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Synthesis and Analgesic and Anti-inflammatory Activity of Some New 6-Acyl-2-benzoxazolinone and 6-Acyl-2-benzothiazolinone Derivatives with Acetic Acid and Propanoic Acid Residues.

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Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
Serdar Ünlüa,
Tijen Önkola,
Yasemin Dündara,
Berna Ökçelika,
Esra Küpelib,
Erdem Yeşiladab,
Ningur Noyanalpana,
M. Fethi Şahina
a
b
Department of
Pharmaceutical Chemistry,
Faculty of Pharmacy,
Gazi University,
06330, Ankara, Turkey
Department of
Pharmacognosy, Faculty of
Pharmacy, Gazi University,
06330, Ankara, Turkey
Novel Analgesic and Anti-inflammatory Benzoxazole Derivatives
353
Synthesis and Analgesic and Anti-inflammatory
Activity of Some New (6-Acyl-2-benzoxazolinone
and 6-Acyl-2-benzothiazolinone Derivatives with
Acetic Acid and Propanoic Acid Residues
In this study for developing potent analgesic and anti-inflammatory compounds, we
synthesized 6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives
with acetic acid and propanoic acid side chain, and performed preliminary screening
of their in vivo analgesic and anti-inflammatory activities at a single dose of
100 mg/kg in mice by a p-benzoquinone-induced writhing test and a Carrageenaninduced hind paw edema model, respectively. We also determined their gastric ulceration effects in the tested animals. Propanoic acid derivatives were generally
found to have higher analgesic and anti-inflammatory activities, and among them,
3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (Compound 4 a) exhibited
the highest analgesic and anti-inflammatory activity. However, all compounds
showed lower anti-inflammatory effects than we observed for indomethacin at
10 mg/kg dose. Consequently, 6-acyl-2-benzoxazolinone/2-benzothiazolinones
having propanoic acid side chain might lead to further studies for developing better
candidates with potent analgesic and anti-inflammatory effects while acetic acid derivatives do not exhibit comparable satisfactory features.
Keywords: 2(3H)-Benzoxazolone; 2(3H)-Benzothiazolone; Aryl acetic acids; Aryl
propanoic acids; Analgesic and Anti-inflammatory compounds
Received: November 18, 2002; Accepted: January 6, 2003 [FP746]
DOI 10.1002/ardp.200300746
Introduction
Early studies demonstrated that 2-benzoxazolinone/
benzothiazolinone derivatives exhibit a variety of pharmacological effects, including analgesic and anti-inflammatory activity. Two decades ago, early reports from
Lespagnol [1] and Renard [2] indicated that (2-benzoxazolinon-3-yl)- and (6-acyl-2-benzoxazolinon-3-yl)alkanoic acids and their ethyl esters (Figure 1) showed a
greater analgesic potential than aspirin. In addition,
Aries [3] demonstrated that 3-acyl-2-benzoxazolinone
derivatives showed anti-inflammatory, analgesic, and
antipyretic activities. Moreover, 2-benzoxazolinone deCorrespondence: Serdar Ünlü, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University,
06330 Etiler, Ankara, Turkey. Phone: +90 312 212-6645, Fax:
+90 312 223-5018, e-mail: sunlu@gazi.edu.tr.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper
Nonsteroidal anti-inflammatory drugs (NSAIDs) show
the same side effects to a certain extent, including
gastrointestinal, renal and hematological toxicities.
Therefore, the development of new compounds in which
their analgesic and anti-inflammatory activities are separated from the above side effects has been a challenge
for many years.
Figure 1.
rivatives bearing the 2-pyridylethyl substituent at position 3 exhibited significant analgesic and anti-inflammatory activies [4].
As our laboratory continuously investigates new analgesic and anti-inflammatory drugs, we have previously reported that 2-(5-chloro-2-benzoxazolinon-3-yl)propanoic acid and (6-acyl-5-chloro-2-benzoxazolinon-3-yl)acetic acids [5, 6] (Figure 2), and 3-(arylpiperidinomethyl)-2benzoxazolinones (Figure 3), [7] especially the acids,
showed potent analgesic activity.
0365-6233/08/0353
354
Ünlü et al.
Figure 2.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
analgesic and anti-inflammatory activities of these compounds, there is no comparative study of the activity of
these derivatives. Therefore, we synthesized a series of
new 3-(6-acyl-5-chloro-2-benzoxazolinon-3-yl)- and
3-(6-acyl-2-benzothiazolinon-3-yl)propanoic acid derivatives to explore and compare their analgesic and antiinflammatory activities. Additionally, we also planned to
synthesize two new (6-acyl-2-benzothiazolinon-3-yl)acetic acids and some previously reported (2-benzoxazolinon-3-yl)- and (2-benzothiazolinon-3-yl)alkanoic
acid derivatives to complete the series and to obtain biological test results for a comparative study.
Results and disussion
Chemistry
Figure 3.
Additionally, 2-benzothiazolinone derivatives have been
reported to be potent analgesic and anti-inflammatory
agents. For instance, 6-benzoyl-2-benzothiazolinone
was screened for analgesic activity and reported as a
peripheral analgesic acting by release of an endogenous circulating opioid-like substance with a certain
anti-inflammatory and antipyretic activity [8]. Among other 2-benzothiazolinone derivatives, Tiaramide is a wellknown analgesic and anti-inflammatory agent (Figure 4)
[4–12].
The structures of the new and previously reported compounds are given in Table 1. 2-Benzoxazolinone, 5-chloro-2-benzoxazolinone, and 2-benzothiazolinone were
used as starting materials (Scheme 1). Acylation of 2benzoxazolinone and 2-benzothiazolinone with benzoic
acid derivatives was carried out in polyphosphoric acid
as reported in the literature. Acetic acid derivatives
(2 a–i) were synthesized by the alkaline hydrolysis of the
corresponding methyl esters (1 a–i) which were prepared by the reaction of 6-acyl-2-benzoxazolinone or 6acyl-2-benzothiazolinone derivatives with methyl chloroacetate in the presence of potassium carbonate. Propanoic acid derivatives (3 a–i) which were obtained from
the reaction of 6-acyl-2-benzoxazolinone or 6-acyl-2benzoxazolinone or 6-acyl-2-benzothiazolinone derivative with acrylonitrile in the presence of triethylamine in
distilled water.
The chemical structures of the compounds were elucidated by their elemental analysis, IR, and 1H-NMR spectral data which are given in the “Experimental Part”.
Methyl ester and propanenitrile derivatives were used to
synthesize corresponding alkanoic acids without further
analysis, except IR.
Figure 4.
Pharmacology
In our recent studies, we showed that (2-benzoxazolinon-3-yl)- or (2-benzothiazolinon-3-yl)acetamides
[13] and 6-acyl derivatives of these acetamides [14] alleviate the induced pain and suppress the induced inflammation with no observed toxicity.
Based on these reports, it is very clear that 2-benzoxazolinone and 2-benzothiazolinone structures are very
important heterocyclic cores for analgesic and anti-inflammatory activity. Although there are some reports on
In this first screening study, all compounds were tested
for their analgesic and anti-inflammatory activities at a
single dose of 100 mg/kg in mice by p-benzoquinone-induced writhing test [17] and Carrageenan-induced hind
paw edema model [4, 18], respectively. For comparison,
the active references aspirin and indomethacin were included in the analgesic and anti-inflammatory activity
tests. Indomethacin was used at a dose of 10 mg/kg according to a published report [4].
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
Novel Analgesic and Anti-inflammatory Benzoxazole Derivatives
355
Table 1. Chemical structures of the synthesized carboxylic acid derivatives.
Compound
X
R
R1
n
Mp (°C)
Crystallization solvent
Yield (%)
2 a [15]
4a
2b
4b
2c
4c
2 d [2]
4 d [2]
2 e [2]
4 e [2]
2 f [16]
4f
2 g [5, 6]
4g
2 h [5, 6]
4h
2 i [16]
4i
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
Cl
Cl
F
F
H
H
Cl
Cl
F
F
H
H
Cl
Cl
F
F
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
251
183–184
216–217
150–151
209–210
145–146
232
182
296
143
193–194
188–189
227
195–196
183
138–139
183
168
Ethanol/Water
Ethanol/Water
Ethanol/Water
Methanol
Methanol/Water
Ethanol/Water
Propanol
½ Dil. Acetic acid
Ethanol/Water
Benzene
Ethanol/Water
Ethanol
n-Butanol
Ethanol/Water
Ethanol/Water
Ethanol/Water
Ethanol/Water
Ethanol/Water
73
75
65
75
60
69
73
80
77
82
93
58
90
78
93
76
90
75
As seen in Table 2, all acetic acid and propanoic acid derivatives except compounds 2 a and 2 e showed equal or
higher analgesic activity than that of aspirin at 100 mg/kg
dose. Especially, in the case of 2-benzothiazolinone derivatives, the compound having unsubstituted 6-acyl
group and 3-propanoic acid side chain (4 a) showed the
highest analgesic activity (78.2 %). In addition, a fluorine
or chlorine substituent at the two-position on the 6-acyl
group of (2-benzothiazolinon-3-yl)propanoic acid derivatives (4 b and 4 c) caused a small decrease in the analgesic activity, although the activity was still higher than
that observed with aspirin. In contrast to propanoic acid
derivatives, the presence of a halogen substituent on the
6-acyl group of (2-benzothiazolinon-3-yl)acetic acids
(2 b and 2 c) caused a greater increase in analgesic activity when compared to the derivative with unsubstituted
6-acyl group (2 a). When we replaced the sulfur fivemembered ring by its oxygen analog i.e., 2-benzoxazolinone, the overall analgesic activity was decreased.
The highest activity in this series was observed with
compound 4 f having a 6-(2-fluorobenzoyl) group and a
propanoic acid side chain although this compound
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
caused gastric lesions in one of the six tested animals.
When the propanoic acid side chain is replaced with an
acetic acid side chain, again the 2-fluorobenzoyl derivative (2 f) exhibited the highest activity although the activity was not very pronounced (56.8 %). However, a chlorine substitution in the ring leading to 5-chloro-6-acyl-2benzoxazolinone derivatives caused a gradually increased analgesic activity in the acetic acid series
(2 g–i) in which the activity was comparable to 6-acyl-2benzothiazolinone derivatives while it did not have any
significant effect on the analgesic activity of the propanoic acid derivatives in the series. As observed with the 2benzothiazolinone and 2-benzoxazolinone derivatives,
the 5-chloro-2-benzothiazolinone derivatives also exhibited potent analgesic activity when they have a propanoic acid instead of an acetic acid side chain. As indicated
in Table 2, all compounds except for 2 c, 4 f, and 4 g did
not cause any gastric lesions and bleeding in the stomachs of tested animals.
The results of anti-inflammatory activity tests are given
in Table 3. Although the anti-inflammatory tests of most
of the compounds gave results reflecting their analgesic
356
Ünlü et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
Table 2. Analgesic activity of the compounds.
Scheme 1. Synthetic route of the title compounds.
Compound
Number
of writhing
± SEM
Control
39.80 ± 3.29
2a
Inhibition
(%)
Ratio of
ulceration
21.70 ± 1.12
45.5***
0/6
2b
14.00 ± 1.37
64.8***
0/6
0/6
2c
15.00 ± 2.08
62.3***
2/6
2d
18.20 ± 1.40
54.3***
0/6
2e
26.50 ± 2.26
33.4***
0/6
2f
17.20 ± 1.30
56.8***
0/6
2g
13.40 ± 0.93
66.3***
0/6
2h
14.20 ± 1.14
64.3***
0/6
2i
13.20 ± 1.08
66.8***
0/6
4a
8.67 ± 1.12
78.2***
0/6
4b
14.5 ± 1.38
63.6***
0/6
4c
11.80 ± 0.60
70.4***
0/6
4d
16.70 ± 2.14
58.0***
0/6
4e
17.30 ± 2.04
56.5***
0/6
4f
11.50 ± 0.92
71.1***
1/6
4g
17.00 ± 0.97
57.3***
3/6
4h
10.05 ± 1.06
73.6***
0/6
4i
19.20 ± 0.79
51.8***
0/6
Aspirin
18.00 ± 1.53
54.8***
0/6
Analgesic activity of the compounds and aspirin were tested at
100 mg/kg doses as described in “Experimental Part”. * P <
0.05; ** P < 0.01; *** P < 0.001.
Table 3. Anti-inflammatory activity of the compounds.
Compound
90 min
Control
2a
2b
2c
2d
43.00 ± 3.15
41.00 ± 4.11
(% 4.7)
34.20 ± 4.29
(% 20.5)
38.00 ± 3.98
(% 11.6)
39.20 ± 4.60
(% 8.8)
Swelling thickness (× 10–2 mm) ± SEM
(% inhibition)
180 min
270 min
50.50 ± 3.49
47.20 ± 3.54
(% 6.5)
40.70 ± 3.83
(% 19.4)
43.80 ± 3.87
(% 13.3)
43.00 ± 4.49
(% 14.9)
54.30 ± 4.15
50.50 ± 3.88
(% 6.9)
43.70 ± 3.64
(% 19.5)
43.80 ± 3.87
(% 19.3)
45.80 ± 3.83
(% 15.7)
360 min
63.00 ± 3.06
55.30 ± 3.40
(% 12.2)
47.00 ± 4.75
(% 25.4)
48.30 ± 4.18
(% 23.3)
50.20 ± 4.14
(% 20.3)
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
Novel Analgesic and Anti-inflammatory Benzoxazole Derivatives
357
Table 3. (continued).
Compound
90 min
Swelling thickness (× 10–2 mm) ± SEM
(% inhibition)
180 min
270 min
360 min
2e
43.00 ± 3.25
(–)
48.20 ± 3.05
(% 4.6)
52.30 ± 2.70
(% 3.7)
55.50 ± 3.74
(% 11.9)
2f
37.00 ± 4.41
(% 13.9)
42.50 ± 3.86
(% 15.8)
47.20 ± 4.01
(% 13.1)
50.80 ± 4.46
(% 19.4)
2g
36.80 ± 3.94
(% 14.4)
41.70 ± 4.43
(% 17.4)
41.20 ± 2.71
(% 24.1)
43.70 ± 3.95
(% 30.6)*
2h
37.20 ± 3.61
(% 13.5)
41.80 ± 3.49
(% 17.2)
43.50 ± 3.68
(% 19.9)
43.70 ± 2.25
(% 30.6)*
2i
35.30 ± 3.09
(% 17.9)
42.50 ± 3.27
(% 15.8)
43.20 ± 3.12
(% 20.4)
46.70 ± 2.99
(% 25.9)
4a
34.20 ± 3.57
(% 20.5)
38.30 ± 2.65
(% 24.2)
33.80 ± 2.90
(% 37.8)*
37.20 ± 3.22
(% 40.9)***
4b
37.00 ± 4.12
(% 13.9)
42.30 ± 4.08
(% 16.2)
43.00 ± 2.46
(% 20.8)
48.00 ± 2.98
(% 23.8)
4c
36.50 ± 4.78
(% 15.1)
40.30 ± 4.86
(% 20.2)
39.50 ± 3.14
(% 27.3)
43.50 ± 3.18
(% 30.9)*
4d
40.00 ± 4.17
(% 6.9)
44.20 ± 4.49
(% 12.5)
47.50 ± 4.54
(% 12.5)
52.20 ± 4.32
(% 17.1)
4e
39.20 ± 4.22
(% 8.8)
45.30 ± 3.68
(% 10.3)
50.00 ± 3.48
(% 7.9)
54.30 ± 3.40
4f
38.30 ± 4.46
(% 10.9)
44.00 ± 4.28
(% 12.9)
47.00 ± 3.69
(% 13.4)
50.70 ± 3.31
(% 19.5)
4g
36.70 ± 4.86
(% 14.7)
43.20 ± 4.69
(% 14.5)
47.70 ± 4.29
(% 12.2)
52.80 ± 3.98
(% 16.2)
4h
32.00 ± 3.09
(% 25.6)
38.00 ± 2.88
(% 24.8)
36.70 ± 2.64
(% 32.4)
39.30 ± 1.94
(% 37.6)**
4i
40.20 ± 4.13
(% 6.5)
46.00 ± 4.20
(% 8.9)
49.20 ± 4.26
(% 9.4)
53.50 ± 4.23
(% 15.1)
Indomethacin
26.3 ± 3.11
(% 38.8)
31.20 ± 3.44
(% 38.2)
29.50 ± 2.05
(% 45.7)***
31.80 ± 2.68
(% 49.5)***
(% 13.8)
Anti-inflammatory activities of the compounds were tested at 100 mg/kg doses and anti-inflammatory activity of indomethacin was
tested at 10 mg/kg dose as described in “Experimental”. * P < 0.05; ** P < 0.01; *** P < 0.001.
activities, the overall anti-inflammatory activities were
lower than that of observed for indomethacin at a does of
10 mg/kg. As expected, compounds with the highest analgesic activity (4 a, 4 c, and 4 h) also exhibited a higher
anti-inflammatory activity.
In conclusion, based on the above and our previously
published data [5, 6] 2-benzothiazolinone can be considered a better heterocyclic core than 2-benzoxazolinone
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
and according to the test results, all propanoic acid derivatives, especially compound 4, might lead to further
studies developing compounds with better analgesic
and anti-inflammatory activity while the feature are not
present to a sufficient extent in the acetic acid derivatives. Futhermore, since the propanoic acid residue
caused an overall increase in the analgesic and anti-inflammatory activity, the compounds bearing a longer
358
Ünlü et al.
chain, such as butanoic acid residue on position 3 of 2benzothiazolinone or the 2-benzoxazolinone ring, might
be investigated as well. Since the 6-acyl-substituted derivatives tested in this study have weak anti-inflammatory activities and, according to the receptor model proposed by Shen [19] based on indomethacin and its analogs, investigations on the analgesic and anti-inflammatory properties of 7-acyl-2-benzothiazolinone/2-benzoxazolinone derivatives which might fit the receptor model
of Shen better are currently under research in our laboratory.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
methyl chloroacetate (5.75 mmol) in 30 mL acetone were heated to reflux and stirred for 4 h. 100 g ice water was added to the
cooled (0–10 °C) reaction mixture. After stirring for 1 h, the precipitated solid product was collected by suction filtration,
washed with water, dried, and crystallized from the appropriate
solvent.
Methyl [6-benzoyl-2-benzothiazolinone-3-yl]acetate (1 a)
Recrystallized from ethanol (yield: 80 %), mp 133–135 °C, IR
νmax cm–1 (KBr): 1734, 1694, 1657.
Methyl [6-(2-chlorobenzoyl)-2-benzothiazolinon-3-yl]acetate
(1 b)
Acknowledgement
Recrystallized from methanol/water (yield 79 %), mp 115–
116 °C, IR νmax cm–1 (KBr): 1735, 1685, 1655.
This study is partly supported by a grant from Gazi University Research Fund (Project No: 01/2001-12).
Methyl [6-(2-fluorobenzoyl)-2-benzothiazolinon-3-yl]acetate
(1 c)
Experimental
Recrystallized from methanol/water (yield 82 %), mp 158–
159 °C, IR νmax cm–1 (KBr): 1733, 1693, 1656.
Chemistry
Methyl [6-(2-chlorobenzoyl)-2-benzoxazolinon-3-yl]acetate (1 e)
Chemicals and all the solvents used in this study were purchased locally from Merck AG, Aldrich Chemical.
Recrystallized from methanol/water (yield 86 %), mp 108–
109 °C, IR νmax cm–1 (KBr): 1779, 1762, 1664.
6-benzoyl-2-benzothiazolinone [15], 6-(2-chlorobenzoyl)-2benzothiazolinone [20], 6-(2-fluorobenzoyl)-2-benzothiazolinone [15, 21], 6-benzoyl-2-benzoxazolinone [2, 22], 6-(2chlorobenzoyl)-2-benzoxazolinone [2], 6-(2-fluorobenzoyl)-2benzoxazolinone [16], 6-benzoyl-5-chloro-2-benzoxazolinone
[5, 6], 6-(2-chlorobenzoyl)-5-chloro-2-benzoxazolinone [5, 6],
6-(2-fluorobenzoyl)-5-chloro-2-benzoxazolinone [16], 3-(6benzoyl-2-benzoxazolinone-3-yl)propanenitrile (3 d) [23], 3[(6-(2-chlorobenzoyl)-2-benzoxazolinone-3-yl])propanenitrile
(3 e) [23], 3-(6-benzoyl-5-chloro-2-benzoxazolinon-3-yl)propanenitrile (3 g) [23], (6-benzoyl-2-benzothiazolinon-3-yl)acetic acid (2 a) [15], (6-benzoyl-2-benzoxazolinon-3-yl)acetic acid
(2 d) [2], [6-(2-chlorobenzoyl)-2-benzoxazolinon-3-yl)]acetic
acid (2 e) [2], [6-(2-fluorobenzoyl)-2-benzoxazolinon-3-yl)]
acetic acid (2 f) [16], (6-benzoyl-5-chloro-2-benzoxazolinon-3yl)acetic acid (2 g) [5, 6], [6-(2-chlorobenzoyl)-5-chloro-2benzoxazolinon-3-yl)] acetic acid (2 h) [5, 6], [6-(2-fluorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl)] acetic acid (2 i) [16],
3-(6-benzoyl-2-benzoxazolinon-3-yl)propanoic acid (4 d) [2],
3-[6-(2-chlorobenzoyl)-2-benzoxazolinone-3-yl)]propanoic acid
(4 e) [2] were synthesized according to the procedures published in the literature.
Melting points were determined using an Electrothermal-9300
Digital Melting Points Apparatus (Electrothermal Inc., Essex,
<uk) and are uncorrected. The IR spectra of the compounds
were recorded on a Bruker Vector 22 IR (Opus Spectroscopic
Software Version 2.0) spectrometer (Bruker Analytik GmbH,
Ettlingen, Germany). The 1H-NMR spectra were recorded on
Bruker 400 MHz NMR spectrometer (Bruker). Chemical shifts
are reported in parts per million relative to internal standard
· tetramethylsilane. Microanalyses were performed by TÜBITAK
Analytical Laboratory (Ankara, Turkey). Elemental data for all
new carboxylic acid derivatives are within ±0.4 % of the theoretical value.
Synthesis of methyl (6-acyl-2-oxobenzazolinbenzoxazolinon/
benzothiazolinone-3-yl)acetate derivatives (1 a–i)
The mixture of 6-acyl-2-benzoxazolinone/benzothiazolinone
derivatives (5 mmol), potassium carbonate (5.75 mmol) and
Methyl [6-(2-fluorobenzoyl)-2-benzoxazolinon-3-yl]acetate (1 f)
Recrystallized from ethanol (yield 83 %), mp 106 °C, IR νmax
cm–1 (KBr): 1768, 1745, 1649.
Methyl [6-benzoyl-5-chloro-2-benzoxazolinon-3-yl]acetate (1 g)
Recrystallized from ethanol (yield 91.9 %), mp 105–106 °C, IR
νmax cm–1 (KBr): 1770, 1730, 1655.
Methyl [6-(2-chlorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]acetate (1 h)
Recrystallized from methanol/water (yield 80 %), mp 104–
105 °C, IR νmax cm–1 (KBr): 1786, 1746, 1673.
Methyl [6-(2-fluorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]acetate (1 i)
Recrystallized from ethanol (yield 81 %), mp 110–112 °C, IR
νmax cm–1 (KBr): 1775, 1755, 1665.
Synthesis of (6-acyl-2-benzoxazolinon/benzothiazolinon-3-yl)acetic acid derivatives (2 a–i)
Methyl (6-acyl-2-benzoxazolinon/benzothiazolinon-3-yl)acetate derivative (2 mmol) and sodium hydroxide (2 mmol) in
30 mL ethanol/water (25:5) was refluxed for 4 h. After cooling to
room temperature, the mixture was acidified with 1 N HCl
(30 mL) to give a solid precipitate.The product was collected by
suction filtration, washed with water, dried, and crystallized
from the appropriate solvent.
[6-(2-chlorobenzoyl)-2-benzothiazolinon-3-yl]acetic acid (2 b)
Recrystallized from ethanol/water (yield 65 %), mp 216–
217 °C, 1H-NMR (DMSO-d6) δ: 12.87 (1 H, s, COOH), 7.98 (1 H,
d, 2-benzothiazolinone-H7), 7.54 (1 H, dd, 2-benzothiazolinone-H5), 7.47 (1 H, m, benzoyl-H3), 7.38 (1 H, m, benzoyl-H6), 7.27 (1 H, d, 2-benzothiazolinone-H4), 7.18 (2 H, m,
benzoyl-H4,H5), 4.72 (2 H, s, CH2-CO). IR νmax cm–1 (KBr):
3253, 1740, 1701, 1683, 1637, 1568. Anal.: C16H10ClNO4S.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
Novel Analgesic and Anti-inflammatory Benzoxazole Derivatives
[6-(2-fluorobenzoyl)-2-benzothiazolinon-3-yl]acetic acid (2 c)
Recrystallized from methanol-water (yield 60 %), mp 209–
210 °C, 1H-NMR (DMSO-d6) δ: 12.94 (1 H, s, COOH), 8.15 (1 H,
d, 2-benzothiazolinone-H7), 7.69 (1 H, dd, 2-benzothiazolinone-H5), 7.60 (2 H, m, benzoyl-H3,H6), 7.51 (2 H, m, benzoyl-H4,H5), 7.46 (1 H, d, 2-benzothiazolinone-H4), 4.79 (2 H,
s, CH2-CO). IR νmax cm–1 (KBr): 3250–2750 (b, m), 3060, 1720,
1683, 1642, 1592. Anal.: C16H10FNO4S.
Synthesis of 3-(6-acyl-2-benzoxazolinon/benzothiazolinon-3yl)propanenitrile derivatives (3 a–i)
Acrylonitrile (12.0 mmol) was added to the solution of 6-acyl-2benzoxazolinone/benzothiazolinone derivative (10.0 mmol)
and triethylamine (12.0 mmol) in 50 mL water. After heating
(6 h) at 50–60 °C while stirring, the mixture was stirred at room
temperature for further 18 h. A solid precipitate formed which
was filtered, washed with water to neutral pH, dried, and crystallized from the appropriate solvent.
3-[6-benzoyl-2-benzothiazolinon-3-yl]propanenitrile (3 a)
Recrystallized from methanol (yield 71 %), mp 102–103 °C, IR
νmax cm–1 (KBr): 2245, 1678, 1647.
3-[6-(2-chlorobenzoyl)-2-benzothiazolinon-3-yl]propanenitrile
(3 b)
Recrystallized from methanol/water (yield 70 %), mp 96–97 °C,
IR νmax cm–1 (KBr): 2250, 1714, 1676.
359
zolinone-H4, benzoyl-H3, H5), 4.22 (2 H, t, N-CH2), 2.68 (2 H, t,
CH2-CO). IR νmax cm–1 (KBr): 3300–2750 (b, m), 3065, 1732,
1643, 1588. Anal.: C17H13NO4S.
3-[6-(2-chlorobenzoyl)-2-benzothiazolinon-3-yl]propanoic acid
(4 b)
Recrystallized from methanol (yield 75 %), mp 150–151 °C, 1HNMR (DMSO-d6) δ: 12.27 (1 H, s, COOH), 8.10 (1 H, d, 2-benzothiazolinone-H7), 7.79 (1 H, dd, 2-benzothiazolinone-H5),
7.62–7.47 (5 H, m, 2-benzothiazolinone-H4, benzoyl-H), 4.20
(2 H, t, N-CH2), 2.65 (2 H, t, CH2-CO). IR νmax cm–1 (KBr):
3250–2700 (b, m), 3060, 2937, 1695, 1667, 1589. Anal.:
C17H12ClNO4.
3-[6-(2-fluorobenzoyl)-2-benzothiazolinon-3-yl]propanoic acid
(4 c)
Recrystallized from ethanol/water (yield 69 %), mp 145–
146 °C, 1H-NMR (DMSO-d6) δ: 12.37 (1 H, s, COOH), 8.15 (1 H,
s, 2-benzothiazolinone-H7), 7.76 (1 H, d, 2-benzothiazolinoneH5), 7.67 (1 H, m, benzoyl-H3), 7.56 (2 H, m, 2-benzothiazolinone-H4, benzoyl-H6), 7.38 (2 H, m, benzoyl-H4,H5), 4.21
(2 H, t, N-CH2), 2.67 (2 H, t, CH2-CO). IR νmax cm–1 (KBr):
3250–2750 (b, m), 2962, 1747, 1655, 1640, 1593. Anal.:
C17H12FNO4S.
3-[6-(2-fluorobenzoyl)-2-benzoxazolinon-3-yl]propanoic acid
(4 f)
3-[6-(2-fluorobenzoyl)-2-benzoxazolinon-3-yl]propanenitrile (3 f)
Recrystallized from ethanol (yield 58 %), mp 188–189 °C, 1HNMR (DMSO-d6) δ: 12.29 (1 H, s, COOH), 7.81 (2 H, m, benzoyl-H3,H6), 7.68 (1 H, d, 2-benzoxazolinone-H7), 7.64 (1 H,
dd, 2-benzoxazolinone-H5), 7.50 (1 H, d, 2-benzoxazolinoneH4), 7.39 (2 H, m, benzoyl-H4,H5), 4.09 (2 H, t, N-CH2), 2.76
(2 H, t, CH2-CO). IR νmax cm–1 (KBr): 3250–2750 (b, m), 3075,
2940, 1769, 1707, 1650, 1594. Anal.: C17H12FNO5.
Recrystallized from methanol (yield 65 %), mp 161 °C, IR νmax
cm–1 (KBr): 2252, 1767, 1648.
3-(6-benzoyl-5-chloro-2-benzoxazolinon-3-yl)propanoic acid
(4 g)
3-[6-(2-chlorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]propanenitrile (3 h)
Recrystallized from ethanol/water (yield 78 %), mp 195–
196 °C, 1H-NMR (DMSO-d6) δ: 12.40 (1 H, s, COOH), 7.87–
7.81 (4 H, m, 2-benzoxazolinone-H4,H7, benzoyl-H2,H6), 7.69
(3 H, m, benzoyl-H3,H4,H5), 4.21 (2 H, t, N-CH2), 2.89 (2 H, t,
CH2-CO). IR νmax cm–1 (KBr): 3200–2500 (b, m), 3060, 1770,
1665, 1600, 1480. Anal.: C17H12ClNO5.
3-[6-(2-fluorobenzoyl)-2-benzothiazolinon-3-yl]pyropanenitrile
(3 c)
Recrystallized from ethanol (yield 71 %), mp 95–97 °C, IR νmax
cm–1 (KBr): 2245, 1660–1650.
Recrystallized from ethanol (yield 65 %), mp 140 °C, IR νmax
cm–1 (KBr): 2245, 1770, 1760.
3-[6-(2-fluorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]propanenitrile (3 i)
Recrystallized from ethanol-water (yield 60.8 %), mp 91–92 °C,
IR νmax cm–1 (KBr): 2250, 1790–1770, 1670.
Synthesis of 3-(6-acyl-2-benzoxazolinon/benzothiazolinon-3yl)propanoic acid derivatives (4 a–i)
3-(6-acyl-2-benzoxazolinon/benzothiazolinon-3-yl)propanenitrile derivative (10.0 mmol) was added to (50 mL) of a N,Ndimethylformamid/water/sulphuric acid mixture (1:1:2). After
stirring at room temperature for 2 hours, the mixture was refluxed for 4 hours, after cooling to the room temperature, it was
poured into ice water (100 g). The precipitate formed was
filtered by suction filtration, washed with water, dried, and
crystallized from the appropriate solvent.
3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (4 a)
Recrystallized from ethanol/water (yield 75 %), mp 183–
184 °C, 1H-NMR (DMSO-d6) δ: 12.39 (1 H, s, COOH), 8.11 (1 H,
d, 2-benzothiazolinone-H7), 7.74 (3 H, m, 2-benzothia-
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
3-[6-(2-chlorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]propanoic acid (4 h)
Recrystallized from ethanol/water (yield 76 %), mp 138–
139 °C, 1H-NMR (DMSO-d6) δ: 12.49 (1 H, s, COOH), 7.80 (1 H,
s, 2-benzoxazolinone-H7), 7.71 (2 H, m, benzoyl-H3,H6), 7.66
(1 H, s, 2-benzoxazolinone-H4), 7.62 (2 H, m, benzoyl-H4,H5),
4.19 (2 H, t, N-CH2), 2.88 (2 H, t, CH2-CO). IR νmax cm–1 (KBr):
3500–3100 (b, m), 3095, 1760, 1690, 1655, 1620, 1600, 1485.
Anal.: C17H11Cl2NO5.
3-[6-(2-fluorobenzoyl)-5-chloro-2-benzoxazolinon-3-yl]propanoic acid (4 i)
Recrystallized from ethanol/water (yield 75 %), mp 168 °C, 1HNMR (DMSO-d6) δ: 12.33 (1 H, s, COOH), 7.74–7.63 (3 H, m, 2benzoxazolinone-H7, benzoyl-H3,H6), 7.57 (1 H, s, 2-benzoxazolinone-H4), 7.35 (2 H, m, benzoyl-H4,H5), 4.06 (2 H, t, NCH2), 2.75 (2 H, t, CH2-CO). IR νmax cm–1 (KBr): 3500–3110 (b,
m), 3100, 1765, 1750, 1660, 1620, 1600, 1480. Anal.:
C17H11ClFNO5.
360
Ünlü et al.
Pharmacology
Animals
Male Swiss albino mice (The Animal Breeding Laboratories of
Refik Saydam Hlfzlslhha Institute, Ankara, Turkey), weighing
20–25 g, were used for all experiments. The animals were kept
in colony cages (6 mice each), maintained on standard pellet
diet, water ad libitum, and left for two days for acclimatization
before the experimental session. The food was withdrawn on
the day before the experiment, but free access of water was allowed. All experiments were carried out according to the suggested ethical guidelines for the care of laboratory animals.
Preparation of test samples for bioassay
Test samples were suspended in a mixture of distilled H2O and
0.5 % sodium carboxymethyl cellulose (CMC) and were given
orally to the test animals. The animals of the control group received the same experimental handling except that the drug
treatment was replaced with appropriate volumes of the dosing
vehicle. Either Indomethacin (10 mg/kg) or acetyl salicylic acid
(ASA) in 0.5 % CMC (100 mg/kg) was used as reference drug.
p-Benzoquinone-induced writhing test [17]
60 min after the oral administration of test samples, the mice
were injected intraperitoneally with 0.1 mL/10 g body weight of
2.5 % (v/v) p-benzoquinone (PBQ) solution in distilled H2O
(PBQ, Merck, Darmstadt, Germany). Control animals received
an appropriate volume of dosing vehicle. The mice were then
kept individually for observation and the total number of abdominal contractions (writhing movements) was counted for
the next 15 min, starting on the 5th min after the PBQ injection.
The data represent average values of the total number of
writhes observed.The analgesic activity was expressed as percentage change from writhing controls.
Carrageenan-induced hind paw edema test
The test was performed according to the method of Kasahara
et al. [4, 18]. The difference in footpad thickness between the
right and left foot was measured with a pair of dial thickness
gauge callipers (Ozaki Co., Tokyo, Japan). Mean values of
treated groups were compared with mean values of a control
group and analyzed using statistical methods. 60 min after the
oral administration of the test sample or dosing vehicle each
mouse was injected with freshly prepared (0.5 mg/25 mL) suspension of carrageenan (Sigma, St. Louis, Mo, USA) in physiological saline (154 mM NaCl) into subplantar tissue of the right
hind paw and 25 µL of saline solution was injected into that of
the left hind paw as secondary control. Measurements were
done and evaluated every 90 min during 360 min after induction
of inflammation, as described above.
Gastric side ulceration effects
After the analgesic activity experiment, mice were killed under
deep ether anesthesia and stomachs were removed. Then the
abdomen of each mouse was opened through great curvature
and examined under the dissecting microscope for lesion or
bleedings.
Statistical analysis of data
Data obtained from the animal experiments were expressed as
the mean standard error (±SEM). Statistical differences between the treatments and the control were tested by ANOVA
test. Data with p < 0.05 value was considered to be significant.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 353–361
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© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Key-Technologies of the Future
VINCENZO BALZANI, Italy,
ALBERTO CREDI, and
MARGHERITA VENTURI, all of
University of Bologna, Italy
Molecular Devices and
Machines
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