Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic ring systems incorporating phenylsulfonyl moiety

Article abstract of DOI:10.1016/j.bmc.2008.05.011

A series of pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-aryl-2-(phenylsulfonyl)prop-2-en-1-one derivatives 2a,b with appropriate nitrogen nucleophiles. The analgesic and anti-inflammatory activities of the newly synthesized compound were investigated in vivo. 3-Bromo-2-phenyl-6-(phenylsulfonyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5e) was found to have an excellent analgesic activity in comparison with indomethacin as a reference drug, while the highest anti-inflammatory effect was observed in the case of 2-(4-bromophenyl)-6-(phenylsulfonyl)-5-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5d). From the structure-activity relationship (SAR) point of view, the analgesic/anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine derivatives was found to be much higher than triazolo[1,5-a]pyrimidine and pyrimido[1,2-a]benzimidazole derivatives.

Full text of DOI:10.1016/j.bmc.2008.05.011

Bioorganic & Medicinal Chemistry 16 (2008) 6344–6352
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic
ring systems incorporating phenylsulfonyl moiety
Mohamed R. Shaaban a, Tamer S. Saleh b, Abdelrahman S. Mayhoub c, Ahmed Mansour d, Ahmad M. Farag a,
*
a Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
b Department of Green Chemistry, National Research Center, Dokki, Giza 12622, Egypt
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
d Department of Pharmacology & toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole ring
systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethyl-
amino)-1-aryl-2-(phenylsulfonyl)prop-2-en-1-one derivatives 2a,b with appropriate nitrogen nucleo-
philes. The analgesic and anti-inflammatory activities of the newly synthesized compound were
investigated in vivo. 3-Bromo-2-phenyl-6-(phenylsulfonyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimi-
dine (5e) was found to have an excellent analgesic activity in comparison with indomethacin as a refer-
ence drug, while the highest anti-inflammatory effect was observed in the case of 2-(4-bromophenyl)-6-
(phenylsulfonyl)-5-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5d). From the structure–activity rela-
tionship (SAR) point of view, the analgesic/anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine
derivatives was found to be much higher than triazolo[1,5-a]pyrimidine and pyrimido[1,2-a]benzimid-
azole derivatives.
Received 16 February 2008
Revised 24 April 2008
Accepted 5 May 2008
Available online 7 May 2008
Keywords:
Analgesic
Anti-inflammatory
Phenylsulfonylpyrazole
Pyrazolo[1,5-a]pyrimidine
Triazolo[1,5-a]pyrimidine
Pyrimido[1,2-a]benzimidazole
Structure–activity relationship (SAR)
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Among different types of NSAIDs, pyrazoles,2–12 and fused pyr-
azole with six-membered rings13–19 occupy central position among
Inflammation is a natural and beneficial reaction in response to
infections and trauma. The inflammation process begins when un-
known antigen gains access to the patient’s tissue and combines
with an antibody in the joint. This activates an antigen comple-
ment–antibody immune complex which precipitates in the syno-
vium and joint fluid. This in turn leads to release of chemical
mediators that cause migration of polymorphonuclear leukocytes,
phagotizing the immune complex. Lysosomal membrane dis-
charges protease and collagenase causing continued inflammation,
tissue destruction, and loss of physical properties of the connective
tissue and joints.1
Management of inflammatory disorders involves a stepwise ap-
proach to the use of therapeutic agents. Relieving of pain and
reduction of inflammation are urgent goals to reduce the severity
of symptoms.1 A generally accepted stepwise approach to treat
the inflammation disorders includes physical therapy, non-steroi-
dal anti-inflammatory drugs (NSAIDs), disease modifying
anti-rheumatic drugs (DMARDs), corticosteroids and finally,
immunosuppressive agents.
those compounds that are used as analgesic and anti-inflammatory
agents. On the other hand, sulfone moiety is usually incorporated
as an active part in many analgesic anti-inflammatory molecules
available as drugs in market such as celecoxib,2,20 valdecoxib,21
rofecoxib,22 parecoxib,23 etoricoxib,24 tenoxicam,25 piroxicam,26
meloxicam,27 lornoxicam,28 ampiroxicam,29 and nimesulide.30
In continuation of our recent work aiming at the synthesis of
heterocyclic systems with remarkable biological importances,31–41
we report here on the utility of b-keto-b-sulfonylenamines as
building blocks for the synthesis of phenylsulfonylpyrazoles, 1H-
pyrazolo[1,5-a]pyrimidines, 1,2,4-triazolo[1,5-a]pyrimidines, and
pyrimido[1,2-a]benzimidazole and study their analgesic and anti-
inflammatory activities in order to get a new compounds that could
be optimized for potent analgesic anti-inflammatory agents.
2. Results and discussion
2.1. Chemistry
Heating of the 1-aryl-2-(phenylsulfonyl)ethanones 1a,b with
N,N-dimethylformamide–dimethylacetal
(DMF–DMA)
under
moisture free conditions, afforded a single product identified as
* Corresponding author. Tel.: +20 12377 3794; fax: +20 235727556.
E-mail address: afarag49@yahoo.com (A.M. Farag).
the corresponding 3-(N,N-dimethylamino)-1-aryl-2-(phenylsulfo-
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.05.011

M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
6345
nyl)prop-2-en-1-one derivatives 2a,b, respectively, in high yields
(Scheme 1). The structures of isolated products were established
on the bases of their elemental and spectral data. For example,
the 1H NMR spectrum of compound 2a displayed a singlet signal
at d 2.42 due to 4-methyl protons, a singlet signal at d 2.98 due
to N,N-dimethyl protons, a singlet signal at d 7.75 due to ethylenic
proton, in addition to an aromatic multiplets in the region d 7.25–
7.62.
Whencompound2awastreatedwithphenylhydrazine, inreflux-
ing ethanol, it afforded a single product that was analyzed correctly
for C22H18N2O2S. The structure of the isolated product was identified
as 1,5-diphenyl-4-(phenylsulfonyl)-1H-pyrazoles (3), based on its
spectral data (Scheme 1). For example, its 1H NMR spectrum re-
vealed a singlet signal at d 8.20 characteristic for a pyrazole CH pro-
ton. Moreover, the mass spectrum of the same product showed a
peak at m/z 374 corresponding to its molecular ion.
The behavior of compounds 2 toward some heterocyclic amines
is also investigated. Thus, when compounds 2a,b were treated with
substituted 5-aminopyrazole derivatives 4a–g in the presence of a
catalytic amount of piperidine, they afforded the corresponding
1H-pyrazolo[1,5-a]pyrimidines derivatives 5a–g (Scheme 2). The
other possible structure 6 was ruled out on the basis of the 1H
NMR spectra of the isolated products. For example, the 1H NMR spec-
trum of compound 5a, taken as atypical example, which revealed a
singlet signal d 9.11 which was assigned for the pyrimidine CH-2
in structure 5 and not CH-4 in structure 6. Although spectral data
seemed of no help in distinguishing between structures 5 and 6.42
However, structure 5 was firmly established for the reaction prod-
ucts by an alternate synthesis. For example, the reaction of 5-amino-
pyrazole 4a with DMF–DMA and subsequent condensation of the
formed amidine, 5-N-(N,N-dimethylaminomethylene)amino-3-
methyl-1H-pyrazole43 (7) with 1-(4-methylphenyl)-2-(phenylsul-
fonyl)ethanone (1a) afforded a product identical in all respects
(mp, mixed mp, and spectra) with those of compound 2-methyl-6-
(phenylsulfonyl)-5-p-tolylpyrazolo[1,5-a]pyrimidine (5a) (Scheme
2).
Treatment of the enaminone derivatives 2a,b with 2-amino-
benzimidazole (8) in pyridine under reflux gave, in each case, only
one isolable product. The isolated products were identified as 2-
aryl-3-(phenylsulfonyl)pyrimido[1,2-a]benzimidazole derivatives
11a,b (Scheme 3). The IR spectrum of the reaction products re-
vealed, in each case, no bands due to amino or carbonyl functions.
Moreover, the 1H NMR spectrum of compound 11a, taken as an
example, revealed two singlet signals at d 2.42 and 9.24 due to
methyl and pyrimidine protons, respectively. The formation of
products 11a,b is assumed to take place via the addition of the exo-
cyclic amino group in 2-aminobenzimidazole to the activated dou-
ble bond in the enaminone 2 to give the acyclic non-isolable
intermediates 10a,b, which undergo intramolecular cyclization
and subsequent aromatization via the loss of dimethylamine and
water molecules under the reaction conditions to afford the final
products 11a,b as depicted in Scheme 3.
The structures of the pyrimido[1,2-a]benzimidazole derivatives
11a,b were further confirmed by their alternate synthesis via the
reactions of 1-aryl-2-(phenylsulfonyl)ethanones 1a,b with N0-
(1H-benzimidazol-2-yl)-N,N-dimethylformamidine
(9)
which
afforded products identical in all respects (mp, mixed mp, TLC,
IR, and mass spectra) with those obtained from the reaction of
the enaminone derivatives 2a,b with 2-aminobenzimidazole (8)
as shown in Scheme 3.
The enaminone derivatives 2a,b react also with 3-amino-1,2,4-
triazole (12) and afforded a high yield of a 7-aryl-6-(phenylsulfo-
nyl)[1,2,4]triazolo[1,5-a]pyrimidine 13a,b. The structures of the
reaction products were assigned based on their elemental analyses
and spectral data (cf. experimental part). The latter products are
assumed to be formed via an initial addition of the amino group
of 3-amino-1,2,4-triazole to the activated double bond in the
enaminones 2a,b followed by elimination of dimethylamine and
water to afford the final products 13a,b.
2.2. Pharmacology
2.2.1. Anti-inflammatory activity
The effect of the tested compounds and indomethacin, as a ref-
erence, was measured before and 1, 2, 3, 4, 5, and 6 h after carra-
geenan injection. Percent edema inhibition was calculated as a
regard to saline control group, as depicted in Table 1 and Figure
1. Most of the tested compounds showed a reasonable inhibition
of edema size in comparison with indomethacin. As shown in Table
1, 2-(4-bromophenyl)-6-(phenylsulfonyl)7-(4-methylphenyl)pyr-
azolo [1,5-a]pyrimidine (5d) was found to be the most potent
anti-inflammatory compound, whereas compounds 11a, 13a, and
13b showed the least inhibitory effect.
From the structure–activity relationship (SAR) viewpoint, the
anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine deriva-
tives 5b–d showed higher activity than the pyrimido[1,2-a]benz-
imidazole 11a and triazolo[1,5-a]pyrimidine 13a,b (Table 1 and
Fig. 1).
The electronic effect of bromine atom on pyrazole ring de-
creases the anti-inflammatory effect as in the case of compound
5e. On the other hand, the electronic effect of bromine atom on
phenyl moiety attached to pyrazole ring increases the anti-inflam-
matory effect as in the case of compound 5d. Replacement of bro-
mine atom with methyl group also decreases the anti-
inflammatory effect as in the case of compound 5c (Table 1 and
Fig. 1).
OMe
Me2N CH
O
O
Ph
O
Ar
N
Ph
O
Ar
OMe
S
S
2.2.2. Analgesic activity
O
O
The analgesic activity of the synthesized compounds was also
investigated. It was assessed by two different models: the acetic
acid-induced writhing test and hot-plate test. Some of the pyrazol-
o[1,5-a]pyrimidine derivatives exhibited analgesic effects as
shown in Tables 2, 3 and Figures 2–4.
1a,b
2a,b
a, Ar = 4-CH3C6H4
b, Ar = 4-BrC6H4
Me
Compared with the control, the analgesic potency of compound
5e was found to be the highest. According to the structure–activity
relationship (SAR), it is clear that the pyrazolo[1,5-a]pyrimidine
ring system is more active than both pyrimido[1,2-a]benzimid-
azole and triazolo[1,5-a]pyrimidine ring systems. Among the same
ring system (i.e., pyrazolo[1,5-a]pyrimidine), it was noticed that
attachment of bromine atom to pyrazole moiety enhances the
analgesic effect as in the case of compound 5e (cf. anti-inflamma-
tory effect in Table 2 and Figs. 2 and 3).
Ph
O
O
S
PhNH-NH2
2a
N
Ph
N
3
Scheme 1.

6346
M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
N
R1
N
Me2NCH(OMe)2
NH
R2
N
7
1
R1
N
R1
NH2
R2
O
N
N
-Me2NH
S
O
NH
2
+
R2
N
Ar
Ph
5a-g
4
R1
N
N
Ar
S
R2
N
Ph
O
O
6a-g
4-6
Ar
R1
R2
a
b
c
d
e
f
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
H
H
H
H
Br
H
H
CH3
C6H5
4-CH3C6H4
4-BrC6H4
C6H5
4-ClC6H4
CH3
g
4-BrC6H4
Scheme 2.
DMF-DMA
NH
1a,b
N
N
NMe2
9
Ph
H
NH
O
Ar
N
H
O
O
O
S
N
8
NH2
H
O
S
Ar
N
-Me2NH
-H2O
N
Ph
N
H
Me2N
N
N
11a,b
10a,b
2a,b
N
NH
Ar
N
O
O
N
NH2
S
N
Ph
12
N
N
a, Ar = 4-CH3C6H4
b, Ar = 4-BrC6H4
13a,b
Scheme 3.
5d,e, respectively. Therefore, it can be concluded that such com-
pounds exert their pharmacological effects by more than one
mechanism, either via inhibition of certain enzyme or intermediate
incorporated in inflammatory reaction, and/or direct action on pain
3. Conclusion
From Tables 1–3, it is clear that the highest anti-inflammatory
and analgesic activities were observed in the case of compounds

M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
6347
regulating receptors. To confirm this suggestion, further studies are
now in progress based on molecular modeling.
4. Experimental
4.1. Chemistry
4.1.1. General
All melting points were measured on a Gallenkamp melting
point apparatus. The infrared spectra were recorded in potas-
sium bromide disks on a pye Unicam SP 3300 and Shimadzu
FT IR 8101 PC infrared spectrophotometers. The NMR spectra
were recorded on a Varian Mercury VX-300 NMR spectrometer.
1H spectra were run at 300 MHz and 13C spectra were run at
75.46 MHz in deuterated chloroform (CDCl3) or dimethyl sulfox-
ide (DMSO-d6). Chemical shifts were related to that of the sol-
vent. Mass spectra were recorded on a Shimadzu GCMS-QP
1000 EX mass spectrometer at 70 eV. Elemental analyses were
carried out at the Microanalytical Center of Cairo University,
Giza, Egypt.
Aminopyrazoles 6a–c,44–46 7,43 and phenylsulfones 1a,b47 were
prepared according to procedures in the literature.
4.1.2. 3-(Dimethylamino)-2-(phenylsulfonyl)-1-p-tolylprop-2-
en-1-one and 1-(4-bromophenyl)-3-(dimethylamino)-2-(phenyl-
sulfonyl)prop-2-en-1-one (2a,b)
A
mixture of 1-aryl-2-(phenylsulfonyl)ethanone 1a,b
(20 mmol) and dimethylformamide–dimethylacetal (DMF–DMA)
(20 mmol) in dry xylene (20 mL) was refluxed for 8 h, then left to
cool to room temperature. The reddish-brown precipitated product
was filtered off, washed with light petroleum (40–60 °C), and
dried. Recrystallization from benzene afforded 2a,b. The physical
and spectral data of compounds 2a–c are listed below.
4.1.2.1. 3-(Dimethylamino)-2-(phenylsulfonyl)-1-p-tolylprop-
2-en-1-one (2a ). Yield (78%); mp 135 °C; IR (KBr) tmax/cmꢀ1
:
1644 (conjugated C@O), 1551 (C@C); 1H NMR (CDCl3): d 2.42 (s,
3H), 2.98 (s, 6H), 7.25–7.62 (m, 9H, ArH’s), 7.75 (s, 1H); 13C NMR
(CDCl3): d 21.20, 62.55, 106.56, 122.26, 125.25, 128.16, 129.33,
133.80, 138.90, 140.71, 142.23, 153.48, 187.29; MS (m/z, %): 329
(M+, 23.7). Anal. Calcd for C18H19NO3S (329.41): C, 65.63; H,
5.81; N, 4.25; S, 9.73%. Found: C, 65.61; H, 5.82; N, 4.28; S, 9.70%.
4.1.2.2. 1-(4-Bromophenyl)-3-(dimethylamino)-2-(phenylsulfonyl)-
prop-2-en-1-one (2b). Yield (70%); mp 161–162 °C; IR (KBr) tmax
/
cmꢀ1: 1644 (conjugated C@O), 1551 (C@C); 1H NMR (CDCl3): d 2.88
(s, 6H), 7.25–7.45 (m, 9H, ArH’s), 7.81 (s, 1H); 13C NMR (CDCl3): d
62.54, 106.73, 126.26, 127.25, 127.93, 128.16, 128.81, 129.38,
130.90, 133.5, 143.71, 153.23, 152.48, 188.01; MS (m/z, %): 395
,
(M+2 30.2), 393 (M+, 31.1). Anal. Calcd for C17H16BrNO3S
(394.28): C, 51.79; H, 4.09; Br, 20.27; N, 3.55; S, 8.13%. Found: C,
51.76; H, 4.11; Br, 20.30; N, 3.56; S, 8.10%.
4.1.3. 1-Phenyl-4-(phenylsulfonyl)-5-p-tolyl-1H-pyrazole (3)
Phenylhydrazine (1.5 mL) was added to a stirred solution of the
enaminone 2a (10 mmol) dissolved in AcOH (30 mL). Stirring was
lasted for 12 h at room temperature. The solid product obtained
was filtered off dried, and recrystallized from DMF. Yield (69%);
mp 175 °C; IR (KBr) tmax/cmꢀ1: 1597 (C@N); 1H NMR (DMSO-d6):
d 2.35 (s, 3H, CH3), 7.00–7.55 (m, 14H, ArH’s), 8.20 (s, 1H, pyra-
zole-3-CH); 13C NMR (DMSO-d6): d 21.30, 123.57, 123.79, 124.91,
127.04, 128.12, 128.53, 128.75, 128.88, 130.23, 132.67, 138.57,
139.84, 140.44, 142.05, 143.61; MS (m/z, %): 374 (M+, 42.6). Anal.
Calcd for C22H18N2O2S (374.46): C, 70.57; H, 4.85; N, 7.48; S,
8.56%. Found: C, 70.54; H, 4.86; N, 7.51; S, 8.53%.

6348
M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
0.3
0.25
0.2
Control
5a
5b
5c
5d
5e
0.15
0.1
5f
5g
11a
13a
13b
Indometh.
0.05
0
1hr
2hr
3hr
4hr
5hr
6hr
Time
Figure 1. Anti-inflammatory potency of the tested compounds (50 mg/kg) and indomethacin (50 mg/kg).
Table 2
Analgesic activity of oral administration of tested compounds (50 mg/kg) and indomethacin (50 mg/kg)
Compound
Reaction time (S)
1 h
0 (X SE)
30 min
(X SE)
Change
(%)
Pot.
Change
(%)
Pot.
2 h
(X SE)
Change
(%)
Pot.
(X SE)
Control
5a
5b
5c
5d
5e
5f
5g
11a
13a
13b
Ind.
5.3 0.3
5.6 0.2*
5.9 0.4*
7.3 0.8*
6.2 0.6*
7.3 0.4*
5.4 0.3*
6.8 0.4
6.5 0.3*
5.6 0.2*
7.3 0.3
7.9 0.4*
5.4 0.3
6.5 0.4*
6.8 0.5*
9.1 0.7*
8.0 0.4*
10.5 0.7*
7.2 0.5*
8.7 0.4*
7.1 0.2*
6.0 0.9*
7.7 0.6*
11.3 0.4*
1.8
16.0
15.2
25
29
43.8
33
27
9.2
7.1
5.4
—
5.4 0.3
6.5 0.3*
7.0 0.5*
12.2 1.0*
9.7 0.4*
13.0 0.3*
9.3 0.4*
9.8 0.8
8.0 0.4*
5.9 0.8*
7.8 0.7
14 0.3
1.8
16.0
18.6
67.1
56.4
78.0
72.2
44.1
23.0
5.3
—
5.4 0.3
5.9 0.3*
6.8 0.4*
11.5 0.9*
9.7 0.4*
12.3 1.0*
8.2 0.6*
9.5 0.5
1.8
5.3
—
0.37
0.35
0.58
0.67
1.02
0.77
0.63
0.21
0.16
0.12
1
0.21
0.24
0.87
0.73
1.02
0.93
0.57
0.30
0.06
0.08
1
0.07
0.19
0.71
0.70
0.84
0.63
0.49
0.26
0
15.2
57.5
56.4
68.4
51.8
39.7
21.5
0
7.9 0.3*
5.6 0.8*
7.7 0.6*
14.3 0.4
6.8
77.2
5.4
81.0
0.06
1
43.0
Data represent mean values SE of six mice per group, shown at the basal (zero time) and three values for each group (saline, indomethacin, and tested compounds) after 0.5,
1, and 2 h. Statistical comparisons between basal (pre-drug values) and post-drug values.
Data were analyzed using one-way ANOVA and Duncan’s multiple comparison test *P < 0.05.
Percentage change was calculated from basal (pre-drug) values and post-drug values.
Potency was calculated as regards the percentage change of the indomethacin.
Values between parentheses represent on increase of reaction time compared to zero time.
Pot., potency; SE, standard error; Ind., indomethacin.
4.1.4. Pyrazolo[1,5-a]pyrimidine derivatives (5a–g)
4.1.4.1. 2-Methyl-6-(phenylsulfonyl)7-p-tolylpyrazolo[1,5-
Method A: To a mixture of the enaminone 2a,b (10 mmol) and
appropriate aminopyrazole derivatives 3 (10 mmol) in absolute
EtOH (25 mL) was added few drops of piperidine and the reaction
mixture was refluxed for 3 h, then left to cool. The formed solid
product was filtered off and recrystallized from EtOH/DMF to af-
ford the pyrazol[1,5-a]pyrimidine derivatives 5a–g in 75–87%
yield. The physical and spectral data of compounds 5a–g are listed
below.
Method B: A solution of 1-(4-methylphenyl)-2-(phenylsulfo-
nyl)ethanone (1a) (10 mmol) and an equivalent molar ratio of 5-
N-(N,N-dimethylaminomethylene)amino-3-methyl-1H-pyrazol (7)
in ethanol (20 mL), in the presence of 0.3 mL piperidine, was
heated under reflux for 6 h. The solvent was removed by distilla-
tion under reduced pressure and the remainder was left to cool.
The precipitated solid product was collected by filtration. Recrys-
tallization from DMF afforded product identical in all respects
(mp, mixed mp, TLC, IR, and mass spectra with 5a).
a]pyrimidine (5a). Yield (85%); mp 160 °C; IR (KBr) tmax/cmꢀ1
1596 (C@N); 1H NMR (DMSO-d6): d 2.37 (s, 3H, CH3), 2.42 (s, 3H,
CH3), 6.77 (s, 1H, pyrazole-4-CH), 7.14–7.42 (m, 9H, ArH’s), 9.11
(s, 1H, pyrimidine-6-CH); 13C NMR (DMSO-d6): d 12.69, 22.28,
95.38, 120.69, 121.01, 121.86, 123.32, 126.26, 128.57, 131.55,
133.60, 135.32, 140.48, 146.25, 150.28, 158.61; MS (m/z, %): 363
(M+, 7.7), 222 (100). Anal. Calcd for C20H17N3O2S (363.43): C,
66.10; H, 4.71; N, 11.56; S, 8.82%. Found: C, 66.18; H, 4.70; N,
11.53; S, 8.85%.
:
4.1.4.2. 2-Phenyl-6-(phenylsulfonyl)7-(4-methylphenyl) pyrazolo
[1,5-a]pyrimidine (5b). Yield (76%); mp 214 °C; IR (KBr) tmax
/
cmꢀ1: 1594 (C@N); 1H NMR (DMSO-d6): d 2.43 (s, 3H, CH3), 6.78
(s, 1H, pyrazole-4-CH), 7.14–7.84 (m, 14H, ArH’s), 9.17 (s, 1H,
pyrimidine-6-CH); 13C NMR (DMSO-d6): d 21.12, 95.14, 120.99,
121.04, 121.91, 124.36, 126.48, 127.26, 128.73, 128.97, 129.66,
131.58, 133.54, 140.36, 140.62, 147.47, 148.96, 150.37, 158.18;

M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
6349
MS (m/z, %): 425 (M+, 3.8), 248 (100). Anal. Calcd for C25H19N3O2S
(425.50): C, 70.57; H, 4.50; N, 9.88; S, 7.54%. Found: C, 70.81; H,
4.51; N, 9.85; S, 7.50%.
Table 3
Analgesic effect of oral administration of tested compounds (50 mg/kg), and
indomethacin (50 mg/kg) on visceral pain by using writhing test in race
Compound
Number of writhing
Change (%)
4.1.4.3. 6-(Phenylsulfonyl)-2,7-di(4-methylphenyl)pyrazolo-
30 min (X SE)
Potency
[1,5-a]pyrimidine (5c ). Yield (82%); mp 240 °C; IR (KBr) tmax
/
Control
5a
5b
5c
5d
5e
5f
5g
11a
13a
13b
Ind.
85 4.4*
59.5 2.2*
61.2 2.0*
21.7 0.9*
29.5 1.4*
12.2 1.1*
28.3 1.6*
37 1.5*
—
—
cmꢀ1: 1596 (C@N); 1H NMR (DMSO-d6): d 2.42 (s, 3H, CH3), 2.43
(s, 3H, CH3), 6.78 (s, 1H, pyrazole-4-CH), 7.15-7.85 (m, 13H, ArH’s),
9.17 (s, 1H, pyrimidine-6-CH); 13C NMR (DMSO-d6): d 21.12, 21.13,
95.58, 120.99, 121.05, 121.96, 124.32, 126.76, 127.36, 128.99,
129.67, 131.64, 133.72, 135.52, 141.68, 147.25, 150.38, 156.42,
158.22, 159.32; MS (m/z, %): 439 (M+, 4.1), 298 (100). Anal. Calcd
for C26H21N3O2S (439.53): C, 71.05; H, 4.82; N, 9.56; S, 7.30%.
Found: C, 71.09; H, 4.85; N, 9.53; S, 7.26%.
30.0
28.0
74.4
65.2
85.6
66.7
56.4
9.1
0.35
0.32
0.86
0.76
0.99
0.77
0.65
0.10
0.0
77.2 4.5*
85.5 4.8*
75.8 3.9*
12 1.0*
—
10.8
85.8
0.12
1
4.1.4.4. 2-(4-Bromophenyl)-6-(phenylsulfonyl)-7-(4-methylphenyl)-
pyrazolo[1,5-a]pyrimidine (5d). Yield (87%); mp 242 °C; IR (KBr)
tmax/cmꢀ1: 1596 (C@N); 1H NMR (DMSO-d6): d 2.32 (s, 3H, CH3),
6.95 (s, 1H, pyrazole-4-CH), 7.33–7.77 (m, 13H, ArH’s), 9.12 (s,
Data represent mean values SE of six mice per group and percentage inhibition of
number of writhing/30 min. Statistical comparison of the difference between saline
control group and treated groups was done by one-way ANOVA and Duncan’s
multiple comparison test *P < 0.05.
Potency was calculated as regards the percentage change of the indomethacine.
SE, Standard error; Ind, indomethacin.
1H, pyrimidine-6-CH); 13C NMR (DMSO-d6):
d 21.12, 55.58,
95.58, 120.99, 121.03, 121.96, 124.32, 127.26, 128.99, 129.57,
1.2
1
Control
5a
5b
0.8
0.6
0.4
0.2
0
5c
5d
5e
5f
5g
11a
13a
13b
Indometh.
30 min
1hr
2hr
Time
Figure 2. Analgesic activity of tested compounds (50 mg/kg) and indomethacin (50 mg/kg).
5c 5d 5e 5f Indometh.
1.2
1
0.8
0.6
0.4
0.2
0
30 min
1 hr
2hr
Time
Figure 3. Analgesic activity of the highest potent tested compounds (50 mg/kg) and indomethacin (50 mg/kg).

6350
M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
1.2
1
-
0.8
0.6
0.4
0.2
0
5a
5b
5c
5d
5e
5f
5g
11a
13a
13b
Ind.
Tested Compound
Figure 4. Analgesic activity of tested compounds (50 mg/kg) and indomethacin (50 mg/kg) for on visceral pain by using writhing test in race.
131.64, 133.70, 135.52, 140.68, 147.25, 150.38, 159.32, 162.61; MS
light petroleum (40–60 °C), and dried. Recrystallization from ben-
zene afforded 9; mp 248–250 °C; IR (KBr) tmax/cmꢀ1: 3460 (NH)
1631 (C@N), 1551 (C@C); 1H NMR (CDCl3): d 3.13 (s, 6H), 6.98–
7.34 (m, 4H, ArH’s), 8.78 (s, 1H), 11.51 (br, NH); MS (m/z, %):
188.11 (M+, 25.7). Anal. Calcd for C10H12N4 (188.23): C, 63.81; H,
6.43; N, 29.77%. Found: C, 63.95; H, 6.32; N, 29.88; S, 9.70%.
(m/z, %): 505 (M+2, 3.0), 503 (M+, 2.9), 264 (100). Anal. Calcd for
C25H18BrN3O2S (504.40): C, 59.53; H, 3.60; N, 8.33; S, 6.36%. Found:
C, 59.47; H, 3.59; N, 8.35; S, 6.35%.
4.1.4.5. 3-Bromo-2-phenyl-6-(phenylsulfonyl)7-(4-methylphenyl)
pyrazolo[1,5-a]pyrimidine (5e). Yield (78%); mp 268 °C; IR (KBr)
tmax/cmꢀ1: 1596 (C@N); 1H NMR (DMSO-d6): d 2.41 (s, 3H, CH3),
7.13–7.80 (m, 14H, ArH’s), 9.27 (s, 1H, pyrimidine-6-CH); 13C
NMR (DMSO-d6): d 21.12, 95.14, 95.58, 120.99, 121.03, 121.96,
124.32, 127.26, 128.99, 129.57, 131.64, 133.70, 135.52, 140.68,
147.25, 150.38, 159.32, 162.61; MS (mz, %): 505 (M+2, 5.1), 503
(M+, 5.3), 262 (100). Anal. Calcd for C25H18BrN3O2S (504.40): C,
59.53; H, 3.60; N, 8.33; S, 6.36%. Found: C, 59.54; H, 3.62; N,
8.30; S, 6.32%.
4.1.6. Synthesis of pyrimido[1,2-a]benzimidazole derivatives
(11a,b)
Method A. A mixture of 3-(dimethylamino)-2-(phenylsulfonyl)-
1-(4-methylphenyl)prop-2-en-1-one (2a) or 1-(4-bromophenyl)-
3-(dimethylamino)-2-(phenylsulfonyl)prop-2-en-1-one
(2b)
(10 mmol) and 2-aminobenzimidazole (8) (1.33 g, 10 mmol) in
pyridine (25 mL) was refluxed for 12 h, then left to cool. The sol-
vent was evaporated in vacuo and the residual solid was taken in
EtOH, then collected by filtration, washed with water, dried, and fi-
nally recrystallized from DMF/H2O to afford the corresponding
pyrimido[1,2-a]benzimidazole derivatives 11a,b, respectively.
Method B. A solution of the appropriate compound 1 (10 mmol)
and N0-(1H-benzimidazol-2-yl)-N,N-dimethylformamidine (9) (1.88 g,
10 mmol) in ethanol (20 mL) and piperidine (0.3 mL) was heated
under reflux for 10 h, then left to cool. The precipitated solid prod-
uct was collected by filtration, washed with ethanol, and finally
recrystallized from DMF/H2O to afford products identical in all re-
spects (mp, mixed mp, TLC, IR, and mass spectra) with compounds
11a,b prepared by Method A above.
4.1.4.6. 7-(4-Bromophenyl)-2-(4-chlorophenyl)-6-(phenylsulfonyl)-
pyrazolo[1,5-a]pyrimidine (5f). Yield (78%); mp 250 °C; IR (KBr)
tmax/cmꢀ1: 1596 (C@N); 1H NMR (DMSO-d6): d 6.75 (s, 1H, pyra-
zole-4-CH), 7.44–7.78 (m, 13H, ArH’s), 9.13 (s, 1H, pyrimidine-6-
CH); 13C NMR (DMSO-d6):
d 94.58, 114.28, 121.32, 123.96,
126.32, 127.22, 127.99, 129.13, 131.64, 133.70, 135.52, 140.68,
141.85, 147.25, 150.38, 158.32, 158.76, 160.61; MS (m/z, %): 526
(M+4,3.3), 524 (M+2, 4.0), 522 (M+, 1.2), 284 (100). Anal. Calcd for
C24H15BrClN3O2S (524.82): C, 54.93; H, 2.88; N, 8.01; S, 6.11%.
Found: C, 54.99; H, 2.88; N, 8.00; S, 6.15%.
4.1.4.7. 7-(4-Bromophenyl)-2-methyl-6-(phenylsulfonyl)pyrazolo-
4.1.6.1. 2-(4-Methylphenyl)-3-(phenylsulfonyl)pyrimido[1,2-
[1,5-a ]pyrimidine (5g). Yield (85%); mp 200 °C; IR (KBr) tmax
/
a]benzimidazole (11a ). Yield (88%); mp 270 °C; IR (KBr) tmax/
cmꢀ1: 1596 (C@N); 1H NMR (DMSO-d6): d 2.31 (s, 3H, CH3), 6.80
(s, 1H, pyrazole-4-CH), 7.24–7.32 (m, 9H, ArH’s), 9.12 (s, 1H, pyrim-
idine-6-CH); 13C NMR (DMSO-d6): d 12.88, 95.58, 120.99, 121.03,
121.96, 124.32, 127.26, 129.57, 133.70, 135.52, 140.68, 147.25,
150.38, 159.32, 162.61; MS (m/z, %): 429 (M+, 13.7); 427 (M+,
13.5), 286 (100). Anal. Calcd for C19H14BrN3O2S (428.30): C,
53.28; H, 3.29; N, 9.81; S, 7.49%. Found: C, 53.24; H, 3.28; N,
9.80; S, 7.46%.
cmꢀ1: 1611 (C@N) cmꢀ1; 1H NMR (DMSO-d6): d 2.42 (s, 3H, CH3),
7.15–7.95 (m, 13H, ArH’s), 9.24 (s, 1H, pyrimidine-4-CH); 13C
NMR (DMSO-d6):
d 21.12, 114.03, 119.50, 120.66, 120.96,
122.917, 127.33, 127.42, 127.62, 127.92, 128.92, 130.64,
133.65, 134.35, 135.47, 139.98, 141.32, 144.84, 160.17; MS
(m/z %): 399 (M+, 31.8), 258 (100). Anal. Calcd for C23H17N3O2S
(399.46): C, 69.15; H, 4.29; N, 10.52; S, 8.03%. Found: C, 69.12;
H, 4.28; N, 10.50; S, 8.01%.
4.1.5. N0-(1H-Benzimidazol-2-yl)-N,N-dimethylformamidine (9)
A mixture of 2-aminobenzimidazole (8) (20 mmol) and dimeth-
ylformamide–dimethylacetal (DMF–DMA) (20 mmol) in dry xylene
(20 mL) was refluxed for 1/2 h, then left to cool to room tempera-
ture. The white precipitated product was filtered off, washed with
4.1.6.2. 2-(4-Bromophenyl)-3-(phenylsulfonyl)pyrimido[1,2-a]-
benzimidazole (11b ). Yield (86%); mp > 300 °C; IR (KBr) tmax
/
cmꢀ1: 1611 (C@N); 1H NMR (DMSO-d6): d7.15–8.65 (m, 13H, ArH’s),
10.34 (s, 1H, pyrimidine-4-CH); 13C NMR (DMSO-d6): d 114.06,
119.60, 120.66, 120.96, 122.917, 127.33, 127.42, 127.62, 127.92,

M. R. Shaaban et al. / Bioorg. Med. Chem. 16 (2008) 6344–6352
6351
128.92, 130.64, 133.65, 134.45, 135.47, 139.98, 141.32, 144.94,
160.27; MS (m/z, %): 465 (M+, 28.9); 463 (M+, 29.2), 322 (100). Anal.
Calcd for C22H14BrN3O2S (464.33): C, 56.91; H, 3.04; N, 9.05; S,
6.91%. Found: C, 56.86; H, 3.03; N, 9.05; S, 6.93%.
rats were divided into 13 groups, each of six animals. One group re-
ceived the reference standard; 11 groups received the tested com-
pound and one group left as a control group. The reference drug,
indomethacin, and the tested compounds were given by oral route
at doses of 5 and 50 mg/kg body weight, respectively. One hour la-
ter, 0.05 mL of carrageenan sodium (1%) was sublunary injected in
the right hind paw. The thickness of the paw was measured after
administration of the compounds at time intervals 1, 2, 3, 4, 5,
and 6 h by using micrometer. The results were expressed as the
percentage inhibition of edema thickness at each time interval ver-
sus that of the standard drug.
4.1.7. Synthesis of triazolo[1,5-a]pyrimidine derivatives (13a,b)
General procedure. To a mixture of 3-(dimethylamino)-2-(phen-
ylsulfonyl)-1-(4-methylphenyl)prop-2-en-1-one (2a) and 1-(4-
bromophenyl)-3-(dimethylamino)-2-(phenylsulfonyl)prop-2-en-
1-one (2b) (10 mmol) and the appropriate 3-amino-l,2,4-triazole
(12) (0.84 g, 10 mmol) in pyridine (25 mL) was refluxed for 12 h,
then left to cool. The solvent was evaporated in vacuo and the
residual solid was taken in EtOH, then collected by filtration,
washed with water, dried, and finally recrystallized from DMF/
H2O to afford the corresponding triazolo[1,5-a]pyrimidine deriva-
tives 13a,b, respectively. The physical and spectral data of com-
pounds 13a,b are listed below.
4.2.6. Anti-nociceptive activity
This activity was determined by measuring the responses of
animals to the thermal and chemical stimuli.
4.2.6.1. Thermal test. Hot-plate test was conducted according to
Eddy and Leimback51 using an electronically controlled hot-plate
(Ugo Basile, Italy) adjusted at 52 °C 0.1 °C and the cut-off time
was 60 s. Nine groups of mice each of six were used. The mice were
divided and received the same doses of tested compounds and
indomethacin as mentioned before. The time taken from introduc-
ing the animal in the hot cylinder till it licked its feet or jumped out
of the glass jar was measured and recorded at time interval 0.5, 1,
and 2 h.
4.1.7.1. 7-(4-Methylphenyl)-6-(phenylsulfonyl)-[1,2,4]triazolo-
[1,5-a]pyrimidine (13a ). Yield (81%); mp 266 °C; IR (KBr) tmax
/
cmꢀ1: 1621 (C@N); 1H NMR (DMSO-d6): d 2.41 (s, 3H, CH3),
7.36–7.73 (m, 9H, ArH’s), 8.62 (s, 1H, triazole-3-CH), 9.16 (s, 1H,
pyrimidine-4-CH); 13C NMR (DMSO-d6): d 21.12, 124.36, 125.77,
127.49, 127.97, 129.20, 131.44, 134.08, 135.94, 139.94, 149.35,
153.37, 155.70, 157.74; MS (m/z, %): 350 (M+, 34.1), 209 (100).
Anal. Calcd for C18H14N4O2S (350.39): C, 61.70; H, 4.03; N, 15.99;
S, 9.15%. Found: C, 61.69; H, 4.03; N, 15.97; S, 9.11%.
4.2.6.2. Chemical test. Acetic acid-induced writhing in mice was
performed according to the convenient published methods.52,53
The mice were divided and received the tested compounds at dose
of 50 mg/kg, and indomethacin at dose of 50 mg/kg. After 30 min
interval, the mice received 0.6% acetic acid ip (0.2 mL/mice). The
number of writhes in 30 min period was counted and compared.
4.1.7.2. 7-(4-Bromophenyl)-6-(phenylsulfonyl)-[1,2,4]-triazolo[1,5-
a]pyrimidine (13b). Yield (79%); mp 291 °C; IR (KBr) tmax/cmꢀ1
:
1620 (C@N); 1H NMR (DMSO-d6): d 7.26–8.60 (m, 9H, ArH’s), 8.69
(s, 1H, triazole-3-CH), 9.54 (s, 1H, pyrimidine-4-CH); 13C NMR
(DMSO-d6): d 124.28, 126.38, 126.77, 127.47, 127.77, 129.01,
130.80, 133.91, 139.92, 150.50, 153.37, 155.76, 157.73; MS (m/z,
%): 415 (M+, 22.5); 413 (M+, 22.5), 273 (100). Anal. Calcd for
4.2.7. Statistical analysis
Data are expressed as means SE. In anti-inflammatory study,
data are expressed as means SE. The results of carrageenan-in-
duced paw edema experiments are also expressed as percentage
of change from control (pre-drug) values. Differences between
vehicle control and treatment groups were tested using one-way
ANOVA followed by multiple comparisons by the Duncan’s multi-
ple rang test. A probability value less than 0.05 was considered sta-
tistically significant.
C17H11BrN4O2S (415.26): C, 49.17; H, 2.67; N, 13.49; S, 7.72%.
Found: C, 49.16; H, 2.66; N, 13.51; S, 7.70%.
4.2. Pharmacology
4.2.1. Animals
Eighty adult albino rats of both sexes weighing 120–150 g and
80 mice weighing 20–25 g were obtained from animal house labo-
ratory Nile company, Cairo, Egypt and acclimatized for 1 week in
the animal facility that has 12 h light/dark cycles with the temper-
ature controlled at 21–23 °C. Normal rat chow and water were
made available.
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