OS: C, 51.27; H, 4.30; N, 23.91. Found: C, 51.48;
H, 4.16; N, 23.73.
5,6-Dihydro-6-(3-methoxyphenyl)-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazole 5l
Mp 192–1948C; yield 75%. 1H NMR (CDCl3, 300 MHz), d 3.88 (s, 3H,
–OCH3), 7.09–7.11 (m, 1H, Ar–H), 7.42–7.46 (m, 3H, Ar–H), 8.08
(s, 1H, S–CH), 10.38 (s, 1H, triazole-H), 10.94 (s, 1H, NH). IR (KBr)
This work was supported by the National Natural Science Foundation of
China (No. 81160382).
cmꢀ1: 1603–1549 (N C). MS m/z 235 (MþH). Anal. Calcd. for
–
–
C10H10N4OS: C, 51.27; H, 4.30; N, 23.91. Found: C, 51.50;
H, 4.19; N, 23.64.
The authors have declared no conflict of interest.
5,6-Dihydro-6-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-b]-
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[1,3,4]thiadiazole 5m
Mp 210–2128C; yield 70%. 1H NMR (CDCl3, 300 MHz), d 3.89 (s, 3H,
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Ar–H), 8.04 (s, 1H, S–CH), 9.90 (s, 1H, triazole-H), 10.18 (s, 1H, NH).
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