S- and C-nucleosidoquinazoline as new nucleoside analogs with potential analgesic and anti-inflammatory activity

Article abstract of DOI:10.1016/j.ejmech.2009.05.025

Thioglycosides and C-glycosides have received considerable attention, because they are widely employed as biological inhibitors, inducers and ligands for affinity chromatography of carbohydrate-processing enzymes and proteins. Moreover, they are promising

Full text of DOI:10.1016/j.ejmech.2009.05.025

European Journal of Medicinal Chemistry 44 (2009) 4249–4258
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
S- and C-nucleosidoquinazoline as new nucleoside analogs with potential
analgesic and anti-inflammatory activity
*
Abdel-Rahman B.A. El-Gazzar , Hend N. Hafez, Hebat-Allah S. Abbas
Photochemistry Department (Heterocyclic and Nucleoside Unit), National Research Centre, El-Tahrrir Street, 12622 Dokki, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Thioglycosides and C-glycosides have received considerable attention, because they are widely employed
as biological inhibitors, inducers and ligands for affinity chromatography of carbohydrate-processing
enzymes and proteins. Moreover, they are promising candidates in synthetic carbohydrate chemistry as
convenient and versatile glycosyl donors. Among these glycosyl donors are the thioglycosyl and N-
glycosyl heterocycles that are sufficiently stable under a variety of reaction conditions and have the
ability to be readily converted into a variety of other functionalities. We report here, the synthesis of 2-
thioxo-quinazolines 1a–c which were used as a base to the synthesis of S-nucleoside of types 10, 11 and
acyclic C-nucleoside analogs of type 14 and their analgesic and anti-inflammatory activities were eval-
uated giving good results.
Received 19 February 2009
Received in revised form
16 May 2009
Accepted 20 May 2009
Available online 28 May 2009
Keywords:
2-Thioxo-quinazoline
S- and C-nucleosidoquinazolines
Anti-inflammatory
Analgesic
Ó 2009 Elsevier Masson SAS. All rights reserved.
Ulcerogenic activities
1. Introduction
Surprisingly, although a tremendous work has been done in the
synthesis of new series of nucleoside analogs, few works have been
Nucleoside analogs constitute an important class of therapeutic
agents in the treatment of cancers and viral infections [1]. The
mode of action of these derivatives is based upon their intracellular
conversation to their phosphorylted forms (nucleotides), which can
interact with different cellubiosynthesis. During the last decades,
an intensive research was dedicated to the discovery of more
effective, selective, and non-toxic new nucleoside derivatives [2].
These efforts have concerned the chemical modification of the base
and/or the sugar moiety of natural nucleosides. In the latter, the
main modifications involved changes in the sugar moiety like,
inversion of hydroxyl group configurations, their elimination
leading to dideoxy- or dideoxy-didehydro nucleosides, their
substitution/functionalization by various synthetic groups, or
cleavage of the sugar ring leading to acyclic nucleosides. Also,
modifications of the sugar moiety of nucleosides may lead to
significant changes in the spectrum of their biological activity and
degree of selective toxicity, as well as in their physico-chemical
properties. In the course of our ongoing research on the synthesis
and biological evaluation of modified heterocyclic and nucleoside
analogs, we became interested in a stereo-selective strategy for the
preparation of S-nucleosides and C-nucleosides.
reported regarding the synthesis of S- and C-nucleosides [3,4]. This
fact prompted us to elaborate a synthetic route to reach such kind
of compounds. Also, The pharmacodynamic versatility of quina-
zoline moiety has been documented not only in many of its
synthetic derivatives but also in several naturally occurring alka-
loids isolated from animals, families of plant kingdoms and from
microoraganism [5–7]. These isolated quinazolines derivatives
were found to have wide range of biological properties including
anti-tumor, sedative, analgesic, antidiabetic, antibacterial, anti-
inflammatory, antifungal and anticancer [8–14]. In addition,
characterization of potential N-methyl-
D-asparatate (NMDA) and
chlolecystokinin antagonists II-lipophilicity studies on quinazoline
are also documented [15].
2. Results and discussion
The key intermediates for the synthesis of thioglycosides and
acyclic glycosides are shown in the Scheme 1. 4-Aryl-7-dimethyl-
3,4,6,8-tetrahydro-2-thioxo-quinazolin-5-ones (1a–c) were prepared
by a one-pot-reaction of 5,5-dimethylcyclohexane-1,3-diones (Dima-
don), aldehydes and thiourea in absolute ethanol in presence of
hydrochloric acid as acid catalyst. Compounds 1a–c on reflux with
hydrazine hydrate (99%) yielded the desired 4-aryl-2-hydrazino-7-
dimethyl-3,4,6,8-tetrahydro-quinazolin-5-ones (2a–c) in good yields
(over 80%), Scheme 1. The IR spectra of compound 1b show intense
* Corresponding author. Tel.: þ202 373 18830; fax: þ202 333 70931.
E-mail address: profelgazzar@yahoo.com (A.-R.B.A. El-Gazzar).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.05.025

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A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
O
O
H
Ar
S
NH
Ar
N2H4.H2O
Ar-CHO
+
+
H2N
NH2
N
H
S
O
1a-c
O
Ar
H
O
H
Ar'
H
NH
Ar'-CHO
AcOH
NH
NHNH2
N
N
N
N
H
2a-c
Ar, a = C6H5
3a-c
a, Ar = 4-ClC6H4 , Ar' = C6H5
b, Ar = Ar' = 4-ClC 6H4
O
Ar
H
b = 4-ClC6H4
c = 4-OCH3C6H4
Ar'
c, Ar = 4-ClC6H4, Ar' = 4-OCH3C6H4
N
3b
N
Ac2O/Pyridine
N
N
H
4b
Scheme 1.
peaks at 3290 cmꢀ1 for (NH), 1704 cmꢀ1 for carbonyl (C]O) and
1225 cmꢀ1 for thioxo (C]S) streatching. 1H NMR spectrum of 1b
corresponding carbon atom (Fig. 1). The signals at
169.9, 170.0 ppm were due to the four acetoxy carbonyl atoms
(4C]O), and the four signals at 35.20-38.50 ppm were assigned to
the acetate methyl carbon atoms. Also, the five signals at 67.90,
69.37, 72.75, 75.56, 80.89 ppm were assigned to C-40, C-20, C-30, C-50
and C-10, respectively. Moreover, the IR spectra of compounds 10
revealed the absence of the stretching signal of a thione group.
Similarly, the reaction of heterocycle base 5 with 2,3,5-tri-O-acetyl-
d 169.3, 169.5,
showed a double duplet at
for aromatic (4H) protons and a two broad signalst at
10.00 ppm indicating the presence of two NHs, in addition to the
signals corresponding to methylene protons around 1.88–
2.18 ppm and two singlet signals at 0.90, 1.05 due to two methyl
d
7.23 (J ¼ 8.1 Hz) and 7.33 (J ¼ 8.1 Hz)
d
d
8.90 and
d
d
d
groups. Data from the elemental analyses have been found to be in
conformity with the assigned structure. Also, the molecular ion
recorded in the mass spectrum is also in agreement with the
molecular weight of the compound. Furthermore, the 13C NMR of
the compound 1b revealed that the signal corresponding to the C-2
a-D-ribofuranosyl bromide (9c) furnished the S-glycosylated
product 10c. The assignment of structures of this product is based on
their elemental analysis and the spectral data (see Tables 4–6).
Furthermore, we developed a preparative alternative for the
quinazoline thioglycosides 10a,b. Silylation of compound 1b affor-
(–C]S) was around
d 174 ppm.
Compounds 1a–c were found to be useful for the syntheses of
the interesting S-glycosides. As a model experiment the alkylation
of 1 was carried out by the reaction of one equivalent of methyl-
iodide with the potassium salt 5 generated in situ by the reaction of
1 with alcoholic potassium hydroxide. The structure of the new 2-
methylthio-quinazoline 6 was confirmed by all spectroscopic data.
The 13C NMR spectrum as an example, reveled that the corre-
ded the intermediate silylated product 7, which reacted with
b-D-
glucose pentaacetate 8a or -galactose pentaacetate 8b in dry
b-D
acetone in the presence of stannic chloride to furnish the S-glycosyl
products 10a,b (Scheme 2).
Also, according to El-Gazzar et al. [16], 2-hydrazino derivative 2b
gave the 2-(aryl-methylenehydrazone)-qunazolin-5-one derivatives
3a–c (Scheme 1) when 2b was treated with the appropriate alde-
hyde in boiling acetic acid for 30 min. Compounds 3a–c gave
compatible spectral and analytical data. The arylhydrazones 3b
could be cyclized into the corresponding 3,4-di(4-chlorophenyl)-7-
dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one
(4), when treated with a mixture of acetic anhydride–pyridine (2:1).
Analogously, the required hydrazones 11a–f were prepared by
condensation of 2-hydrazino-quinazoline 2b with the appropriate
aldohexoses and aldopentoses (Scheme 3). The structures of the
new hydrazones 11a–f were confirmed by their elemental analyses
and spectral data (Tables 4–6). Stirring of 2-(glycosylhydrazon)-7-
dimethyl-3,4,6,8-tetrahydro-quinazolin-5-one derivatives (11a–f) at
room temperature in a mixture of acetic anhydride–pyridine (2:1)
afforded the respective 3-(penta-O-acetylglycosyl/or tetra-O-
acetylglycosyl)-4-aryl-7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo-
[3,4-b]quinazolin-6-ones (13a–f). The structures of the acetylated
derivatives were deduced from their combustion analyses, spectral
(IR, 1H NMR and 13C NMR) data and as depicted in Scheme 3.
Surprisingly, in this case, 3-(penta-O-acetylglycosyl/or tetra-O-
acetylglycosyl)-4-aryl-7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo-
[3,4-b]quinazolin-6-one derivatives 13 were obtained directly from
sponding signal of the C-2 (C–SCH3) appeared at
d 159 ppm. The
NMR spectrum of the 2-thioxo- (1) and 2-methylthio-quinazoline
(6) indicated that the site of the alkylation is the sulfur atom rather
than the nitrogen atom (Fig. 1).
Analogously, the reaction of potassium salt 5 with 2,3,4,6-tetra-
O-acetyl-a-D-glucopyranosyl bromide (9a) or 2,3,4,6-tetra-O-acetyl-
a-D-galactopyranosyl bromide (9b) in acetone afforded the
S-glycosylated nucleosides 10a,b in good yields (62–70%), (Scheme
2). Thin layer chromatography (chloroform: methanol, 8:2) indi-
cated the formation of the pure compounds. The structures of the
S-glycoside 10a,b were confirmed by elemental analysis and spectral
data (IR, 1H NMR, 13C NMR) (see Tables 4–6). The 1H NMR spectrum
of compound 10a as an example, showed the anomeric proton of the
glucose moiety as a doublet at
J ¼ 11.00 Hz indicating -configuration of the anomeric center. The
other protons of the glucopyranose ring resonated at 4.02-
5.39 ppm, while the four acetoxy groups appeared as four singlets at
2.12–2.33 ppm. The 13C NMR revealed the absence of the thione
carbon atom at about 174 ppm and a resonance of –N]C–N– carbon
atom (C-2) at 158 ppm was indicated to the chemical shift of the
d 5.55 ppm with a coupling constant
b
d
d
d

A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
4251
O
Ar
H
H
S
158 ppm
O
Ar
H
N
N
159 ppm
O
174 ppm
Ar
H
H
H
N
N
AcO
H
O
S
N
H
N
OAc
SCH3
1
6
OAc
OAc
10
Fig. 1.
the reaction of 2-glycosylhydrazones 11 with acetic anhydride
without separating the 3-N-acetyl derivatives 12 (Scheme 3).
De-protection of the acyclic C-nucleosides 13a–f could be ach-
ieved when they were stirred in methanolic ammonia solution
(10%) at room temperature to give in a moderate to good yields of 3-
(glycosyl)-4-aryl-7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-
b]quinazolin-6-ones (14a–f). Structures 14 were confirmed by
spectral and elemental analyses (see Tables 4 and 5). Their 1H NMR
spectra showed no absorption signals for the acetyl protons but
showed the multiplet signal supported to the hydroxyl protons in
The 1H NMR spectrum of 14a, as an example showed three
multiplet absorption bands for three methylene groups around
1.63–2.80, and very broad absorption bands at
d 3.51 supported to
the five hydroxyl groups (D2O exchangeable) and the signals at
d
3.86 (m, 1H, H-40), 4.19 (m, 2H, H-50, H-500), 4.47 (m, 1H, H-30), 4.72
(m, 1H, H-20), 5.65 (m, 1H, H-10), which supported the CHs of the
sugar moiety and in between the singlet signal due to the proton at
C-5 at
H, J ¼ 8.4 Hz), 7.42 (d, 2H, Ar-H, J ¼ 8.4 Hz) and the broad signal at
9.15 corresponding to NH, D2O exchangeable, respectively (Table
d 5.27. Also showed the aromatic protons at d 7.18 (d, 2H, Ar-
d
the region
d
3.51-3.84 (D2O exchangeable), the signals due to the
3.77–5.72. In addition, the signals
5). Also the 13C NMR spectrum of 14b showed two signals at
and 21.64 corresponding to 2CH3 groups, three signals at
d
21.30
protons of the sugar moiety at
d
d 28.31,
supported the two methylene and the two methyl protons.
29.17 and 30.95 due to 3CH2 groups, the signals at d 67.15, 67.45,
O
O
O
H
Ar
H
Ar
H
Ar
NH
Silylation
NH
NH
SCH3
N
SSiMe3
N
N
H
S
6
7
1b
Cl
Ar =
KOH
H
CH3I
O
H
Ar
O
Ar
AcO
O
NH
Br
NH
AcO
OAc
9c
N
S
AcO
OAc
AcO
R1
OAc
R2
-
+
Method A
O
O
N
S K
5
OAc
8a,b
10c
AcO
OAc
AcO
Method B
Sugar
bromide
R1
O
OAc
O
Br
OAc
H
Ar
R2
O
Ar
NH
H
H
N
9a,b
Method A,B
NH
S
S
N
N
S
N
AcO
R1
OAc
R2
AcO
AcO
H
R1
R2
R1
R2
Ar
O
O
O
O
OAc
OAc
OR
OAc
OAc
OAc
10a,b
I
II
a, R1 = H, R2 = OAc
b, R1 = OAc, R2 = H
Scheme 2.

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A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
OH
O
OH
Ar
H
H
Ar
O
OH
OH
(CH)n
H
NH
aldosugar
N H
OH
N
dioxane/piperidine
N
N
H
NHNH2
N
2b
Ar = 4-Cl-C6H4
11a-f
Ac2O/pyridine
OAc
OAc
O
OAc
Ar
H
OAc
O
Ar
H
OAc
OAc
(CH)n
H
OAc
OAc
N
Ac
N
AcO
N
(CH)n
AcO
N
N
H
N
N
N
H
12a-f
13a-f
OH
OH
O
H
Ar
N
a = Glucosyl,
n = 1
OH
OH
b = Mannosyl, n = 1
c = Galactosyl, n = 1
d = Arabinosyl, n = 0
(CH)n
OH
N
e = Ribosyl,
f = Xylosyl ,
n = 0
n = 0
N
N
H
14a-f
Scheme 3.
70.18 and 71.60 due to the carbon atoms of the sugar moiety (4 CH),
activity (56.6), whereas 3-arabinosyl-triazolo[3,4-b]quinazolin-6-
one (14d) derivative showed significant analgesic activity (71%).
The compounds that were screened for analgesic activity were
further screened for their ulcerogenic activity (Table 3). All the
compounds were tested at an oral dose 200 mg kgꢀ1 body mass.
The maximum reduction in ulcerogenic activity (mean severity
index ꢁ SEM, n ¼ 6 was 0.5 ꢁ 0.2), found in triazolo[3,4-b]quina-
zolin-6-one (14a), having the 3-glucosyl group at position 3. In
triazolo[3,4-b]quinazolin-6-one derivative, maximum reduction
(0.5 ꢁ 0) was found in compound (14e), having ribosyl group,
also the signals corresponding to C-4 and C-7 at
d 90.52 and 91.31,
eight lines around 126.68-158.56 supported to ten sp2 carbon
atoms and the absorption signal correspond to the carbonyl group
at
d 191.41 (Table 6).
3. Pharmacological screening
Anti-inflammatory activity of the synthesized compounds 1a–c,
2b, 4,10a–c and 14a–f were evaluated by carrageenan-induced paw
oedema method. The compounds were tested at an oral dose of
70 mg kgꢀ1 body mass and were compared with the standard drug
ibuprofen at the same oral dose. The tested compounds showed
anti-inflammatory activity ranging from 50 to 86% (Table 1), and
the standard drug ibuprofen showed 92% inhibition after 4 h. 1,2,4-
Triazolo[3,4-b]quinazolin-6-one derivative (14a) having an gluco-
syl group showed the maximum activity (86%), whereas the
2-hydrazine quinazoline (2b) showed moderate activity and for the
starting material 2-thiooxo-quinazoline (1a) the activity was found
to be minimal (50%). It was observed that 1,2,4-triazolo[3,4-b]qui-
nazolin-6-one derivatives 14a–f having C-glycosyl (Glucosyl,
mannosyl, galactosyl, arabinosyl, ribosyl and xylosyl) groups at the
3rd position showed high activity (86, 82, 85, 82, 82 and 84%)
respectively. However, the activity was found to be reduced for S-
nucleoside derivatives 10a–c.
The compounds that showed anti-inflammatory activity higher
than80% were testedforanalgesicactivity(Table 2). Compounds 14a–
f showed analgesic activity ranging from 57 to 73%, whereas the
standard drug ibuprofen showed 84% at a 70 mg kgꢀ1 oral dose.
Among all the tested compounds, the C-glycosyl derivative having 3-
glucosylgroup14a showedmaximumactivity(73%).Whenthisgroup
is replaced by 3-galactosyl 14c and 3-mannosyl 14b, there was
asignificantdecreaseintheactivity. Amongallthetestedcompounds,
3-ribosyl-triazolo[3,4-b]quinazolin-6-one (14e) showed minimum
Table 1
Anti-inflammatory effect of compounds against carrageenan-induced hind paws
oedema in rats.
Compound no.
Dose (mg kgꢀ1, 1% CMC)
Anti-inflammatory activitya
(mean inhibition ꢁ SEM %)
Control
1a
1b
1c
2b
–
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
50 ꢁ 3.0b
69 ꢁ 3.0b
71 ꢁ 5.0d
71 ꢁ 2.6b
68 ꢁ 2.7b
75 ꢁ 2.0b
76 ꢁ 3.0c
76 ꢁ 2.1b
86 ꢁ 1.7c
82 ꢁ 1.7c
85 ꢁ 1.9c
82 ꢁ 0.9b
82 ꢁ 2.0d
84 ꢁ 2.0d
92 ꢁ 1.0
4
10a
10b
10c
14a
14b
14c
14d
14e
14f
Ibuprofen
Anti-inflammatory activity of the tested compounds were measured with respect to
the control and compared with respect to the standard drug.
a
n ¼ 6.
b
P < 0.0001.
c
P < 0.001.
P < 0.05.
d

A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
4253
Table 2
Effects of the compounds on acetic acid induced abdominal writhing test in mice.
Table 4
Physical constants of newly synthesized compounds.
Compound no.
Dose (mg kgꢀ1, 1% CMC)
Analgesic activitya
No.
Yield (%)
M.p. (ꢂC)
Mol. form. (Mol. wt.)
Microanalysis
(mean inhibition ꢁ SEM %)
–
C
H
N
Control
14a
14b
14c
14d
14e
14f
Ibuprofen
1a
83
89
80
76
90
86
80
81
78
65
76
70
68
62
76
78
71
67
59
57
80
85
79
72
68
74
64
61
67
53
58
60
220–222
245–247
237–239
263–265
258–260
226–229
190–192
179–181
228–230
307–309
179–181
169–171
193–195
154–157
259–261
267–270
239–241
227–230
245–248
219–221
211–213
224–226
201–203
187–190
164–167
172–174
231–233
240–243
219–221
213–216
205–207
195–197
C16H18N2OS
(286.4)
C16H17ClN2OS
(320.8)
C17H20N2O2S
(316.4)
C16H20N4O
(284.3)
67.10
67.11
59.89
59.85
64.52
64.51
67.58
67.55
60.28
60.26
64.94
64.89
67.89
67.84
62.59
62.53
65.97
65.95
62.87
62.85
60.97
61.02
55.34
55.38
55.34
55.41
55.56
55.49
54.94
54.91
54.94
54.90
54.94
54.93
55.94
55.92
55.94
55.99
55.94
55.89
55.77
55.73
55.77
55.75
55.77
55.74
56.45
56.39
56.45
56.41
56.45
56.48
55.17
55.13
55.17
55.1
6.33
6.29
5.34
5.29
6.37
6.34
7.09
7.13
9.78
9.80
8.73
8.69
8.85
70
70
70
70
70
70
70
73 ꢁ 0.9b
57 ꢁ 0.9b
59 ꢁ 0.5b
71 ꢁ 1.2b
56.6 ꢁ 1.1b
59.5 ꢁ 0.5b
83.5 ꢁ 0.7b
1b
1c
8.83
2a
19.70
19.67
17.57
17.59
17.82
17.79
13.77
13.69
12.69
12.71
12.82
12.69
12.75
12.71
8.36
8.39
4.30
4.28
4.30
4.33
4.84
4.79
11.65
11.67
11.65
11.64
11.65
11.63
12.43
12.38
12.43
12.40
12.43
12.47
8.13
8.09
8.13
8.10
8.13
8.08
9.08
9.11
9.08
Analgesic activity of the tested compounds were measured with respect to the
control and compared with respect to the standard drug.
2b
C16H19ClN4O
6.01
6.04
7.05
7.02
5.69
5.65
5.02
4.97
5.77
5.73
4.59
4.56
5.72
5.69
5.42
5.29
5.42
5.35
5.40
5.39
6.08
6.11
6.08
6.09
6.08
6.09
6.04
6.08
6.04
6.06
6.04
6.02
5.41
5.39
5.41
5.40
5.41
5.43
5.39
5.41
5.39
5.37
5.39
5.40
5.68
5.71
5.68
5.65
5.68
5.69
5.61
5.57
5.61
5.63
5.61
5.58
(318.79)
C17H22N4O2
(314.3)
C23H23ClN4O
(406.9)
C23H22Cl2N4O
(441.3)
C24H25ClN4O2
(436.9)
C23H20Cl2N4O
(439.3)
C17H19ClN2OS
(334.8)
a
n ¼ 6.
2c
b
P < 0.0001.
3a
whereas the galactosyl group present in triazolo[3,4-b]quinazolin-
6-one derivative 14c showed the maximum severity index
(0.8 ꢁ 0.2). The other three compounds 14b,d and 14f 3-mannosyl,
3-ribosyl and 3-xylosyl-triazolo[3,4-b]quinazolin-6-one deriva-
tives, respectively, showed moderate severity indexes. The stan-
dard drug ibuprofen showed a high severity index of 1.8 ꢁ 0.2.
3b
3c
4
6
4. Experimental
10a
10b
10c
11a
11b
11c
11d
11e
11f
13a
13b
13c
13d
13e
13f
14a
14b
14c
14d
14e
14f
C30H35ClN2O10
(651.1)
S
S
C30H35ClN2O10
4.1. Chemistry
(651.1)
C27H31ClN2O8S
(579.0)
C22H29ClN4O6
(480.9)
C22H29ClN4O6
(480.9)
All melting points were taken on Electrothermal IA 9100 series
digital melting point apparatus. Microanalytical data (in accord
with the calculated values) were performed by Vario, Elementar
apparatus (Shimadzu), (Table 4). The IR spectra (KBr) were recorded
on a Perkin–Elmer 1650 spectrometer (USA). 1H and 13C NMR
spectra were determined on a JEOL EX-270 and JEOL ECA-500.
Chemical shifts were expressed in ppm relative to SiMe4 as internal
standards and DMSO-d6 as solvent. Mass spectra were recorded on
70 eV EI Ms-QP 1000 EX (Shimadzu, Japan), (Tables 5 and 6).
C22H29N4ClO6
(480.9)
C21H27ClN4O5
(450.9)
C21H27ClN4O5
(450.9)
C21H27ClN4O5
(450.9)
4.2. 4-(Aryl)-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-5-one-2-
C32H37ClN4O11
thiones (1a-c)
(689.1)
C32H37ClN4O11
(689.1)
C32H37ClN4O11
(689.1)
General procedure. A mixture of 5,5-dimethylcyclohexan-1,3-
dione (Dimadon) (0.01 mol), aldehydes (0.01 mol) and thiourea
(0.01 mol) in absolute ethanol (30 ml) in presence of concentrated
hydrochloric acid (37%, 3 ml) was refluxed for 10–18 h (TLC), then
allowed to cool and poured into cold water (100 ml) and neutral-
ized the solution with ammonium hydroxide. The solid product
was collected and crystallized from ethanol to give (1a–c), as white
crystal in good yields.
C29H33ClN4O9
(617.0)
C29H33ClN4O9
(617.0)
C29H33ClN4O9
(617.0)
C22H27ClN4O6
(478.9)
9.12
9.08
9.06
11.70
11.65
11.70
11.67
11.70
11.73
12.48
12.39
12.48
12.54
12.48
12.37
C22H27ClN4O6
Table 3
Ulcerogenic activity.a
(478.9)
C22H27ClN4O6
(478.9)
C21H25ClN4O5
(448.9)
C21H25ClN4O5
(448.9)
55.17
55.12
56.19
56.23
56.19
56.18
56.19
56.18
Compound no.
Dose (mg kgꢀ1
1% CMC)
,
Ulcerogenic activitya (mean
severity index ꢁ SEM)
Control
14a
14b
14c
14d
14e
14f
Ibuprofen
0.0 ꢁ 0.0b
0.5 ꢁ 0.2b
0.6 ꢁ 0.1c
0.8 ꢁ 0.2d
0.6 ꢁ 0.2c
0.5 ꢁ 0.0b
0.5 ꢁ 0.1c
1.8 ꢁ 0.2
200
200
200
200
200
200
200
C21H25ClN4O5
(448.9)
Ulcerogenic activities of the tested compounds were compared with respect to the
standard drug.
4.2.1. 4-Phenyl-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-5-one-2-
thione (1a)
The compound was obtained from the reaction of benzaldehyde,
as a white powder crystallized from ethanol.
a
n ¼ 6.
b
P < 0.0001.
c
P < 0.001.
d
P < 0.05.

4254
A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
Table 5
Mass, IR, 1H NMR spectral data of newly synthesized compounds.
Compd. no.
Mass (m/z) (%)
IR (
n
, cmꢀ1
)
1H NMR (
0.91 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.00–2.02 (d, 2H, CH2), 2.17–2.20 (d, 2H, CH2), 5.32 (s, 1H, C5-H),
6.73–7.00 (m, 2H, Ar-H), 7.10–7.23 (m, 2H, Ar-H), 8.35, 9.80 (2br, 2H, 2NH).
d, ppm) (DMSO-d6)
1a
[Mþ], 286
(100)
3300 (br, NH’s),
1700 (C]O),
d
2939 (CH alkyl),
1235 (C]S)
3290 (br, NH’s),
1704 (C]O),
1b
1c
[Mþ þ 1],
d
0.90 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.88–2.18 (m, 4H, 2CH2), 5.38 (br, 1H, C5-H), 7.23 (d, 2H, J ¼ 8.1 Hz, Ar-H),
321 (29), [Mþ],
320 (100)
7.33 (d, 2H, J ¼ 8.1 Hz, Ar-H), 8.90, 10.00 (2br, 2H, 2NH).
1225 (C]S)
[Mþ], 316 (100)
3310 (br, NH’s),
3025 (CH aryl),
1238 (C]S),
d 0.90 (s, 3H, CH3), 0.99 (s, 3H, CH3), 2.01–2.04 (d, 2H, CH2), 2.19-2.23 (d, 2H, CH2), 3.47 (br, 2H,
2NH with H2O of DMSO), 3.63 (s, 3H, OCH3), 5.09 (s, 1H, C5-H), 6.73 (d, 2H, J ¼ 8.1 Hz, Ar-H),
7.02 (d, 2H, J ¼ 8.1 Hz, Ar-H).
1706 (C]O)
2a
2b
2c
3a
3b
3c
4
[Mþ], 284 (100)
3285 (br, NH’s),
3032 (CH aryl),
2920 (CH alkyl),
1703 (C]O)
3295 (br, NH’s),
3038 (CH aryl),
2927 (CH alkyl),
1700 (C]O)
3340 (br, NH’s),
3040 (CH aryl),
2917 (CH alkyl),
1702 (C]O)
3350 (br, NH’s),
3026 (CH aryl),
2937 (CH alkyl),
1698 (C]O)
3325 (br, NH’s),
3051 (CH aryl),
2943 (CH alkyl),
1700 (C]O)
3290 (br, NH’s),
3034 (CH aryl),
2923 (CH alkyl),
1699 (C]O)
3250 (br, NH),
3024 (CH aryl),
2919 (CH alkyl),
1689 (C]O)
3320 (br, NH),
3039 (CH aryl),
1688 (C]O)
3280 (br, NH),
3037 (CH aryl),
2928 (CH alkyl),
1690–1715 (5C]O)
3300 (br, NH),
3029 (CH aryl),
2914 (CH alkyl),
1692–1715 (5C]O)
3320 (br, NH),
3032 (CH aryl),
2916 (CH alkyl),
1689–1710 (4C]O)
3500–3200
d
0.94 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.93–2.00 (d, 2H, CH2), 2.13–2.18 (d, 2H, CH2), 5.17 (s, 1H, C–H),
7.09–7.16 (m, 2H, Ar-H), 7.20–7.26 (m, 2H, Ar-H), 8.25 (br, 2H, NH2), 9.10, 10.65 (2br, 2H, 2NH).
[Mþ þ 1],
d
0.85 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.86–2.14 (m, 4H, 2CH2), 5.30 (s, 1H, C5-H), 5.74 (br, 1H, NH),
320 (31), [Mþ],
319 (87)
7.23 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.33 (d, 2H, J ¼ 8.1 Hz, Ar-H), 8.15 (br, 2H, NH2), 9.30 (br, 1H, NH).
[Mþ], 314 (100)
d
0.86 (s, 3H, CH3), 0.98 (s, 3H, CH3), 2.00 (d, 2H, CH2), 2.18 (d, 2H, CH2), 3.87 (s, 3H, OCH3), 5.27 (s, 1H, C5-H),
6.89 (d, 2H, J ¼ 8.3 Hz, Ar-H), 7.11 (d, 2H, J ¼ 8.3 Hz, Ar-H), 8.07 (br, 2H, NH2), 9.60, 10.40 (2br, 2H, 2NH).
[Mþ þ 1],
d 0.89 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.89–2.00 (d, 2H, CH2), 2.10–2.16 (d, 2H, CH2), 5.28 (s, 1H, C5-H),
407 (27), [Mþ],
406 (100)
7.00 (d, 2H, Ar-H, J ¼ 8.0 Hz)), 7.11–7.18 (m, 2H, Ar-H), 7.23–7.34 (m, 3H, Ar-H), 7.41 (d, 2H, Ar-H, J ¼ 8.0 Hz),
8.25 (s, 1H, azomethin proton), 9.30, 10.60 (2br, 2H, 2NH).
[Mþ þ 1],
d
0.92 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.95–2.30 (m, 4H, 2CH2), 5.34 (s, 1H, C5-H), 7.25 (d, 2H, J ¼ 8.2 Hz, Ar-H),
442 (25), [Mþ],
441 (76)
7.30 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.56 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.72 (d, 2H, J ¼ 8.2 Hz, Ar-H),
8.50 (s, 1H, azomethin proton), 8.90, 10.00 (2br, 2H, 2NH).
[Mþ þ 1],
d 0.90 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.93–2.31 (m, 4H, 2CH2), 3.89 (s, 3H, OCH3) 5.30 (s, 1H, C5-H),
437 (30), [Mþ],
436 (100)
7.11 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.22 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.54 (d, 2H, J ¼ 8.2 Hz, Ar-H),
7.60 (d, 2H,J ¼8.2 Hz, Ar-H), 8.23 (s,1H, azomethin proton), 8.75, 10.20 (2br, 2H, 2NH).
[Mþ þ 1],
d
0.94 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.90–2.25 (m, 4H, 2CH2), 5.46 (s, 1H, C5-H), 7.24 (d, 2H, J ¼ 8.2 Hz, Ar-H),
440 (23), [Mþ],
439 (89)
7.32 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.58 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.80 (d, 2H, J ¼ 8.2 Hz, Ar-H), 10.30 (br, 1H, NH).
6
[Mþ þ 1],
335 (20) [Mþ ],
334 (100)
–
d
0.98 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.02 (m, 4H, 2CH2), 3.10 (s, 3H, SCH3), 5.35 (s, 1H, C5-H),
7.26 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.35 (d, 2H, J ¼8.2 Hz, Ar-H), 10.15 (br,1H, NH).
10a
d
0.89 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.82–2.04 (m, 4H, 2CH2), 2.12–2.33 (4s, 12H, 4CH3CO), 4.02 (m, 1H, H-50),
4.26 (m, 2H, H-60, H-600), 5.10 (t, 1H, H-40), 5.21 (m, 1H, H-20), 5.39 (t, 1H, J ¼ 9.34 Hz, H-30), 5.40 (s, 1H,C5-H),
5.73 (d, 1H, J ¼11.0, H-10), 7.29 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.43 (d, 2H, J ¼ 8.1 Hz, Ar-H), 9.80 (br, 1H, NH).
10b
10c
11a
–
–
d
0.87 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.89–2.04 (m, 4H, 2CH2), 2.14–2.29 (4s, 12H, 4CH3CO), 3.92 (m, 1H, H-50),
4.20 (m, 2H, H-60, H-600), 5.07 (t, 1H, H-40), 5.11 (m, 1H, H-20), 5.39 (s, 1H, C5-H), 5.43 (t, 1H, J ¼ 9.40 Hz, H-30),
5.69 (d,1H, J ¼10.8,H-10), 7.18 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.38 (d, 2H, J ¼ 8.5 Hz, Ar-H), 10.00 (br, 1H, NH).
d
0.88 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.89–2.09 (m, 4H, 2CH2), 2.11–2.31 (3s, 9H, 3CH3CO),
3.52 (m, 2H, H-50, H-500), 3.71 (m, 1H, H-40), 3.96 (m, 1H, H-30), 4.21 (m, 1H, H-20), 4.58 (d, 1H, J ¼3.72 Hz, H-10),
5.33 (s, 1H,C5-H), 7.20 (d, 2H, J ¼ 8.3 Hz, Ar-H), 7.36 (d, 2H, J ¼ 8.3 Hz, Ar-H), 9.80 (br,1H, NH).
[Mþ þ 1],
d
0.92 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.89–2.05 (m, 4H, 2CH2), 3.59 (m, 5OH, D2O exchangeable), 3.78 (m, 1H, H-50), 4.30
481 (19) [Mþ],
480 (100)
(br, OH, NH),
(m, 2H, H-60, H-600), 4.41 (m, 1H, H-40), 4.54 (m, 1H, H-30), 5.22 (s, 1H, C5-H), 5.49 (m, 1H, H-20), 7.17
3040 (CH aryl),
2935 (CH alkyl),
1705 (C]O)
3500–3180
(br, OH, NH),
3039 (CH aryl),
2917 (CH alkyl),
1700 (C]O)
3500–3150
(br, OH, NH),
(d, 2H, J ¼ 8.3 H, Ar-H), 7.31 (d, 2H, J ¼ 8.3 Hz, Ar-H), 8.01 (m, 1H, H-10), 9.10, 10.25 (2brs, 2NH, D2O exchangeable).
11b
11c
[Mþ þ 1],
d
0.90 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.86–2.06 (m, 4H, 2CH2), 3.52 (m, 5OH), 3.79 (m, 1H, H-50), 4.22 (m, 2H, H-60,
481 (23) [Mþ],
480 (100)
H-600),4.47 (m, 1H, H-40),4.55 (m, 1H, H-30), 5.19 (s, 1H, C5-H), 5.43 (m, 1H, H-20), 7.19 (d, 2H, Ar-H, J ¼ 8.2 Hz), 7.29
(d, 2H, Ar-H, J ¼ 8.2 Hz), 7.93 (m, 1H, H-10), 9.35, 10.60 (2brs, 2NH).
[Mþ þ 1],
d
0.88 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.82–2.03 (m, 4H, 2CH2), 3.54 (m, 5OH), 3.80 (m, 1H, H-50), 4.17 (m, 2H, H-60, H-600),
481 (20) [Mþ],
480 (89)
4.39 (m, 1H, H-40), 4.52 (m, 1H, H-30), 5.19 (s, 1H, C5-H), 5.59 (m, 1H, H-20), 7.23 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.34
3037 (CH aryl),
2924 (CH alkyl),
1702 (C]O)
(d, 2H, J ¼ 8.0 Hz, Ar-H), 8.00 (m, 1H, H-10), 8.95, 10.00 (2brs, 2NH).

A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
4255
Table 5 (continued )
Compd. no.
Mass (m/z) (%)
IR (n
, cmꢀ1
)
1H NMR (
d, ppm) (DMSO-d6)
11d
[Mþ þ 1],
3460–3120
(br, OH, NH),
3028 (CH aryl),
2928 (CH alkyl),
1710 (C]O)
3400–3100
(br, OH, NH),
3021 (CH aryl),
2929 (CH alkyl),
1708 (C]O)
d
0.87 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.80–2.00 (m, 4H, 2CH2), 3.68 (m, 4H, 4OH, D2O exchangeable), 4.35 (m, 1H, H-30),
451 (36) [Mþ],
450 (76)
4.49 (m, 1H, H-40), 4.67 (m, 2H, H-50, H-500), 5.12 (dd, 1H, H-20, J ¼ 7.80 Hz), 5.23 (s, 1H, C5-H), 7.26 (d, 2H, J ¼8.4 Hz,
Ar-H), 7.45 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.67 (d, 1H, H-10, J ¼ 7.80 Hz), 9.20, 10.30 (2brs, 2NH, D2O exchangeable).
11e
11f
[Mþ þ 1],
d
0.91 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.83–2.03 (m, 4H, 2CH2), 3.63 (m, 4H, 4OH), 4.32 (m, 1H, H-30), 4.44 (m, 1H, H-40),
451 (19) [Mþ],
450 (69)
4.69 (m, 2H, H-50, H-500), 5.10 (dd, 1H, H-20, J ¼ 7.67 Hz), 5.20 (s, 1H, C5-H), 7.22 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.40 (d, 2H,
J ¼ 8.5 Hz, Ar-H), 7.78 (d, 1H, H-10, J ¼ 7.75 Hz), 9.80, 10.70 (2brs, 2H, 2NH).
[Mþ þ 1],
3430–3150
(br, OH, NH),
d
0.89 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.87–2.09 (m, 4H, 2CH2), 3.65 (m, 4H, 4OH), 4.29 (m, 1H, H-30), 4.37 (m, 1H, H-40),
451 (30) [Mþ],
450 (88)
4.69 (m, 2H, H-50, H-500), 5.13 (dd, 1H, H-20, J ¼ 7.72 Hz), 5.26 (s, 1H, C5-H), 7.18 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.31 (d, 2H,
3018 (CH aryl),
2931 (CH alkyl),
1705 (C]O)
3270 (br, NH) 3036
(CH aryl),
J ¼ 8.1 Hz, Ar-H), 7.67 (d, 1H, H-10, J ¼ 7.83 Hz), 9.15, 10.45 (2brs, 2NH).
13a
13b
13c
13d
13e
13f
[Mþ þ 1],
d
0.90 (s, 3H, CH3), 1.07(s, 3H, CH3), 1.80–2.30 (m, 19H, 2CH2 þ5CH3), 3.98–4.20 (m, 2H, H-50, H-500), 4.40 (m, 1H, H-40),
690 (17) [Mþ],
689 (68)
5.10 (t, 1H, H-30, J ¼ 8.23 Hz), 5.25 (t, 1H, H-20, J ¼ 7.86 Hz), 5.36 (s, 1H, C5-H), 5.95 (d, 1H, H-10, J ¼ 8.27 Hz), 7.23 (d, 2H,
2919 (CH alkyl),
1687–1720 (6C]O)
3250 (br, NH),
3038 (CH aryl),
2923 (CH alkyl),
1688–1715 (6C]O)
3290 (br, NH)
3029 (CH aryl),
2927 (CH alkyl),
1690–1718 (6C]O)
3300 (br, NH)
3023 (CH aryl),
2919 (CH alkyl),
1692–1719 (5C]O)
3320 (br, NH)
3027 (CH aryl),
2909 (CH alkyl),
1695–1715 (5C]O)
3390 (br, NH),
3030 (CH aryl),
2931 (CH alkyl),
1689–1723 (5C]O)
3500–3100
J ¼ 8.2 Hz, Ar-H), 7.38 (d, 2H, J ¼ 8.2 Hz, Ar-H), 9.90 (br, NH, D2O exchangeable)
[Mþ þ 1],
d
0.82 (s, 3H, CH3), 0.99(s, 3H, CH3), 1.93–2.36 (m, 19H, 2CH2 þ5CH3), 3.97–4.14 (m, 2H, H-50, H-500), 4.30–4.41 (m, 1H,
690 (22) [Mþ],
689 (91)
H-40), 4.88–4.99 (m, 2H, H-30, H-20), 5.74 (s,1H, C5-H), 5.97 (d,1H, H-10, J ¼8.19 Hz) 7.20 (d, 2H, Ar-H, J ¼ 8.2 Hz), 7.35 (d,
2H, Ar-H, J ¼ 8.2 Hz), 9.79 (br, NH).
[Mþ þ 1],
d
0.83 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.90–2.34 (m, 19H, 2CH2 þ 5CH3), 3.95–4.18 (m, 2H, H-50, H-500), 4.29–4.34 (m, 1H,
690 (19) [Mþ],
689 (88)
H-40), 4.83–4.95 (m, 2H, H-30, H-20), 5.68 (s, 1H, C5-H), 5.93 (d, 1H, H-10, J ¼ 8.21 Hz) 7.26 (d, 2H, Ar-H, J ¼ 8.1 Hz), 7.38
(d, 2H, Ar-H, J ¼8.1 Hz), 9.79 (br, NH).
[Mþ þ 1],
d
0.87 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.95–2.36 (4 CH3þ 2CH2), 4.23–4.34 (m, 2H, H-40, H-400), 5.25 (t, 1H, H-30,
618 (27) [Mþ],
617 (100)
J ¼ 8.6 Hz), 5.23 (s, 1H, C-H), 5.40 (t,1H, H-200, J ¼ 8.6 Hz), 5.60 (d, 1H, H-10, J ¼ 8.5 Hz), 7.20 (d, 2H, Ar-H, J ¼ 8.4 Hz), 7.42
(d, 2H, Ar-H, J ¼ 8.4 Hz), 10.40 (br, NH).
[Mþ þ 1],
d
0.90 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.99–2.38 (4 CH3þ 2CH2), 4.19–4.30 (m, 2H, H-40, H-400), 5.23 (t, 1H, H-30,
618 (19) [Mþ],
617 (87)
J ¼ 8.5 Hz), 5.28 (s, 1H, C5-H), 5.39 (t, 1H, H-200, J ¼ 8.7 Hz), 5.64 (d, 1H, H-10, J ¼ 8.5 Hz), 7.16 (d, 2H, Ar-H, J ¼ 8.4 Hz),
7.38 (d, 2H, Ar-H, J ¼ 8.4 Hz), 10.20 (br, NH).
[Mþ þ 1],
d
0.89 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.89–2.29 (4 CH3þ 2CH2), 4.17–4.27 (m, 2H, H-40, H-400), 5.20 (t, 1H, H-30,
618 (17) [Mþ],
617 (69)
J ¼ 8.3 Hz), 5.26 (s, 1H, C-H), 5.42 (t, 1H, H-200, J ¼ 8.6 Hz), 5.68 (d, 1H, H-10, J ¼ 8.4 Hz), 7.19 (d, 2H, Ar-H, J ¼ 8.3 Hz), 7.35
(d, 2H, Ar-H, J ¼8.3 Hz), 11.00 (br, NH).
14a
[Mþ þ 1],
d
0.90 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.89–2.06 (m, 4H, 2CH2), 3.51 (m, ,5H,5OH, D2O exchangeable), 3.86 (m, 1H, H-40),
4.19 (m, 2H, H-50, H-500), 4.47 (m, 1H, H-30), 4.72 (m, 1H, H-20), 5.27 (s, 1H, C5-H), 5.65 (m, 1H, H-10), 7.18 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 7.42 (d,2H, J ¼ 8.4 Hz,Ar-H), 9.15 (br, NH).
479 (29) [Mþ],
478 (73)
(br, OH, NH),
3039 (CH aryl),
2932 (CH alkyl),
1692 (C]O)
3500–3100
(br, OH, NH),
3033 (CH aryl),
2928 (CH alkyl),
1698 (C]O)
3500–3150
(br, OH, NH),
3040 (CH aryl),
2938 (CH alkyl),
1695 (C]O)
3430–3100
(br, OH, NH),
3023 (CH aryl),
2939 (CH alkyl),
1716 (C]O)
3500–3100
(br, OH, NH),
14b
14c
14d
14e
14f
[Mþ þ 1],
d
0.94 (s, 3H, CH3),1.09 (s, 3H, CH3),1.86–2.03 (m, 4H, 2CH2), 3.60 (m, 5OH), 3.89 (m,1H, H-40), 4.17 (m, 2H, H-50, H-500),
4.54 (m, 1H, H-30), 4.76 (m, 1H, H-20), 5.25 (s, 1H, C5-H), 5.67 (m, 1H, H-10), 7.21 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.39 (d, 2H,
J ¼8.2 Hz, Ar-H), 9.70 (br, NH).
479 (18) [Mþ],
478 (65)
[Mþ þ 1],
d
0.86 (s, 3H, CH3),1.01 (s, 3H, CH3),1.83–2.00 (m, 4H, 2CH2), 3.62 (m, 5OH), 3.77 (m, 1H, H-40), 4.16 (m, 2H, H-50, H-500),
4.52 (m, 1H, H-30), 4.71 (m, 1H, H-20), 5.30 (s, 1H, C5-H), 5.72 (m, 1H, H-10), 7.18 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.33 (d, 2H,
J ¼8.1 Hz, Ar-H), 10.00 (br, NH).
479 (22) [Mþ],
478 (64)
[Mþ þ 1],
d
0.89 (s, 3H, CH3),1.07 (s, 3H, CH3),1.88–2.03 (m, 4H, 2CH2), 3.84 (m, 4OH, D2O exchangeable), 4.33 (m,1H, H-30), 4.56
(m, 2H, H-40, H-400), 5.17 (t, 1H, H-20, J ¼ 7.6 Hz), 5.31 (s, 1H, C5-H), 5.61 (d, 1H, H-10, J ¼ 7.8 Hz), 7.16 (d, 2H, J ¼ 8.4 Hz,
Ar-H), 7.28 (d, 2H, J ¼ 8.4 Hz, Ar-H), 10.30 (br, NH).
449 (18) [Mþ],
448 (68)
[Mþ þ 1],
d
0.92 (s, 3H, CH3),1.12 (s, 3H, CH3), 1.89–2.06 (m, 4H, 2CH2), 3.78 (m, 4OH), 4.29 (m,1H, H-30), 4.59 (m, 2H, H-40, H-400),
5.21 (s, 1H, C5-H), 5.29 (t, 1H, H-20, J ¼ 7.4 Hz), 5.64 (d, 1H, H-10, J ¼ 7.9 Hz), 7.20 (d, 2H, J ¼ 8.6 Hz, Ar-H), 7.36 (d, 2H,
J ¼ 8.6 Hz, Ar-H), 10.15 (br, NH).
449 (17) [Mþ],
448 (73)
3021 (CH aryl),
2930 (CH alkyl),
1715 (C]O)
[Mþ þ 1],
3440–3100
d
0.85 (s, 3H, CH3),1.05 (s, 3H, CH3),1.87–2.02 (m, 4H, 2CH2), 3.73 (m, 4OH), 4.35 (m,1H, H-30), 4.57 (m, 2H, H-40, H-400),
449 (20) [Mþ],
448 (76)
(br, OH, NH), 3024 5.15 (t, 1H, H-20, J ¼ 7.7 Hz), 5.30 (s, 1H, C5-H), 5.69 (d, 1H, H-10, J ¼ 7.8 Hz), 7.19 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.40 (d, 2H,
(CH aryl), 2929
(CH alkyl),
J ¼ 8.4 Hz, Ar-H), 10.55 (br, NH).
1710 (C]O)

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Table 6
4.4. 4-(4-Chlorophenyl)-2-(arylmethylenehydrazon)-7-dimethyl-
3,4,6,8-tetrahydro-quinazolin-5-one (3a–c)
13C NMR spectral data of some newly synthesized compounds.
Compd. 13C NMR (
no.
d, ppm) (DMSO-d6)
General procedure. A mixture of 2b (0.01 mol) and the appro-
priate aromatic aldehyde (0.01 mol) was stirred under reflux in
glacial acetic acid (30 mL) for 30 min. The reaction mixture was
allowed to cool to room temperature, whereby the solid formed
was filtered off and crystallized from appropriate solvent to
produce (3a–c) in high yield.
1b
2b
6
d
20.39, 20.49 (2CH3), 27.39, 28.64 (2 CH2), 91.20, 91.34 (2C, C-4 þ C-7),
127.98, 129.21, 133.19, 140.95, 142.78, 153.74 (6 line for 8 sp2 carbons),
174.3 (C]S), 192.20 (C]O).
d
20.36, 20.45 (2CH3), 27.41, 28.63 (2 CH2), 90.77, 91.21 (2C, C-4 þ C-7),
127.85, 129.34, 133.29, 140.79, 142.95, 153.86, 158.90 (7 line for 9 sp2
carbons), 191.15 (C]O).
d
20.50, 20.64 (2CH3), 27.33, 28.78 (2 CH2), 31.42 (1C, SCH3), 91.09, 91.75
(2C, C-4 þ C-7), 128.45, 129.54, 133.89, 140.73, 142.79, 153.96, 159.00 (7
4.4.1. 4-(4-Chlorophenyl)-2-(phenylmethylenehydrazon)-7-dimethyl-
3,4,6,8-tetrahydro-quinazolin-5-one (3a)
line for 9 sp2 carbons), 192.00 (C]O).
10a
d 20.40, 21.26 (2CH3), 28.51, 29.36 (2 CH2), 34.87 (CH2), 35.20, 36.13,
36.78, and 38.50 (4 CH3), 67.90 (C-40), 69.37 (C-20), 72.75 (C-30), 75.56 (C-
50), 80.69 (C-10), 89.73, 90.45 (2C, C-4 þ C-7), 127.29, 128.56, 133.47,
141.85, 144.46, 153.89, 158.00 (7 line for 9 sp2 carbons), 169.31, 169.54,
169.95, 169.98 (4C]O ester) 190.65 (C]O).
It was obtained from compound 2b (0.01 mol) and benzalde-
hyde (0.01 mol) as yellow crystals, crystallized from DMF.
4.4.2. 4-(4-Chlorophenyl)-2-(4-chlorophenylmethylenehydrazon)-
7-dimethyl-3,4,6,8-tetrahydro-quinazolin-5-one (3b)
It was obtained from compound 2b (0.01 mol) and 4-chlor-
obenzaldehyde (0.01 mol) as yellow crystals, crystallized from DMF.
11b
13b
d 20.39, 21.12 (2CH3), 28.40, 29.21 (2 CH2), 32.86 (CH2), 67.29, 67.68, 70.31
and 71.53 (4 CH), 90.23, 91.18 (2C, C-4 þ C-7), 126.30, 128.16, 133.49,
140.90, 142.52, 143.78, 153.87, 158.66 (8 line for 10 sp2 carbons), 190.65
(C]O)
d
20.41, 20.50 (2CH3), 28.21, 29.13 (2 CH2), 32.38 (CH2), 38.15, 38.57, 38.88,
39.81, 40.71 (5 CH3), 67.04, 67.24, 70.03 and 70.83 (4 CH), 90.77, 91.21 (2C,
C-4 þ C-7), 127.85, 129.34, 133.29, 140.79, 141.27, 142.95, 153.86, 158.90 (8
line for 10 sp2 carbons), 168.90, 169.31, 169.54, 169.95, 169.98 (5C]O
ester), 192.78 (C]O)
4.4.3. 4-(4-Chlorophenyl)-2-(4-anisylmethylenehydrazon)-7-
dimethyl-3,4,6,8-tetrahydro-quinazolin-5-one (3c)
It was obtained from compound 2b (0.01 mol) and 4-anisalde-
hyde (0.01 mol) as yellow crystals, crystallized from DMF.
14b
d 21.30, 21.64 (2CH3), 28.31, 29.17 (2 CH2), 30.95 (CH2), 67.15, 67.45, 70.18
and 71.60 (4 CH), 90.52, 91.31 (2C, C-4 þ C-7), 126.68, 128.56, 134.41,
141.80, 142.33, 143.86, 153.95, 158.56 (8 line for 10 sp2 carbons), 191.41
(C]O)
4.5. 3,4-Di(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-1,2,4-
triazolo[3,4-b]quinazolin-6-one (4)
A solution of compound 3b (0.01 mol) in acetic anhydride–
pyridine (30 ml, 2:1) was stirred at room temperature for 24 h,
poured onto water (100 ml) and the solid formed was collected by
filtration and crystallized from dioxane to afford 4.
4.2.2. 4-(4-Chlorophenyl)-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-
5-one-2-thione (1b)
The compound was obtained from the reaction of 4-chlor-
obenzaldehyde, as a white powder crystallized from ethanol.
4.6. 4-(4-Chlorophenyl)-2-methylthio-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (6)
4.2.3. 4-(4-Anisyl)-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-5-
one-2-thione (1c)
The compound was obtained from the reaction of 4-anisalde-
hyde, as a white powder crystallized from ethanol.
To a warmed ethanolic KOH solution (prepared by dissolving
0.01 mol of KOH in 50 mL ethanol) was added each of compound 1b
(0.01 mol), the heating was continued for 30 min and the mixture
was allowed to cool to room temperature, and the proper meth-
yliodide (0.012 mol) was added. The mixture was stirred under
reflux for 5 h, then cooled to room temperature, poured into cold
water (100 mL). The solid product precipitated was filtered off
washed with 100 mL water. The product was dried to produce (6),
as pale yellow crystals, crystallized from ethanol.
4.3. 4-Aryl-2-hydrazino-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-
5-one (2a–c)
General procedure. A suspension of compound 1a–c (0.01 mol) in
hydrazine hydrate (99%, 20 ml) was stirred under reflux for 10 h.
The reaction mixture was allowed to cool to room temperature. The
solid precipitated was filtered off, washed with ethanol, dried and
crystallized from dimethylformamide to produce 2a–c in high
yields.
4.7. Preparation of the acetylated thionucleosides (10a–c)
Method A. To a solution of 1b (0.01 mol) in aqueous potassium
hydroxide (0.01 mol) in distilled water (5 ml) was added a solution
of 2,3,4,6-tetra-O-acetyl-
a-
D-gluco-/or galactopyranosyl bromide
4.3.1. 4-Phenyl-2-hydrazino-7-dimethyl-3,4,6,8-tetrahydro-quinazolin-
5-one (2a)
The compound was obtained from the reaction of 1a, as a yellow
powder, crystallized from DMF.
(9a,b) or 2,3,5-tri-O-acetyl-a-D
-ribofuranosyl bromide (9c)
(0.015 mol) in acetone (40 ml). The reaction mixture was stirred at
room temperature for 24 h (under TLC control). The solvent was
evaporated under reduced pressure at 40 ꢂC, and the crude product
was filtered off and washed with distilled water to remove KBr
formed. The product was dried, and crystallized from ethanol to
afford 10a–c.
4.3.2. 4-(4-Chlorophenyl)-2-hydrazino-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (2b)
The compound was obtained from the reaction of 1b, as a yellow
powder, crystallized from DMF.
Method B. Compound 1b (0.01 mol) was stirred under reflux,
and dry conditions in 50 ml hexamethyldi-silane (HMDS) in the
presence of ammonium sulfate (0.01 mol) for 50–60 h. The clear
solution formed was cooled and the solvent was evaporated in
vacuo to give the silylated compound 7 as yellow oil. The latter oil
was dissolved in acetonitrile (10 ml) and was added to a solution of
sugar acetate in acetonitrile (5 ml) followed by addition of SnCl4
4.3.3. 4-(4-Anisyl)-2-hydrazino-7-dimethyl-3,4,6,8-tetrahydro-
quinazolin-5-one (2c)
The compound was obtained from the reaction of 1c, as a yellow
powder, crystallized from DMF.

A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
4257
(1.8 ml). The reaction mixture was stirred at room temperature for
4.8.6. 4-(Chlorophenyl)-2-(xylosylhydrazon)-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (11f)
It was obtained from D-xylose (10 mmol), as a white powder,
crystallized from ethanol.
16–20 h (under TLC control). The mixture was poured into satu-
rated sodium bicarbonate solution and extracted the thioglycosides
by diethylether þ ethylacetate (1:1, 100 ml). Evaporate the solvent
under reduced pressure to furnish crude nucleosides which were
purified by column chromatography (30% ethylacetate in ether) to
afford the pure thioglycosides 10a,b.
4.9. 3-(Penta-O-acetyl/or tetra-O-acetlyglycosyl)-4-aryl-7-
dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one
(13a-f)
4.7.1. 4-(4-Chlorophenyl)-7-dimethyl-3,4,6,8-tetrahydro-2-
(20,30,40,60-tetra-O-acetyl-
5-one-2-thione (10a)
b-D-glucopyranosyl-thio)-3H-quinazolin-
It was obtained from compound 1b (0.01 mol) and 2,3,4,6-tetra-
O-acetyl- -glucopyranosyl)bromide (9a) (0.01 mol) as yellow
powder, crystallized from benzene.
General procedure. A solution from each of 11a–f (10 mmol) in
a mixture of acetic anhydride-pyridine (40 mL, 2:1), was stirred at
room temperature for 24 h, poured onto water (100 mL). The
mixture was then extracted with chloroform several times
(150 mL), after the removal of chloroform under reduced pressure;
the precipitate was filtered off, dried, and crystallized from the
proper solvent to obtain 13a–f.
a-D
4.7.2. 4-(4-Chlorophenyl)-7-dimethyl-3,4,6,8-tetrahydro-2-
(20,30,40,60-tetra-O-acetyl-
b-D-galactopyranosyl-thio)-3H-
quinazolin-5-one-2-thione (10b)
It was obtained from compound 1b (0.01 mol) and 2,3,4,6-tetra-
O-acetyl-
a
-D-galactopyranosyl)bromide (9b) (0.01 mol) as yellow
4.9.1. 3-(10,20,30,40,50-Penta-O-acetylglucosyl)-4-(4-chlorophenyl)-
7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-
one (13a)
powder, crystallized from n-hexane.
4.7.3. 4-(4-Chlorophenyl)-7-dimethyl-3,4,6,8-tetrahydro-2-
It was obtained from 11a as white powder, crystallized from
benzene.
(20,30,50-tri-O-acetyl-
2-thione (10c)
b-D-ribofuranosyl-thio)-3H-quinazolin-5-one-
It was obtained from compound 1b (0.01 mol) and 2,3,5-tri-O-
acetyl- -ribofuranosyl)bromide (9c) (0.01 mol) as yellow
4.9.2. 3-(10,20,30,40,50-Penta-O-acetylmannosyl)-4-
(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-1,2,-4-triazolo
[3,4-b]quinazolin-6-one (13b)
a-D
powder, crystallized from n-hexane.
It was obtained from 11b as white powder, crystallized from
benzene.
4.8. 4-(Chlorophenyl)-2-(glycosylhydrazon)-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (11a–f)
4.9.3. 3-(10,20,30,40,50-Penta-O-acetylglactoosyl)-4-
(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo
[3,4-b]quinazolin-6-one (13c)
General procedure. A mixture of 2b (0.01 mol), the appropriate
mono-sacchride (aldohexoses and or aldopentoses) (0.01 mol) and
a catalytic amount of piperidine was heated at reflux in dioxane
(50 mL) for 15–20 h, the reaction mixture was allowed to cool to
room temperature, the precipitate was filtered off, washed with
ethanol, dried and crystallized to afford the title compounds.
It was obtained from 11c as white powder, crystallized from
cyclohexane.
4.9.4. 3-(10,20,30,40-Tetra-O-acetylarabinosyl)-4-(4-chlorophenyl)-
7-dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-
one (13d)
It was obtained from 11d as white powder, crystallized from
benzene.
4.8.1. 4-(Chlorophenyl)-2-(glucosylhydrazon)-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (11a)
It was obtained from
D-glucose (10 mmol), as a white powder,
4.9.5. 3-(10,20,30,40-Tetra-O-acetylribosyl)-4-(4-chlorophenyl)-7-
dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one
(13e)
crystallized from dioxane.
4.8.2. 4-(Chlorophenyl)-2-(mannosylhydrazon)-7-dimethyl-
3,4,6,8-tetrahydro-quinazolin-5-one (11b)
It was obtained from 11e as white powder, crystallized from
cyclohexane.
It was obtained from
crystallized from ethanol.
D-mannose (10 mmol), as a white powder,
4.9.6. 3-(10,20,30,4’-Tetra-O-acetylxylosyl)-4-(4-chlorophenyl)-7-
dimethyl-1,4,6,8-tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one
4.8.3. 4-(Chlorophenyl)-2-(galactosylhydrazon)-7-dimethyl-
(13f)
3,4,6,8-tetrahydro-quinazolin-5-one (11c)
It was obtained from 11f as white powder, crystallized from
It was obtained from
D-galactose (10 mmol), as a white powder
benzene.
crystallized from dioxane.
4.8.4. 4-(Chlorophenyl)-2-(arabinosylhydrazon)-7-dimethyl-
3,4,6,8-tetrahydro-quinazolin-5-one (11d)
4.10. 3-(Glycosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-
It was obtained from
D-arabinose (10 mmol), as a white powder,
tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one (14a–c)
crystallized from ethanol.
General procedure. A solution from each of 13a–f (0.05 mol) in
methanol (10% ammonia solution, 50 mL), was stirred at room
temperature for 24 h, and then neutralized with hydrochloric acid
solution (pH control). The precipitate formed was filtered off, wash
with cold water, dried and crystallized, to obtain 14a–f respectively.
4.8.5. 4-(Chlorophenyl)-2-(ribosylhydrazon)-7-dimethyl-3,4,6,8-
tetrahydro-quinazolin-5-one (11e)
It was obtained from D-ribose (10 mmol), as a white powder,
crystallized from ethanol.

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A.-R.B.A. El-Gazzar et al. / European Journal of Medicinal Chemistry 44 (2009) 4249–4258
4.10.1. 3-(Glucosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-
1,2,4-triazolo[3,4-b]quinazolin-6-one (14a)
It was obtained from 13a as a white powder, crystallized from
ethanol.
70 mg kgꢀ1 body mass. The compounds which exhibited good anti-
inflammatory activity comparable to that of ibuprofen were
screened for analgesic activity. All compounds were dissolved in
1.0% CMC solution. One group was kept as control and received p.o.
1% CMC. After 1 h of drug administration, 0.10 mL of 1% acetic acid
solution was given to mice intraperitoneally. The acetic acid
induced writhing test [19] showed stretching movements involving
arching of the back, elongation of the body and extension of hind
limbs which were counted for 5–15 min of acetic acid injection.
4.10.2. 3-(Mannosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-
tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one (14b)
It was obtained from 13b as a white powder, crystallized from
ethanol.
4.10.3. 3-(Galactosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-
tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one (14c)
It was obtained from 13c as a white powder, crystallized from
ethanol.
4.11.3. Ulcerogenicty activity
Acute ulcerogenesis test was done according to Cioli et al. [20].
Wister rats were divided into different groups consisting of six
animals each. Ulcerogenic activity was evaluated after p.o. admin-
istration of the test compounds or ibuprofen at the dose
200 mg kgꢀ1 body mass. Control rats received p.o. the vehicle
(suspension of 1% methylcellulose). Food but not water was
removed 24 h before administration of the test compounds. After
the drug treatment, the rats were fed normal diet for 17 h and were
then sacrificed. The stomach was removed and opened along the
greater curvature, washed with distilled water and cleaned gently
by dipping in saline. The mucosal damage was examined by means
of a magnifying glass. For each stomach the mucosal damage was
assessed according to the following scoring system: 0.5 redness; 1.0
spot ulcers; 1.5 hemorrhagic streaks; 2.0 ulcers >3 but ꢃ5; 3.0
ulcers >5. The mean score of each treated group minus the mean
score of control group was regarded as severity index of gastric
mucosal damage.
4.10.4. 3-(Arabinosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-
tetrahydro-1,2,4-triazolo[3,4-b]quinazolin-6-one (14d)
It was obtained from 13d as a white powder, crystallized from
ethanol.
4.10.5. 3-(Ribosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-
1,2,4-triazolo[3,4-b]quinazolin-6-one (14e)
It was obtained from 13e as a white powder, crystallized from
ethanol.
4.10.6. 3-(Xylosyl)-4-(4-chlorophenyl)-7-dimethyl-1,4,6,8-tetrahydro-
1,2,4-triazolo[3,4-b]quinazolin-6-one (14f)
It was obtained from 13f as a white powder crystallized from
ethanol.
Acknowledgment
4.11. Pharmacological screening
Authors thank Prof. Dr. W. El-Eraky, Professor of Pharmacology
and Head of Pharmaceutical Unit department, National Research
Center, Cairo, Egypt, for the help.
Adult male Sprague-Dawley rats, weighing 150–200 g were
used for anti-inflammatory and ulcerogenic activity, whereas Swiss
albino mice of both sex weighing 25–30 g were used for analgesic
activity. International principles and local regulations concerning
the care and used of laboratory animals were taken into account
[17]. The animals had free access to standard commercial diet and
water adlibitum and were kept in rooms maintained at 22 ꢁ1 ꢂC
with 12 h light dark cycle. The experimental protocol was approved
by the animal ethics committee of National Research Center, Cairo,
Egypt. All the compounds (70 mg kgꢀ1 body mass) and the refer-
ence NSAID Ibuprofen (70 mg kgꢀ1 body mass) were suspended in
1% carboxymethyl cellulose (CMC) and administered orally using
animal feeding needle. The control groups received appropriate
volumes of vehicle (1% CMC, oral) only.
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4.11.1. Anti-inflammatory assay
This activity was performed by the following procedure of
Winter et al. [18], on groups of six animals each. A freshly prepared
suspension of carrageenan (1.0% m/V, 0.1 mL) was injected in the
planer region of the right hind paw of each rat. One group was kept
as control and the animals of other group were pretreated with the
test drugs (70 mg kgꢀ1 body mass) suspended in 1.0% CMC given
orally 1 h before the carrageenan treatment. The volume was
measured before and after 4 h of carrageenan treatment using
a pleythysmometer.
[17] E.D. Olfert, B.M. Cross, A.A. Mc William (Eds.), second ed.Guide to the Care and
Use of Experimental Animals, vol. 1 Canadian Council on Animal Care, Ontario,
Canada, 1993 211 pp.
[18] C.A. Winter, E.A. Risley, G.W. Nuss, Proc. Soc. Exp. Biol. Med. 111 (1962)
544–547.
[19] A. Kumar, D. Bansal, K. Bajaj, S. Sharma, V.K. Srivastava, Bioorg. Med. Chem. 11
(2003) 5281–5291.
[20] V. Cioli, S. Putzolu, V. Rossi, S.P. Barrcellona, C. Corradino, Toxicol. Appl.
Pharmacol. 50 (1979) 283–289.
4.11.2. Analgesic activity
Mice were kept individually in the test cage before acetic acid
injection and habituated for 30 min. Screening of analgesic activity
was performed after p.o. administration of test drugs at a dose of