420
H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
4.1.3. Synthesis of 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-
1-yl)benzenesulfonamides 15aed
4.1.4.1. 1-Phenyl-2-(phenylsulfonyl)ethanone
(73%); m.p. 120e2 ꢂC; IR 3230e2940 (OH) cmꢁ1; 1H NMR (DSMO-
d6) 4.95 (s, 2H, CH2), 7.35e7.37 (m, 3H, ArH), 7.56e7.59 (m, 2H,
oxime(16a). Yield
n
The appropriate 1-aryl-2-(arylsulfonyl) ethanones 11ae
d (10 mmol) was added to a stirred ethanolic sodium ethoxide
solution [prepared from sodium metal (0.23 g, 10 mmol) and 50 mL
of absolute ethanol]. After stirring for 20 min, 2-oxo-N0-(4-
sulfamoylphenyl)propanehydrazonoyl chloride (13) (2.76 g,
10 mmol) was added and the reaction mixture was left to stir at
room temperature for 12 h. Then added to cold water, the solid
product was collected by filtration, washed with water and dried.
Recrystallization from ethanol afforded 1H-pyrazoles 15aed.
d
ArH), 7.64e7.66 (m, 2H, ArH), 7.69e7.72 (m, 1H, ArH), 7.75e7.77 (m,
2H, ArH), 11.79 (s, D2O exchangeable, 1H, OH); 13C NMR (DSMO-d6)
d
51.37, 126.34, 127.77, 128.18, 128.96, 129.01, 133.83, 134.50, 139.71,
145.54; MS (ESI) m/z 275.1 (Mþ). Anal. Calcd for C14H13NO3S
(275.32): C, 61.07; H, 4.76; N, 5.09. Found: C, 61.30; H, 4.85; N, 5.11.
4.1.4.2. 1-(4-Methylphenyl)-2-(phenylsulfonyl)ethanone oxime(16b).
Yield (68%); m.p. 155e7 ꢂC; IR
n ;
3246e2922 (OH) cmꢁ1 1H NMR
(DSMO-d6)
d
2.32 (s, 3H, CH3), 4.92 (s, 2H, CH2), 7.16 (d, J ¼ 8 Hz, 2H,
4.1.3.1. 4-(3-Acetyl-5-phenyl-4-(phenylsulfonyl)-1H-pyrazol-1-yl)
ArH), 7.54 (d, J ¼ 8 Hz, 2H, ArH), 7.56e7.59 (m, 2H, ArH), 7.69e7.72
(m, 1H, ArH), 7.75e7.76 (m, 2H, ArH), 11.66 (s, D2O exchangeable,
benzenesulfonamide(15a). Yield (54%); m.p. 248e50 ꢂC; IR
n
3272
(NH2), 1705 (C]O) cmꢁ1
;
1H NMR (DSMO-d6)
d
2.60 (s, 3H, CH3),
1H, OH); 13C NMR (DSMO-d6)
d 20.76, 51.38, 126.27, 127.76, 127.88,
7.42e7.47 (m, 5H, ArH), 7.49 (s, 2H, D2O exchangeable, 2H, NH2),
7.58 (d, J ¼ 8.5 Hz, 2H, ArH), 7.61e7.62 (m, 2H, ArH), 7.67e7.73 (m,
1H, ArH), 7.80 (d, J ¼ 8.5 Hz, 2H, ArH), 7.91 (d, J ¼ 7.0 Hz, 2H, ArH);
128.15, 128.77, 131.75, 133.79, 138.53, 139.73, 145.42; MS (ESI) m/z
289.3 (Mþ). Anal. Calcd for C15H15NO3S (289.35): C, 62.26; H, 5.23;
N, 4.84. Found: C, 62.27; H, 5.17; N, 4.97.
13C NMR (DSMO-d6)
d 28.20, 121.04, 126.37, 126.87, 127.37, 127.99,
128.89, 129.97, 130.67, 133.35, 140.26, 141.75, 144.43, 147.93, 148.28,
192. MS (ESI) m/z 479.8 (Mþ ꢁ 1). Anal. Calcd for C23H19N3O5S2
(481.54): C, 57.37; H, 3.98; N, 8.73. Found: C, 57.56; H, 4.07; N, 8.79.
4.1.5. Synthesis of 1-(1-(aryl)-2-(phenylsulfonyl)ethylidene)-2-
phenylhydrazines 17a, b
To a solution of the appropriate 1-aryl-2-arylsulfonyl ethanones
11a, b (10 mmol) in ethanol (50 mL) and phenyl hydrazine (1.08 g,
10 mmol), catalytic amount of acetic acid were added. The reaction
mixture was refluxed for 1 h. After cooling, the precipitated product
was filtered off, washed with ethanol and dried. Recrystallization
from EtOH afforded compounds 17a, b, respectively.
4.1.3.2. 4-(3-Acetyl-4-(phenylsulfonyl)-5-p-tolyl-1H-pyrazol-1-yl)
benzenesulfonamide(15b). Yield (58%); m.p. 260e2 ꢂC; IR
n
3265
2.34 (s, 3H, CH3),
2.59 (s, 3H, CH3), 7.22e7.23 (m, 2H, ArH), 7.30e7.34 (m, 2H, ArH),
7.51 (s, 2H, D2O exchangeable, 2H, NH2), 7.55e7.92 (m, 9H, ArH); 13
NMR (DSMO-d6) 20.97, 28.23, 120.97, 126.40, 126.88, 127.37,
(NH2), 1702 (C]O) cmꢁ1 1H NMR (DSMO-d6)
; d
C
d
4.1.5.1. 1-Phenyl-2-(1-phenyl-2-(phenylsulfonyl)ethylidene)hydrazi-
127.97, 128.63, 128.88, 129.16, 129.20, 129.26, 129.65, 130.53, 133.31,
133.91, 139.56, 140.35, 141.83, 144.39, 144.87, 148.02, 148.37, 192.20;
MS (ESI) m/z 493.1 (Mþ ꢁ 1). Anal. Calcd for C24H21N3O5S2 (495.57):
C, 58.17; H, 4.27; N, 8.48. Found: C, 58.36; H, 4.18; N, 8.33.
ne(17a). Yield (66%); m.p. 160e2 ꢂC; IR 3349 (NH) cmꢁ1; 1H NMR
n
(DSMO-d6) d 5.17 (s, 2H, CH2), 6.82e6.84 (m, 1H, ArH), 7.13e7.14 (m,
2H, ArH), 7.23e7.30 (m, 5H, ArH), 7.51e7.54 (m, 2H, ArH), 7.59e7.60
(m, 1H, ArH), 7.70e7.72 (m, 2H, ArH), 7.88e7.90 (m, 2H, ArH), 9.75
(s, D2O exchangeable, 1H, NH); 13C NMR (DSMO-d6)
d 51.75, 112.95,
4.1.3.3. 4-(3-Acetyl-5-(4-bromophenyl)-4-(phenylsulfonyl)-1H-pyr-
119.85, 125.60, 127.34, 127.93, 128.10, 128.90, 128.96, 129.35, 133.89,
azol-1-yl)benzenesulfonamide(15c). Yield (52%); m.p. 265e7 ꢂC; IR
137.557, 139.38, 144.69; MS (ESI) m/z 349.5 (Mþ ꢁ 1). Anal. Calcd for
n
3270 (NH2), 1706 (C]O) cmꢁ1; 1H NMR (DSMO-d6)
d
2.58 (s, 3H,
C20H18N2O2S (350.43): C, 68.55; H, 5.18; N, 7.99. Found: C, 68.59; H,
CH3), 7.45 (d, J ¼ 8 Hz, 2H, ArH), 7.50 (s, 2H, D2O exchangeable, 2H,
5.04; N, 8.12.
NH2), 7.60e7.76 (m, 7H, ArH), 7.84 (d, J ¼ 8.5 Hz, 2H, ArH), 7.94 (d,
J ¼ 7.5 Hz, 2H, ArH); 13C NMR (DSMO-d6)
d
28.07, 121.25, 123.78,
4.1.5.2. 1-Phenyl-2-(2-(phenylsulfonyl)-1-p-tolylethylidene)hydrazi-
126.36, 126.49, 127.01, 127.43, 128.90, 131.07, 132.81, 133.40, 140.12,
141.65, 144.58, 146.94, 148.10, 191.88; MS (ESI) m/z 558.9 (Mþ ꢁ 1).
Anal. Calcd for C23H18BrN3O5S2 (560.44): C, 49.29; H, 3.24; N, 7.50.
Found: C, 49.24; H, 3.40; N, 7.37.
ne(17b). Yield (70%); m.p. 147e9 ꢂC; IR 3344 (NH) cmꢁ1; 1H NMR
n
(DSMO-d6)
d 2.29 (s, 3H, CH3), 5.19 (s, 2H, CH2), 6.80e6.83 (m, 1H,
ArH), 7.08e7.12 (m, 4H, ArH), 7.22e7.24 (m, 2H, ArH), 7.53e7.54 (m,
2H, ArH), 7.60e7.61 (m, 3H, ArH), 7.88e7.89 (m, 2H, ArH), 9.64 (s,
D2O exchangeable, 1H, NH); 13C NMR (DSMO-d6)
d 20.68, 51.79,
4.1.3.4. 4-(3-Acetyl-5-(4-bromophenyl)-4-tosyl-1H-pyrazol-1-yl)
112.85,119.68,125.59,128.08,128.56,128.90,129.56,133.85,134.88,
benzenesulfonamide(15d). Yield (57%); m.p. 271e3 ꢂC; IR
n
3259
136.74, 139.41, 144.78; MS (ESI) m/z 364.3 (Mþ). Anal. Calcd for
(NH2), 1706 (C]O) cmꢁ1
;
1H NMR (DSMO-d6)
d
2.39 (s, 3H, CH3),
C21H20N2O2S (364.46): C, 69.20; H, 5.53; N, 7.69. Found: C, 69.46; H,
2.58 (s, 3H, CH3), 7.42e7.43 (m, 3H, ArH), 7.50 (s, 2H, D2O
exchangeable, 2H, NH2), 7.59e7.65 (m, 4H, ArH), 7.74e7.85 (m, 5H,
5.55; N, 7.82.
ArH); 13C NMR (DSMO-d6)
d
21.05, 28.10, 121.70, 23.75, 126.40,
4.2. Anti-inflammatory activity
126.49, 126.98, 127.559, 128.05, 129.33, 129.64, 131.06, 131.78,
132.81, 138.80, 140.13, 143.96, 144.55, 146.63, 148.07, 191.92; MS
(ESI) m/z 573.4 (Mþ ꢁ 1). Anal. Calcd for C24H20BrN3O5S2 (574.47):
C, 50.18; H, 3.51; N, 7.31. Found: C, 49.96; H, 3.46; N, 7.42.
Male SpraugeeDawley rats weighing 250 g were purchased
from local source and kept at room temperature (22 ꢀ 2 ꢂC) in a
light-controlled room with an alternating 12 h light/dark cycle.
They were fasted with free access to water at least 16 h prior to
experiments. The tested compounds were prepared as suspension
in vehicle (0.5% methyl cellulose) and celebrex (Celecoxib) was
used as a standard drug. The positive control group animals
received the reference drug while the negative control received
only the vehicle. The anti-inflammatory activity was evaluated
using in vivo rat carrageenan-induced foot paw edema model re-
ported previously [40]. Edema was produced by injecting 0.2 mL of
4.1.4. Synthesis of 1-(aryl)-2-(phenylsulfonyl)ethanone oximes 16a,
b
A mixture of the appropriate 1-aryl-2-arylsulfonyl ethanones
11a, b (10 mmol), hydroxyl amine hydrochloride (1.1 g, 15 mmol)
and anhydrous sodium acetate (1.2 g, 15 mmol) in ethanol (50 mL)
was refluxed for 1 h, then left to cool. The reaction mixture was
poured into cold water and the solid product was filtered off,
washed with water, dried and finally recrystallized from EtOH to
afford compounds 16a, b, respectively [31,36].
a solution of 1%
l-carrageenan in the hind paw. The rats were
injected intraperitoneally with 1 mL suspension in 0.5% methyl