Synthesis, analgesic and antiinflammatory properties of certain 5-/6-acyl-3-(4-substituted-1-piperazinyl-methyl)-2-benzoxazolinones derivatives

Article abstract of DOI:10.1002/ardp.200400937

The synthesis of a novel series of Mannich bases of 5-/6-acyl-5-methyl-2- benzoxazolinones has been described. The structures attributed to compounds 2a, 3a, 4a, 4b, 9a, 9b, 5a-5g, 6a-6g, 1Oa, 1Og, 11a, 11g have been elucidated using IR and ¹H NMR spectroscopic techniques besides elemental analysis. The compounds have been evaluated for their in vivo analgesic and antiinflammatory activities using the p-benzoquinone-induced writhing test and the carrageenan hind paw oedema test in mice, respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested derivatives most promising results were obtained for the compounds bearing a 6-(4-chlorobenzoyl) at C-6 position and 2-/4-fluorophenyl at C-3 position of 2-benzoxazolinone ring (11c, 11d).

Full text of DOI:10.1002/ardp.200400937

Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
DOI 10.1002/ardp.200400937
117
Synthesis, Analgesic and Antiinflammatory proper-
ties of Certain 5-/6-Acyl-3-(4-substituted-1-piperazinyl-
methyl)-2-benzoxazolinones Derivatives
a
b
c
c
b
˘
Meric Köksal , Nesrin Gökhan , Esra Küpeli , Erdem Yesilada , Hakkı Erdogan
¸
a Yeditepe University, Faculty of Pharmacy, Istanbul, Turkey
b Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey
c Gazi University, Faculty of Pharmacy, Department of Pharmacognosy, Ankara, Turkey
The synthesis of a novel series of Mannich bases of 5-/6-acyl-5-methyl-2-benzoxazolinones has been
described. The structures attributed to compounds 2a, 3a, 4a, 4b, 9a, 9b, 5aϪ5g, 6aϪ6g, 10a, 10g,
11a, 11g have been elucidated using IR and 1H NMR spectroscopic techniques besides elemental
analysis. The compounds have been evaluated for their in vivo analgesic and antiinflammatory activities
using the p-benzoquinone-induced writhing test and the carrageenan hind paw oedema test in mice,
respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested
derivatives most promising results were obtained for the compounds bearing a 6-(4-chlorobenzoyl) at
C-6 position and 2-/4-fluorophenyl at C-3 position of 2-benzoxazolinone ring (11c, 11d).
Keywords: 5-/6-Acyl-2-Benzoxazolinones; Mannich Reaction; Analgesic and Antiinflammatory Activities
Received: August 8, 2004; Accepted: February 1, 2005 [FP937]
Introduction
few articles on the synthesis of 5-acyl-2-benzoxazolinones
in the literature [14, 15]. Therefore, we wanted to evaluate
the effect of changing the 6-acyl moiety into a 5-acyl moiety
since this isosterism seemed compatible with retention of
biological activity, considering that 7-acyl derivatives had
antinociceptive activity [16].
Prostaglandins (PGs) and nitric oxide (NO) are involved in
various pathophysiological processes including inflam-
mation and carcinogenesis, and inducible isoforms of cyclo-
oxygenase (COX-2) and nitric oxide synthase (iNOS) are
mainly responsible for the production of large amounts of
these mediators [1, 2]. Two isoforms of COX catalyze the
biosynthesis of PGs from arachidonic acid [3]. Nitric oxide
synthase (iNOS) is another important enzyme involved in
regulation of inflammation [4].
In view of these facts and as a continuation of the previous
efforts carried out in our laboratory, it was thought worth-
while synthesizing a new series of 5-methyl-5-/6-acyl-/
3-(4-substitutedϪ1-piperazinylmethyl)-2-benzoxazolinone
derivatives and investigate the effect of such molecular
variation on the analgesic-antiinflammatory activities.
In the literature survey, the Mannich bases of various
heterocyclic ring systems have been reported as antiinflam-
matory/analgesic compounds [5Ϫ7], among them is the
benzoxazolinone ring system. Some of them have turned
out to be potent inhibitors of the iNOS [8]. The introduc-
tion of (4-aryl-piperazine-1-yl)alkyl moieties on various het-
erocyclic nuclei such as benzoxazolinones [5, 9], oxazolopyr-
idine [6, 10], pyridazine [11, 12], and pyrazolotriazine [13]
led to favourable antinociceptive compounds.
Results and discussion
In an effort to develop novel analgesic compounds contain-
ing arylpiperazinyl groups, we have synthesized Mannich
bases of 5-/6-acyl-2-benzoxazolinone derivatives. Although
many reports on the synthesis and biological activity of 6-
acyl-2-benzoxazolinone derivatives exist, there are only a
One series of novel derivatives of 5-/6-acyl-3-(4-substituted-
1-piperazinylmethyl)-2-benzoxazolinones has been synthe-
sized (Scheme 1 and 2) in an attempt to find improved anal-
gesic-antiinflammatory agents. One of the most interesting
characteristic of these novel compounds is their basic na-
ture, which differentiates them from the classical, acidic non
steroidal antiinflammatory agents (NSAID). It was of inter-
est therefore to study analgesic-antiinflamatory properties
of these novel compounds.
Correspondence: Nesrin Gökhan, Hacettepe University, Faculty of
Pharmacy, Department of Pharmaceutical Chemistry, 06100,
Sıhhıye, Ankara, Turkey. Phone: ϩ90 312 305-3017, Fax: ϩ90 312
311-4777, e-mail: onesrin@hacettepe.edu.tr
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

118
Gökhan et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
inones was previously reported [14, 17] and also noted that
acylation proceed with saticfactory rate and yield, only
when the ratio AlCl3-DMF/substrate was in the range of
7:11. Therefore, 6-acyl-2-benzoxazolinones were synthesized
as previously reported taking advantage of the AlCl3-DMF
complex used as Friedel-Crafts catalyst.
5-Acyl-2-benzoxazolinone derivatives were synthesized by
the C-acylation of 2-(N-acetylamino)phenol at position 4
and subsequent cyclization of the acyl derivative to 2-benz-
oxazolinone ring [14, 15]. The donor effects of amino and
phenol groups could be considered as more or less equiva-
lent and in the presence of Friedel Crafts catalysts, C-acyl-
ation could occur at position 4 and/or 5. Therefore, it is
essential to protect the amino group by acetylation. Since
the phenolic hydroxyl group has a better electron donating
effect than the acetyl amino group, 2-acetylamino-4-(2-/4-
chlorobenzoyl)phenol derivatives were synthesized in good
yield and without any isomer. Subsequently, these inter-
mediates were hydrolyzed to aromatic amine derivatives by
refluxing with aqueous (10%) sodium hydroxide solution.
5-benzoyl-2-benzoxazolinone derivatives were obtained in
good yields by the cyclization of 4-benzoyl-2-aminophenol
with urea in HCl under heating. The classical Mannich pro-
cedure using 5-methyl-5-/6-(2-/4-chlorobenzoyl)-2-benz-
oxazolinone, formaldehyde, and substituted piperazine de-
rivatives yielded the corresponding 3-substituted derivatives
in 61Ϫ90% yield.
Scheme 1. Synthesis of 5-acyl-3-(4-substituted-1-piperazin-
ylmethyl)-2-benzoxazolinone derivatives.
Chemistry
According to the Scheme 1 and Scheme 2, isomeric 2-benzo-
xazolinones bearing chlorobenzoyl side chain in either 5, or
6-position (A) were used as starting materials to prepare the
target compounds of structure (B). The use of the alu-
minium chloride-N,N-dimethylformamide (AlCl3-DMF) in
the Friedel-Crafts C-acylation reaction of 2-benzoxazol-
The structures of the isolated compounds were charac-
terized by spectral methods and elemental analysis (Table
1). The IR spectrum of the compounds displayed strong
absorption bands in the ranges of 1769Ϫ1798 cmϪ1 and
1636Ϫ1681 cmϪ1, characteristic of lactam CϭO and ketone
CϭO stretching frequency, respectively. 1H NMR spectra of
Scheme 2. Synthesis of 6-acyl-3-(4-substituted-1-piperazinylmethyl)-2-benzoxazolinone derivatives.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Synthesis of 5-acylbenzoxazolones
119
Table 1. Physicochemical data of the newly prepared compounds.
Comp. Cl
No.
R
mp. [°C]
Yield Molecular Formulae
(Cryst. Sol.) [%]
IR (KBr) ν [cmϪ1], H-NMR (CHCl3-d1) δ [ppm]
2a
2
237Ϫ238
(Aceton)
64
C15H12ClNO3 (289.71)
Calcd: C: 62.29; H: 4.17; N:4.83
3400, 1663, 1650/1.90 (s; 3H; COCH3), 6.73Ϫ6.75
(d; 1H; J: 8.48, H6), 7.06Ϫ7.09 (dd; 1H; J ϭ 8.48,
Found: C: 62.34; H: 4.20; N: 4.82 1.82; H5), 7.18Ϫ7.36 (m; 4H; H3’-H6’), 8.10Ϫ8.11
(d; 1H; J ϭ 1.82, H3), 9.11 (s; 1H; -NH-), 10.87
(s; 1H; -OH)
3a
4a
2
2
167Ϫ169
(Toluen)
65
28
C13H10ClNO2 (247.68)
3375, 3284, 1650/6.50Ϫ8.00 (m; H3, H5, H6,
Calcd: C: 63.04; H: 4.07; N: 5.66 H3’-H6Ј)
Found: C: 63.04; H: 4.07; N: 5.66
209Ϫ210
(EtOH)
C14H8ClNO3 (253.25)
3200, 1787, 1687/00Ϫ7.90 (m; H4, H6, H7, H3Ј-
Calcd: C: 61.44; H: 2.95; N: 5.12 H6Ј)
Found: C: 62.03; H: 2.42; N: 5.27
4b
9a
4
2
215Ϫ216
(MeOH)
74
73
Ref. 15
206Ϫ207
(MeOH)
C15H10ClNO3 (287.70)
3261, 1781, 1764, 1676/2.40 (s; 3H; CH3),
Calcd: C: 62.62; H: 3.50; N: 4.87 7.00Ϫ7.80 (m; 6H; H4, H7, H3Ј-H6Ј)
Found: C: 62.81; H: 3.60; N: 5.20
9b
5a
5b
5c
5d
5e
5f
4
2
2
2
2
2
2
2
4
195Ϫ196
(EtOH)
81
68
64
72
67
68
71
78
70
C15H10ClNO3 (287.70)
1803, 1785, 1654/2.30 (s; 3H; -CH3), 6.95 (s; 1H;
Calcd: C: 62.62; H: 3.50; N: 4.87 H4), 7.11 (s; 1H; H7), 7.37Ϫ7.40 (d; 2H; J ϭ 8.44;
Found: C: 62.46; H: 3.72; N: 4.8 H3Ј, H5Ј), 7.65Ϫ7.67 (d; 2H; J ϭ 8.44; H2Ј ve H6Ј),
8.77 (s; 1H; -NH-)
C6H5
130Љ131
(EtOH)
C25H22ClN3O3 (447.91)
1782, 1651/3.05Ϫ3.40 (t; 4H; pip. H2, H6),
Calcd: C: 67.04; H: 4.95; N: 9.38 3.45Ϫ3.80 (t; 4H; pip. H3, H5), 5.15 (s; 2H; N-
Found: C: 67.54; H: 4.53; N: 9.46 CH2-N), 7.00Ϫ8.15 (m; 12 H; H4, H6, H7, H3Ј-
H6Ј, H2Љ-H6Љ)
2-C6H5N
4-FC6H5
2-FC6H5
162Ϫ163
(EtOH)
C24H21ClN4O3 (448.90)
1797, 1668/2.55Ϫ2.95 (t; 4H; pip. H2, H6),
Calcd: C: 64.21; H: 4.72; N: 12.48 3.45Ϫ3.65 (t; 4H; pip. H3, H5), 4.65 (s; 2H; N-
Found: C: 64.47; H: 5.06; N: 12.35 CH2-N ), 6.50Ϫ8.20 (m; 11 H; H4, H6, H7, H3Ј-
H6Ј, H3Љ-H6Љ)
132Ϫ134
(EtOH)
C25H21ClFN3O3 (465.90)
1791, 1673/2.60Ϫ2.95 (t; 4H; pip. H2, H6),
Calcd: C: 64.45; H: 4.54; N: 9.02 3.00Ϫ3.15 (t; 4H; pip. H3, H5), 4.75 (s; 2H; N-
Found: C: 64.46; H: 4.39; N: 8.96 CH2-N ), 6.70Ϫ7.80 (m; 11 H; H4,H6-H7, H3Ј-
H6Ј, H2Љ-H3Љ, H5Љ, H6Љ)
147Ϫ148
(EtOH)
C25H21ClFN3O3 (465.90)
1782, 1652/2.60Ϫ2.95 (t; 4H; pip. H2, H6),
Calcd: C: 64.45; H: 4.54; N: 9.02 3.00Ϫ3.15 (t; 4H; pip. H3, H5), 4.75 (s; 2H; N-
Found: C: 64.10; H: 4.65; N: 8.95 CH2-N ), 6.70Ϫ7.80 (m; 11 H; H4, H6, H7, H3Ј-
H6Ј, H3Љ-H6Љ
)
2-CH3OC6H5 100Ϫ102
C26H24ClN3O4 (477.94)
1787, 1670/2.85Ϫ3.00 (t; 4H; pip. H2, H6),
(EtOH)
Calcd: C: 65.34; H: 5.06; N: 8.79 3.00Ϫ3.20 (t; 4H; pip. H3, H5), 3.90 (s; 3H; O-
Found: C: 65.75; H: 5.47; N: 8.65 CH3), 4.85 (s; 2H; N-CH2-N), 6.80Ϫ7.85 (11 H;
m; H4, H6, H7, H3Ј-H6Ј, H3Љ-H6Љ)
3-CF3C6H5
187Ϫ188
(EtOH)
C26H21ClF3N3O3 (515.91)
1775, 1666/2.70Ϫ3.05 (t; 4H; pip. H2, H6),
Calcd: C: 60.53; H: 4.10; N: 8.14 3.05Ϫ3.40 (t; 4H; pip. H3, H5), 4.75 (s; 2H; N-
Found: C: 60.64; H: 3.94; N: 8.11 CH2-N ), 6.90Ϫ7.85 (m; 11 H; H4, H6, H7, H3Ј-
H6Ј, H2Љ, H4Љ-H6Љ)
5g
6a
4-CH3COC6H5 155Ϫ156
C27H24ClN3O4 (489.95)
1787, 1664/2.50 (s; 3H; CO-CH3), 2.70Ϫ3.00 (t;
(EtOH)
Calcd: C: 66.19; H: 4.94; N: 8.58 4H; pip. H2, H6), 3.25Ϫ3.50 (t; 4H; pip. H3, H5),
Found: C: 66.55; H: 5.41; N: 8.64 4.85 (s; 2H; N-CH2-N ), 6.70Ϫ8.00 (m; 11 H; H4,
H6, H7, H3Ј-H6Ј, H2Љ, H3Љ, H5Љ, H6Љ)
C6H5
138Ϫ140
(EtOH)
C25H22ClN3O3 (447.91)
1796, 1636/2.85 (t; 4H; pip. H2, H6), 3.16 (t; 4H;
Calcd: C: 67.04; H: 4.95; N: 9.38 pip. H3, H5), 4.72 (s; 2H; N-CH2-N ), 6.73Ϫ6.93
Found: C: 66.60; H: 4.62; N: 8.95 (m; 5H; H2Љ-H6Љ ), 7.20Ϫ7.22 (d; 1H; J ϭ 8.29;
H7), 7.40Ϫ7.42 (d; 2H; J ϭ 8.46; H3Ј, H5Ј),
7.47Ϫ7.49 (dd; 1H;
J ϭ
8.29, 1.53; H6),
7.59Ϫ7.60 (d; 1H; J ϭ 1.53; H4), 7.66Ϫ7.68 (d;
2H; J ϭ 8.46; H2Ј, H6Ј)
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

120
Gökhan et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Table 1. (continued).
Comp. Cl
No.
R
mp. [°C]
Yield Molecular Formulae
(Cryst. Sol.) [%]
IR (KBr) ν [cmϪ1], H-NMR (CHCl3-d1) δ [ppm]
6b
4
2-C6H5N
143Ϫ144
(EtOH)
67
77
C24H21ClN4O3 (448.90)
1793, 1637/2.84-2.87 (t; 4H; pip. H2, H6),
Calcd: C: 64.21; H: 4.72; N: 12.48 3.03Ϫ3.05 (t; 4H; pip. H3, H5), 4.73 (s; 2H; N-
Found: C: 64.62; H: 4.76; N: 12.29 CH2-N ), 6.54Ϫ8.10 (m; 11H; H4, H6, H7, H2Ј,
H3Ј, H5Ј, H6Ј, H3Љ-H6Љ)
6c
4
4-FC6H5
159Ϫ160
(EtOH)
C25H21ClFN3O3 (465.90)
1788, 1643/2.85 (t; 4H; pip. H2, H6), 3.03Ϫ3.07
Calcd: C: 64.45; H: 4.54; N: 9.02
(t; 4H; pip. H3, H5), 4.71 (s; 2H; N-CH2-N ),
Found: C: 65.06; H: 4.32; N: 9.00 6.80Ϫ6.97 (m; 4H; H2Љ, H3Љ,H5Љ, H6Љ),
7.20Ϫ7.22 (d; 1H; Jϭ 8.40; H7), 7.40Ϫ7.42 (d;
2H; J ϭ 8.45; H3Ј, H5Ј), 7.47Ϫ7.49 (dd; 1H;
J ϭ 8.40, 1.62; H6), 7.59Ϫ7.60 (d; 1H; J ϭ
1.62; H4), 7.6Ϫ7.68 (d; 2H; J ϭ 8.45; H2Ј, H6Ј)
6d
6e
4
4
2-FC6H5
160Ϫ161
(EtOH)
81
69
C25H21ClFN3O3 (465.90)
Calcd: C: 64.45; H: 4.54; N: 9.02
1782, 1651/2.84Ϫ2.87 (t; 4H; pip. H2, H6),
3.03Ϫ3.05 (t; 4H; pip. H3, H5), 4.73 (s; 2H; N-
Found: C: 64.93; H: 4.20; N: 8.99 CH2-N), 6.77Ϫ7.01 (m; 4H; H3Љ-H6Љ),
7.20Ϫ7.22 (d; 1H; J ϭ 8.30, H7), 7.40-7.42 (d;
2H; J ϭ 8.49; H3Ј, H5Ј), 7.47Ϫ7.50 (dd; 1H;
J ϭ 8.30, 1.63; H6), 7.58Ϫ7.59 (d; 1H; J ϭ
1.63; H4), 7.65Ϫ7.68 (d; 2H; J ϭ 8.49; H2Ј,
H6Ј)
2-CH3OC6H5 143Ϫ144
C26H24ClN3O4 (477.94)
1797, 1668/2.88 (t; 4H; pip. H2, H6), 3.01 (t;
(EtOH)
Calcd: C: 65.34; H: 5.06; N: 8.79
4H; pip. H3, H5), 3.76 (s; 3H; -OCH3), 4.75
Found: C: 65.32; H: 4.71; N: 8.76 (s; 2H; N-CH2-N ), 6.77Ϫ6.79 (d; 1H; H6Љ),
6.85Ϫ6.86 (d; 2H; H4Љ, H5Љ), 6.92Ϫ6.94 (d; 1H;
H3Љ), 7.20Ϫ7.22 (d; 1H;
J
ϭ
8.33, H7),
J ϭ
8.46; H3Ј, H5Ј),
7.40Ϫ7.42 (d; 2H;
7.46Ϫ7.49 (dd; 1H; J ϭ 8.33, 1.52; H6),
7.58Ϫ7.59 (d; 1H; J ϭ 1.52; H4), 7.65Ϫ7.68 (d;
2H; J ϭ 8.46; H2Ј, H6Ј)
6f
4
4
3-CF3C6H5
146Ϫ148
(EtOH)
82
88
C26H21ClF3N3O3 (515.91)
1791, 1673/2.82Ϫ2.85 (t; 4H; pip. H2, H6),
Calcd: C: 60.53; H: 4.10; N: 8.14
3.18Ϫ3.22 (t; 4H; pip. H3, H5), 4.72 (s; 2H; N-
Found: C: 60.98; H: 3.65; N: 8.10 CH2-N ), 6.96Ϫ6.98 (d; 1H; H6Љ), 7.01Ϫ7.03
(d; 1H; H4Љ), 7.05Ϫ7.10 (t; 1H; H5Љ), 7.21Ϫ7.23
(d; 1H; J ϭ 8.26, H7), 7.39Ϫ7.42 (d; 2H; J ϭ
8.43; H3Ј, H5Ј), 7.47Ϫ7.50 (dd; 1H; J ϭ 8.26,
1.93; H6), 7.61Ϫ7.64 (d; 1H; J ϭ 1.93; H4),
7.66Ϫ7.68 (d; 2H; J ϭ 8.43; H2Ј, H6Ј)
6g
4-CH3COC6H5 183Ϫ184
C27H24ClN3O4 (489.95)
1782, 1652/2.44 (s; 3H; -COCH3), 2.79Ϫ2.82
(t; 4H; pip. H2, H6), 3.30Ϫ3.32 (t; 4H; pip. H3,
(EtOH)
Calcd: C: 66.19; H: 4.94; N: 8.58
Found: C: 65.88; H: 4.50; N: 8.54 H5), 4.71 (s; 2H; N-CH2-N ), 6.76Ϫ6.78 (d;
2H; H3Љ, H5Љ), 7.20-7.22 (d; 1H; J ϭ 8.33, H7),
7.40Ϫ7.42 (d; 2H;
J ϭ
8.35; H3Ј, H5Ј),
7.46Ϫ7.50 (dd; 1H; J ϭ 8.30, 1.29; H6), 7.57-
7.61 (d; 1H; Jϭ 1.29; H4), 7.65Ϫ7.67 (d; 2H;
J ϭ 8.35; H2Ј, H6Ј), 7.77Ϫ7.80 (d; 2H; H2Љ,
H6Љ
)
10a
10b
10c
2
2
2
C6H5
159Ϫ161
(EtOH)
79
81
86
C26H24ClN3O3 (461.94)
1787, 1670/2.70 (s; 3H; -CH3), 2.75Ϫ3.00 (t;
4H; pip. H2, H6), 3.00Ϫ3.35 (t; 4H; pip. H3,
Calcd: C: 67.60; H: 5.24; N: 9.10
Found: C: 67.78; H: 5.04; N: 9.57 H5), 4.80 (s; 2H; N-CH2-N ), 6.70Ϫ7.50 (m; 11
H; H4, H7, H3Ј-H6’, H2Љ-H6Љ)
2-C6H5N
4-FC6H5
134-5
(EtOH)
C25H23ClN4O3 (442.51)
1775, 1666/2.60 (s; 3H; -CH3), 2.70Ϫ2.95 (t;
Calcd: C: 64.86; H: 5.01; N: 12.10 4H; pip. H2, H6), 3.20Ϫ3.70 (t; 4H; pip. H3,
Found: C: 65.10; H: 4.89; N: 11.82 H5), 4.70 (s; 2H; N-CH2-N ), 6.40Ϫ8.20 (m; 10
H; H4, H7, H3Ј-H6Ј, H3Љ-H6Љ)
145-147
(EtOH)
C26H23ClFN3O3 (479.93)
1787, 1664/2.60 (s; 3H; -CH3), 2.70Ϫ2.95 (t;
4H; pip. H2, H6), 2.95Ϫ3.05 (t; 4H; pip. H3,
Calcd: C: 65.07; H: 4.83; N: 8.76
Found: C: 65.30; H: 4.65; N: 8.28 H5), 4.80 (s; 2H; N-CH2-N ), 6.60Ϫ7.50 (m; 10
H; H4, H7, H3Ј-H6Ј, H2Љ, H3Љ, H5Љ, H6Љ)
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Table 1. (continued).
Synthesis of 5-acylbenzoxazolones
121
Comp. Cl
No.
R
mp. [°C]
Yield Molecular Formulae
(Cryst. Sol.) [%]
IR (KBr) ν [cmϪ1], H-NMR (CHCl3-d1) δ [ppm]
1796, 1636/2.60 (s; 3H; -CH3), 2.70Ϫ3.00 (t; 4H;
10d
10e
10f
10g
2
2
2
2
2-FC6H5
110Ϫ111
(EtOH)
82
61
85
90
C26H23ClFN3O3 (479.93)
Calcd: C: 65.07; H: 4.83; N: 8.76 pip. H2, H6), 3.00Ϫ3.20 (t; 4H; pip. H3, H5), 4.70
Found: C: 65.53; H: 4.36; N: 8.94 (s; 2H; N-CH2-N), 6.80Ϫ7.50 (m; 10 H; H4, H7,
H3Ј-H6’, H3Љ-H6Љ)
2-CH3OC6H5 128Ϫ130
C27H26ClN3O4 (491.97)
1793, 1637/2.70 (s; 3H; -CH3), 2.80Ϫ2.95 (t; 4H;
(EtOH)
Calcd: C: 65.92; H: 5.33; N: 8.54 pip. H2, H6), 2.95Ϫ3.30 (t; 4H; pip. H3, H5), 3.75
Found: C: 65.95; H: 5.23; N: 8.12 (s; 3H; -O-CH3), 4.75 (s; 2H; N-CH2-N),
6.70Ϫ7.50 (10 H; m; H4, H7, H3Ј-H6Ј,H3Љ-H6Љ)
3-CF3C6H5
136Ϫ138
(EtOH)
C27H23ClF3N3O3 (529.94)
1788, 1643/2.60 (s; 3H; -CH3), 2.70Ϫ3.00 (t; 4H;
Calcd: C: 61.19; H: 4.37; N: 7.93 pip. H2, H6), 3.00Ϫ3.20 (t; 4H; pip. H3, H5), 4.70
Found: C: 61.45; H: 4.05; N: 7.78 (s; 2H; N-CH2-N), 6.80Ϫ7.60 (10 H; m; H4, H7,
H3Ј-H6’,H2Љ, H4Љ-H6Љ)
4-CH3COC6H5 155Ϫ6
C28H26ClN3O4 (503.98)
1781, 1669/2.45 (s; 3H; COCH3), 2.59 (s; 3H;
(EtOH)
Calcd: C: 66.73; H: 5.20; N: 8.34 CH3), 2.79Ϫ2.82 (t; 4H; pip. H2, H6), 3.32Ϫ3.34
Found: C: 67.07; H: 5.53; N: 8.14 (t; 4H; pip. H3, H5), 4.66 (s; 2H; N-CH2-N),
6.77Ϫ6.79 (d; 2H; H2Љ, H6Љ), 6.96 (s; 1H; H4), 7.10
(s; 1H; H7), 7.29Ϫ7.41 (m; 4H; H3Ј-H6Ј),
7.78Ϫ7.80 (d; 2H; H3Љ, H5Љ)
11a
11b
11c
11d
11e
11f
4
4
4
4
4
4
C6H5
132Ϫ133
(EtOH)
86
82
86
82
83
87
C26H24ClN3O3 (461.94)
1781/2.40 (s; 3H; CH3), 2.60Ϫ3.00 (t; 4H; pip. H2,
Calcd: C: 67.60; H: 5.24; N: 9.10 H6), 3.00Ϫ3.40 (t; 4H; pip. H3, H5), 4.80 (s; 2H;
Found: C: 67.38; H: 4.97; N: 8.95 N-CH2-N), 6.75Ϫ7.90 (m; 11 H; H4, H7, H2’-H6Ј,
H2Љ-H6Љ)
2-C6H5N
4-FC6H5
2-FC6H5
127Ϫ8
(EtOH)
C25H23ClN4O3 (442.51)
1794, 1665/2.40 (s; 3H; CH3), 2.60Ϫ2.95 (t; 4H;
Calcd: C: 64.86; H: 5.01; N: 12.10 pip. H2, H6), 3.20Ϫ3.60 (t; 4H; pip. H3, H5), 4.80
Found: C: 65.10; H: 4.60; N: 12.07 (s; 2H; N-CH2-N), 6.70Ϫ8.30 (m; 10 H; H4, H7,
H2Ј, H3Ј, H5Ј, H6Ј, H3Љ-H6Љ)
127Ϫ128
(EtOH)
C26H23ClFN3O3 (479.93)
1795, 1660/2.40 (s; 3H; CH3), 2.60Ϫ3.00 (t; 4H;
Calcd: C: 65.07; H: 4.83; N: 8.76 pip. H2, H6), 3.00Ϫ3.30 (t; 4H; pip. H3, H5), 4.70
Found: C: 64.76; H: 4.86; N: 8.73 (s; 2H; N-CH2-N), 6.80Ϫ7.80 (m; 10 H; H4, H7,
H2Ј, H3Ј, H5Ј, H6Ј, H2Љ, H3Љ, H5Љ, H6Љ)
138Ϫ140
(EtOH)
C26H23ClFN3O3 (479.93)
1769, 1662/2.40 (s; 3H; CH3), 2.60Ϫ3.00 (t; 4H;
Calcd: C: 65.07; H: 4.83; N: 8.76 pip. H2, H6), 3.00Ϫ3.30 (t; 4H; pip. H3, H5), 4.75
Found: C: 64.83; H: 4.96; N: 8.79 (s; 2H; N-CH2-N), 6.7Ϫ7.80 (m; 10 H; H4, H7,
H2Ј, H3Ј, H5Ј, H6Ј, H3Љ-H6Љ)
2-CH3OC6H5 133-134
(EtOH)
C27H26ClN3O4 (491.97)
1798, 1660/2.40 (s; 3H; CH3), 2.70Ϫ3.00 (t; 4H;
Calcd: C: 65.92; H: 5.33; N: 8.54 pip. H2, H6), 3.00Ϫ3.30 (t; 4H; pip. H3, H5), 4.80
Found: C: 65.49; H: 5.30; N: 8.55 (s; 2H; N-CH2-N), 6.7Ϫ7.90 (m; 10 H; H4, H7,
H2Ј, H3Ј, H5Ј, H6Ј, H3Љ-H6Љ)
3-CF3C6H5
158Ϫ160
(EtOH)
C26H23ClF3N3O3 (529.94)
1797, 1658/2.34 (s; 3H; -CH3), 2.87Ϫ3.04 (t; 4H;
Calcd: C: 61.19; H: 4.37; N: 7.93 pip. H2, H6), 3.20Ϫ3.24 (t; 4H; pip. H3, H5), 4.70
Found: C: 60.98; H: 3.95; N: 8.10 (s; 2H; N-CH2-N), 6.93 (s; 1H; H2Љ), 6.98 (s; 1H;
H4) 7.01Ϫ7.00 (d; 1H; H6Љ), 7.03Ϫ7.04 (d; 1H;
H4Љ), 7.11 (s; 1H; H7), 7.27Ϫ7.30 (t; 1H; H5Љ)
7.39-7.42 (d; 2H; J ϭ 8.52; H3Ј, H5’), 7.64Ϫ7.66
(d; 2H; J ϭ 8.52; H2’ ve H6Ј)
11g
4
4-CH3COC6H5 183Ϫ184
90
C28H26ClN3O4 (503.98)
1786, 1667/2.40 (s, 3H, -COCH3), 2.50 (s; 3H;
(EtOH)
Calcd: C: 66.73; H: 5.20; N: 8.34 CH3), 2.65Ϫ3.05 (t; 4H; pip. H2, H6), 3.30Ϫ3.50
Found: C: 67.25; H: 4.92; N: 8.36 (t; 4H; pip. H3, H5), 4.80 (s; 2H; N-CH2-N),
6.80Ϫ8.00 (m; 10 H; H4, H7, H2Ј, H3Ј, H5Ј, H6Ј,
H2Љ, H3Љ, H5Љ, H6Љ)
the compounds showed a singlet at about δ 4.65Ϫ5.15 ppm
integrated for two protons attributed to methylene bridge
protons. Other protons were seen at the expected chemical
shifts.
Pharmacology
Analgesic activities of the resulting compounds were investi-
gated by the p-benzoquinone-induced writhing test [18]
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

122
Gökhan et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Table 2. Percent analgesic activity and inhibition of carrageenan paw oedema (CPE) of compounds 4a, 4b, 9a, 9b, 5aϪ5g,
6aϪ6g, 10aϪ10g, 11aϪ11g.
Antiinflammatory Activityc
Swelling in thickness (؋ 10؊2 mm) SEM
(% inhibition)
Analgesic Activity
Number of writhing
SEM
Comp.
No.
Ratio of ulceration
(% Inhibition)
90 min
180 min
270 min
360 min
Control
4a
45.7 3.90
40.0 3.91
52.5 4.40
45.2 3.98
(5.8)
60.3 4.70
49.5 3.65
(8.3)
65.7 5.20
55.3 3.93
(12.5)
49.0 3.00
36.3 2.58
(21.9)
0/6
0/6
4b
40.8 3.49
44.5 3.55
(7.3)
42.5 3.90
(19.0)
40.2 2.30
(23.4)
44.0 2.89
(8.3)
47.2 2.66
(1.6)
34.3 2.68
(28.5)
35.2 3.31
(26.7)
36.3 3.18
(24.4)
39.5 3.23
(17.7)
42.0 4.13
(12.5)
37.7 3.46
(21.5)
40.5 4.03
(15.6)
48.2 3.45
(10.7)
49.5 4.10
(17.9)
51.3 3.39
(18.8)
54.2 3.90
(17.5)
37.2 2.95
(20.0)
38.3 3.30
(21.8)
35.8 3.50
(26.9)
36.3 4.22
(21.9)
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
0/6
3/6
0/6
0/6
0/6
1/6
0/6
0/6
0/6
0/6
1/6
0/6
0/6
3/6
0/6
1/6
0/6
0/6
9a
36.7 4.10
(19.7)
35.2 2.70
(22.9)
9b
45.2 2.10
49.5 4.00
(25.0)†
(24.7)†
5a
42.0 3.04
48.2 3.19
(10.7)
50.7 3.45
(6.1)
51.5 3.27
(18.5)
55.0 3.17
(12.9)
5b
43.0 2.54
38.8 4.96
(16.6)
5c
30.2 2.77
(24.1)
30.7 3.02
(22.9)
32.5 3.14
(18.4)
35.2 3.24
(11.6)
38.3 3.95
(3.8)
33.7 3.36
(15.3)
36.8 3.89
(7.5)
26.7 2.59
(32.9)
37.8 2.63
38.8 3.08
26.8 3.36
(30.0)†
(38.6)‡
(42.4)‡
5d
38.2 3.04
(29.3)
40.0 3.34
(25.9)
43.3 3.62
(19.8)
45.5 4.23
(15.7)
41.8 3.55
(22.6)
45.5 4.19
(15.7)
41.8 3.31
(33.9)†
30.0 2.63
(35.5)†
5e
44.2 3.30
30.7 2.97
(30.1)†
(33.9)†
5f
45.7 3.32
(27.7)
49.0 4.29
(22.5)
47.3 3.67
(25.2)
50.7 4.59
(19.8)
34.0 2.45
(26.9)
36.8 3.39
(20.9)
35.7 2.81
(23.2)
36.0 2.81
(22.6)
5g
6a
6b
6c
31.2 2.46
36.7 2.64
41.0 3.62
26.2 2.40
(35.0)†
(32.0)†
(35.1)‡
(43.7)‡
6d
30.7 4.25
(22.9)
40.3 3.58
34.8 4.01
(27.5)
44.3 3.87
(7.7)
38.3 3.40
(20.2)
42.2 4.79
(12.1)
46.0 3.00
(12.4)
43.7 5.20
(16.8)
38.3 3.05
(29.1)†
47.3 3.87
(12.4)
41.2 2.63
(23.7)
46.5 4.67
(13.9)
49.2 3.10
(18.4)
48.2 5.10
(20.1)
40.7 3.19
(35.6)‡
50.8 4.14
(19.6)
25.5 2.35
(45.2)‡
36.3 3.02
(21.9)
32.5 2.05
(30.1)
34.5 2.81
(25.8)
38.8 2.50
(20.8)
37.7 2.40
(23.1)
6e
6f
35.2 2.83
(11.6)
36.8 4.81
(7.5)
42.2 2.60
(7.7)
39.2 5.50
(14.2)
32.5 2.90
(28.9)
33.5 3.00
(26.7)
36.3 3.50
(20.6)
35.8 4.30
(21.7)
44.3 3.57
(29.9)†
6g
50.5 4.26
(20.1)
53.3 3.00
(18.9)
52.5 4.60
(20.1)
10a
10b
10c
10d
10e
10f
10g
11a
11b
34.7 2.30
36.8 2.00
39.3 2.10
27.3 2.40
(33.9)†
(38.9)§
(40.2)§
(44.3)§
35.8 2.10
(31.8)†
37.7 3.20
(28.2)
39.2 3.80
(25.3)
36.8 3.50
(29.9)
39.8 4.20
(24.2)
43.5 4.10
(17.1)
39.0 3.00
(35.3)‡
41.0 3.40
(37.6)§
29.5 2.60
(39.8)§
42.5 3.70
46.0 4.60
31.3 3.00
(29.5)†
(29.9)‡
(36.1)‡
41.5 2.90
(31.2)†
43.3 2.50
(34.1)‡
30.5 2.50
(37.8)‡
34.0 3.60
(25.6)
35.7 4.00
(21.9)
39.2 4.10
(14.2)
40.5 3.40
43.7 3.40
30.0 2.00
(32.8)‡
(33.5)‡
(38.8)§
44.5 3.80
(26.2)†
46.8 4.20
(22.4)
46.2 2.60
(29.7)‡
51.3 3.90
(21.9)
33.7 2.50
(31.2)‡
36.8 3.60
(24.9)
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Table 2. (continued).
Synthesis of 5-acylbenzoxazolones
123
Antiinflammatory Activityc
Analgesic Activity
Comp.
No.
Swelling in thickness (؋ 10؊2 mm) SEM
Number of writhing
Ratio of ulceration
(% inhibition)
SEM
(% Inhibition)
90 min
180 min
270 min
360 min
11c
29.5 3.20
(35.4)
36.2 4.10
(20.8)
41.5 2.60
(9.2)
35.5 3.40
(22.3)
37.5 3.90
(17.9)
30.7 4.20
(29.7)
32.5 3.30
(38.1)†
39.0 3.60
(25.7)
44.8 2.80
(14.7)
39.3 2.90
(25.1)
35.5 3.20
(41.1)§
35.7 3.70
(45.7)§
22.3 2.00
(54.5)§
0/6
0/6
0/6
0/6
2/6
11d
40.8 3.30
42.5 3.40
26.7 2.20
(32.3)†
(35.3)§
(45.5)§
11e
47.3 3.00
(21.6)
49.0 3.40
(25.4)†
35.3 2.70
(27.9)†
11f
44.3 2.90
48.0 2.80
32.8 3.80
(26.5)†
(26.9)†
(33.1)‡
11g
39.5 3.40
(24.8)
42.0 3.50
(30.3)†
44.7 2.80
(31.9)‡
30.7 4.00
(37.3)‡
0/6
INDO
33.0 3.40
35.3 3.30
34.2 3.10
(37.1)†
(39.9)†
(45.5)§
Ϫ
ASA
Ϫ
Ϫ
Ϫ
Ϫ
19.8 1.42
(57.4)§
2/6
†
‡
§
p < 0.05, p < 0.01, p < 0.001.
INDO Ϫ indomethacin.
ASA Ϫ acetylsalicylic acid (Aspirin).
which is a well established method for testing the analgesic
activity of compounds and sufficiently sensitive to detect
the effect of analgesics which are less active than Aspirin.
Antiinflammatory activities of the compounds were as-
sessed by utilizing the carrageenin-induced hind paw
oedema model [19]. Since the carrageenan oedema has been
used in the development of Indometacin, many researchers
adopted this procedure for screening potential antiinflam-
matory compounds. Results of the preliminary screening
study are summarized in Table 2.
ogenesis. Among the compounds, the derivatives 4a, 4b, 9a,
9b, which did not carry any substitution on the third posi-
tion, were found weaker than those bearing an aminoalkyl
residue on this position. When acyl derivatives were taken
into consideration within them, it was determined that 6-
(o-/p-chlorobenzoyl)-2-benzoxazolinone derivatives (9a, 9b)
have higher activity than those of 5-(o-/p-chlorobenzoyl)-2-
benzoxazolinones (4a, 4b). It is noteworthy that chlorine
substitution (2-Cl or 4-Cl) on the acyl group did not induce
any remarkable change in the activity of 6-acyl derivatives.
A analgesic activity comparable to Aspirin was observed
for 6-(2-/4-chlorobenzoyl)-2-benzoxazolinone derivatives
(10aϪ11g) bearing a aminoalkyl group on position 3. When
the piperazine portion was substituted with an phenyl (a
derivatives), 2-pyridil bearing a lone pair of electrons (b de-
rivatives) and a electron donating group, such as 2-meth-
oxyphenyl (e derivatives); the observed efficacy decreased
slightly compared to o-/p-fluorophenyl, 3-trifluoromethyl-
phenyl, and 4-acetylphenyl groups. A noteworthy effect was
observed when we used small electron withdrawing substitu-
ents such as fluor on the phenyl ring bound to piperazine.
This effect was consistent with other electron withdrawing
substituent (CF3). Less remarkable, but worthy of note re-
sults were obtained in the compounds carrying 4-chloroben-
zoyl at fifth position of the main ring. Among this group of
compounds, 6d carrying p-fluorophenyl on the piperazine
ring was found as the most promising compound. The com-
pound 6c also showed activity without inducing ulcerogen-
esis but was less potent than 6d. However, the compounds
10g and 11g in spite of their potent activities were ulcerog-
Carrageenan-induced oedema is a non-specific inflam-
mation maintained by the release of histamine, 5-hydroxy-
tryptamine, kinins, and later by prostaglandins [20]. The in-
hibitory effect of acid NSAIDs, such as Indometacin, is usu-
ally weak in the first phase (1Ϫ2 h), in contrast with their
strong inhibition in the second phase (3Ϫ4 h) [21]. Good
inhibition of the second phase of carrageenan-induced
oedema was observed for the tested compounds, suggesting
that they interfere with prostaglandin synthesis.
As a result of pharmacological studies it can be concluded
that significant differences in activity were observed de-
pending on the positions of acyl groups and the substituent
on the piperazine at the third position of the main ring.
Antiinflammatory activity of the synthesized compounds
demonstrated a parallel result with their corresponding an-
algesic activities. A 100 mg/kg dose of the main skeletons
(5aϪ6g, 10aϪ11g) showed some antinociceptive and anti-
inflammatory activity but was insignificant in statistical
evaluation. They were also safe from the view point of ulcer-
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

124
Gökhan et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
(Philadelphia, PA, USA) at the Scientific and Technical Research
Council of Turkey, Instrumental Analysis Laboratory in Ankara.
enic in a 100 mg/kg dose. The efficacy of compound 10g
was better than that of 11g.
Although we had first planned to do iNOS inhibitory ac-
tivity experiments for our compounds, we couldn’t do them
due to the of lack substances in our laboratory so far.
4-Benzoyl-2-acetylaminophenols
N,N-Dimethylformamide (DMF) (0.11 mol) was added dropwise to
anhydrous aluminium chloride (0.4 mol) at 0Ϫ10°C, stirring con-
stantly and protecting the reaction mixture from atmospheric mois-
ture. After the addition was completed, the mixture was stirred for
further 10 min. The appropriate benzoyl chloride derivative (0.07
mol) was added portionwise to this mixture over 15 min. After ad-
dition of 2-acetylamino-4-chlorophenol (0.05 mol), the mixture was
heated for 6 h at 120°C, cooled and poured into 1 L ice-water. The
product precipitated, it was filtered, washed with water to neutral
pH, dried, and crystallized from the appropriate solvent.
Conclusion
In conclusion, 6-acyl derivatives are more active than 5-acyl
derivatives in terms of the analgesic and antiinflammatory
activities. Taking the chemical structures of the active com-
pounds into consideration, it appears that acetylphenyl and
trifluoromethyl derivatives show good potency compared to
the methoxyphenyl substituent (except 5e). It is clear that
compounds, named c and d derivatives bearing the 2-/4-
fluorophenyl residue, display the best activity, which indi-
cates that the larger size of the substituents may be detri-
mental to the overall activity. As for the ulcerogenic effects
of the synthesized compounds, compound 5g causes severed
damage to the gastric mucosa at 100 mg/kg dose. According
to the results of in vivo studies conducted in the present
study, the analgesic and antiinflammatory activities of 11c
and 11d are comparable to that of known drugs, i.e. Aspirin
and Indometacin without inducing any visible gastric dam-
age.
4-Acyl-2-aminophenols
2-Acetylamino-4-benzoylphenol derivative (0.1 mol) was added to
300 mL of 40% sodium hydroxide solution and 200 mL ethanol.
This solution was refluxed for 7 h, evaporated under vacuum to
remove ethanol, and cooled. After adding 500 mL water, the solu-
tion was filtered to remove insoluble material and acidified with
acetic acid to pH 5.5. The precipitated product was filtered, washed
with water to neutral pH, dried, and crystallized from appropriate
solvent.
5-Acyl-2-benzoxazolinones
A mixture of 0.03 mol 4-acyl-2-aminophenol, 7 mL HCl and 0.15
mol urea were heated at 140°C for 1.5 h and at 170°C for 2.5 h,
respectively. The melt was allowed to cool; and 30 mL water were
added. The resulting slurry was mixed at room temperature for 1 h.
The precipitated product was filtered, washed with water to neutral
pH, dried, and crystallized from appropriate solvent.
Finally, 5-/6-acyl-2-benzoxazolinone nuclei are important
classes for potent analgesic and antiinflammatory activities
and these type of compounds deserves further studies to
develop better candidates for COX-2 and iNOS selectivity
with potent analgesic and antiinflammatory activities.
5-Methyl-6-acyl-2-benzoxazolinones
Dimethylformamide (0.11 mol) was slowly added to aluminum chlo-
ride (0.4 mol) in ice under stirring. The mixture was stirred until it
became homogenous. Then, benzoyl chloride (0.07 mol) and 5-
methyl-2-benzoxazolinone (0.05 mol) were added slowly, respec-
tively. The reaction mixture was heated at 120°C under stirring for
6 hours, poured into 1 L ice-water and the crude product was col-
lected by filtration, air-dried, and crystallized.
Acknowledgments
This study was supported by the Hacettepe University
Research Fund (Project number: 00.02.301.002) and the
Scientific and Technical Research Council of Turkey.
5-Methyl-6-/5-acyl-3-substituted piperazinomethyl-2-benzoxazolinones
Experimental
Formaline (1 mL, 35%) was added to cyclic amine in 10 mL meth-
anol. A solution of 5-methyl-6-acyl-2-benzoxazolinone (0.002 mol)
in 10 mL was mixed with that mixture at room temperature. The
resulting precipitate was filtered and purified by crystallization with
appropriate solvents.
Chemistry
All chemicals were supplied from Aldrich Chemical Co. (Steinheim,
Germany). Melting points (°C) were detected with a Thomas Ho-
over capillary melting point apparatus (Philadelphia, PA, USA) and
are uncorrected. The IR spectra (KBr) were recorded on a Bruker
Vector 22 FT-IR spectrophotometer (Opus Spectroscopic, Software
Version 2.0) (Bruker Analytische Messtechnik, Karlruhe, Ger-
many). The 1H NMR spectra were obtained by Bruker AC 80 MHz
and Bruker 400 MHz (Bruker, Rheinstetten, Germany) FT NMR
instruments using CDCl3 as solvent and tetramethylsilane as in-
ternal standard. Splitting patterns were designated as follows: s:
singlet, d: doublet, t: triplet, q: quartet, and m: multiplet. All chemi-
cal shift values were recorded as δ (ppm). The purity of the com-
pounds were controlled by thin layer chromatography (Merck, sili-
cagel, HF254-366, Type 60, 0.25 mm, Darmstadt, Germany). The el-
emental analyses were performed on a Leco CHNS 932 analyzer
Pharmacology
Male Swiss albino mice (20Ϫ25 g) were purchased from the animal
breeding laboratories of Refik Saydam Hıfzısıhha Institute (Ankara,
Turkey). The animals were left for two days for acclimatization to
the animal room conditions and were maintained on standard pellet
diet and water ad libitum. The food was withdrawn on the day be-
fore the experiment, but free access of water was allowed. Test
samples and reference compounds were suspended in 0.5% carboxy-
methyl cellulose and administered to each mouse by using gastric
gavage needle. The control group animals, however, received the
same volume of dosing vehicle. In the pharmacological studies, the
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 117−125
Synthesis of 5-acylbenzoxazolones
125
animals were first administered a 100 mg/kg (body weight) dose of
the test drugs.
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© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim