4-(5-Chloro-2(3H)-benzoxazolon-3-yl) Butanoic Acid Derivatives: Synthesis, Antinociceptive and Anti-inflammatory Properties

Article abstract of DOI:10.1002/ardp.200300722

In this study, 4-(5-chloro-2(3H)-benzoxazolone-3-yl)butanoic acid and its ethyl ester as well as its ten new amide derivatives have been synthesized. Their structures have been elucidated by IR, ¹H-NMR spectra and elemental analysis. The compounds were screened for antinociceptive and anti-inflammatory activities. The highest antinociceptive and anti-inflammatory activities were exhibited by Compound 11 which has carboxylic acid structure. A various decrease in antinociceptive and anti-inflammatory activity was observed by amidation of the carboxylic acid moiety of this compound.

Full text of DOI:10.1002/ardp.200300722

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 477–482
4-(5-Chloro-2(3H)-Benzoxazolon-3-yl)Butanoic acid derivatives 477
Hayrettin Ozan Gulcana,
4-(5-Chloro-2(3H)-benzoxazolon-3-yl) Butanoic Acid
Derivatives: Synthesis, Antinociceptive and
Anti-inflammatory Properties
Esra Kupelib,
Serdar Unlua,
Erdem Yesiladab,
Mustafa Fethi Sahina
In this study, 4-(5-chloro-2(3H)-benzoxazolone-3-yl)butanoic acid and its ethyl ester
as well as its ten new amide derivatives have been synthesized. Their structures
have been elucidated by IR, H-NMR spectra and elemental analysis. The com-
pounds were screened for antinociceptive and anti-inflammatory activities. The
highest antinociceptive and anti-inflammatory activities were exhibited by Com-
pound 11 which has carboxylic acid structure.A various decrease in antinociceptive
and anti-inflammatory activity was observed by amidation of the carboxylic acid
moiety of this compound.
a
Department of
1
Pharmaceutical Chemistry,
Faculty of Pharmacy,
Gazi University,
06330, Etiler, Ankara, Turkey
Department of
b
Pharmacognosy,
Faculty of Pharmacy,
Gazi University,
06330, Etiler, Ankara, Turkey
Keywords: 2(3H)-Benzoxazolone; Butanamides; Synthesis; Antinociceptive; Anti-
inflammatory
Received: August 21, 2002; Accepted: December 11, 2003 [FP722]
DOI 10.1002/ardp.200300722
Meanwhile, Dogruer reported the antinociceptive and
anti-inflammatory activities of some (2(3H)-benzoxazo-
Introduction
Considerable numbers of research efforts on developing
new analgesic and anti-inflammatory drugs are being
made since the many of the currently used non- steroidal
anti-inflammatory drugs (NSAIDs) have serious side ef-
fects including gastrointestinal and renal toxicity.There-
fore, developing agents without or with minimal side ef-
fects is an evolving area in the design of new NSAIDs.
lon-3-yl) and (2(3H)-benzothiazolon-3-yl)acetic acid de-
rivatives [10–11]. Onkol and co-workers pointed out that
(2(3H)-benzoxazolon-3-yl)propanamide and propanoic
acid derivatives also had more pronounced antinocicep-
tive and anti-inflammatory activity than the correspond-
ing acetic acid derivatives [12–13].
These studies have directed us to synthesize new
2(3H)-benzoxazolone derivatives carrying butanamide
moiety in the position 3 of the ring and to test their antino-
ciceptive, anti-inflammatory activities at 100 mg/kg
single dose.
Although 2(3H)-benzoxazolone derivatives which have
been associated with various types of biological proper-
ties such as hypnotic, antipyretic, muscular relaxant and
antibacterial [1–5], this class of compounds have
emerged during the last two decades as potential anal-
gesic and anti-inflammatory agents.
After the report made by Close and co-workers [6] on the
analgesic activities of 2(3H)-benzoxazolones, they have
been structurally modified at the positions 3, 5 and 6 in
order to screen for their antinociceptive properties.
Results and discussion
Chemistry
Renard [7] and Lespagnol [8] synthesized 3-alkanoic ac-
idderivatives of 2(3H)-benzoxazolonewithanalgesic ac-
tivity activities that were more potent than aspirin.
4-(5-chloro-2(3H)-benzoxazolon-3-yl)butanoic acid and
its ethyl ester as well as its ten new amide derivatives
were synthesized by using 2(3H)-benzoxazolone as the
starting material.The chemical structures of the synthe-
sized compounds are reported in Table 1 and a scheme
of the synthetic route is shown in Figure 1.
(6-Acyl-2(3H)-benzoxazolone-3-yl)alkanoic acid and
ethyl ester derivatives also exhibited analgesic activity
[9].
In the synthesis of title compounds, the sodium salt of
5-chloro-2(3H)-benzoxazolonewaspreparedby treating
2(3H)-benzoxazolone with sodium ethoxyde in absolute
ethanol and evaporated to dryness. Then, the sodium
salt was reacted with ethyl 4-chlorobutanoate.The prod-
uct of this reaction was hydrolyzed to free acid in the
presence of acid catalyst. After treatment of free acid
Correspondence: Mustafa Fethi Sahin, Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi
University, 06330, Etiler, Ankara, Turkey. Phone:
+90 312 2126645, Fax: +90 312 2235018, e-mail:
mfsahin@tr.net
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

478 Gulcan et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 477–482
Table 1. Chemical structures of synthesized compounds.
Figure 1. Synthetic route of the title compounds.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 477–482
4-(5-Chloro-2(3H)-Benzoxazolon-3-yl)Butanoic acid derivatives 479
Table 2. Antinociceptive activity of compounds 1–12.
with SOCl2, the amide derivatives were obtained by the
reaction of acid chloride with appropriate amines.
Com-
pound
Number of
writhing
± SD
Antinoci-
ceptive
activity (%) tested animals
Gastric lesion
incidence in
In the IR spectra of butanamide derivatives, carbonyl
stretching bands of the amide function were seen at
about 1635–1650 cm–1 and the 2(3H)-benzoxazolone
ring was seen at about 1760–1780 cm–1.The data of the
Control
33 4.86
23.5 4.42
13 3.16
18.5 3.45
28.0 5.47
16 4.47
0/6
1
2
3
4
5
6
7
8
9
28.8**
60.6***
43.9***
15.2
51.5***
60.6***
31.2**
67.6***
63.0***
57.6***
69.7***
43.0***
50.6***
0/6
2/6
1/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
1/6
1
IR and H-NMR spectra are presented in the mono-
graphs of the compounds.
Pharmacology
13 2.76
22.7 2.73
10.7 2.50
12.2 2.14
14 3.74
10 2.00
18.8 3.43
The antinociceptive and anti-inflammatory activities of
the compounds were screened by the p-benzoquinone-
induced stretching test and carrageenan- induced paw
edema model using aspirin and indomethacin as the ref-
erences, respectively.
10
11
12
According to the test results (Table 2 and 3), the highest
antinociceptive and anti-inflammatory activities were ex-
hibited by Compound 11, which has carboxylic acid
Aspirin 16.3 3.39
*: p < 0.05
**: p < 0.01
***: p < 0.001
Table 3. Anti-inflammatory activity of the compounds 1–12.
Compound
Dose mg/kg
Swelling in thickness (× 10–2 mm) ± SEM (% Inhibition)
90 min
180 min
270 min
360 min
Control
40.2 4.61
32.2 3.36
(19.6)
32.7 3.44
(18.6)
34.5 3.09
(14.1)
36.7 3.35
(8.7)
35.2 4.36
(12.4)
31.3 2.88
(22.0)
33.8 2.75
(15.9)
34.3 3.09
(14.6)
35.7 3.84
(11.1)
36.5 2.59
(03.4)
34.2 3.95
(14.9)
35.0 3.45
(12.9)
46.0 4.07
38.8 2.49
(15.6)
38.8 3.55
(15.6)
37.2 1.11
(19.1)
41.7 3.38
(9.3)
36.5 2.57
(20.6)
36.0 3.25
(21.7)
40.2 2.49
(12.6)
35.5 2.23
(22.8)*
36.3 3.58
(21.0)
40.2 2.98
(14.1)
33.5 3.80
(27.1)*
40.0 3.72
(13.0)
52.8 3.91
39.0 2.32
(26.1)*
39.2 3.51
(25.7)*
40.5 1.23
(23.2)*
42.8 2.26
(18.9)
38.0 2.35
(28.0)**
36.0 2.73
(31.8)**
41.5 3.57
(21.4)
35.2 2.10
(33.3)**
34.0 3.52
(35.6)**
41.0 2.76
(29.1)*
35.0 3.19
(33.7)**
42.3 3.53
(19.8)
59.0 4.03
44.5 1.96
(24.5)**
38.2 2.65
(35.2)**
42.8 1.74
(27.4)**
47.7 3.72
(19.1)
38.0 3.49
(33.9)**
36.8 3.88
(37.6)**
43.3 2.49
(26.6)**
37.3 2.23
(36.7)***
36.3 2.74
(38.4)***
43.8 4.39
(34.8)**
32.0 1.61
(45.7)***
43.0 2.97
(27.1)**
1
100
100
100
100
100
100
100
100
100
100
100
100
10
2
3
4
5
6
7
8
9
10
11
12
Indomethacin
26.5 2.06
(29.9)*
27.3 1.91
(41.7)**
27.2 2.76
(52.9)***
29.0 1.07
(56.8)***
*: p < 0.05
**: p < 0.01
***: p < 0.001
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

480 Gulcan et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 477–482
structure.Avariousdecreaseinantinociceptiveandanti-
inflammatory activity was observed in the amide deriva-
tives of these compounds.The amide derived from Com-
pound 11 with 4-(2- or 4-flouorophenyl)piperazine re-
sulted in the lowest antinociceptive and anti-inflammato-
ry activity (Compound 1 and 7). However, Compound 2,
6, 8, 9, 10 and 11 showed higher antinociceptive activity
than aspirin, although anti-inflammatory activities of
these compounds are lower than that of indomethacin.
Compounds 2, 6, 8 and 9 showed the highest biological
activity among the amide derivatives. The most active
compounds except compound Compound 2 caused no
gastric side effect.Therefore, we aim to search the inhibi-
tion effects of all compounds on COX enzymes.
lution was stirred for further 30 min.and evaporated to dryness.
The residue was dissolved in 30 mL acetone, triethylamine hy-
drochloride was filtered off by suction filtration and then the
product was collected by evaporating to dryness and crystalliz-
ing from appropriate solvent.
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-(4-
fluorophenyl)piperazine (1)
1
Crystallized from ethanol (yield 49%, m.p. 69°C). H-NMR
(DMSO-d6).– δ 7.06–6.6 (m, 7H, 2-benzoxazolinone-H4-6-7 and
phenyl-H2-3-5-6), 3.84 (t, 2H, butanoyl-H4), 3.65 (t, 2H, pipera-
zine-H6(2)), 3.42 (t, 2H, piperazine-H2(6)), 2.94 (m, 4H, pipera-
zine-H3-5), 2.31 (t, 2H, -CH2-CO-), 2.03 ppm (m, 2H, butanoyl-
H3). IR (KBr cm–1). – 1772 (C=O lactam), 1638 (C=O amide).
Anal. C21H21ClFN3O3.
1-[4-(5-Chloro-2(3H)-benzoxazolone-3-yl)butanoyl]-4-benzyl-
piperazine (2)
1
Crystallized from ethanol (yield 55%, m.p. 89°C). H-NMR
(DMSO-d6). – δ 7.32–7.06 (m, 5H, phenylH2-3-4-5-6), 7.06–6.85
(m, 3H, 2-benzoxazolinone-H4-6-7), 3.79 (t, 2H, butanoyl-H4),
3.51 (t, 2H, piperazine-H6(2)), 3.42 (s, 2H, -N-CH2-Ph), 3.29 (t,
2H, piperazine-H2(6)), 2.30 (m, 6H, piperazine-H3-5 and -CH2-
CO-), 1.97 ppm (m, 2H, butanoyl-H3). IR (KBr cm–1). – 1784
(C=O lactam), 1637 (C=O amide). Anal. C22H24ClN3O3.
Experimental
Chemistry
All the chemicals were purchased from E. Merck (Darmstadt,
FRG) and Aldrich (Milwaukee, WI USA) locally. Melting points
were determined on Electrothermal Melting Point Apparatus
and are uncorrected. IR spectra were recorded on Bruker Vec-
tor 22. 1H-NMR spectra were recorded on Bruker 400 MHz in
DMSO-d6 with tetramethylsilane as the internal standard. Ele-
mental analyses were determined in Turkish Scientific and
Technological Research Center, Ankara (Turkey), and the re-
sults were within the range of 0.4% of calculated values.
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-(2-pyri-
dinyl)piperazine (3)
Crystallized from ethanol (yield 55%, m.p. 124°C). 1H-NMR
(DMSO-d6).– δ 8.12 (d, 1H, pyridine-H6), 7.39 (t, 1H, pyridine-
H4), 6.81–7.07 (m, 3H, 2-benzoxazolinone-H4-6-7), 6.52(m, 2H,
pyridine-H3-5), 3.70 (t, 2H, butanoyl-H4), 3.64 (t, 2H, piper-
azine-H6(2)), 3.50 (t, 2H, piperazine-H2(6)), 3.40 (m, 4H, piper-
azine-H3-5), 2.31(t, 2H, -CH2-CO-), 2.01ppm(m, 2H, butanoyl-
H3). IR (KBr cm–1). – 1780 (C=O lactam), 1639 (C=O amide).
Anal. C20H21ClN4O3.
Ethyl 4-(5-chloro-2(3H)-benzoxazolon-3-yl)butanoate (12) [14]
2(3H)-benzoxazolone (0.01 mol) was reacted with equimolar
sodium ethoxyde in ethanol to synthesize sodium salt of 5-chlo-
ro-2(3H)-benzoxazolone.After evaporating to dryness an equi-
molar amount of ethyl 4-chlorobutanoate was added to the so-
lution of sodium salt of 5-chloro-2(3H)-benzoxazolone in 30 mL
DMF. The mixture was heated at 80°C for 8 h., then cooled to
room temperature and poured into ice-water. The precipitate
formed was filtered and crystallized from ethanol-water (yield
85%, m.p. 42°C). 1H-NMR (DMSO-d6). – δ 7.31–7.11 (m, 3H,
2-benzoxazolinone-H4-6-7), 4.29 (q, 2H, -O-CH2-), 4.0 (t, 2H,
-N-CH2-), 2.56 (t, 2H, -CH2-CO-), 2.23 (m, 2H, -C-CH2-C-),
1.41 ppm (t, 3H, -O-C-CH3). IR (KBr cm–1). – 1778 (C=O
lactam), 1724 (C=O ester). Anal. C13H14ClNO4.
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-phenyl-
piperazine (4)
Crystallized from ethanol (yield 40%, m.p. 105°C). 1H-NMR
(DMSO-d6). – δ 7.29–7.06 (m, 2H, phenyl-H2-6), 7.06–6.89 (m,
3H,
2-benzoxazolinone-H4-6-7),
6.89–6.64
(m,
3H,
phenyl-H3-4-5), 3.83 (t, 2H, butanoyl-H4), 3.66 (t, 2H, pipera-
zine-H6(2)), 3.45 (t, 2H, piperazine-H2(6)), 3.05 (m, 4H, pipera-
zine-H3-5), 2.32 (t, 2H, -CH2-CO-), 2.02 ppm (m, 2H, butanoyl-
H3). IR (KBr cm–1). – 1780 (C=O lactam), 1639 (C=O amide).
Anal. C21H22ClN3O3.
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-piper-
onylpiperazine (5)
4-(5-Chloro-2(3H)-benzoxazolinon-3-yl)butanoic acid (11)
Crystallized from ethanol (yield 63%, m.p. 138°C). 1H-NMR
(DMSO-d6). – δ 7.06–6.87 (m, 3H, 2-benzoxazolinone-H4-6-7),
6.75 (s, 1H, piperonyl-H2), 6.67–6.52 (m, 2H, piperonyl-H5-6),
5.75 (s, 2H, -O-CH2-O-), 3.78 (t, 2H, butanoyl-H4), 3.51 (s, 2H,
-N-CH2-Ph), 3.41–3.15 (m, 4H, piperazine-H2-6), 2.44–2.14 (m,
6H, piperazine-H3-5 and -CH2-CO-), 1.96 ppm (m, 2H, bu-
tanoyl-H3). IR (KBr cm–1). – 1776 (C=O lactam), 1634 (C=O
amide). Anal. C23H24ClN3O5.
Ethyl
[4-(5-chloro-2(3H)-benzoxazolinon-3-yl)]butanoate
(0.01 mol) was dispersed in 30 mL concentrate HCl (37%) and
refluxed for 0.5 h.The mixture was cooled, filtered and the pre-
cipitate was crystallized from water (yield 95%, m.p. 150°C).
1H-NMR (DMSO-d6). – δ 7.22–6.96 (m, 3H, 2-benzoxa-
zolinone-H4-6-7), 3.92 (t, 2H, -N-CH2-), 2.51 (t, 2H, -CH2-CO),
2.13 (m, 2H, -C-CH2-C-). IR (KBr cm–1). – 1758 (C=O lactam),
1700 (C=O acid). Anal. C11H10ClNO4.
4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanamide derivatives
(1–10) [10]
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-(2-
methoxyphenyl)piperazine (6)
Thionyl chloride (0.012 mol) was added to the solution of 4-(5-
chloro-2(3H)-benzoxazolon-3-yl)butanoic acid (0.01 mol) in
dichloromethane.After refluxing for 5 h the solution was evapo-
rated to dryness and the residue was dissolved in 30 mL dichlo-
romethan. The solution of triethylamine (0.01 mol) and appro-
priate amine derivative (0.01 mol) in 20 mL dichloromethane
was added dropwise to the solution with stirring at 0°C.The so-
Crystallized from ethanol-water (yield 48%, m.p. 136°C). 1H-
NMR (DMSO-d6). – δ 7.22–6.62 (m, 7H, 2-benzoxazolinone-
H4-6-7 and phenyl-H3-4-5-6), 3.90–3.56 (m, 7H, butanoyl-H4, pip-
erazine-H6(2) and -O-CH3), 3.45 (t, 2H, piperazine-H2(6)), 2.88
(m, 4H, piperazine-H3-5), 2.33 (2H, t, -CH2-CO-), 2.03 ppm (m,
2H, butanoyl-H3). IR (KBr cm–1). – 1764 (C=O lactam), 1640
(C=O amide). Anal. C22H24ClN3O4.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 477–482
4-(5-Chloro-2(3H)-Benzoxazolon-3-yl)Butanoic acid derivatives 481
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-(2-fluoro-
phenyl)piperazine (7)
pounds (100 mg/kg) carrageenan was injected subcuta-
neously (0.5 mg/25 µL) into the plantar surface of the
right hind paw.Indomethacin was used as the reference.
The differences in foot pad thickness between the right
and left foot was measured in 90- minutes interval with a
pair of dial thickness gauge calipers.
Crystallized from ethanol (yield 55%, m.p. 120°C). 1H-NMR
(DMSO-d6). – δ 7.08–6.63 (m, 7H, 2-benzoxazolinone-H4-6-7
and phenylH3-4-5-6), 3.82 (t, 2H, butanoyl-H4), 3.64 (t, 2H, piper-
azine-H6(2)), 3.44 (t, 2H, piperazine-H2(6)), 2.92 (m, 4H, pipera-
zine-H3-5), 2.31 (t, 2H, -CH2-CO-), 2.02 ppm (m, 2H, butanoyl-
H3). IR (KBr cm–1). – 1773 (C=O lactam), 1637 (C=O amide).
Anal. C21H21ClFN3O3.
Gastric Side Effects
After the analgesic activity experiment mice were killed
under deep ether anaesthesia and stomach was re-
moved.Then the abdomen of each mouse was opened
through great curvature and examined under a dissect-
ing microscope for lesions or bleedings.
N-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]morpholine
(8)
Crystallized from ethanol (yield 38%, m.p. 123°C). 1H-NMR
(DMSO-d6). – δ 7.06–6.85 (m, 3H, 2-benzoxazolinone-H4-6-7),
3.85 (t, 2H, butanoyl-H4), 3.54 (m, 6H, morpholine-H2-6-5(3)),
3.26 (t, 2H, morpholine-H3(5)), 2.25 (t, 2H, -CH2-CO-), 2.02
ppm (m, 2H, butanoyl-H3).IR (KBr cm–1).– 1775 (C=O lactam),
1654 (C=O amide). Anal. C15H17ClN2O4.
Acknowledgements
N-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]piperidine (9)
1
This work is financially supported by Gazi University
Research Fond, Ankara, (Turkey). (Project No:
02/2001-12).
Crystallized from ethanol (yield 53%, m.p. 63°C). H-NMR
(DMSO-d6). – δ 7.08–6.84 (m, 3H, 2-benzoxazolinone-H4-6-7),
3.79 (t, 2H, butanoyl-H4), 3.58–3.04 (m, 4H, piperidine-H2-6),
2.24 (t, 2H, -CH2-CO-), 1.97 (m, 2H, butanoyl-H3), 1.46 ppm
(m, 6H, piperidine-H3-4-5). IR (KBr cm–1). – 1782 (C=O lactam),
1641 (C=O amide). Anal. C16H19ClN2O3.
1-[4-(5-Chloro-2(3H)-benzoxazolon-3-yl)butanoyl]-4-benzyl-
piperidine (10)
References
[1] E. Groenvik: 2-Oxo-benzoxazolin, Benzoxazolon, 2-Oxy-
benzoxazol, Bull. Soc. Chim. France, 1876, 25(2), 178.;
Ref. Beilstein 27(177).
Crystallized from ethanol (yield 35%, m.p. 145°C). 1H-NMR
(DMSO-d6). – δ 7.29–6.79 (m, 8H, 2-benzoxazolinone-H4-6-7
and phenyl-H2-3-4-5-6), 4.49 (s, 1H, piperidine-H2-axial), 3.78 (t,
2H, butanoyl-H4), 3.6 (s, 1H, piperidine-H2-equatorial), 2.77 (s,
1H, piperidine-H6-axial), 2.43 (m, 3H, piperidine-H6-equatorial and
-CH2-Ph), 2.20 (t, 2H, -CH2-CO-), 1.97 (m, 2H, butanoyl-H3),
1.55(m, 4H, piperidine-H3-5), 1.0ppm(m, 1H, piperidineH4).IR
(KBr cm–1). – 1780 (C=O lactam), 1629 (C=O amide). Anal.
C23H25ClN2O3.
[2] C. Lespagnol, A. Marcincal-Lefebvre: La Benzoxa-
zolinone et Ses Derivees Consideeres Sous I’angle de La
Chimie Therapeutique, Extr. Bull. Chim.Ther., 1967, 2(5),
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[3] R. Aries: 3-Acyl-2(3H)-benzoxazolone Derivatives having
Anti-inflammatory, Antirheumatic, Analgesic, Antipyretic
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066 03 July.
Pharmacology
Antinociceptive activity [15–16]
[4] R.S.Varma, W.L.Nobles:Synthesis and Antibacterial Ac-
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Local breed male albino mice weighting 22 2 g were used in
these experiments. All the animals were housed in groups of
six.They were allowed to get accustomed to their environment
with free access to food and water for at least two days before
the experiments. The synthesized compounds were adminis-
tered orally (100 mg/kg) in carboxymethylcellulose (5%) solu-
tion 1 hour prior to the intraperitoneal injection with 0.1 mL/10 g
body weight of 2.5% (v/v) p-benzoquinone (PBQ – Merck) so-
lution in distilled water. The control group received car-
boxymethylcellulose (5%) 1 h before p-benzoquinone injec-
tion.Animals were placed in cages after p-benzoquinone injec-
tion and the number of stretching per animal were recorded
during the following 15 minutes. Percent analgesic activity was
calculated as follows:
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Key-Technologies of the Future
VINCENZO BALZANI, Italy,
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