Synthesis and antinociceptive activity of some 3-substituted benzothiazolone derivatives

Article abstract of DOI:10.1016/S0014-827X(99)00111-1

Thirteen 3-substituted benzothiazolone derivatives have been synthesized. Their chemical structures have been elucidated by IR and NMR spectral data and by elemental analyses. Among these compounds, 1-{3-[2(3H)- benzothiazolon-3-yl]propanoyl}morpholine (5

Full text of DOI:10.1016/S0014-827X(99)00111-1

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 846–851
Short Communication
Synthesis and antinociceptive activity of some 3-substituted
benzothiazolone derivatives
Bilge C¸ akir a, Aysel Ulucay b, Deniz S. Dogruer a, Askin Isimer b, M. Fethi Sahin a,*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi Uni6ersity, Hipodrom, Ankara 06330, Turkey
b Center of Pharmaceutical Sciences, Gulhane Military Medical Academy, Etlik, Ankara, Turkey
Received 4 March 1999; accepted 6 August 1999
Abstract
Thirteen 3-substituted benzothiazolone derivatives have been synthesized. Their chemical structures have been elucidated by IR
and NMR spectral data and by elemental analyses. Among these compounds, 1-{3-[2(3H)-benzothiazolon-3-yl]pro-
panoyl}morpholine (5b); 1-{3-[2(3H)-benzothiazolon-3-yl]propanoyl}-4-benzylpiperidine (5c); 1-{3-[2(3H)-benzothiazolon-3-yl]-
propanoyl}-4-phenylpiperazine (5d); 3 - [3 - (4 - benzylpiperidine - 1 - yl)propyl] - 2(3H)-benzothiazolone (5k); 3 - [3 - (4 - benzyl-
piperazine-1-yl)propyl]-2(3H)-benzothiazolone (5l); 3-[3-(4-phenylpiperazine-1-yl)propyl]-2(3H)-benzothiazolone (5m) have been
found to be significantly more active than the others. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Antinociceptive activity; Benzothiazolone derivatives; Synthesis
1. Introduction
benzothiazolinone derivatives, 4-[(5-chloro-2-oxo-3-
benzothiazolinyl)acetyl]-1-piperazinylethanol hydro-
As it is widely accepted there are two classes of
compounds which are used in clinical analgesia: (a)
peripheral analgesics, which can be divided into two
subclasses namely cyclooxygenase inhibitors (NSAIDs)
and peripheral opioids, dipyrone can be added to this
group; (b) central opioids. However, each class has
disadvantages. NSAIDs frequently cause gastrointesti-
nal disorders, while opiates lead to tolerance, physical
dependency and addiction. The aim of current analgesic
research is to develop new NSAIDs without such side
effects [1,2].
Benzothiazolinone derivatives have also been re-
ported as potent analgesic agents. In 1995, Ferreira and
co-workers screened the antinociceptive activity of 6-
benzoylbenzothiazolone and concluded that it might
release an endogenous, opioid like substance from the
adrenal glands exerting the antinociceptive activity [3].
The compound was claimed to have little or no anti-
inflammatory activity. On the other hand, one of the
chloride (Tiaramide HCl, Fig. 1) is a well-known anti-
inflammatory agent. It was also proven to have anal-
gesic antihistaminic activity with a low incidence of
mild side effects [4,5].
Fig. 1. Tiaramide hydrochloride.
* Corresponding author. Tel.: +90-312-223 5018.
Fig. 2. The general formula of the compounds to be synthesized.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00111-1

B. C¸ akir et al. / Il Farmaco 54 (1999) 846–851
847
Scheme 1. Synthesis of the title compounds.
On the other hand several benzoxazolone and oxa-
2. Chemistry
zolopyridine derivatives have been synthesized and
claimed to have significant analgesic activity, and the
authors claimed that if these compounds have a three-
carbon chain, between the two nitrogens on the sub-
stituents at position three, they exhibit better analgesic
activity. The authors also stressed the significance of
phenylpiperazino grouping at the side chain on the
oxazole nitrogen of the ring of the compound they
synthesized [6,7].
Therefore, in order to evaluate the importance of the
feature of the side chain mentioned above in the title
compounds, the synthesis and investigation of the anti-
nociceptive activity of the compounds shown in Fig. 2
was pursued.
The syntheses of the title compounds have been
realized as illustrated in Scheme 1. Synthesis of 2(3H)-
benzothiazolone (1) was carried out by the reaction of
o-aminothiophenol with urea [8]. 2(3H)-Benzothia-
zolone was reacted either with 3-chloropropanamide
derivatives 2, or 3-chloropropanoic acid (3) followed by
thionyl chloride to give the acid chloride, which after-
wards was reacted with an appropriate amine to obtain
the final compounds 5a–5h. 2(3H)-Benzothiazolone
was also reacted with bromochloropropane (4) and an
amine in the presence of potassium carbonate to form
the final compounds 5i–5m (Scheme 1). In the synthesis
of the aminopropylbenzothiazolinone derivatives, the

848
B. C¸ akir et al. / Il Farmaco 54 (1999) 846–851
symmetrical amines could have been obtained. There-
fore, it was thought to reduce the corresponding amides
to aminopropylbenzothiazolinones but this attempt was
not successful. As a result the above mentioned syn-
thetic method was utilized. There was a possibility to
obtain symmetrical diamines instead of the expected
compounds, however, in the work-up step the title
compounds were obtained pure.
coal. The acetone was evaporated and the residue was
crystallized from an acetone–water mixture.
3.1.2.2. Method B. The compound 2(or 3)-(2-oxoben-
zothiazolin-3-yl) propanoyl chloride (0.03 mol) was dis-
solved in 120 ml of heptane. Triethylamine (0.03 mol)
and phenylpiperazine (0.03 mol) were added. The even-
tual mixture was stirred for 18 h at room temperature.
The organic solvent was evaporated and the residue
was treated with 50 ml of water, stirred for an extra
hour at room temperature, then extracted with chloro-
form, dried over sodium sulfate, and filtered. Chloro-
form was evaporated to dryness and the residue was
crystallized with ethanol–water mixture.
3. Experimental
3.1. Chemistry
All the chemicals used in this study were purchased
from either Aldrich or Merck AG. 3-[2(3H)-Benzothia-
zolon-3-yl]propanoic acid and 3-[2(3H)-benzothia-
zolon-3-yl]propanoyl chloride were synthesized in our
laboratory. The melting points are 142°C for the acid
and 67°C for the acid chloride, which were in accor-
dance with those cited in the literature [9]. Therefore,
they were used in the next steps without further
analysis.
The melting points of the compounds were deter-
mined using an Electrothermal 9000 melting point ap-
paratus and were uncorrected.
The IR spectra of the compounds were recorded on a
Perkin–Elmer 1330 IR spectrophotometer. The 1H
NMR spectra were recorded on a Bruker 200 FT NMR
spectrometer.
Compounds 5c and 5e were purified through column
chromatography on silica gel 230–400 mesh and using
a 2:3 benzene–ethyl acetate mixture as eluent.
3.1.3. Synthesis of 3-(3-aminopropyl)-2-oxobenzo-
thiazoline hydrochlorides (5i–5m)
A total of 0.1 mol of 2(3H)-benzothiazolone, 0.03
mol of potassium carbonate, 1-bromo-3-chloropropane
and an appropriate amine were placed in 30 ml of
anhydrous ethanol and refluxed for 12 to 20 h depend-
ing on the amine used. Ethanol was evaporated at the
end of the reaction and the residue was treated with 50
ml of water and extracted with ether. The ethereal
portions were pooled and dried over sodium sulfate,
concentrated on a rotary evaporator and treated with
ethereal HCl. The precipitate thus formed, was filtered
and dried at room temperature, crystallized out from
an appropriate solvent and dried at room temperature.
3.1.1. Synthesis of 2(or 3)-chloropropanoylamines
A total of 0.03 mol of amine was dissolved in 30 ml
of chloroform and 0.01 mol of 2- or 3-chloropropanoyl
chloride was added dropwise while stirring. The mix-
ture was stirred for 5 min while cooling and refluxed for
a further 10 min on a water bath. The chloroform
solution was extracted with 5% HCl and washed with
water, dried over anhydrous sodium sulfate, and
filtered. Chloroform was evaporated under diminished
pressure. The crude amide was obtained.
3.2. Biology
3.2.1. Animals
Albino mice of both sexes (2393.0 g), which are a
local breed, were employed. The animals were housed
in groups of eight, with food and tap water ad libitum,
and were received in the laboratory at least 2 days
before the experiments to allow them to get accustomed
to the environment. The food was withdrawn on the
day before the experiment, but they were allowed free
access to tap water. The treatment was performed in
full awareness of the test animals. Acetic acid (Merck
A.G), carboxymethyl cellulose sodium salt (CMC Na)
(Aldrich) and aspirin (Bayer) were used.
3.1.2. Synthesis of the amides (5a–5h)
3.1.2.1. Method A. Metallic sodium (0.01 mol) was
dissolved in 30 ml of ethanol. The ethanol was evapo-
rated. The residue was dissolved in 20 ml of N,N-
dimethylformamide and 0.01 mol of 2-oxobenzothia-
zoline, and 0.01 mol of the corresponding chloro-
amide was added. The eventual solution was refluxed
and the reaction progression was monitored through
TLC on silica gel using a 1:4 methanol–chloroform
mixture as the solvent system. When the reaction was
completed the mixture was poured into 50 ml of ice-
cold water and stirred. The oil that separated was taken
into 50 ml of acetone and treated with activated char-
3.2.2. Analgesic acti6ity test
A modified Koster’s test was employed [10]. The
Koster test was first used by Koster et al. in mice for a
dosage of 60 mg/kg acetic acid (0.6 percentage solution)
by intraperitoneal injection to produce repeated charac-
teristic stretching movements [11]. Safak et al. used
acetic acid at a dose level of 300 mg/kg (3% solution)

B. C¸ akir et al. / Il Farmaco 54 (1999) 846–851
849
Table 1
Chemical structure, yield percentages, melting points and crystallization solvents of the compounds synthesized
Comp.
n
R1
R2
Empirical formula
C15H18N2O2S
M.p. (°C)
80–83
Yield (%)
48
Method of
synthesis
Cryst. solvent
acetone–water
5a
2
H
A
5b
2
H
C14H16N2O3S
C22H24N2O2S
100–103
19.2
A
acetone–water
5c
5d
2
2
H
H
93–98
12.4
21.9
A
B
C
20H21N3O2S
126–128
ethanol–water
5e
5f
2
1
H
C16H20N2O2S
C14H16N2O3S
oil
31.5
48.3
A
A
CH3
102–104
acetone–water
5g
5h
1
1
CH3
CH3
C20H21N3O2S
C16H20N2O2S
176–179
74–77
32.7
39.1
B
acetone–water
cyclohexane
A
5`ı
3
3
3
3
3
H
H
H
H
H
C
15H20N2OS.HCl
189–191
191–194
265–270
244–247
302
57.0
48.3
31.8
53.7
25.6
acetone
5j
C14H18N2O2S.HCl
C22H26N2OS.HCl
C21H25N3OS.HCl
C20H23N3OS.HCl
acetone
5k
5l
methanol–ether
acetone
5m
ethanol–ether

850
B. C¸ akir et al. / Il Farmaco 54 (1999) 846–851
Table 2
NMR spectral data of the compounds 5a–5m
Comp.
Solvent
CDCl3
1H MNR (l ppm)
5a
1.44–1.50 (m, 4H), 1.54–1.62 (m, 2H), 2.78 (t, 2H), 3.32 (t, 2H), 3.51 (t, 2H), 4.30 (t, 2H), 7.14 (t, 1H), 7.22 (d,
1H), 7.32 (t, 1H), 7.41 (d, 1H)
5b
5c
DMSO-d6
DMSO-d6
2.70 (t, 2H), 3.10–3.80 (m, 8H), 4.15 (t, 2H), 7.00–7.75 (m, 4H)
0.89–0.95 (m, 2H), 1.49 (t, 2H), 1.65–1.75 (m, 1H), 2.39–2.45 (m, 2H), 2.66–2.84 (m, 6H), 4.13–4.17 (m, 2H),
7.11–7.21 (m, 4H), 7.26 (t, 2H), 7.36 (d, 2H), 7.63 (d, 1H)
5d
DMSO-d6
2.67 (t, 2H), 2.92–2.97 (m, 4H), 3.40 (t, 2H), 3.45 (t, 2H), 4.06 (t, 2H), 6.67 (t, 1H), 6.80 (d, 2H), 7.05–7.11 (m,
3H), 7.24–7.27 (m, 2H), 7.52 (d, 1H)
5e
5f
5g
5h
5I
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
0.90–1.80 (m, 9H), 1.90–3.30 (m, 5H), 4.00–4.30 (t, 2H), 7.00–7.80 (m, 4H)
1.50 (d, 3H), 2.90–3.70 (m, 8H), 5.60 (q, 1H), 7.00–7.90 (m, 4H)
1.50 (d, 3H), 3.00–3.50 (m, 8H), 5.65 (q, 1H), 6.50–7.80 (m, 9H)
1.00–1.80 (m, 12H), 2.80 (m, 3H), 5.50 (q, 1H), 7.10–7.80 (m, 4H)
1.51–1.92 (m, 4H), 2.09–2.14 (m, 2H), 3.08 (t, 2H), 3.31–3.36 (m, 6H), 4.03 (t, 2H), 7.22 (t, 1H), 7.40 (t, 1H), 7.47
(d, 1H), 7.67 (d, 1H), 10.50 (s, 1H)
5j
CDCl3
2.32–2.39 (m, 2H), 3.21 (t, 2H), 3.33–3.42 (m, 4H), 3.82–4.02 (m, 4H), 4.12 (t, 2H), 7.19 (t, 1H), 7.30 (d, 1H),
7.36 (t, 1H), 7.47 (d, 1H), 12.4 (s, 1H)
5k
5l
CDCl3
1.54–1.81 (m, 3H), 2.02–2.11 (m, 2H), 2.44–2.67 (m, 6H), 3.00–3.03 (m, 2H), 3.46–3.55 (m, 2H), 4.09 (t, 2H), 7.10
(d, 2H), 7.16–7.22 (m, 3H), 7.27 (t, 2H), 7.36 (t, 1H), 7.44 (d, 1H), 12.4 (s, 1H)
1.74–2.27 (m, 2H), 3.20–3.61 (m, 10H), 4.03 (t, 2H), 4.31 (s, 2H), 7.21 (t, 1H), 7.36–7.48 (m, 5H), 7.63–7.67 (m,
3H), 12.00 (s, 1H)
1.66–1.70 (m, 2H), 2.20 (t, 2H), 2.26 (t, 4H), 2.89 (t, 4H), 3.85 (t, 2H), 6.59 (t, 1H), 6.72 (d, 2H), 7.02 (t, 3H),
7.19–7.25 (m, 2H), 7.46 (d, 1H)
DMSO-d6
DMSO-d6
5m
[10]. It was preferred to utilize a 300 mg/kg acetic acid
dose in this study. Acetylsalicylic acid (ASA) was used
as the reference drug.
and data obtained from IR (the IR spectra indicated
the presence of two carbonyl bands at 1685–1655 and
1645 and 1625 cm−1 for the ring carbonyl and amide
carbonyl, respectively, for compounds 5a–5h) and
NMR spectral analyses. Compounds 5i–5m have been
obtained as their hydrochloride salts. Tables 2 and 4
illustrate the 1H NMR spectral data and elemental
analyses, respectively.
Table 3 lists the antinociceptive activity of the com-
pounds as the percentage inhibition of stretching move-
ment of the animals in comparison to the control
group. Eight out of 13 compounds were found to be
Each compound was suspended in 0.5% car-
boxymethyl cellulose at a concentration of 10 mg/ml
and given orally to mice in groups of eight at the 100
mg/kg dose. One hour after this administration, pain
was induced by intraperitoneal injection of 3% solution
of acetic acid at the 300 mg/kg level. The control group
received carboxymethyl cellulose 1 h prior to injection
of acetic acid. Animals were placed in private cages 5
min after acetic acid injection and the number of
‘stretching’ per animal was recorded during the follow-
ing 10 min; percentage analgesic activity was calculated
by using the formula:
Table 3
Antinociceptive activity of the compounds 5a–5m
n−n%
Comp.
Antinociceptive
activity (%)
Activity compared with
aspirin
Precentage antinociceptive activity=
×100
n
n=average number of ‘stretching’ of the control group
n%=average number of ‘stretching’ of the test group
Aspirin
5a
5b
5c
5d
5e
5f
5g
5h
5I
5j
5k
5l
5m
40.96
21.46
71.76 *
77.52 *
77.74 *
55.16
35.59
15.99
15.99
60.08
1.00
0.52
1.75
1.89
1.82
1.34
0.87
0.39
0.39
1.46
0.66
2.14
1.86
2.37
The reference was administered according to the test
protocol.
4. Results and discussion
27.27
87.89 *
76.47 *
97.17 *
Thirteen 2(3H)-benzothiazolone derivatives were syn-
thesized. Their chemical structures, melting points and
percentage yields are shown in Table 1. Their chemical
structures have been elucidated by elemental analysis
* PB0.05.

B. C¸ akir et al. / Il Farmaco 54 (1999) 846–851
851
Table 4
Acknowledgements
Elemental analysis of the compounds synthesized
The Turkish Scientific and Technological Council
have supported this study (TUBITAK: project num-
ber SBAG/AYD 200).
Comp.
Calc. elemental analysis (Found) (%)
C
H
N
5a
5b
5c
5d
5e
5f
5g
5h
5i
62.04 (61.69)
57.52 (57.93)
69.45 (70.21)
65.37 (65.64)
63.13 (63.18)
57.52 (57.61)
65.37 (65.41)
63.13 (63.68)
57.59 (58.17)
53.41 (53.92)
64.68 (64.78)
57.27 (56.49)
67.95 (68.37)
6.25 (5.73)
5.52 (5.64)
6.36 (5.67)
5.76 (5.45)
6.62 (6.87)
5.52 (5.59)
5.76 (5.76)
6.62 (6.76)
6.44 (6.46)
6.08 (6.01)
6.72 (7.47)
6.18 (6.38)
6.55 (5.92)
9.65 (9.56)
9.59 (9.52)
7.36 (7.14)
11.44 (11.42)
9.20 (8.81)
9.59 (9.55)
11.44 (11.30)
9.20 (9.06)
8.95 (9.03)
8.90 (8.85)
7.18 (6.99)
9.54 (9.64)
11.89 (11.72)
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