Microwave-assisted synthesis of 1,3-benzothiazol-2(3 H)-one derivatives and analysis of their antinociceptive activity

Article abstract of DOI:10.1055/s-0032-1327613

A rapid and efficient method was developed for synthesis of 6-acyl-1,3-benzothiazol-2(3H)-one derivatives under microwave irradiation (MWI) conditions. The reaction times were shortened compared to conventional heating. Additionally, we synthesized acetic acid and acetamide derivatives of 1,3-benzothiazol-2(3H)-one, 6-acyl-1,3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzothiazol-2(3H)-one and 6-acyl-5-chloro-1,3-benzothiazol-2(3H)- one with the microwave-assisted method and analyzed their antinociceptive activity with the tail flick, tail clip, hot plate and writhing tests. Among the synthesized compounds, 3-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-1,3- benzothiazol-2(3H)-one (6a), 5-chloro-3-{2-oxo-2-[4-(propan-2-yl) piperazin-1-yl]ethyl}-1,3-benzothiazol-2(3H)-one (7e) and 3-[2-(4- butylpiperazin-1-yl)-2-oxoethyl]-5-chloro-1,3-benzothiazol-2(3H)-one (8e) showed significant antinociceptive activity in the tail clip, tail flick, hot plate and writhing tests. Supporting Information available online at http://www.thieme-connect.de/ejournals/toc/amf.

Full text of DOI:10.1055/s-0032-1327613

Original Article 571
Microwave-Assisted Synthesis of 1,3-Benzothiazol-
2(3H)-one Derivatives and Analysis of Their
Antinociceptive Activity
Authors
T. Önkol1, Y. Dündar1, E. Yıldırım2, K. Erol2, M. F. Şahin1
Affiliations
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
2 Department of Pharmacology, Faculty of Medicine, Osmangazi University, Eskişehir, Turkey
Key words
Abstract
activity with the tail flick, tail clip, hot plate
and writhing tests. Among the synthesized
compounds, 3-[2-(4-ethylpiperazin-1-yl)-2-
▶
1,3-benzothiazol-2(3H)-one
tail flick test
tail clip test
hot plate test
writhing test
microwave-assisted
synthesis
●
▼
▶
●
A rapid and efficient method was developed for
synthesis of 6-acyl-1,3-benzothiazol-2(3H)-one
derivatives under microwave irradiation (MWI)
conditions. The reaction times were shortened
compared to conventional heating. Additionally,
we synthesized acetic acid and acetamide deriva-
tives of 1,3-benzothiazol-2(3H)-one, 6-acyl-1,
3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzo-
thiazol-2(3H)-one and 6-acyl-5-chloro-1,3-ben-
zothiazol-2(3H)-onewiththemicrowave-assisted
method and analyzed their antinociceptive
▶
●
oxoethyl]-1,3-benzothiazol-2(3H)-one (6a), 5-
c h l o r o - 3 - { 2 - o xo - 2 - [ 4 - ( p r o p a n - 2 - y l )
piperazin-1-yl]ethyl}-1,3-benzothiazol-2(3H)-
one (7e) and 3-[2-(4-butylpiperazin-1-yl)-2-
oxoethyl]-5-chloro-1,3-benzothiazol-2(3H)-one
(8e) showed significant antinociceptive activity
in the tail clip, tail flick, hot plate and writhing
tests.
▶
●
▶
●
▶
●
Supporting Information available online at http://
www.thieme-connect.de/ejournals/toc/amf
only in Japan. Tiaramide shows no inhibitory
effect on COX enzymes and the mechanism of
action has not yet been elucidated in detail. In
1985, Shizuko Takano reported that tiaramide
inhibits platelet phospholipase A2 through mech-
anisms other than blocking Ca-influx and intrac-
ellularCamobilizationorcalmodulinantagonism.
Inomata and co-workers showed that tiaramide
Introduction
▼
Nonsteroidal anti-inflammatory drugs (NSAID),
which are nonselective inhibitors of cyclooxygen-
ases (COX-1 and COX-2), have been most widely
used for the treatment of inflammatory diseases
such as rheumatoid arthritis and osteoarthritis
[1,2]. However, the chronic use of NSAIDs has cer-
tain limitations since they can result in gastroin-
testinal, renal and hematological toxicity [1–3].
Although the discovery of selective COX-2 inhibi-
tors has solved some of these problems, COX-2
inhibitors cause serious cardiovascular complica-
tions [1,2]. Recently, NO-NSAIDs, dual COX/LOX
inhibitors and anti-TNF therapy were found to be
novel compounds allowing an effective anti-
inflammatory therapy [1]. In addition, microsomal
prostaglandin E2 synthase-1 (mPGES-1) and pros-
taglandin H2 synthase-1 (PGHS-1) as well as E
prostanoid receptor (EP)were identified as promis-
ing therapeutic targets [2,4]. Consequently, there
is an emerging need for developing new anti-
inflammatory drugs with novel modes of action.
Tiaramide (I) (5-chloro-3-{2-[4-(2-hydroxyethyl)
piperazin-1-yl]-2-oxoethyl}-1,3-benzothia-
zol-2(3H)-one hydrochloride) is a nonsteroidal
anti-inflammatory drug developed and approved
received 29.06.2012
accepted 14.09.2012
Bibliography
DOI http://dx.doi.org/
10.1055/s-0032-1327613
Published online:
October 19, 2012
Arzneimittelforschung 2012;
62: 571–575
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0004-4172
is
a relatively safe alternative for Japanese
patients with NSAID-induced urtiacaria and/or
angioedema [5–7]. Previously, some tiaramide
derivatives (II) were prepared in our laboratory
and tested for their antinociceptive activity.
Among these compounds, morpholin, 4-fluor-
ophenylpiperazin,
4-chlorophenylpiperazin,
4-hydroxypiperidin and 4,6-dimethyl-2-pyridi-
namino derivatives were found to be more active
Correspondence
Y. Dündar, PhD
Department of Pharmaceutical
Chemistry
Faculty of Pharmacy
Gazi University
Taç st, 06330 Etiler
Ankara
▶
than tiaramide and aspirin [8] ( Fig. 1). S-14080
●
(6-benzoylbenzothiazolone) (III) was tested in
clinical trials up to phase II as analgesic and was
found to inhibit not only the inflammatory cas-
cade of arachidonic acid, but also to induce the
release of an opioid peptide in periphery [9,10].
In addition, Ünlü et al. synthesized 6-acyl-1,3-
benzothiazol-2(3H)-one derivatives (IV) with
acetic acid and propanoic acid moieties and per-
T u r k e y
Tel.: +90/312/2023 237
Fax: +90/312/2235 018
yasemina@gazi.edu.tr
Önkol T et al. Microwave-Assisted Synthesis of 1,3-Benzothiazol-2(3H)-one… Arzneimittelforschung 2012; 62: 571–575

572 Original Article
Fig. 1 Formulae of some 1,3-benzothiazol-2(3H)-
one derivatives and the general structure of the
synthesized compounds.
O
O
N
N
Cl
Cl
X: C, N, O
N
S
N
S
X
N
O
O
R
OH
(II)
(I)
(CH 2)nCOOH
H
N
N
O
S
O
R: H, Cl, F
n: 1,2
S
O
R
O
(III)
(IV)
O
CH 2COOH
X: H, Cl
N
X
N
O
S
X
N
S
R': H, 4-fluorobenzoyl, 4-methylbenzoyl,
4-methoxybenzoyl
N
O
R''
R'
R'
R'': methyl, ethyl, isopropyl, butyl
(V)
(VI)
Fig. 2 Synthesis of 1,3-benzothiazol-2(3H)-one 1a.
Conventional heating
180oC, 24 h
%71
%85
H
N
O
NH2
SH
O
+
H2N
NH2
S
Microwave irradiation
140oC, 10 min
1a
Fig. 3 Synthesis of 6-acyl-1,3-benzothiazol-
2(3H)-one derivatives. R: 4-fluorobenzoyl 1b,
4-methylbenzoyl 1c, 4-methoxybenzoyl 1d.
Conventional heating
120–160oC, 3–4 h
% 45–64
R
O
OH
H
N
H
N
O
O
+
S
S
O
Microwave irradiation
120oC, 45 min
R
1b–1d
1a
% 54–66
formed a preliminary screening of their in vivo analgesic and
Result and Discussion
▶
anti-inflammatory activity [11] ( Fig. 1) .
●
▼
These results led us to investigate the analgesic and anti-inflam-
matory activity of 6-acyl-2(3H)-benzothiazolone and its amide
derivatives as a starting point for the discovery of new therapeutic
agents. In this study, we describe the synthesis and preliminary
evaluation of the biological activity of 1,3-benzothiazol-2(3H)-
one, 6-acyl-1,3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzothia-
zol-2(3H)-one and 6-acyl-5-chloro-1,3-benzothiazol-2(3H)-one
and of their acetic acid and acetamide derivatives (V and VI) as
The synthetic routes for the synthesized compounds are out-
▶
lined in Figs. 2–4. The starting compound, 1,3-benzothiazol-
●
2(3H)-one (1a), was synthesized by both conventional and
microwave-assisted methods [12–14] ( Fig. 2). Compound 1a
▶
●
was prepared by reacting urea with o-aminothiophenol. Rea-
gents were used in the same quantity for both methods. The
conventional method was carried out with an external heat
source (oil bath), and the yield was 71%. The microwave-assisted
method relied on efficient internal heating with microwave irra-
diation (MWI) and the reaction time was reduced from 24h to
10min compared with the conventional heating method. The
yield was 85% [12]. Microwave-assisted synthesis of 1a has been
developed in our laboratory. 5-Chloro-1,3-benzothiazol-2(3H)-
one (1e) was also obtained with the microwave-assisted method
as reported previously [15].
molecules composed of tiaramide and 6-benzoyl-1,3-benzothia-
▶
zol-2(3H)-one derived moieties ( Fig. 1) .
●
Materials and Methods
▼
Detailed experimental protocols and physicochemical data of the
synthesized compounds are available as Supporting Information.
Önkol T et al. Microwave-Assisted Synthesis of 1,3-Benzothiazol-2(3H)-one… Arzneimittelforschung 2012; 62: 571–575

Original Article 573
Fig. 4 Synthesis of acid and amide derivatives.
O
O
Reagents: (i) ethyl bromoacetate, K2CO3, acetone,
MWI; (ii) KOH, ethanol/water, MWI; (iii) SOCl2,
toluene, MWI; (iv) appropriate amine, K2CO3, THF,
MWI.
H
N
OH
X
O
X
N
S
X
i
ii
N
S
O
O
O
S
R'
R'
R'
3a–3g
2a–2g
1a–1g
O
O
N
Cl
X
X
N
S
N
S
iv
iii
N
O
O
R''
R'
R'
4a–4g
5a–8g
Table 1 Comparable data for synthesis of 6-acyl-1,3-benzothiazol-2(3H)-one with conventional heating and microwave irradiation.
Conventional heating
Yield (%)
Microwave irradiation
Yield (%)
Comp
Reaction time
Temp. (°C)
Reaction time
Temp. (°C)
1b
1c
1d
3h
4h
4h
64
130–160 [19,20]
130–160 [19,20]
120–123 [22]
45min
45min
45min
54
65
66
120
120
120
58
45 [21]
6-Acyl-1,3-benzothiazol-2(3H)-one derivatives are commonly
prepared by reacting 1,3-benzothiazol-2(3H)-one with acyl hal-
ide and aluminum chloride (Friedel-Crafts acylation) [16,17].
This procedure is hampered by significant consumption of AlCl3.
Ucar et al. suggested a new protocol in which AlCl3 is used as
well and which involves migration of the acyl group from the
N-atom to the 6C-atom of the heterocyclic ring (Fries-Like rear-
rengement) [18]. Although total yield of the desired product was
high, this method was rather time consuming and required 2
steps. An alternative method for obtaining 6-acyl-1,3-benzothi-
azol-2(3H)-one is acylation of 1,3-benzothiazol-2(3H)-one with
benzoic acid derivatives in polyphosphoric acid (PPA) [11,19–
22]. PPA, however, is very viscous and is difficult to heat homo-
geneously with conventional methods. We therefore developed
a rapid, practical and efficient microwave-assisted method for
the presence of potassium carbonate under MWI conditions,
▶
with good yields ( Fig. 4). Acid derivatives were reacted with
●
SOCl2 to give acyl halides. The corresponding amides were
obtained by reacting acyl halides with the appropriate amine
under MWI conditions. Ethyl (2-oxo-1,3-benzothiazol-3(2H)-yl)
acetate (2a) [23], ethyl (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-
yl)acetate (2e) [24], (2-oxo-1,3-benzothiazol-3(2H)-yl)acetic
acid (3a) [23], (6-(4-methylbenzoyl)-2-oxo-1,3-benzothiazol-
3-yl)acetic acid (3c) [19], (5-chloro-2-oxo-1,3-benzothiazol-
3(2H)-yl)acetic acid (3e) [24] and 5-chloro-3-[2-(4-methy
lpiperazin-1-yl)-2-oxoethyl]-1,3-benzothiazol-2(3H)-one (5e)
[25–27] have been reported previously.
In this preliminary study, the antinociceptive activity of the title
compounds was tested with the tail clip [28,29], tail flick [30],
▶
hot plate [31,32] and writhing tests [33] ( Table 2). The tail
●
preparation of 6-acyl-1,3-benzothiazol-2(3H)-one derivatives
clip, tail-flick and hot plate tests are used to assess central anti-
nociceptive activity at the spinal level; the hot plate test also
measures antinociceptive activity at the supraspinal level. The
acetic acid-induced writhing test is used to assay peripheral
antinociceptive activity, which typically mimics human clinical
pain conditions [34–36]. Acetic acid-induced writhing behavior
involves COXs and PGs. All compounds were administered at the
same dose of 100mg/kg except for 7a and 5e. Compounds 7a
and 5e were tested at 25mg/kg because the higher dose was
found to be toxic to mice. In reference publications, aspirin has
usually been used at a dose of 100mg/kg.
▶
(1b–d) in PPA ( Fig. 3). MWI resulted in efficient heating of PPA
●
and the use of WeflonTM-coated stirring bars also positively
affected homogeneous heating because they are strongly micro-
wave-absorbing passive heating sources. The obtained yields
(54–66%) were similar to the ones obtained with classical proto-
cols (45–64%). The significant advantage of this procedure is its
short duration. Synthesis of the 6-acyl-1,3-benzothiazol-2(3H)-
one derivatives (1b–d) with the microwave-assisted method
took only 45min compared to 3 or 4h with the conventional
▶
heating protocols ( Table 1). The conventional method for syn-
●
thesis of acyl derivatives has been reported earlier [19–22].
5-Chloro-6-(4-fluorobenzoyl)-1,3-benzothiazol-2(3H)-one (1f)
and 5-chloro-6-(4-methylbenzoyl)-1,3-benzothiazol-2(3H)-one
(1g) were also synthesized with the microwave-assisted method.
Although the reaction time, reagent quantities and temperature
were varied, 5-chloro-6-(4-methoxybenzoyl)-1,3-benzothiazol-
2(3H)-one was obtained neither with the conventional nor the
microwave protocol.
Acetic acid derivatives (3a–g) were synthesized by alkaline
hydrolysis of the corresponding ethyl esters (2a–g), which were
prepared by reacting 1,3-benzothiazol-2(3H)-one and 5-chloro-
1,3-benzothiazol-2(3H)-one (1a–g) with ethyl bromoacetate in
All compounds except for 5d, 6d, 8f and 3g showed significant
activity in the tail clip test. Compounds 5a and 6a, 1,3-benzothi-
azol-2(3H)-one derivatives, were more active than aspirin in the
tail clip test. Compounds 5e, 6e, 7e, 8e, 5f, 7f and 7g, 5-chloro-
1,3-benzothiazol-2(3H)-one derivatives, were active as well
with compound 6e being the most active in the tail clip test.
Compounds 6a, 8a, 6b, 7b, 6c, 7c, 7e, 8e, 5f and 6g at 100mg/kg
were at least as active as aspirin in the tail flick test with com-
pounds 6a, 6b, 7b, 7e and 8e being the most active ones. In the
hot plate test, compounds 5a, 6a, 6c, 3d, 5e, 6e, 7e, 8e and 6g at
100mg/kg were at least as active as aspirin. Results from the
writhing test indicated that 5-chloro-1,3-benzothiazol-2(3H)-
Önkol T et al. Microwave-Assisted Synthesis of 1,3-Benzothiazol-2(3H)-one… Arzneimittelforschung 2012; 62: 571–575

574 Original Article
Table 2 Antinociceptive activity of the synthesized compounds.
O
R''
X
N
S
O
R'
Comp.a
X
R′
R″
Tail Clip Testb.c
Tail Flick Testb.c
Hot Plate Testb.c
Writhing Testc
Control
3a
–
–
–
3.11±0.93
18.10±2.91
66.67±8.60 *
76.18±6.84 *
100 *
7.15±1.06
12.03±4.47
42.58±5.98 *
71.21±9.88 *
11.48±3.40
26.13±9.03
7.06±2.27
45.67±6.69
27.33±6.07
20.17±4.40 *
13.33±4.91 *
31.50±5.13
23.00±5.82 *
5.60±1.84 *
32.17±4.78
15.00±5.15 *
7.83±2.31 *
31.50±3.12
21.17±4.71 *
14.83±5.17 *
22.33±5.05 *
10.67±2.65 *
23.80±4.91 *
22.60 ±6.06 *
45.00±1.57
27.00±4.37 *
23.67 ±5.77 *
19.00±6.65 *
7.17±2.48 *
17.83±6.89 *
9.00±2.91 *
0.83±0.30 *
2.00±0.55 *
27.00±5.81
13.83±4.07 *
19.00±6.02 *
25.00±4.05 *
25.67±8.92
35.60±3.57
18.00±6.24 *
30.17±2.94
22.67±5.28 *
14.83±4.71 *
16.78±4.77*
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
C l
C l
C l
C l
C l
Cl
Cl
Cl
Cl
Cl
–
H
H
H
H
H
OH
18.94±6.64 *
95.93±4.06 *
83.33±16.66 *
36.17±7.17 *
19.42±6.57 *
21.91±7.30*
11.62±2.73 *
46.23±16.37 *
25.04±7.67 *
19.72±4.77 *
50.46±9.04 *
28.34±6.31 *
49.91±16.16 *
59.90±16.07 *
37.23±12.55 *
56.95±16.80 *
1.31±0.31
5a
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
6a
7a**
8a
33.33±8.60
83.98±16.01 *
32.42±7.23
28.54±6.18
100 *
3b
5b
6b
7b
8b
3c
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methoxybenzoyl
4-methoxybenzoyl
4-methoxybenzoyl
4-methoxybenzoyl
4-methoxybenzoyl
H
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
18.76±5.33
22.51±7.68
23.88±5.92 *
14.22±3.35
11.47±1.99
6.09±1.98
100 *
20.77±5.94
52.87±8.66 *
55.51±8.36 *
83.33±16.66 *
87.81±10.94 *
73.53±17.72 *
43.29±16.54 *
35.47±13.49
50.47±18.65
77.92±14.36 *
52.66±8.68 *
46.77±8.44 *
66.67±21.07 *
60.00±22.35 *
100 *
5c
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
6c
49.75±1.54 *
29.69±6.66 *
6.08±2.14
7c
8c
3d
5d
6d
7d
8d
3e
48.28±12.97 *
11.80±4.06
18.71±3.74 *
22.81±5.72 *
15.64±3.79 *
16.60±5.55
31.80±5.37 *
46.30±13.18 *
56.65±15.72 *
52.69±16.31 *
10.91±4.04
30.11±10.59
13.99±2.44 *
2.62±0.44 *
6.99±1.89
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
1.47±0.53
21.89±5.39 *
52.66±8.68*
32.42±8.33 *
73.04±13.28 *
100 *
5e**
6e
H
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
H
7e
H
91.84±6.75 *
98.22±1.77 *
27.23±6.79 *
83.33±16.66 *
50.00±9.12 *
70.99±7.42 *
10.96±3.85
8e
H
100 *
3f
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4 - fluorobenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
4-methylbenzoyl
–
57.46±18.21
87.89±12.10 *
76.98±16.60 *
64.48±8.36 *
63.44±15.68 *
41.60±15.89
74.91±16.64 *
84.12±15.87 *
68.93±19.72 *
10.64±3.83
80.79±13.16*
5f
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
OH
6f
7f
8f
3g
5g
6g
7g
8g
Aspirin
6.55±1.71
5.22±1.72
4-methylpiperazin-1-yl
4-ethylpiperazin-1-yl
4-(propan-2-yl)piperazin-1-yl
4-butylpiperazin-1-yl
–
47.67±18.53 *
69.89±19.10 *
71.87±13.44 *
47.28±17.90 *
70.54±14.57*
13.78±4.39
40.31±14.06 *
7.10±1.00
11.19±2.72
10.18±1.96
a All synthesized compounds were tested at 100mg/kg. b The results are expressed as percentage of the maximal possible effect (%MPE±SE). c All values are given as X±stand-
ard error. n: 6. *p<0.05. **Compounds 7a and 5e were tested at 25mg/kg because a dose of 100mg/kg was found to be toxic to mice
one acid and amide derivatives (3e-8e) showed the highest
antinociceptive activity. Compounds 3b, 6b and 7b with a
4-fluorobenzoyl moiety were significantly active in the writhing
test. Additionally, compounds 6a, 5c, 7c, 5f and 8g had moderate
antinociceptive activity and showed higher activity if compared
totheaspirinandcontrolgroupswhereas6-(4-methoxybenzoyl)-
1,3-benzothiazol-2(3H)-one derivatives had no a significant
activity in all used tests.
This led us to investigate the analgesic and anti-inflammatory
activity of 6-acyl-2(3H)-benzothiazolone and its amide deriva-
tives composed of a tiaramide and 6-benzoylbenzothiazolone
moiety. We synthesized acetic acid and acetamide derivatives of
1,3-benzothiazol-2(3H)-one,
6-acyl-1,3-benzothiazol-2(3H)-
one, 5-chloro-1,3-benzothiazol-2(3H)-one and 6-acyl-5-chloro-
1,3-benzothiazol-2(3H)-ones and assayed their antinociceptive
activity with the tail flick, tail clip, hot plate and writhing tests
with the intention of comparing their central and peripheral
effects.
Conclusions
▼
Our results showed that compounds 6a, 7e and 8e were more
active than aspirin at 100mg/kg in the tail clip, tail flick, hot
plate and writhing tests. These results suggest that these 3 com-
pounds could possibly be both central and peripheral antinocic-
eptive agents. Compounds 6b, 7b, 7c, 6e and 5f have both central
Tiaramide is a nonsteroidal anti-inflammatory drug developed
and approved only in Japan. S-14080, 6-benzoylbenzothia-
zolone, was tested in clinical trials up to phase II as an analgesic.
Önkol T et al. Microwave-Assisted Synthesis of 1,3-Benzothiazol-2(3H)-one… Arzneimittelforschung 2012; 62: 571–575

Original Article 575
13 Claasz M. Thionylindigo. Ber Dtsch Chem Ges 1912; 45: 1015–1032
and peripheral antinociceptive activity as well. On the other
hand, compounds 5a, 8a, 6c and 6g could be centrally acting
antinociceptive agents whereas compounds 3b, 3e and 5c are
likely to act at the periphery.
In conclusion, the synthesized compounds could provide a start-
ing point for the design and development of new and more
active antinociceptive agents. The mode of action of these com-
pounds remains to be studied.
14 Önkol T, Dündar Y, Sırmagül B et al. (2-Oxobenzazolin-3-yl)alkanoic
acid derivatives and antinociceptive activity. J Fac Pharm Gazi 2002;
19 (1): 15–24
15 Adak S. Synthesis of some 5-chloro-6-(thiazole-4-yl)-2-oxo-3H-ben-
zothiazol derivatives and studies of their inhibitor effects on cyclooxy-
genase [dissertation]. Ankara: Gazi University, 2007
16 Yous S, Poupaert JH, Lesieur I et al. AlCl3-DMF reagent in the Friedel-
Crafts reaction. Application to the acylation reaction of 2(3H)-benzo-
thiazolones. J Org Chem 1994; 59 (6): 1574–1576
17 Dushamov DA, Mukhamedov NS, Aliev NA et al. Benzazoles. 2. Rela-
tive activity of catalysts and 4-substituted benzoyl chlorides in the
acylation of benzothiazolin-2-ones. Chem Heterocycl Comp 2002;
38 (4): 438–441
18 Ucar H, Van der Poorten K, Depovere P et al. “Fries like” rearrangement:
a novel and efficient method for the synthesis of 6-acyl-2(3H)-ben-
zoxazolones and 6-acyl-2(3H)-benzothiazolones. Tetrahedron 1998;
54 (9): 1763–1772
19 Petrov OI, Antonova ATS, Kalcheva VB et al. Synthesis of 6-benzoyl-
2(3H)-benzothiazolones and compounds of their reduction and
alkylation. Dokl Bolg Akad Nauk 1994; 47 (3): 31–34
Acknowledgements
▼
This study was supported by The Scientific and Technical
Research Council of Turkey. (Project Number 108T192). We
respectfully commemorate Prof. Dr. Cemil Öğretir who died on
19 January 2011 and managed this study until his death.
20 Yous S, Lebegue N, Poupaert JH et al. Lipid-lowering properties of
6-benzoyl-2(3H)-benzothiazolone and structurally related com-
pounds. J Enzyme Inhib Med Chem 2005; 20 (6): 525–532
21 Yous S, Poupaert JH, Chavatte P et al. Synthesis and pharmacological
evaluation of analgesic 6-substituted 2(3H)-benzothiazolones. Drug
Des Discov 2001; 17 (4): 331–336
Conflict of Interest
▼
The authors declare that they have no conflict of interest.
22 Lesieur D, Lespagnol C, Yous S. Preparation of 6-acylbenzothiazolinones
and analogs as drugs. Eur Patent Application EP 395526 A1 19901031;
1990
23 Nimmich W. Benzothiazolinone-3-yl carboxylic acids. J Prakt Chem
1965; 27 (3–4): 220–224
24 D’Amico JJ, Bollinger FG. Synthesis of 2-oxo-3-benzothiazolineacetyl
chloride, 5-chloro-2-oxo-3-benzothiazolineacetyl chloride and deriv-
atives. J Heterocycl Chem 1988; 25 (4): 1183–1190
25 Arakawa S, Ogawa S, Arakawa E et al. 2-Benzothiazolinone deriva-
tives. Jpn Kokai Tokkyo Koho JP60228467 A 19851113; 1985
26 Umios S. N-Substituted and N,N-disubstituted aminocarbonylalkyl
compounds. U.S. Patent Application US 3661921 A 19720509; 1972
27 Toshiyuki T, Yohichi K, Shigenobu K. Pharmacological investigations
of benzothiazoline derivatives. ArzneimittelForschung 1972; 22 (4):
711–715
References
1 Praveen Rao PN, Knaus EE. Evolution of nonsteroidal anti-inflamma-
tory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J
Pharm Pharm Sci 2008; 11 (2): 81–110
2 Patrono C, Rocca B. Nonsteroidal antiinflammatory drugs: Past, present
and future. Pharmacol Res 2009; 59 (5): 285–289
3 Graham DY, Chan FKL. NSAIDs, risks, and gastroprotective strategies:
Current status and future. Gastroenterology 2008; 134 (4): 1240–
1246
4 Koeberle A, Werz O. Inhibitors of the microsomal prostaglandin E2
synthase-1 as alternative to non steroidal anti-inflammatory drugs
(NSAIDs) – a critical review. Curr Med Chem 2009; 16 (32): 4274–
4296
5 Fujiyoshi T, Dozen M, Ikeda K et al. Involvement of prostaglandins in
kaolin-induced writhing reaction in mice. J Pharmacobiodyn 1989;
12 (8): 476–482
6 Takano S. Inhibition of phospholipase A2 by tiaramide in rabbit plate-
lets. Jpn J Pharmacol 1985; 39 (3): 307–316
7 Inomata N, Osuna H, Yamaguchi J et al. Safety of selective cyclooxy-
genase-2 inhibitors and a basic non-steroidal anti-inflammatory drug
(NSAID) in Japanese patients with NSAID-induced urticaria and/or
angioedema: comparison of meloxicam, etodolac and tiaramide.
Dermatol 2007; 34 (3): 172–177
8 Önkol T, Doğruer DS, Ito S et al. Synthesis and antinociceptive activ-
ity of (5-chloro-2-benzothiazolinon-3-yl)acetamide derivatives. Arch
Pharm 2000; 333 (10): 337–340
9 Ferreira SH, Lorenzetti BB, Devissaguet M et al. S14080, a peripheral
analgesic acting by release of an endogenous circulating opioid-like
substance. Br J Pharmacol 1995; 114 (2): 303–308
28 Bianchi C, Franceschini J. Experimental observations of Haffner’s
method for testing analgesic drugs. Br J Pharmacol 1954; 9: 280–284
29 Dajani EZ, Larsen KR, Taylor J et al. 1,1-Dimethylheptyl-8-tetrahy-
drocannabinol-11-oic acid: A novel orally active cannabinoid with
analgesic and antiinflammatory properties. J Pharmacol Exp Ther
1999; 291 (1): 31–38
30 D’Amour FE, Smith DL. A method for determining loss of pain sensa-
tion. J Pharmacol Exp Ther 1941; 72: 74–79
J
31 Eddy NB, Leimbach D. Synthetic analgesic (II): Diethylbutenyl and
diethylbutylamines. J Pharmacol Exp Ther 1953; 107: 385–393
32 Noble F, Smadja C, Raques BP. Role of endogenous cholecystokinin in
the facilitation of mu-mediated antinociception by delta-opioid ago-
nists. J Pharmacol Exp Ther 1994; 271 (3): 1127–1134
33 Koster R, Anderson M, Beer EJ. Acetic acid for analgesic screening. Phar-
macology 1958; 412: 1626
34 Ferrira SH, Vane JR. New aspects on the model of action of nonsteroid
anti-inflammatory drugs. Annu Rev Pharmacol 1974; 14: 57–73
35 Perianayagam JB, Sharma SK, Joseph A et al. Evaluation of anti-pyretic
and analgesic activity of Emblica officinalis Gaertn. J Ethnopharmacol
2004; 95 (1): 83–85
10 Poupaert J, Carato P, Colacino E. 2(3H)-benzoxazolone and bioisosters
as “privileged scaffold” in the design of pharmacological probes. Curr
Med Chem 2005; 12 (7): 877–885
11 Ünlü S, Önkol T, Dündar Y et al. Synthesis and analgesic and anti-
inflammatory activity of some new 6-acyl-2-benzoxazolinone and
6-acyl-2-benzothiazolinone derivatives with acetic acid and propa-
noic acid residues. Arch Pharm 2003; 336 (8): 353–360
36 Kilic FS, Erol K. Central components in the antinociceptive activity
of dipyrone in mice. Inflammopharmacology 2000; 8 (3): 259–265
12 Uzun L. Synthesis of some 6-(substitute-thiazole-4-yl)-2-oxo-3H-ben-
zothiazol derivatives and studies of their inhibitor effects on cyclooxy-
genase [dissertation]. Ankara: Gazi University, 2007
Önkol T et al. Microwave-Assisted Synthesis of 1,3-Benzothiazol-2(3H)-one… Arzneimittelforschung 2012; 62: 571–575