Synthesis and pharmacological evaluation of novel triazolo [4, 3-a] tetrahydrobenzo (b) thieno [3, 2-e] pyrimidine-5(4H)-ones

Article abstract of DOI:10.1002/jhet.1989

Triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (5a-m) were synthesized and characterized by spectral analysis. All 13 derivatives were evaluated for central nervous system (CNS) depressant and skeletal muscle relaxant activities in Swiss albino mice. All the activities were compared with diazepam as a standard drug at a dose of 5 mg/kg. The most active derivatives 5d, 5e, 5k, and 5l in CNS depressant and skeletal muscle relaxant activities were selected for anticonvulsant activity. The active derivatives were found to protect 100% mice at the dose of 6-11 mg/kg, where as standard diazepam protect the animal at a dose of 2.5 mg/kg.

Full text of DOI:10.1002/jhet.1989

Month 2014
Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3-a]
tetrahydrobenzo (b) thieno [3, 2-e] pyrimidine-5(4H)-ones
a
a
b
*
S. N. Thore, Sunil V. Gupta, and Kamalkishor G. Baheti
aDeogiri College, Padampura, Aurangabad 431005, India
bCharak College of Pharmacy and Research, Wagholi, Pune 412 207, India
*
E-mail: snthore@rediffmail.com
Received September 12, 2012
DOI 10.1002/jhet.1989
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
N
CH3
CH3
N
O
N
N
O
N
N
N
N
N
N
CF3
S
N
N
Zolpidem
Compd 5l
CL218872
Triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (5a–m) were synthesized and
characterized by spectral analysis. All 13 derivatives were evaluated for central nervous system (CNS)
depressant and skeletal muscle relaxant activities in Swiss albino mice. All the activities were compared
with diazepam as a standard drug at a dose of 5 mg/kg. The most active derivatives 5d, 5e, 5k, and 5l in
CNS depressant and skeletal muscle relaxant activities were selected for anticonvulsant activity. The active
derivatives were found to protect 100% mice at the dose of 6–11 mg/kg, where as standard diazepam protect
the animal at a dose of 2.5 mg/kg.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
an increase in GABA-induced chloride is modulated by
benzodiazepine and non-benzodiazepine agents. Among
the non-benzodiazepine agent’s zopiclone [6], CL 218872
and zolpidem [7] are found useful (Fig. 1).
Some non-benzodiazepine ligands are apparently selec-
tive for GABAA receptors, which have reduced sedation than
benzodiazepine. All these non benzodiazepine ligands were
found to contain common polyaza system. The condensed
triazole and 1, 2, 4-triazole are also found to contain polyaza
ring system.
The literature survey reveals that triazoles were reported
for analgesic, anti-inflammatory, anti-allergic, and CNS
depressant activities. Number of references [8–13] showed
that condensed 1, 2, 4-triazoles exhibited excellent CNS
depressant and anticonvulsant activities. Significant CNS
depressant activity was reported for triazoles, especially
triazoloquinazoline [14], triazoloquinazolinediones [15],
triazolopyrimidines [16], triazolothienopyrimidine [17],
1,3,4-thiadiazolotetrahydrobenzothienopyrimidine [18], and
1,3,4-thiadiazole-quinazoline [19] have given an impetus to
synthesize some non-benzodiazepine ligands (bioisosteric
triazolotetrahydrobenzo(b)thienopyrimidines), which are
devoid of typical benzodiazepine mediated side effect such
as physical dependence, amnesia, and over sedation.
As a part of our ongoing medicinal chemistry research
program, we have documented that 1-substituted triazolo
[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-
ones [20] exhibited good CNS depressant, skeletal muscle
Chronic anxiety and epilepsy are common and serious
disorder of central nervous system (CNS). Anxiety is even
more common with a lifetime prevalence of 5% for general-
ized anxiety disorder. Although the genesis and appearance
of anxiety differ from epilepsy but both can be treated by
modulation of GABAA receptor [1]. Central nervous system
(CNS) depressant agents are an important class of drugs,
which are useful in the treatment of anxiety and related
emotional disorders. Among the different classes of CNS
depressant agents, benzodiazepines have good activity and
well accepted by patients. They are acting through benzodi-
azepine receptors, which are adjacent to major inhibitory
neurotransmitter g-amino butyric acid (GABA) receptors in
the brain and controls excitability of many CNS pathways.
GABA exerts its physiological effects by binding to the
different receptor types in the neuronal membrane: GABAA,
GABAB, and GABAC receptors. The GABAB receptor
belongs to the G-protein coupled receptors super family,
whereas the GABAA [2] and GABAC [3] are ligand-gated
chloride ion channel complex. GABAA receptors are respon-
sible for the majority of neuronal inhibition in the mamma-
lian CNS and mediate the action of many pharmacological
useful agents viz. benzodiazepines, barbiturates, neuroactive
steroids, anesthetics, and convulsants [4,5]. At least two
classes of compounds have been identified by their ability
to modulate GABA neurotransmission by interacting with
receptor complex. GABA neurotransmission that leads to
© 2014 HeteroCorporation

S. N. Thore, S. V. Gupta, and K. G. Baheti
Vol 000
Figure 1. Structures of non-benzodiazepine ligands and most active compound (5I).
Scheme 1. Synthesis of hydrazino intermediate (4).
relaxant, and anticonvulsant activities. The present work is
an extension of our ongoing efforts towards the development
and identification of new molecules for better CNS activity.
In our previous study [20], we have reported the effect of
electron withdrawing group chlorine on the biological
activity. But as zolpidem possess the electron donating
group methyl substituent in the aromatic ring, we thought
to replace chloro group with methyl group in our targeted
structure with the motto to change the electronic character
of a molecule and study its effects on biological activity.
On this fact, we have synthesized a series of 13 novel
derivatives of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]
pyrimidine-5(4H)-ones. The synthesized compounds were
tested for CNS depressant, skeletal muscle relaxant, and anti-
convulsant activities.
compounds showed intense peaks at1675–1685 cmꢁ1 for
carbonyl (C═O) stretching. The formation of 4 was con-
firmed by the presence of NH and NH2 signals around
3340–3225 cmꢁ1 in the IR spectra. It also showed a peak
for carbonyl (C═O) at around 1685 cmꢁ1. The NMR spec-
trum of the compound 4 showed signals at d 5.0 (bs, 2H,
NHNH2), and 8.7 (bs, 1H, NHNH2). The formation of
cyclic product is indicated by the disappearance of
peaks due to NH and NH2 of the starting material at
3400–3200 cmꢁ1 in IR spectra of all the compounds (5a–m).
The NMR spectrum of (5a–m) showed the absence of NH
and NH2 signals. A two doublet signals at 7.25–7.60
integrating for aromatic protons were observed. The mass spec-
tra of the synthesized final compounds gave molecular ion peak
exactly at M + 1 indicated that the data are in agreement with
the predicted structures. The structures of these new com-
pounds were confirmed by elemental and spectral analysis.
RESULTS AND DISCUSSION
Chemistry.
The key intermediate 2-hydroxy-3-(4-
methylphenyl)-5,6,7,8-tetrahydrobenzo(b)thiophene[2,3-d]
pyrimidine-4(3H)-one (2) was prepared by refluxing 2-
amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo(b) thiophene
[21] (1) with solution of p-tolylisocyanate [22] at 90ꢀC
in dichloroethane followed by cyclization with potassium
hydroxide solution. The compound (2) on treatment with
mixture of phosphorus oxychloride and phosphoruspenta-
chloride yielded the 2-chloro-3-(4-methylphenyl)-5,6,7,
8-tetrahydrobenzo(b)thiophene[2,3-d] pyrimidine-4(3H)-
one (3) at refluxing condition. The chloro derivative (3)
on treatment with hydrazine hydrate in methanol yielded
3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo
(b)thiophene[2,3-d]pyrimidine-4(3H)–one (4) as shown
in Scheme 1. The title compounds (5a–j) were obtained in
fair to good yield through the cyclization of hydrazino
derivative (4) with one carbon donors such as triethyl
orthoformate, triethyl orthoacetate, propionic acid, butyric
acid, isobutyric acid, chloroacetyl chloride, cyanogens
bromide, methyl isothiocyanate and carbon disulphide at
reflux temperature [23–28].
Pharmacological activity. The title derivatives (5a–m)
were evaluated for CNS depressant activity and skeletal
muscle relaxant activity (Motor coordination) at a dose of
5 mg/kg in Swiss albino mice. The activity was compared
with diazepam as a standard drug. Of the various compounds
tested for CNS depressant and skeletal muscle relaxant
activities, the most active four derivatives 5d, 5e, 5k, and 5l
were evaluated for anticonvulsant activity at different dose
levels. The results of the various activities are presented in
Tables 1, 2, 3, 4, and 5.
Compounds (5k–m) were obtained by nucleophilic
displacement of chlorine of compound 5j with various
alicyclic amines such as pyrrolidine, piperidine, and
morpholine. The title compounds (5a–m) were synthesized
by the route depicted in Scheme 2. The IR spectra of these
All the derivatives were tested for CNS depressant
activity by photoactomer. The decrease in the locomotor
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3-a] tetrahydrobenzo
(b) thieno [3, 2-e] pyrimidine-5(4H)-ones
Scheme 2. Synthesis of target compounds (5a–m).
Table 1
CNS Depressant activity by Photoactometer (n = 6 animals; dose 5 mg/kg i.p.).
Compound
Photoactometer countsa
%CNS depressant activity
30 min after
60 min after
Prior(control)
Administration of test compound
After 30 min
After 60 min
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
Diazepam
96 ꢂ 1.74
110 ꢂ 1.78
112 ꢂ 1.83
115 ꢂ 1.77
123 ꢂ 1.67
114 ꢂ 1.73
118 ꢂ 1.74
138 ꢂ 1.69
107 ꢂ 1.70
135 ꢂ 1.76
120 ꢂ 1.75
111 ꢂ 1.68
125 ꢂ 1.71
102 ꢂ 1.60
25 ꢂ 1.28
31 ꢂ 1.44
30 ꢂ 1.44
22 ꢂ 1.23
22 ꢂ 1.44
30 ꢂ 1.20
32 ꢂ 1.40
42 ꢂ 1.48
37 ꢂ 1.22
34 ꢂ 1.47
17 ꢂ 1.15
14 ꢂ 1.11
30 ꢂ 1.34
14 ꢂ 1.21
20 ꢂ 1.28
19 ꢂ 1.25
19 ꢂ 1.28
15 ꢂ 1.17
14 ꢂ 1.24
25 ꢂ 1.24
21 ꢂ 1.26
35 ꢂ 1.32
12 ꢂ 1.13
25 ꢂ 1.25
12 ꢂ 1.12
10 ꢂ 1.10
21 ꢂ 1.30
10 ꢂ 1.17
73.95
71.81
73.21
80.86
82.11
73.68
72.88
69.56
65.42
74.81
85.83
87.38
76.00
86.27
79.16
82.72
83.03
86.95
88.61
78.07
82.20
74.63
70.09
81.48
90.00
90.99
83.20
90.19
CNS, central nervous system.
aEach score represents the means ꢂ SEM of six mice, significantly different from the control score at p < 0.05 (Student’s t-test).
activity indicates the CNS depressant activity. All com-
pounds showed the decrease in locomotor activity between
70.0 to 91.0% after 60 min, when compared with diazepam
as reported (Table 1). The four derivatives 5d, 5e, 5k, and
5l showed comparable CNS depressant activity at a dose of
5 mg/kg i. p. after 60 min of administration to that of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Thore, S. V. Gupta, and K. G. Baheti
Vol 000
standard drug diazepam (90.0%) at a dose of 5 mg/kg.
Compounds 5k and 5l were equipotent to diazepam in
decreasing % locomotor activity. All the compounds
except 5a, 5f, 5h, and 5i exhibited more than 80% decrease
in locomotor activity after 60 min. In a similar study using
swim pool test, the immobility time after administration of
the test compounds was compared with diazepam (Table 2).
Except for 5a, 5f, and 5i, other tested compounds were
found to exhibit potent CNS depressant activity as indi-
cated by increased immobility time.
compounds have also been calculated and found in the range
of 4.50 to 9.50 mg/kg, whereas that of diazepam showed the
ED50 1.0 (Table 5).
The pharmacological results indicated that the series
of compounds exhibited comparable CNS depressant
and skeletal muscle relaxant than anticonvulsant activities.
1-Propyl, isopropyl, pyrrolidinemethyl, piperidinemethyl,
and morpholinomethyl substituted compounds 5d, 5e, 5k,
5l, and 5m possessed better CNS activities as compared
The title derivatives were also tested for skeletal muscle
relaxant activity (Motor coordination) by rotarod method
(Table 3). In this model, the four derivatives 5d, 5e, 5k,
and 5l showed the better activity in the range from 101.0
to 107.0% when compared to diazepam (100%) at a dose
of 5 mg/kg. The other derivative showed the activity in
the range of 63.0 to 93.0% to that of standard drug. The
most active four derivatives 5d, 5e, 5k, and 5l among the
series were evaluated for anticonvulsant activity (Table 4).
The dose required for protecting the animal from
pentylenetetrazole (PTZ) induced clonic convulsions was
determined. All the four compounds offered good protection
to the animals from the PTZ induced clonic convulsions at
the dose levels of 6.0–11.0 mg/kg body weight, whereas
diazepam shown 100% protection at the dose of 2.5 mg/kg.
Again, the compound 5l exhibited the anticonvulsant activity
by protecting 100% animal at dose of 6.0 mg/kg body
weight. The ED50 values for anticonvulsant activity of four
Table 3
Skeletal muscle relaxant activity (Motor coordination) by Rotarod method
(n = 6 animals; dose 5 mg/kg, i.p.).
Mean number of
falls/min
Mean increase
in number of
falls/mina
% CNS
depressant
activity
Compound
(Control)a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
Diazepam
2.86 ꢂ 0.22
2.82 ꢂ 0.34
2.70 ꢂ 0.33
2.44 ꢂ 0.35
2.83 ꢂ 0.19
2.90 ꢂ 0.26
2.84 ꢂ 0.36
2.78 ꢂ 0.35
2.98 ꢂ 0.38
2.80 ꢂ 0.20
2.56 ꢂ 0.31
2.80 ꢂ 0.16
2.65 ꢂ 0.15
3.12 ꢂ 0.22
6.25 ꢂ 0.52
6.40 ꢂ 0.71
6.75 ꢂ 0.30
6.40 ꢂ 0.61
7.45 ꢂ 0.38
6.25 ꢂ 0.53
6.50 ꢂ 0.74
6.15 ꢂ 0.32
6.00 ꢂ 0.31
6.55 ꢂ 0.37
6.90 ꢂ 0.55
7.65 ꢂ 0.28
6.44 ꢂ 0.29
8.15 ꢂ 0.14
73.52
78.74
93.04
100.67
101.26
71.65
79.94
75.19
62.86
83.07
105.16
107.44
88.71
100.00
CNS, central nervous system.
Table 2
aEach value represents the means ꢂ SEM of six mice, significantly
different from the control value at p < 0.05 (Student’s t-test).
CNS study on triazolo[4, 3-a]tetrahydrobenzo(b) thieno[3, 2-e]
pyrimidine-5(4H)-one derivatives for CNS depressant by Forced Swim
Pool test.
Immobility timeb
Table 4
Anticonvulsant activity (n = 6 animals, orally).
Control
(24 h prior)
Post treatment
(60 min after)
Compounda
Dose
(mg/kg)
% of animal protected against PTZ
induced clonic convulsions
Compound
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
114.33 ꢂ 7.56
54.10 ꢂ 13.71
96.12 ꢂ 6.22
124.56 ꢂ 10.89
90.45 ꢂ 13.65
145.37 ꢂ 10.11
118 ꢂ 12.11
5d
9.0
10.0
11.0
8.0
9.0
10.0
5.0
6.0
7.0
4.0
5.0
33.33
83.33
100.00
33.33
66.66
100.00
16.66
83.33
100.00
16.66
66.66
100.00
16.66
50.00
83.33
100.00
63.56 ꢂ 12.44
120.45 ꢂ 11.55
65.67 ꢂ 7.98
190.34 ꢂ 10.67
70.65 ꢂ 8.76
5e
101.56 ꢂ 10.43
78.43 ꢂ 9.69
127.65 ꢂ 8.87
98.23 ꢂ 10.54
60.48 ꢂ 12.96
176.48 ꢂ 9.61
201.98 ꢂ 11.33
221.88 ꢂ 12.35
199.54 ꢂ 9.39
233.29 ꢂ 15.03
5k
49.54 ꢂ 12.22
133.49 ꢂ 8.34
125.41 ꢂ 10.22
134.77 ꢂ 11.65
105.20 ꢂ 8.76
120.44 ꢂ 14.29
5l
5m
Diazepama
6.0
0.5
1.0
2.0
Diazepam
CNS, central nervous system.
aThe compounds and diazepam were tested at a dose of 5 mg/kg (i p.).
Each group consisted of six mice.
2.5
bEach value represents the means ꢂ SEM of six mice, significantly
different from the control value at p < 0.05 (Student’s t-test).
CNS, central nervous system; PTZ, pentylenetetrazole.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3-a] tetrahydrobenzo
(b) thieno [3, 2-e] pyrimidine-5(4H)-ones
Table 5
4-methylphenylisocyanate in dichloroethane, a solution of
2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo(b)thiophene 1
(22.5 g, 0.1 mol) in dichloroethane (100 mL) was added
and refluxed for 3 h. Excess of solvent was removed under
reduced pressure, and the crude residue of N2-(3-
carbethoxy)-N1-(4-methylphenyl)-5,6,7,8-tetrahydrobenzo(b)
thieno-2-yl urea was cyclized with potassium hydroxide
solution (300 mL, 10%) for 3 h at reflux. The reaction
mixture was cooled and filtered; and filtrate was acidified
with dilute hydrochloric acid to yield compound (2).
The separated solid was filtered, washed with water,
dried, and recrystallized from ethanol. Yield: 22 g (71%);
Effective dose (ED50) protecting 50% population from pentylenetetrazole
(85 mg/kg, orally) induced clonic convulsions (n = 6 animals) in mice.
Compound
ED50 mg/kg
5d
5e
5k
5l
9.50
8.50
5.50
4.50
1.00
Diazepam
mp: 264–267ꢀC; IR (KBr): 3220 (OH), 1680 (C═O) cmꢁ1
MS (m/z): 313 (M + 1).
;
with remaining substituted compounds. Present study
explored that substitution of 1-chloromethyltriazole with
pyrrolidine and piperidine moiety leads to the development
of new chemical entities with potent CNS activity.
Synthesis of 2-chloro-3-(4-methylphenyl)-5, 6, 7, 8-tetrahydro-
benzo (b) thieno [2, 3-d] pyrimidin- 4(3H)-one (3). A mixture of
2-hydroxy-3-(4-methylphenyl)-5,6,7,8-tetrahydrobenzo(b)thieno-
[2,3-d] pyrimidin-4(3H)-one 2 (10g, 0.032 mol), phosphorus
oxychloride (100mL), and phosphorus pentachloride (5.0g)
was refluxed for 18 h at 90ꢀC. Excess of phosphorus oxychloride
was removed under reduced pressure. The residue obtained was
dissolved in ethyl acetate, and organic layer was washed with
saturated aqueous sodium bicarbonate solution and organic
layer concentrated under reduced pressure. A crude compound
obtained was purified by column chromatography through silica
gel using a 20% ethyl acetate in n-hexane as an eluent to yield
compound (3).
CONCLUSION
In the present investigation, 13 new triazolo[4,3-a]
tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones
derivatives were synthesized and characterized by spectral
data. They were screened for CNS depressant, skeletal
muscle relaxant, and anticonvulsant activities; and
compounds 5d, 5e, 5k, and 5l exhibited promising activi-
ties, which are comparable to the standard. The activity
was attributed to the presence of propyl, isopropyl,
pyrrolidinemethyl, and piperidinemethyl groups at position
1 on the condensed heterocyclic system containing
tetrahydrobenzothiophenepyrimidine fused with triazole
in the backbone structure of title compounds.
Yield: 6.2 g (59%); mp: 102–105ꢀC; IR (KBr): 1680 (C═O),
723 (C–Cl) cmꢁ1; MS (m/z): 331 (M + 1).
Synthesis of 2-hydrazino-3-(4-methylphenyl)-5, 6, 7, 8-
tetrahydrobenzo (b) thieno-[2, 3-d] pyrimidin-4(3H)-one (4).
A
mixture of 2-chloro-3-(4-methylphenyl)-5, 6, 7, 8-tetrahydrobenzo
(b) thieno-[2, 3-d] pyrimidin-4(3H)-one 3 (5 g, 0.015 mol) and
hydrazine hydrate (1.5 mL, 0.030 mol) in 50 mL of methanol
was refluxed for 15 min and cooled to get white solid. The
crude product was purified by recrystallization from ethanol.
Yield: 3.4 g (69%); mp:197–200ꢀC; IR (KBr): 3340, 3225
(NH2), 1685 (C═O), 1600 (NH) cmꢁ1 1H NMR (CDCl3,
;
EXPERIMENTAL
400 MHz, d ppm): 8.70 (bs, 1H, NH), 7.40 (d, J = 8.2 Hz, 2H,
Ar–H), 7.24 (d, J = 8.2Hz, 2H, Ar–H), 5.0 (bs, 2H, NH2),
2.91–2.96 (t, J= 6.0Hz, 2H, CH at C-8), 2.70–2.76 (m, 2H,
CH2 at C-5), 2.46 (s, 3H, CH3), 1.74–1.86 (m, 4H, 2CH2 at
C-6, C-7); MS (m/z):327 (M + 1).
Synthesis of 4-(4-methylphenyl)-6, 7, 8, 9-tetrahydro[1, 2, 4]
triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5(4H)-one
(5a). A mixture of 2-hydrazino-3-(4-methylphenyl)-5, 6, 7, 8-
Chemistry.
All chemicals and solvents were supplied by
Merck, S.D. Fine Chemical Limited, Mumbai. All the solvents
were distilled and dried before use. The reactions were
monitored with the help of thin-layer chromatography using
pre-coated aluminum sheets with GF254 silica gel, 0.2 mm layer
thickness (E. Merck). Melting points of the synthesized
compounds were recorded on the Veego (VMP-MP) melting
point apparatus. IR spectrum was acquired on a Shimadzu
Infrared Spectrometer (model FTIR-8400S, Japan).1H NMR
spectra were recorded on a Bruker Avance II (400 MHz,
Germany) spectrometer, and the chemical shifts are reported in
parts per million (d) downfield from tetramethylsilane as
internal standard. Electron ionization mass spectra were
tetrahydrobenzo (b) thieno-[2, 3-d] pyrimidin-4(3H)-one
4
(0.5 g, 0.0015 mol) and triethylorthoformate (10 mL) containing
one drop of hydrochloric acid was refluxed for 5 h. The reaction
mixture was cooled and separated solid was filtered, washed,
dried, and recrystallized from ethanol. Yiꢁel1d: 0.41 g (68%); mp:
230–233ꢀC; IR (KBr): 1690 (C═O) cm
;
1H NMR (CDCl3,
recorded on
a VG-250 spectrometer (VG Labs., Tritech
400 MHz, d ppm): 8.41 (s, 1H, CH), 7.42 (d, J = 8.3 Hz, 2H,
Ar–H), 7.25 (d, J = 8.3 Hz, 2H, Ar–H), 3.10 (t, 2H, J = 6.1 Hz,
CH2 at C-9), 2.79–2.81 (m, 2H,CH2 at C-6), 2.44 (s, 3H, CH3),
1.83–1.91 (m, 4H, 2CH2 at C-7, C-8); MS (m/z): 337 (M + 1);
Anal. Calcd. for C18H16N4OS: C, 64.27; H, 4.79; N, 16.65.
Found: C, 64.22; H, 4.75; N, 16.68.
England) with ionization energy maintained at 70 eV. Elemental
analyses were obtained with an acceptable range (ꢂ0.4%) using
a Perkin–Elmer 2400B CHN analyzer.
Synthesis of 2-hydroxy-3-(4-methylphenyl)-5, 6, 7, 8-tetrahydro-
benzo (b) thieno-[2, 3-d] pyrimidin-4(3H)-one (2). Solution of
bis (trichloromethyl) carbonate (29.6 g, 0.1 mol) in dichloroethane
(300 mL) heated at 70ꢀC then added dropwise solution of
4-methylphenylamine (10.7 g, 0.1 mol) in dichloroethane
(100 mL) and reflux for 2 h. To the resultant solution of
Synthesis of 4-(4-methylphenyl)-1-methyl-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b)thieno[3, 2e]pyrimidine-5(4H)-one
(5b).
Prepared from compound 4 (0.5 g, 0.0015 mol) and
triethylorthoacetate by using the same procedure as mentioned in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Thore, S. V. Gupta, and K. G. Baheti
Vol 000
5a. Yield: 0.45g (85%); mp: 276–279ꢀC; IR (KBr): 1684 (C═O)
0.001 mol) in methanol containing potassium hydroxide (0.06 g,
0.001 mol) was added dimethylsulfate (0.22 g, 0.001 mol) drop by
drop with stirring. The reaction mixture was allowed to stand at
room temperature for 10h and poured onto ice water mixture. The
solid separated was filtered, washed, and dried. It was
recrystallized from ethanol. Yield: 0.35g (85%); mp: 233–236ꢀC;
1
cmꢁ1; H NMR (CDCl3, 400MHz, d ppm): 7.41 (d, J = 8.3 Hz,
2H, Ar–H), 7.31 (d, J = 8.3 Hz, 2H, Ar–H), 3.12 (t, J = 6.0 Hz, 2H,
CH2 at C-9), 3.01 (s, 3H, CH3), 2.81–2.85 (m, 2H,CH2 at C-6),
2.33 (s, 3H, CH3), 1.87–1.91 (m, 4H, 2CH2 at C-7, C-8); MS (m/
z): 351 (M+ 1);Anal. Calcd. for C19H18N4OS: C, 65.12; H, 5.18;
N,15.99. Found: C, 65.10; H, 5.13; N, 15.97.
IR (KBr): 1682 (C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d
;
Synthesis of 1-ethyl-4-(4-methylphenyl)-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b)thieno[3, 2-e]pyrimidine-5(4H)-
one (5c). A mixture of compound 4 (0.5 g, 0.0015 mol) and
propionic acid (10 mL) was refluxed for 10 h. The reaction
mixture was poured on ice-water mixture and the separated
solid was filtered, washed with water, dried, and recrystallized
from ethanol. Yield: 0.30 g (55%); mp: 251–253ꢀC; IR (KBr):
ppm): 7.41 (d, J = 8.3 Hz, 2H, Ar–H), 7.32 (d, J = 8.3 Hz, 2H,
Ar–H), 3.14 (t, J = 6.0 Hz, 2H, CH2 at C-9), 2.83–2.88 (m, 2H,
CH2 at C-6), 2.62 (s, 3H, SCH3), 2.41 (s, 3H, CH3), 1.81–1.88
(m, 4H, 2CH2 at C-7, C-8); MS (m/z): 383 (M+ 1); Anal. Calcd.
for C19H18N4OS2: C, 59.66; H, 4.74; N,14.65. Found: C, 59.65;
H, 4.71; N, 14.64.
Synthesis of 4-(4-methylphenyl)-1-methylamino-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b) thieno[3,2-e]pyrimidine-
1
1675 (C═O) cmꢁ1; H NMR (CDCl3, 400 MHz, d ppm): 7.53
5(4H)-one (5h).
To the solution of compound 4 (0.5g,
(d, J = 8.3 Hz, 2H, Ar–H), 7.39 (d, J = 8.3 Hz, 2H, Ar–H), 2.97
(t, 2H, J = 6.1 Hz, CH2 at C-9), 2.82–2.86 (m, 2H, CH2 at C-
6), 2.82 (q, 2H, CH2), 2.35 (s, 3H, CH3), 1.84–189 (m, 4H,
2CH2 at C-7, C-8), 1.39 (t, J = 7.8 Hz, 3H, CH3); MS (m/z):
365 (M + 1); Anal. Calcd. for C20H20N4OS: C, 65.91; H, 5.53;
0.0015mol) in ethanol (20mL) was added methyl isothiocyanate
(0.11 g, 0.0015 mol). The mixture was refluxed on water bath for
6 h. Then it is cooled to room temperature, the separated solid was
filtered, washed with ethanol, dried, and recrystallized from
ethanol. Yield: 0.38g (69%); mp: 153–156ꢀC; IR (KBr): 3370
N, 15.37. Found: C, 65.88; H, 5.49; N, 15.35.
1
(NH), 1688 (C═O) cmꢁ1; H NMR (CDCl3, 400 MHz, d ppm):
Synthesis of 4-(4-methylphenyl)-1-propyl-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5(4H)-
one (5d ). Prepared from the solution of compound 4 (0.5 g,
0.0015 mol) and butyric acid (10 mL) by using the same
procedure as mentioned in 5c. Yield: 0.35 g (61%); mp: 210–213ꢀC;
IR: 1680 (C═O) cmꢁ1; 1H NMR (CDCl3, 400 MHz, d ppm): 7.51
(d, J = 8.2 Hz, 2H, Ar–H), 7.35 (d, J = 8.2 Hz, 2H, Ar–H), 3.00 (t,
J = 6.0 Hz, 2H, CH2 at C-9), 2.80–2.84 (m, 2H,CH2 at C-6), 2.58
(t, J = 6.6Hz, 2H, CH2), 2.37 (s, 3H, CH3),1.82–1.87 (m, 4H,
2CH2 at C-7, C-8) 1.71 (m, 2H, CH2), 1.10 (t, J = 7.3 Hz, 3H,
CH3); MS (m/z): 379 (M+ 1); Anal. Calcd. for C21H22N4OS: C,
66.64; H, 5.86; N, 14.80. Found: C, 66.64; H, 5.81; N, 14.79.
Synthesis of 1-isopropyl-4-(4-methylphenyl)-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5(4H)-
7.43 (d, J = 8.2 Hz, 2H, Ar–H), 7.35 (d, J = 8.2 Hz, 2H, Ar–H),
5.21 (bs, 1H, NH), 3.81 (d, J = 8.5Hz, 3H, CH3), 3.10
(t, J = 6.1 Hz, 2H, CH2 at C-9), 2.77–2.82 (m, 2H,CH2 at C-6),
2.42 (s, 3H, CH3), 1.84–1.89 (m, 4H, 2CH2 at C-7, C-8); MS
(m/z): 366 (M+ 1); Anal. Calcd. for C19H19N5OS: C, 62.45; H,
5.24; N, 19.16. Found: C, 62.43; H, 5.25; N, 19.14.
Synthesis of 1-amino-4-(4-methylphenyl)-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5(4H)-
one (5i).
Mixture of compound 4 (0.5 g, 0.0015 mol) and
cyanogen bromide (0.16 g, 0.0015 mol) in ethanol (20 mL)
was refluxed for 5 h. The solid was filtered, washed with
water, dried, and recrystallized from ethanol. Yield: 0.48 g
(91%); mp: 270–273ꢀC; IR (KBr): 3350, 3290 (NH), 1685
(C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d ppm): 7.45
;
one (5e).
Prepared from compound 4 (0.5 g, 0.0015 mol) and
(d, J = 8.2 Hz, 2H, Ar–H), 7.36 (d, J = 8.2 Hz, 2H, Ar–H),
4.40 (bs, 2H, NH2), 3.14 (t, J = 6.1 Hz, 2H, CH2 at C-9),
2.75–2.81 (m, 2H,CH2 at C-6), 2.42 (s, 3H, CH3), 1.89–1.95
(m, 4H, 2CH2 at C-7, C-8); MS (m/z): 352 (M + 1); Anal.
Calcd. for C18H17N5OS: C, 61.52; H, 4.88; N,19.93. Found:
C, 61.50; H, 4.87; N, 19.92.
Synthesis of 1-chloromethyl-4-(4-methylphenyl)-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5
(4H)-one (5j). Mixture of compound 4 (1.0 g, 0.003 mol) and
chloroacetyl chloride (0.346g, 0.003mol) in glacial acetic acid
isobutyric acid (10 mL) by using the same procedure as mentioned
in 5c. Yield: 0.40 g (67%); mp: 181–183ꢀC; IR (KBr): 1685
(C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d ppm): 7.55 (d,
;
J= 8.3 Hz, 2H, Ar–H), 7.42 (d, J= 8.3 Hz, 2H, Ar–H), 3.21–3.33
(m, 1H, CH), 3.10 (t, J =6.2Hz, 2H, CH2 at C-9), 2.83–2.87
(m, 2H,CH2 at C-6), 2.43 (s, 3H, CH3),1.81–1.86 (m, 4H, 2CH2
at C-7, C-8),1.23 (d, J= 7.8 Hz, 6H, CH3); MS (m/z): 379 (M + 1);
Anal. Calcd. for C21H22N4OS: C, 66.64; H, 5.86; N, 14.80.
Found: C, 66.60; H, 5.86; N, 14.78.
Synthesis of 1-mercapto-4-(4-methylphenyl)-6,7,8,9-tetrahydro
[1,2,4]triazolo[4,3-a]benzo(b) thieno [3,2-e]pyrimidine-5(4H)-one
(10 mL) was refluxed for 10h, and reaction mixture was poured
on ice water mixture and the separated solid was filtered, washed
with water, dried, and recrystallized from ethanol. Yield: 0.8g
(5f).
To the solution of compound 4 (0.5 g, 0.0015 mol) in
pyridine (10 mL) was added carbon disulfide (1 mL) at room
temperature. The reaction mixture was refluxed for 2 h and allowed
to cool to room temperature and poured on ice water. The solid
separated was filtered, washed with water, dried, and recrystallized
from ethanol. Yield: 0.46 g. (81%); mp: 279–281ꢀC; IR (KBr): 1695
1
(68%); mp: 178–181ꢀC; IR (KBr): 1688 (C═O) cmꢁ1; H NMR
(CDCl3, 400 MHz, d ppm): 7.44 (d, J = 8.2 Hz, 2H, Ar–H), 7.37
(d, J = 8.2 Hz, 2H, Ar–H), 5.24 (s, 2H, CH2), 3.12 (t, J = 6.2 Hz,
2H, CH2 at C-9), 2.72–2.78 (m, 2H,CH2 at C-6), 2.42 (s, 3H,
CH3), 1.79–1.84 (m, 4H, 2CH2 at C-7, C-8); MS (m/z): 385
(M+ 1); Anal. Calcd. for C19H17ClN4OS: C, 59.29; H, 4.45; N,
14.56. Found: C, 59.28; H, 4.42; N, 14.51.
Synthesis of 4-(4-methylphenyl)-1-pyrrolidin-1-ylmethyl-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5
(4H)-one (5k). Mixture of 1-chloromethyl-4-(4-methylphenyl)-
6,7,8,9-tetrahydro[1,2,4]triazolo[4,3-a]benzo(b)thieno[3, 2-e]
pyrimidine-5(4H)-one 5j (0.2 g 0.00052 mol), pyrrolidine
(0.18 g,0.0025 mol), and anhydrous potassium carbonate (100mg)
;
(C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d ppm): 7.36
(d, J= 8.2 Hz, 2H, Ar–H), 7.26 (d, J= 8.2 Hz, 2H, Ar–H) 4.67
(s, 1H, SH), 3.01 (t, J=6.1Hz, 2H, CH2 at C-9), 2.80–2.85 (m, 2H,
CH2 at C-6), 2.47 (s, 3H, CH3) 1.80–1.87 (m, 4H, 2CH2 at C-7,
C-8); MS (m/z): 369 (M + 1); Anal. Calcd. for C18H16N4OS2: C,
58.67; H, 4.38; N,15.20. Found: C, 58.65; H, 4.35; N, 15.18.
Synthesis of 1-methylsulfanyl-4-(4-methylphenyl)-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b) thieno[3,2-e]pyrimidine-
5(4H)-one (5g).
To the solution of compound 5f (0.4 g,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3-a] tetrahydrobenzo
(b) thieno [3, 2-e] pyrimidine-5(4H)-ones
in dioxane (10mL) was put in a round bottomed flask and refluxed
for 12h, cooled, and poured into ice water. The solid obtained was
filtered, washed with water, dried, and recrystallized from ethanol.
Yield: 0.12 g (57%); mp: 108–111ꢀC; IR (KBr): 1680 (C═O)
animals were kept into the photoactometer chamber, and the
counts were noted for 10 min after a 10 min rest in the
chamber. The same procedure was repeated after 50 min.
Decrease in the number of counts for each group was
calculated, and the % CNS depressant activity was
determined by the following formula.
1
cmꢁ1; H NMR (CDCl3, 400MHz, d ppm): 7.48 (d, J = 8.3 Hz,
2H, Ar–H), 7.39 (d, J = 8.3 Hz, 2H, Ar–H), 3.78 (s, 2H, CH2),
3.05 (t, J = 6.2 Hz, 2H, CH2 at C-9), 2.74–2.80 (m, 2H,CH2 at C-
6), 2.41 (s, 3H, CH3), 1.78–1.83 (m, 4H, 2CH2 at C-7, C-8),
1.41–1.61 (m, 4H,CH2-pyrrolidinyl), 1.10–1.25 (m, 4H, CH2-
pyrrolidinyl); MS (m/z): 420 (M+ 1); Anal. Calcd. for
C23H25N5OS: C, 65.85; H, 6.01; N, 16.69. Found: C, 65.83; H,
6.00; N, 16.68.
% CNS depressant activity
¼ ðcontrol reading ꢁ in count=control readingÞ ꢃ 100
The observations are tabulated in Table 1.
CNS depressant activity by forced swim pool method
[31]. CNS depressant activity of test compounds (5a–m)
Synthesis of 4-(4-methylphenyl)-1-piperidin-1-ylmethyl-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5
(4H)-one (5l). Prepared from compound 5j (0.2g, 0.00052 mol)
and piperidine (0.22 g, 0.0025 mol) by adapting same procedure as
mentioned in 5k. Yield: 0.10g (45%); mp: 121–124ꢀC; IR (KBr):
was measured in Albino mice using Forced Swimming
Test. Albino mice were placed in chamber (diameter
45cm, height 20 cm) containing water up to a height
of 15 cm at 25 ꢂ 2ꢀC for 15min. At 5 to 6 min later,
immobility reached a plateau, where the mice remained
immobile for approximately 80% of the time. After 15min
in the water, the mice were removed and allowed to dry in
a heated enclosure before being returned to their home
cages. They were again placed in the chamber after 24h,
and animals were administrated (5 mg/kg) the test
compound i.p. 30 min before the test session. The period of
immobility (passive floating without struggling, making
only those movements which are necessary to keep its head
above the surface of water) during the 5-min test period
was measured. The increase in immobility period indicates
that the compound exhibited CNS depressant activity. The
results are presented in Table 2.
1679 (C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d ppm): 7.34
;
(d, J= 8.2 Hz, 2H, Ar–H), 7.26 (d, J= 8.2 Hz, 2H, Ar–H), 3.84
(s, 2H, CH2), 3.13 (t, J= 6.2 Hz, 2H, CH2 at C-9), 2.72–2.78
(m, 2H,CH2 at C-6), 2.34 (s, 3H, CH3) 1.82–1.88 (m, 4H, 2CH2 at
C-7, C-8), 1.41–1.63 (m, 4H, CH2-piperidyl), 0.88–1.11 (m, 6H,
CH2-piperidyl); MS (m/z): 434 (M+1); Anal. Calcd. for
C24H27N5OS: C, 66.49; H, 6.28; N, 16.15. Found: C, 66.45; H,
6.26; N, 16.18.
Synthesis of 4-(4-methylphenyl)-1-morpholin-4-ylmethyl-6,7,8,9-
tetrahydro[1,2,4]triazolo[4,3-a]benzo(b)thieno[3,2-e]pyrimidine-5
(4H)-one (5m). Prepared from compound 5j (0.2 g, 0.00052 mol)
and morpholine (0.21 g, 0.0025 mol) by adapting same procedure as
mentioned in 5k. Yield: 0.14 g (64%); mp: 141–144ꢀC; IR (KBr):
1691 (C═O) cmꢁ1 1H NMR (CDCl3, 400 MHz, d ppm): 7.32
;
(d, J= 8.3 Hz, 2H, Ar–H), 7.22 (d, J= 8.3 Hz, 2H, Ar–H), 3.82
(s, 2H, CH2), 2.94 (t, 2H, J=6.1Hz, CH2 at C-9), 2.71–2.77
(m, 2H,CH2 at C-6), 2.33 (s, 3H, CH3),1.82–1.89 (m, 4H, 2CH2 at
C-7, C-8), 1.70–1.75 (m, 4H,CH2-morpholinyl), 1.20–1.41 (m, 4H,
CH2-morpholinyl); MS (m/z): 436 (M + 1); Anal. Calcd. for
C23H25N5O2S: C, 63.43; H, 5.79; N, 16.08. Found: C, 63.44; H,
5.77; N, 16.00.
Skeletal muscle relaxant activity (Motor coordination) by
rotarod method [32].
Motor coordination was tested
using rotarod apparatus. The mice weighing 25–30 g
were divided into group of six animals each. The mice
were trained to stay on an accelerating rotarod that
rotated at 6 rpm. The test compounds were suspended in
1% CMC solution in distilled water and administered at a
dose of 5 mg/kg i.p. of the body weight. Each group is
served as its control. One of the groups was treated with
diazepam as the standard at a dose of 5 mg/kg. After
30 min of administration of test compound, the animals
were placed on the rotarod apparatus and again the
number of falls per min was recorded. Mean increase in
number of falls per minute for each group was calculated
and skeletal muscle relaxation activity was determined by
following the formula.
PHARMACOLOGICAL SCREENING
CNS depressant activity by photoactometer method. The
title compounds (5a–m) were screened for their
CNS depressant activity using photoactometer [29,30]
at 30min and 1 h after drug administration. The CNS
depressant activity of animal inside the photometer
chamber was recorded as a photoactometer counts.
Decreased score suggests the CNS depressant activity.
The Swiss albino mice of either sex weighing 25–30g
were used. They were divided into groups of six animals
each and each group was allowed to get acquainted for
10min. Thereafter, the photoactometer counts were noted
for a period of 10 min, which was the initial reading
(control). The test compounds were suspended in 1%
CMC solution in distilled water and administered at a
dose of 5 mg/kg i.p. of the body weight. Each group is
served as its own control. One of the groups was treated
with diazepam as the standard at a dose of 5 mg/kg.
After 20 min of administration of test compound, the
% Muscle relaxant relaxant activity
À
¼ Mean reading in no: of falls
ꢁ Mean control reading=Mean control readingÞ ꢃ 100
The observations are tabulated in Table 3.
Anticonvulsant activity (PTZ induced seizure test) [33]. Of
the various compounds tested for CNS depressant activity,
the most active four derivatives 5d, 5e, 5k and 5l were
evaluated for anticonvulsant activity. The dose required for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Thore, S. V. Gupta, and K. G. Baheti
Vol 000
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protecting the animal from PTZ induced clonic convulsions
was determined for tested compound (Table 4). Aqueous
solution of PTZ (dose 85 mg/kg) was administered orally
to group of six mice, 30 min after the administration of
the test compound as suspension in 1% CMC i.p. Mice
were then observed for a period of 20 min for the
symptoms of clonic convulsions. Number of animals in
each group, which were protected against PTZ induced
clonic convulsions, was used as a percentage response
parameter for calculating the effective anticonvulsant dose
(ED50) of the test compound.
All the tested compounds offered good protection to the
animals from the PTZ induced clonic convulsions at the dose
levels 6.0–12.0 mg/kg, body weight. The compound 5l
exhibited the best anticonvulsant activity by protecting 100%
animals at dose of 6.0 mg/kg body weight. ED50 of these com-
pounds have also been calculated and tabulated in Table 5.
Statistical analysis.
Data obtained for each set of
CNS depressant activity were expressed as mean change
in photoactometer count ꢂ SEM, and data from muscle
relaxant activity by rotarod method were expressed as
mean fall of time ꢂ SEM, and both activities were analyzed
by one way analysis of variance followed by Student’s
t-test. All statistical calculations were performed using
evaluation version of Graph Pad Prism 3.0 (USA)
statistical software.
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Acknowledgment. The authors are thankful to Head, Department
of Chemistry, Deogiri College, Aurangabad, Maharashtra-431
005 (India) for providing necessary facility for work and SIFC,
Chandigarh University, Chandigarh, India for providing spectra
of compounds.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet