Synthesis and some pharmacological studies of new benzenesulfonamide derivatives

Article abstract of DOI:10.1007/s007060200003

New benzenesulfonamide derivatives containing pyrazole and oxadiazole moieties were prepared starting from sodium saccharin. The structures of the novel compounds were characterized by elemental analyses and spectroscopic methods. The new compounds are structurally related to the COX-2 inhibitor celecoxib (Celebrex). A pharmacological study of the pyrazoles revealed that several compounds possess higher analgesic and antiinflammatory activities than celecoxib, particularly 11 and 17. Most of the pyrazoles showed a significant increase in the sleeping time of thiopentone anaesthesized mice and also protected mice against the convulsive and lethal effects of pentylenetetrazole. Moreover, the ulcerogenic activity of those compounds showing a pronounced antiinflammatory effect was also studied.

Full text of DOI:10.1007/s007060200003

Monatshefte fuÈr Chemie 133, 255±266 ꢀ2002)
Synthesis and Some Pharmacological
Studies of New Benzenesulfonamide
Derivatives
Eatedal H. Abdel Aal1, Osama I. El-Sabbagh1;Ã, Shaker Youssif 2,
and Sameh M. El-Nabtity3
1
Departments of Pharmaceutical, Organic, and Medicinal Chemistry, Faculty of Pharmacy,
Zagazig University, Zagazig, Egypt
2
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
3
Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University,
Zagazig, Egypt
Summary. New benzenesulfonamide derivatives containing pyrazole and oxadiazole moieties were
prepared starting from sodium saccharin. The structures of the novel compounds were characterized
by elemental analyses and spectroscopic methods. The new compounds are structurally related to the
COX-2 inhibitor celecoxib ꢀCelebrex1). A pharmacological study of the pyrazoles revealed that
several compounds possess higher analgesic and antiin¯ammatory activities than celecoxib,
particularly 11 and 17. Most of the pyrazoles showed a signi®cant increase in the sleeping time of
thiopentone anaesthesized mice and also protected mice against the convulsive and lethal effects of
pentylenetetrazole. Moreover, the ulcerogenic activity of those compounds showing a pronounced
antiin¯ammatory effect was also studied.
Keywords. Sodium saccharin; Benzenesulfonamide derivatives; Pyrazoles; Analgesic; Antiin¯am-
matory.
Introduction
Several pyrazole and oxadiazole derivatives have been reported to exhibit
analgesic and antiin¯ammatory activity [1±3]. Moreover, many drugs containing
the pyrazole moiety are still used clinically as analgesic and antiin¯ammatory
agents, e.g. antipyrine and aminopyrine [1, 2]. Recently, the selective cycloox-
ygenase-2 ꢀCOX-2) inhibitor celecoxib [4±6], a benzenesulfonamide derivative
carrying a pyrazole moiety, has been introduced into medicine as an analgesic and
antiin¯ammatory agent. The use of celecoxib for treatment of in¯ammation and
pain avoided many side effects of the nonsteroidal antiin¯ammatory drugs because
of its selectivity as COX-2 inhibitor [7, 8]. In this article, new benzenesulfonamide
derivatives containing a pyrazole moiety were designed and synthesized which
are structurally related to celecoxib in order to produce potent analgesic and
Ã
Corresponding author. E-mail: syoussif41@hotmail.com

256
E. H. Abdel Aal et al.
antiin¯ammatory agents with no or less tendency to evoke gastric ulceration. In
addition, new benzenesulfonamide derivatives containing an oxadiazole moiety
were prepared.
Results and Discussion
Chemistry
The preparation of the new compounds is outlined in Scheme 1. N-Alkyl
saccharins ꢀ2, 3, and 13) were prepared via the reaction of ethyl iodide [9, 10], allyl
bromide [11±13], or ethyl bromoacetate [11] with sodium saccharin by heating
the reactants in DMF for 2 h according to a reported procedure [9]. The hydrazide
key intermediates 4, 5, and 14 were prepared either by stirring 2 or 3 with excess
hydrazine hydrate at room temperature for 10±20 min [9] ꢀ4, 5) or by heating
equimolar amounts of 13 and hydrazine hydrate in ethanol under re¯ux for 1 h ꢀ14).
The hydrazides were cyclized [14] with ꢀ-diketones such as ethyl acetoacetate,
acetylacetone, or benzoylacetone by heating equimolar amounts of the reactants
under re¯ux in ethanol containing 2 cm3 acetic acid for 12 h to afford the novel
antiin¯ammatory pyrazole derivatives 6±11 and 15±17 in high yields. Moreover,
the hydrazides 4 and 14 were condensed with maleic anhydride by heating the
reactants in glacial acetic acid for 8 h to give the novel maleimido derivatives 12
and 18.
The novel benzenesulfonamide derivatives containing an oxadiazole moiety
were prepared as shown in Scheme 2. 2-ꢀ5-Mercapto-1,3,4-oxadiazol-2-yl)-N-
ethylbenzenesulfonamide ꢀ19) was obtained in high yield according to Young and
Wood [15] by re¯uxing 4 with carbon disul®de in aqueous ethanol in the presence
of potassium hydroxide. 19 was allowed to react with different alkyl or aralkyl
halides in ethanol containing potassium hydroxide at room temperature to afford
2-ꢀ5-substituted-thio-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamides 20±23.
Pharmacology
The novel compounds 6±12 and 17 were tested for their analgesic and
antiin¯ammatory activities using celecoxib for comparison. In addition, the effects
of these compounds on the sleeping time of thiopentone anaesthesized mice and
their anticonvulsant activities were studied.

New Benzenesulfonamide Derivatives
257
Scheme 1

258
E. H. Abdel Aal et al.
Scheme 2
The results presented in Table 1 illustrate the analgesic activity [16] of the
test compounds following their intraperitoneal ꢀi.p.) injection at a dose level of
1.7 mg=kg body weight of mice. Obviously, 7 and 12 have no signi®cant analgesic
effect. Compounds 6, 8, 9, 10, 11 and 17 show analgesic activity as they increase
the reaction time. The effect decreases in the order 17 > 11 > 9 > celecoxib >
8 > 6 > 10.
The intradermal injection of carrageenin ꢀ10%) at a dose of 0.1 cm3 in the rat
paw of the hind limb [17] signi®cantly increased its thickness after 1, 2, 3 and 4
hours after injection. Likewise, the i.p. injection of the test compounds at a dose of
18 mg=kg body weight of rat signi®cantly decreased the thickness of rat paw after
two hours till the end of the experiment as shown in Table 2. The antiin¯ammatory
effect decreases in the order 17 > 11 > 9 > 12 > 8 > celecoxib > 10 > 7 > 6.
The results presented in Table 3 reveal that the i.p. injection of the test
compounds at a dose level of 1.7 mg=kg body weight signi®cantly prolonged the
Table 1. Analgesic activity evaluation of the test compounds 6±12 and 17 administered i.p. in a dose
of 1.7 mg=kg to mice ꢀn ˆ 6)
Reaction time in seconds after
10 min
20 min
30 min
60 min
90 min
120 min
Control
12.1 Æ 0.47 12.33 Æ 0.46 13.2 Æ 0.54 13.72 Æ 0.75 14.2 Æ 0.73 15.11 Æ 0.81
Celecoxib
23 Æ 2.2c
22 Æ 3.1b
12 Æ 0.34
15 Æ 0.49b
22 Æ 2.3b
32 Æ 2.5c
26 Æ 2.8c
14 Æ 0.22
28 Æ 3.1c
35 Æ 2.6c
35 Æ 2.6c
26 Æ 2.7c
14 Æ 0.38
33 Æ 3.2c
41 Æ 2.7c
17 Æ 0.55b
67 Æ 3.4c
17 Æ 1.2
36 Æ 2.1c
28 Æ 2.2c
14 Æ 0.32
35 Æ 4.1c
50 Æ 2.3c
33 Æ 2c
31.6 Æ 2.2c
21 Æ 0.58b
15 Æ 0.78
29 Æ 3.3c
6
7
23 Æ 1.5b
15 Æ 0.82
35 Æ 3.8c
53 Æ 2.4c
8
9
55 Æ 2.82c
10
11
12
17
15 Æ 0.32b 15.3 Æ 0.38b
18 Æ 0.91a 19 Æ 1.0a 18.2 Æ 0.87
42 Æ 2.3c
13 Æ 0.58
33 Æ 1.9c
48 Æ 3.2c
16.3 Æ 0.95a
45 Æ 2.1c
70 Æ 3.3c
18.2 Æ 1.4
69 Æ 3.1c
57 Æ 2.8c
18 Æ 1.2
68 Æ 3.2c
53 Æ 2.2c
17.3 Æ 1.1
67 Æ 2.1c
65 Æ 3.2c
a
b
c
P < 0.05; P < 0.01; P < 0.001 ꢀP: probability level)

New Benzenesulfonamide Derivatives
259
Table 2. Antiin¯ammatory activity evaluation of the test compounds 6±12 and 17 administered i.p. in
a dose of 18 mg=kg to mature rats ꢀn ˆ 6)
Initial volume Thickness of paw skin in mm after
ꢀzero time)
1 hour
2 hours
3 hours
4 hours
Control
ꢀCarrageenin
10%, 0.1 cm3)
0.4 Æ 0.02
0.71 Æ 0.06
1.32 Æ 0.074
1.56 Æ 0.08
1.68 Æ 0.073
Celecoxib
0.41 Æ 0.06
0.43 Æ 0.07
0.52 Æ 0.068 0.59 Æ 0.088a
0.72 Æ 0.071a
0.78 Æ 0.049a
0.76 Æ 0.025a
0.70 Æ 0.04a
0.68 Æ 0.068a
0.71 Æ 0.033a
0.53 Æ 0.06a
0.69 Æ 0.067a
0.45 Æ 0.075a
0.72 Æ 0.041a
0.82 Æ 0.048a
0.81 Æ 0.072a
0.70 Æ 0.073a
0.69 Æ 0.044a
0.75 Æ 0.059a
0.58 Æ 0.038a
0.70 Æ 0.058a
0.51 Æ 0.043a
6
7
0.6 Æ 0.033 0.73 Æ 0.043a
0.42 Æ 0.033 0.67 Æ 0.03
0.71 Æ 0.069a
8
0.42 Æ 0.063 0.51 Æ 0.032 0.57 Æ 0.055a
9
0.43 Æ 0.05
0.44 Æ 0.06
0.41 Æ 0.06
0.51 Æ 0.078 0.55 Æ 0.079a
0.49 Æ 0.067 0.56 Æ 0.076a
0.46 Æ 0.029 0.49 Æ 0.085a
10
11
12
17
0.40 Æ 0.033 0.49 Æ 0.086 0.55 Æ 0.070a
0.42 Æ 0.07
0.43 Æ 0.087 0.45 Æ 0.034a
a
P < 0.001
Table 3. Effect of the test compounds 6±12 and 17 on the sleeping time of thiopentone anaesthesized
mice administered i.p. in a dose of 1.7 mg=kg body weight ꢀn ˆ 6)
Sleeping time=min
Control
16 Æ 1.33
ꢀThiopentone-Na, 20 mg=kg)
Celecoxib ‡ Thiopentone-Na
6 ‡ Thiopentone-Na
7 ‡ Thiopentone-Na
8 ‡ Thiopentone-Na
9 ‡ Thiopentone-Na
10 ‡ Thiopentone-Na
11 ‡ Thiopentone-Na
12 ‡ Thiopentone-Na
17 ‡ Thiopentone-Na
94 Æ 5.3a
80 Æ 3.2a
120 Æ 6.1a
92 Æ 4.3a
70 Æ 2.1a
67 Æ 1.5a
145 Æ 6.2a
127 Æ 5.4a
105 Æ 3.4a
a
P < 0.001
sleeping time of thiopentone anesthesized mice [18] decreasing in the order
11 > 12 > 7 > 17 > celecoxib > 8 > 6 > 9 > 10.
It is evident from Table 4 that the i.p. injection of the test compounds at a dose
level of 1.7 mg=kg body weight signi®cantly prolonged the time of onset of
convulsion and time of death of mice when compared with the control group [19]
in the order 17 > celecoxib > 7 > 8 > 6 > 11 > 10 > 9 > 12.
The pyrazoles showing the highest antiin¯ammatory activity ꢀ8, 9, 10, 11, 17,
and celecoxib) were tested for their ulcerogenic activity [20, 21]; indomethacin
was used as reference drug. The results presented in Table 5 show that the order
of potency of ulcerogenic activity is indomethacin > 11 > 9 > 17 > 10 > 8 >
celecoxib.

260
E. H. Abdel Aal et al.
Table 4. Effect of the test compounds 6±12 and 17 administered i.p. in a dose of 1.7 mg=kg on
pentylenetetrazole-induced convulsions in mice ꢀn ˆ 6)
Time of onset=min
Time of death=min
Control
ꢀPentylenetetrazole,
10 mg=kg)
1.20 Æ 0.08
3.5 Æ 0.21
Celecoxib ‡ Pentylenetetrazole
6 ‡ Pentylenetetrazole
7 ‡ Pentylenetetrazole
8 ‡ Pentylenetetrazole
9 ‡ Pentylenetetrazole
10 ‡ Pentylenetetrazole
11 ‡ Pentylenetetrazole
12 ‡ Pentylenetetrazole
17 ‡ Pentylenetetrazole
3.23 Æ 0.32a
2.58 Æ 0.22a
2.2 Æ 0.11a
3.1 Æ 0.41a
2.3 Æ 0.16a
3.11 Æ 0.24a
2.1 Æ 0.50a
2.51 Æ 0.18a
3.54 Æ 0.23a
121 Æ 4.3a
26 Æ 1.5a
113 Æ 4.2a
102 Æ 5.1a
12.5 Æ 0.35a
23 Æ 1.2a
23.6 Æ 2.1a
9.66 Æ 0.44a
149 Æ 8.3a
a
P < 0.001
Table 5. Ulcerogenic activity of the test compounds 8±11, 17, and celecoxib ꢀn ˆ 6)
Incidence of
Mean ulcer score
Ulcer index
gastric ulceration
Control
0.00
0.00
0.00
475
Indomethacin
100%
100%
100%
100%
100%
100%
100%
4.75 Æ 0.25
1.25 Æ 0.25
1.30 Æ 0.30b
1.80 Æ 0.20b
1.50 Æ 0.15b
3.66 Æ 0.34a
1.66 Æ 0.20b
Celecoxib
125
8
9
130
180
10
11
17
150
366
166
a
b
Compared with indomethacin, P < 0.05; P < 0.001
Conclusions
The main objective of this study was to develop effective analgesic and anti-
in¯ammatory agents. To achieve this goal, several structural changes on the potent
and selective cyclooxygenase-2 inhibitor celecoxib which is commercially used
were performed. Our investigation resulted in the following observations:
replacement of tri¯ouromethyl by methyl did not affect the activity; ®ve-
membered ring such as pyrazole or its isostere maintain the activity as observed for
compound 12 ꢀTable 2); a phenyl ring attached to the pyrazole at position 5
enhances the activity; a sulfonamido group at the ortho position is as active as at
the para position of the phenyl ring ꢀTables 1, 2); cyclic sulfonamides ꢀ17) have
higher analgesic=antiin¯ammatory effects than celecoxib ꢀTables 1, 2) and possess
a weak ulcerogenic activity ꢀTable 5); compound 8 has nearly the same
antiin¯ammatory and ulcerogenic activity as celecoxib ꢀTables 2, 5).

New Benzenesulfonamide Derivatives
261
Most of the novel benzenesulfonamide derivatives containing a pyrazole moi-
ety showed potent analgesic and antiin¯ammatory activities. The compounds are
structurally related to the selective COX-2 inhibitor celecoxib, and some of them
are more active than celecoxib as analgesic and antiin¯ammatory agents. Moreover,
some of the pyrazoles with the highest antiin¯ammatory properties showed lower
ulcerogenic activity as compared to indomethacin. Further studies are required to
investigate their binding at COX-2 and to determine their selectivity.
Experimental
General
Melting points were determined with a Gallenkamp Digital melting point apparatus in open
capillaries and are uncorrected. IR spectra ꢀKBr) were recorded using a Testscan Shimadzu FTIR
1
8000 spectrophotometer. H NMR spectra were determined on Varian EM-390, Bruker AC 250,
and Varian Mercury 300 NMR spectrometers using TMS as internal standard ꢀchemical shifts in
ꢁ ꢀppm)). Mass spectra were measured on a Hewlett Packard MS-5988 mass spectrometer at 70 eV.
Elemental analyses were performed at the microanalytical center, Faculty of Science, Cairo
University, Cairo, Egypt. Their results corresponded to the calculated values within experimental
error. TLC was performed on silica gel G ꢀMerck), and spots were visualized by iodine vapour or by
irradiation with UV light ꢀ254 nm). Compounds 2, 3, 4, and 13 were prepared according to reported
procedures [9, 13].
2-Hydrazinocarbonyl-N-allylbenzenesulfonamide ꢀ5; C10H13N3O3S)
A mixture of N-allyl-saccharin ꢀ3; 10 mmol) and hydrazine hydrate ꢀ30 mmol) was stirred at room
temperature for 20 min. The separated product was ®ltered, washed with H2O, dried, and re-
crystallized from EtOH.
Yield: 90%; m.p.: 99±100ꢀC; IR: ꢂ ˆ 3355 ꢀNH2), 3200 ꢀNH), 3088 ꢀCH, aromatic), 2971 ꢀCH,
aliphatic), 1655 ꢀCˆO), 1615 ꢀCˆC), 1327 ꢀSO2) cmÀ1
;
1H NMR ꢀ250 MHz, ꢁ, DMSO-d6):
3.28±3.48 ꢀm, 2H, CH2), 4.1 ꢀs, 2H, NH2, exch.), 4.85±5.00 ꢀm, 2H, ˆCH2), 5.35 ꢀt, 1H, NH, exch.),
5.49±5.58 ꢀm, 1H, CˆCH), 7.20±7.89 ꢀm, 4H, ArH), 9.03 ꢀs, 1H, NH, exch.) ppm; MS: m=z ꢀrel.
‡
int.) ˆ 255 ꢀM , 0.36), 224 ꢀ45.61), 198 ꢀ99.74), 184 ꢀ34.58), 76 ꢀ100).
General procedure for the preparation of 6±11
To a solution of the acid hydrazide 4 or 5 ꢀ10 mmol) in 30 cm3 EtOH containing 2 cm3 glacial acetic
acid, an equimolar amount of ethyl acetoacetate or acetylacetone or benzoylacetone was added. The
reaction mixture was heated under re¯ux for 12 h, concentrated to a small volume, cooled, and added
to 30 cm3 ice-cold water. The separated product was ®ltered, washed with H2O, and recrystallized
from the appropriate solvent.
2-&3-Methyl-5-oxo-1H-pyrazolin-1-ylcarbonyl)-N-ethylbenzenesulfonamide ꢀ6; C13H15N3O4S)
Yield: 85%; m.p.: 102±104ꢀC ꢀEtOH); IR: ꢂ ˆ 3440 ꢀNH), 3093 ꢀCH, aromatic), 2977 ꢀCH,
aliphatic), 1735 ꢀCˆO), 1589 ꢀCˆN), 1458 ꢀCˆC), 1326 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ,
CDCl3): 1.0 ꢀt, 3H, CH3), 2.0 ꢀs, 3H, CH3), 2.8±3.0 ꢀm, 2H, CH2), 4.2 ꢀs, 2H, CH2 of pyrazoline),
‡
5.87 ꢀt, 1H, NH, exch.), 7.25±8.0 ꢀm, 4H, ArH) ppm; MS: m=z ꢀrel. int.) ˆ 309 ꢀM , 2.84), 211 ꢀ15),
196 ꢀ100), 183 ꢀ4.17), 104 ꢀ30), 76 ꢀ39.2).

262
E. H. Abdel Aal et al.
2-&3-Methyl-5-oxo-1H-pyrazolin-1-ylcarbonyl)-N-allylbenzenesulfonamide ꢀ7; C14H15N3O4S)
Yield: 80%; m.p.: 150±152ꢀC ꢀbenzene=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3340 ꢀNH), 3087 ꢀCH,
aromatic), 2940 ꢀCH, aliphatic), 1720 ꢀCˆO), 1580 ꢀCˆN), 1455 ꢀCˆC), 1325 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ, CDCl3): 2.00 ꢀs, 3H, CH3), 3.4±3.55 ꢀm, 2H, CH2), 4.3 ꢀ2H, s, CH2 of
pyrazoline), 5.0±5.18 ꢀm, 2H, ˆCH2), 5.51 ꢀt, 1H, NH), 5.59±5.70 ꢀm, 1H, CˆCH), 7.3±8.0 ꢀm, 4H,
ArH) ppm.
2-&3,5-Dimethyl-1H-pyrazol-1-ylcarbonyl)-N-ethylbenzenesulfonamide ꢀ8; C14H17N3O3S)
Yield: 78%; m.p.: 152±154ꢀC ꢀEtOH=H2O); IR: ꢂ ˆ 3320 ꢀNH), 3090 ꢀCH, aromatic), 2920 ꢀCH,
aliphatic), 1630 ꢀCˆO), 1590 ꢀCˆN), 1470 ꢀCˆC), 1328 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ,
CDCl3): 1.0 ꢀt, 3H, CH3), 1.8 ꢀs, 3H, CH3), 1.9 ꢀs, 3H, CH3), 2.85±3.1 ꢀm, 2H, CH2), 5.3 ꢀt, 1H, NH,
exch.), 7.1±7.8 ꢀm, 5H, ArH ‡ CH of pyrazole) ppm.
2-&3-Methyl-5-phenyl-1H-pyrazol-1-ylcarbonyl)-N-ethylbenzenesulfonamide
ꢀ9; C19H19N3O3S)
Yield: 80%; m.p.: 147±149ꢀC ꢀEtOH); IR: ꢂ ˆ 3310 ꢀNH), 3090 ꢀCH, aromatic), 2930 ꢀCH,
aliphatic), 1640 ꢀCˆO), 1580 ꢀCˆN), 1490 ꢀCˆC), 1325 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ,
CDCl3): 1.0 ꢀt, 3H, CH3), 2.1 ꢀs, 3H, CH3), 2.9±3.1 ꢀm, 2H, CH2), 5.6 ꢀt, 1H, NH, exch.), 7.2±8.1 ꢀm,
10H, ArH ‡ CH of pyrazole) ppm.
2-&3,5-Dimethyl-1H-pyrazol-1-ylcarbonyl)-N-allylbenzenesulfonamide ꢀ10; C15H17N3O3S)
Yield: 75%; m.p.: 118±120ꢀC ꢀbenzene=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3294 ꢀNH), 3085 ꢀCH,
aromatic), 2931 ꢀCH, aliphatic), 1620 ꢀCˆO), 1496 ꢀCˆN), 1442 ꢀCˆC), 1326 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ, DMSO-d6): 1.8 ꢀs, 3H, CH3), 1.9 ꢀs, 3H, CH3), 3.3±3.5 ꢀm, 2H, CH2), 4.8±5.1
ꢀm, 2H, ˆCH2) 5.3±5.6 ꢀm, 1H, CˆCH), 6.9 ꢀt, 1H, NH, exch.), 7.1±7.7 ꢀm, 5H, ArH ‡ CH of
pyrazole) ppm.
2-&3-Methyl-5-phenyl-1H-pyrazol-1-ylcarbonyl)-N-allylbenzenesulfonamide
ꢀ11; C20H19N3O3S)
Yield: 73%; m.p.: 114±116ꢀC ꢀEtOH=H2O); IR: ꢂ ˆ 3290 ꢀNH), 3080 ꢀCH, aromatic), 2925 ꢀCH,
aliphatic), 1640 ꢀCˆO), 1520 ꢀCˆN), 1470 ꢀCˆC), 1330 ꢀSO2) cmÀ1
;
1H NMR ꢀ250 MHz, ꢁ,
CDCl3): 1.98 ꢀs, 3H, CH3), 3.3±3.5 ꢀm, 2H, CH2), 4.91±5.11 ꢀm, 2H, ˆCH2), 5.5 ꢀt, 1H, NH, exch.),
5.58±5.69 ꢀm, 1H, CˆCH), 7.30±7.99 ꢀm, 10H, ArH ‡ CH of pyrazole) ppm.
2-&N-Maleimidoaminocarbonyl)-N-ethylbenzenesulfonamide ꢀ12; C13H13N3O5S)
A mixture of acid hydrazide 4 ꢀ5 mmol) and maleic anhydride ꢀ5 mmol) in 20 cm3 glacial acetic acid
was heated under re¯ux for 8 h. The reaction mixture was cooled and then poured into 30 cm3 ice
water. The separated product was ®ltered and recrystallized from EtOH.
Yield: 85%; m.p.: 226±228ꢀC; IR: ꢂ ˆ 3225 ꢀNH), 3080 ꢀCH, aromatic), 2930 ꢀCH, aliphatic),
1730, 1630 ꢀCˆO), 1520 ꢀCˆC), 1325 ꢀSO2) cmÀ1; 1H NMR ꢀ300 MHz, ꢁ, DMSO-d6): 1.05 ꢀt, 3H,
CH3), 2.9±3.05 ꢀm, 2H, CH2), 5.93 ꢀt, 1H, NH, exch.), 7.12±7.95 ꢀm, 6H, ArH ‡ CHˆCH), 10.52
ꢀs, 1H, NH, exch.) ppm.

New Benzenesulfonamide Derivatives
263
&1,2-Benzoisothiazol-3&2H)one-1,1-dioxid-2-yl)-acetic acid hydrazide ꢀ14; C9H9N3O4S)
A mixture of equimolar amounts ꢀ10 mmol) of ester 13 and hydrazine hydrate in 30 cm3 EtOH was
heated under re¯ux for 1 h. The reaction mixture was cooled and then poured into 30 cm3 cold H2O.
The separated product was ®ltered, washed with H2O, dried, and recrystallized from aqueous EtOH.
Yield: 93%; m.p.: 150±152ꢀC; IR: ꢂ ˆ 3386 ꢀNH2), 3293 ꢀNH), 3091 ꢀCH, aromatic), 2975 ꢀCH,
1
aliphatic), 1670, 1616 ꢀCˆO), 1570 ꢀCˆC), 1336 ꢀSO2) cmÀ1; H NMR ꢀ300 MHz, ꢁ, DMSO-d6):
3.44 ꢀs, 2H, CH2), 4.13 ꢀs, 2H, NH2, exch.), 7.49±7.89 ꢀm, 4H, ArH), 9.08 ꢀs, 1H, NH, exch.) ppm;
‡
MS: m=z ꢀrel. int.) ˆ 255 ꢀM , 4.9), 224 ꢀ21.8), 196 ꢀ100), 169 ꢀ17.8), 132 ꢀ15.1), 104 ꢀ36.0), 77
ꢀ45.3).
General procedure for the preparation of 15±17
An equimolar amount ꢀ10 mmol) of acid hydrazide 14 and ethyl acetoacetate or acetylacetone or
benzoylacetone was reacted similarly as described for 6±11.
2-&3-Methyl-5-oxo-1H-pyrazolin-1-ylcarbonylmethyl)-1,2-benzoisothiazol-3&2H)one-1,1-
dioxide ꢀ15; C13H11N3O5S)
Yield: 72%; m.p.: 110±112ꢀC ꢀethyl acetate=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3080 ꢀCH,
aromatic), 2900 ꢀCH, aliphatic), 1690, 1610 ꢀCˆO), 1510 ꢀCˆN), 1470 ꢀCˆC), 1330 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ, CDCl3): 1.96 ꢀs, 3H, CH3), 3.81 ꢀs, 2H, CH2), 4.2 ꢀs, 2H, CH2 of pyrazoline),
7.39±7.92 ꢀm, 4H, ArH) ppm.
2-&3,5-Dimethyl-1H-pyrazol-1-ylcarbonylmethyl)-1,2-benzoisothiazol-3&2H)one-1,1-
dioxide ꢀ16; C14H13N3O4S)
Yield: 70%; m.p.: 103±105ꢀC ꢀethyl acetate=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3075 ꢀCH,
aromatic), 2970 ꢀCH, aliphatic), 1720, 1660 ꢀCˆO), 1570 ꢀCˆN), 1520 ꢀCˆC), 1330 ꢀSO2) cmÀ1
;
1H NMR ꢀ90 MHz, ꢁ, CDCl3): 1.8 ꢀs, 3H, CH3), 1.9 ꢀs, 3H, CH3), 3.9 ꢀs, 2H, CH2), 7.2±7.8 ꢀm, 5H,
ArH ‡ CH of pyrazole) ppm.
2-&3-Methyl-5-phenyl-1H-pyrazol-1-ylcarbonylmethyl)-1,2-benzoisothiazol-3&2H)one-1,1-
dioxide ꢀ17; C19H15N3O4S)
Yield: 73%; m.p.: 125±127ꢀC ꢀEtOH=H2O); IR: ꢂ ˆ 3076 ꢀCH, aromatic), 2975 ꢀCH, aliphatic),
1
1738, 1673 ꢀCˆO), 1583 ꢀCˆN), 1512 ꢀCˆC), 1335 ꢀSO2) cmÀ1; H NMR ꢀ300 MHz, ꢁ, CDCl3):
2.0 ꢀs, 3H, CH3), 3.85 ꢀs, 2H, CH2), 7.25±7.85 ꢀm, 10H, ArH ‡ CH of pyrazole) ppm.
2-&N-Maleimido-acetamide)-1,2-benzoisothiazol-3&2H)one-1,1-dioxide ꢀ18; C13H9N3O6S)
A mixture of equimolar amounts ꢀ5 mmol) of the acid hydrazide 14 and maleic anhydride was
reacted as described for 12.
Yield: 82%; m.p.: 288±290ꢀC ꢀEtOH); IR: ꢂ ˆ 3224 ꢀNH), 3070 ꢀCH, aromatic), 2939 ꢀCH,
1
aliphatic), 1735, 1627 ꢀCˆO), 1496 ꢀCˆC), 1326 ꢀSO2) cmÀ1; H NMR ꢀ300 MHz, ꢁ, DMSO-d6):
4.40 ꢀs, 2H, CH2), 7.22±8.21 ꢀm, 6H, ArH ‡ CHˆCH), 10.48 ꢀs, 1H, NH, exch.) ppm.
2-&5-Mercapto-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamide ꢀ19; C10H11N3O3S2)
To a solution of acid hydrazide 4 ꢀ10 mmol) in 80 cm3 EtOH ꢀ90%) containing KOH ꢀ15 mmol),
10 cm3 CS2 were added. The reaction mixture was heated under re¯ux for 8 h while stirring, then

264
E. H. Abdel Aal et al.
concentrated, cooled, and acidi®ed with diluted HCl. The separated product was ®ltered, washed
with H2O, and recrystallized from aqueous EtOH.
Yield: 90%; m.p.: 150±152ꢀC; IR: ꢂ ˆ 3294 ꢀNH), 3163 ꢀCH, aromatic), 2977 ꢀCH, aliphatic),
1
2561 ꢀSH), 1596 ꢀCˆN), 1488 ꢀCˆC), 1326 ꢀSO2) cmÀ1; H NMR ꢀ300 MHz, ꢁ, CDCl3 ‡ D2O):
1.09 ꢀt, 3H, CH3), 3.05 ꢀq, 2H, CH2), 7.25±8.26 ꢀm, 4H, ArH) ppm.
General procedure for the preparation of 20±23
A mixture of 19 ꢀ1 mmol) and the appropriate alkyl or aralkyl halide ꢀ1 mmol) in 30 cm3 EtOH
containing KOH ꢀ1.2 mmol) was stirred at room temperature for 2 h. The reaction mixture was
poured into 30 cm3 ice water. The separated product was ®ltered and recrystallized from the proper
solvent.
2-&5-Methylthio-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamide ꢀ20; C11H13N3O3S2)
Yield: 85%; m.p.: 110±112ꢀC ꢀacetone=H2O); IR: ꢂ ˆ 3290 ꢀNH), 3160 ꢀCH, aromatic), 2970
1
ꢀCH, aliphatic), 1590 ꢀCˆN), 1480 ꢀCˆC), 1320 ꢀSO2) cmÀ1; H NMR ꢀ250 MHz, ꢁ, CDCl3): 1.1
ꢀt, 3H, CH3), 2.77 ꢀs, 3H, CH3), 3.05±3.13 ꢀm, 2H, CH2), 7.11 ꢀt, 1H, NH, exch.), 7.6±8.2 ꢀm, 4H,
ArH) ppm.
2-&5-Ethylthio-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamide ꢀ21; C12H15N3O3S2)
Yield: 90%; m.p.: 68±70ꢀC ꢀacetone=H2O); IR: ꢂ ˆ 3294 ꢀNH), 3163 ꢀCH, aromatic), 2977 ꢀCH,
aliphatic), 1596 ꢀCˆN), 1488 ꢀCˆC), 1326 ꢀSO2) cmÀ1; 1H NMR ꢀ300 MHz, ꢁ, CDCl3): 0.9 ꢀt, 3H,
CH3), 1.1 ꢀt, 3H, CH3), 2.85 ꢀq, 2H, CH2), 3.10±3.18 ꢀm, 2H, CH2), 7.0 ꢀt, 1H, NH, exch.),
7.55±8.20 ꢀm, 4H, ArH) ppm.
2-&5-Allylthio-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamide ꢀ22; C13H15N3O3S2)
Yield: 92%; m.p.: 60±62ꢀC ꢀethyl acetate=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3298 ꢀNH), 3150 ꢀCH,
aromatic), 2960 ꢀCH, aliphatic), 1570 ꢀCˆN), 1475 ꢀCˆC), 1330 ꢀSO2) cmÀ1; 1H NMR ꢀ90 MHz, ꢁ,
CDCl3): 1.09 ꢀt, 3H, CH3), 3.07±3.15 ꢀm, 2H, CH2), 3.30 ꢀd, 2H, CH2), 4.81±4.91 ꢀm, 2H, ˆCH2),
5.41±5.53 ꢀm, 1H, ˆCH), 7.05 ꢀt, 1H, NH, exch.), 7.42±8.12 ꢀm, 4H, ArH) ppm.
2-&5-Benzylthio-1,3,4-oxadiazol-2-yl)-N-ethylbenzenesulfonamide ꢀ23; C17H17N3O3S2)
Yield: 87%; m.p.: 85±87ꢀC ꢀCHCl3=petroleum ether 60±80ꢀC); IR: ꢂ ˆ 3220 ꢀNH), 3100 ꢀCH,
aromatic), 2980 ꢀCH, aliphatic), 1620 ꢀCˆN), 1560 ꢀCˆC), 1325 ꢀSO2) cmÀ1; 1H NMR ꢀ300 MHz,
ꢁ, DMSO-d6): 0.94 ꢀt, 3H, CH3), 2.84±2.88 ꢀm, 2H, CH2), 4.55 ꢀs, 2H, CH2), 7.3±7.47 ꢀm, 5H, ArH),
‡
7.6 ꢀt, 1H, NH, exch.), 7.82±8.05 ꢀm, 4H, ArH) ppm; MS: m=z ꢀrel. int.) ˆ 375 ꢀM , 4.5), 268
ꢀ19.3), 212 ꢀ18.5), 132 ꢀ32.6), 91 ꢀ100).
Analgesic activity evaluation
The hot plate method of Jacob and Bosovski [16] was used to evaluate the analgesic activity. Mature
albino mice of both sex weighing 20±25 g were classi®ed into ten groups ꢀeach of six). The ®rst
group was left as control and injected i.p. with the solvent ꢀDMSO), whereas the second group was
injected i.p. with celecoxib at a dose of 1.7 mg=kg. Each of the remaining groups was injected i.p.
with a test compound at a dose of 1.7 mg=kg. Ten minutes later, each mouse was placed in a two
liter-beaker immersed in a water bath thermostatically controlled at 56ꢀC. The time elapsed till the

New Benzenesulfonamide Derivatives
265
mouse licks its paw or jumps was considered as the reaction time and was taken as a measure of the
analgesic effect. Readings were taken at 10, 20, 30, 60, 90, and 120 minutes post treatment ꢀTable 1).
Antiin¯ammatory activity evaluation
The rat hind paw oedema method [17] was applied to determine the antiin¯ammatory activity of the
test compounds using celecoxib as a standard. Mature albino rats of both sex weighing 200±250 g
were used. The animals were divided into ten equal groups ꢀeach of six). The ®rst group was left as
control, while the second group was injected ꢀi.p.) with celecoxib at a dose of 18 mg=kg. The test
compounds were injected ꢀi.p.) to the remaining groups at a dose of 18 mg=kg. One hour later,
oedema in the right hind paw was induced by injection of 0.1 cm3 of 10% carrageenin. The thickness
of the paw was measured 60, 120, 180 and 240 minutes after carrageenin injection to determine the
antiin¯ammatory activity of the test compounds ꢀTable 2).
Effect of the test compounds on the sleeping time of thiopentone anaesthesized mice
The method described by Alpermann [18] was applied for evaluation of the test compounds. Mature
male albino mice weighing 20±25 g were divided into ten equal groups ꢀeach of six). The ®rst group
was left as control, while the second group was injected i.p. with celecoxib at a dose of 1.7 mg=kg.
Each of the remaining groups was injected i.p. with the test compound at a dose of 1.7 mg=kg. One
hour later, all animals were injected i.p. with thiopentone-Na at a dose of 20 mg=kg body weight.
The time from losing consciousness to that of regaining the righting re¯ex was determined as the
sleeping time ꢀTable 3).
Anticonvulsant activity screening
The ability of the test compounds to protect animals against the convulsive and lethal effects of
pentylenetetrazole was used as described by Wallenstein [19]. Mature albino mice of both sex
weighing 20±25 g were divided into ten equal groups ꢀeach of six). The ®rst group was left as a
control, while the second group was injected i.p. with celecoxib at a dose of 1.7 mg=kg. The test
compounds were injected i.p. to the other groups at a dose of 1.7 mg=kg. Ten minutes later, all
animals were injected i.p. with pentylenetetrazole at a dose of 10 mg=kg and observed for the
appearance of seizures and the onset of each ꢀTable 4).
Ulcerogenic activity
Compounds 8, 9, 10, 11, 17 and celecoxib were tested for their ulcerogenic activity using
indomethacin as reference drug. Male albino rats weighing 150±200 g were fasted for 12 h prior to
drug administration. Water was given ad libitum. The animals were divided into eight equal groups
ꢀeach of six). The ®rst group received 1% gum acacia ꢀsuspending vehicle) orally once a day and was
left as a control, whereas the second group received indomethacin at a dose of 18 mg=kg=day orally.
The third group received celecoxib at a dose of 18 mg=kg=day orally. The remaining groups received
the test compounds at a dose of 18 mg=kg=day orally. The drugs were administered once a day for
three successive days. The animals were killed by an overdosage of ether 6 h after the last dose. The
stomach was removed, opened along the greater curvature, and examined for ulceration. The number
and severity of discrete areas of damage in the glandular mucosa were scored ꢀTable 5). The ulcer
score was calculated according to the 1 to 5 scoring system of Wilhelmi and Menasse-Gdynia [20] as
follows: 1) 1 or 2 minute sporadic punctate lesions; 2) several small lesions; 3) one extensive lesion
or multiple moderate-sized lesions; 4) several large lesions; 5) several large lesions with stomach
perforation. Stomach ulceration was expressed in terms of ulcer index ꢀU.I. ˆ mean ulcer score of a
group of animals similarly treated  % of ulcerated animals of this group [21].

266
E. H. Abdel Aal et al.: New Benzenesulfonamide Derivatives
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Received August 20, 2001. Accepted &revised) November 19, 2001