Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents

Article abstract of DOI:10.1007/s12272-012-0507-y

Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated

Full text of DOI:10.1007/s12272-012-0507-y

Arch Pharm Res Vol 35, No 5, 807-821, 2012
DOI 10.1007/s12272-012-0507-y
Synthesis of Novel Pyrazole and Dihydropyrazoles Derivatives as
Potential Anti-inflammatory and Analgesic Agents
1
Nagwa M. Abd-El Gawad , Hanan H. Georgey , Nashwa A. Ibrahim , Noha H. Amin , and
1
2,3
2
4
Rania M. Abdelsalam
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt,
2
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suief University, 62111, Beni-Suef, Egypt, Department
of Medicinal Chemistry, Faculty of Pharmacy, Umm Al-Qura University, 13174, Makkha, Kingdom of Saudi Arabia, and
4
Department of Pharmacology, Faculty of Pharmacy, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt
(Received July 22, 2011/Revised November10, 2011/Accepted December 22, 2011)
Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The
structures of the newly synthesized compounds were elucidated by spectral and elemental
analyses. The anti-inflammatory activity of all new compounds was evaluated using the car-
rageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs.
The most active derivatives as anti-inflammatory agents were accordingly tested for their
analgesic activity using the
p-benzoquinone-induced writhing method in mice and results
revealed that these compounds had also good analgesic activity. The ulcerogenic liability of
the selected compounds was also evaluated. Results showed that the selected derivatives had
anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching
about 82% inhibition with a considerable gastric safety profile.
Key words: Pyrazole, Dihydropyrazole, Anti-inflammatory, Analgesic
variety of responses including the up regulation of
cycloxygenases (COX). COX is the rate limiting enzyme
INTRODUCTION
Inflammation is the response of the tissue to injury, in the arachidonic acid metabolism through catalyzing
which is oftenly caused by invading pathogens. Inflam- the biosynthesis of free arachidonic acid to eicosanoids
mation can be classified as either acute or chronic. that include prostanoids (prostaglandins, prostacyclins
Acute inflammation is the initial response of the body and thromboxanes) and leukotrienes (Jachak, 2006).
to harmful stimuli and is achieved by the increased It exists in two isoforms; namely, COX-1 and COX-2,
movement of plasma and leucocytes especially granulo- the constitutive and inducible forms, respectively
cytes from the blood into the injured tissue (Jachak, (Szabó et al., 2008).
2006). This process is mediated by the release of
histamine, bradykinin and cytokines (inflammatory matory diseases are frequently associated with increased
mediators) such as interleukine-1 (IL-1) and tumor risk of cancers (Coussens and Werb, 2002; Macarthur
necrosis factor-
(TNF- ) (Black, 2005; Jachak, 2006; et al., 2004; Philip et al., 2004), and that the develop-
Epidemiologic studies support that chronic inflam-
α
α
Lacerda et al., 2009). These mediators are thought to ment of cancer from inflammation might be a process
increase the release of fatty acid precursors of pro- driven by inflammatory cells as well as a variety of me-
staglandins (PGs) and therefore increase the rate of diators, including cytokines, chemokines, and enzymes,
prostaglandin synthesis via the induction of a wide which altogether establish an inflammatory microen-
vironment (Coussens and Werb, 2002). Consequently,
finding new anti-inflammatory agents represents a
Correspondence to: Hanan H. Georgey, Pharmaceutical Chem-
concrete strategy in fighting not only different inflam-
istry Department, Faculty of Pharmacy, Cairo University, Cairo
matory diseases but also cancer.
11562, Egypt
Tel: 2-0175600699, Fax: 2-023628426
Non-steroidal anti-inflammatory drugs (NSAIDs) are
E-mail: hanan-hanna@hotmail.com
recognized as an important class of therapeutic agents
807

808
N. M. A.-E. Gawad et al.
for the treatment of acute and chronic inflammation,
pain and fever (Kadar, 1998; Laufer and Luik, 2010).
Nevertheless, NSAIDs are the most widely used drugs
and their long term clinical use is associated with
several side effects such as gastrointestinal mucosal
damage, bleeding and renal toxicity (Kadar, 1998).
Thus, great efforts had been employed to discover
new classes of anti-inflammatory agents with high
gastric mucosal tolerance. Interest has been generated
in the chemistry and the biological activity particular-
ly the anti-inflammatory potency of pyrazole derivatives
as a potential source of new anti-inflammatory and
analgesic agents with lower gastrointestinal mucosal
toxicity (Satyanarayana and Rao, 1995; Penning et
Fig. 2. General structures of the target compounds.
al., 1997; Barsoum et al., 2006; Gökhan-Kelekçi et al., analgesic activities and devoid of the gastrointestinal
2007; Szabó et al., 2008). Accordingly, the well known side effects.
agents containing the pyrazole scaffold such as pheny-
butazone
et al., 1997; Szabó et al., 2008), IIIa
2006; Gökhan-Kelekçi et al., 2007), IV (Satyanarayana
and Rao, 1995), morazone (Reynold, 1993), and fa-
I
(Kadar, 1998), various coxibs IIa
-d (Penning
MATERIALS AND METHODS
,b
(Barsoum et al.,
Chemistry
V
All the starting materials were purchased from
morofazone VI (Reynold, 1993) were reported as anti- VWR International Merck, Germany or from Sigma-
inflammatory agents with lower GIT toxicity (Fig. 1). Aldrich and used without further purification. All the
In this respect, we aim to design, synthesize and bio- reactions were followed by TLC using silica gel F254
logically evaluate a number of novel pyrazole derivatives plates (Merck) using chloroform: ethyl acetate 6: 4 as
having the general formula A, B, and C (Fig. 2) hoping an eluting system and were visualized by UV-lamp.
that they might have potential anti-inflammatory, Melting points are uncorrected and were carried out
Fig. 1. Structures of pyrazole compounds with anti-inflammatory activity.

New Pyrazoles as Potential Anti-inflammatory Agents
809
by open capillary tube method using IA 9100MK-Digital aromatic), 2931, 2856 (CH aliphatic), 1686 (C=O),
1
Melting Point Apparatus. IR spectra were made on 1311, 1151 (SO ). H-NMR (CDCl ):
δ
2.03 (s, 3H,
Bruker Vector 22 or Jasco FTIR plus 460 and were ex- CH ), 3.00 (s, 3H, SO CH ), 5.25 (d, 1H, CCH , = 1.5
= 1.5 Hz), 7.10-8.22 (m, 4H,
2
3
J
2
3
2
3
−
1
pressed in wave number (cm ) using potassium bromide Hz), 5.34 (d, 1H, CCH ,
J
2
1 +
disc. Proton magnetic resonance H-NMR and carbon aromatic H). MS, m/z (%): M 224 (100%). Anal. Calcd.
13
magnetic resonance C-NMR spectra were recorded for C H O S (224.05): C, 58.91; H, 5.39. Found: C,
11 12
3
on a Varian Mercury VX-300 NMR spectrometer. The 58.40; H, 5.33.
spectra were run at 300 MHz in the specified solvent.
Chemical shifts were quoted in units, were related to
that of the solvents. values are given in Hz. As for
the proton magnetic resonance, D O was carried out
δ
General method for preparation of compounds
4a,b
A solution of the previously synthesized enones 3a
J
,b
2
for NH and OH exchangeable protons. Mass spectra (5.2 mmol), hydrazine hydrate (24.6 mL) in absolute
were recorded on Finnigan MAT, SSQ 7000 (70 eV) ethanol (20 mL) was refluxed for 3 h under dry
mass spectrometer. All mass spectra were recorded in nitrogen. After cooling of the reaction mixture to room
EI mode unless otherwise stated. Elemental microa- temperature, it was concentrated to half its volume
nalyses were carried out using Heraew and Vario EL and ice water was added to the mixture. For compound
III (elementar), CHNS analyzer at the Microanalytical 4a, the precipitate formed was dried off, washed with
Center, Cairo University. IUPAC chemical nomencla- water (2 × 30 mL) and dried to give white needle
ture was assigned using ACDLABS ChemSketch ver- crystals. As for compound 4b, extraction was performed
sion 12.0. Compounds 2a (Humphries and Finefield, with methylene chloride (3 × 50 mL) and the organic
2006), 2b (Burton and Hu, 1948),
9
(Grosscurt et al., layer was dried over anhydrous sodium sulfate to give
, respectively.
1979; Alberto et al., 1988) and 13 (Organ and Mayer, the products 4a,b
2003) were prepared according to the reported method.
4-Methyl-3-[4-(methylsulfanyl)phenyl]-4,5-dihydro-
-pyrazole (4a)
White needle crystals, m.p. 110-112 C, yield 75%, IR
1H
General method for preparation of compounds
3a,b
o
−
/cm : 3341 (NH), 3065 (CH aromatic), 2966, 2922,
max
1
Piperidine (1.2 mL, 12.1 mmol), glacial acetic acid
υ
1
(1.2 mL, 20.8 mmol) and formaline (4 mL, 37% aqueous 2862 (CH aliphatic). H-NMR (CDCl ):
δ
1.09 (d, 3H,
3
solution, 53.2 mmol), were successively added to a CHCH , J = 6.6 Hz), 1.12-1.17 (m, 1H, CHCH ), 2.51
3 3
magnetically stirred solution of the previously prepar- (s, 3H, SCH ), 2.56 (d, 2H, CHCH , J = 6.9 Hz), 5.39
3 2
ed propiophenones 2a,b (12.8 mmol) in methanol (50 (s, 1H, pyrazole NH, (D O exch.)), 7.21-7.85 (m, 4H,
2
13
mL). The reaction mixture was left to stir under reflux aromatic H). C-NMR (CDCl ): 9.70 (CHCH ), 14.31
3
3
for 12 h and then concentrated under vaccum. The (SCH ), 18.13 (CHCH ), 21.58 (CHCH ), 125.76, 126.21,
3 3 2
residue was triturated with water and then extracted 127.09, 127.77, 135.08 and 138.44 (C aromatic), 150.94
+
with methylene chloride (2 × 30 mL). The organic (C=N olefinic). MS, m/z (%): M 206 (90), 205 (100%).
layer was separated, washed with water (3 × 50 mL), Anal. Calcd. for C H N S (206.09): C, 64.04; H, 6.84;
11 14 2
dried over Na SO , filtered, and evaporated. The pro- N, 13.58. Found: C, 64.09; H, 6.64; N, 13.80.
2 4
duct was dried to give yellow oil.
4-Methyl-3-[4-(methylsulfonyl)phenyl]-4,5-dihydro-
-pyrazole (4b)
Yellow oil, yield 61%, IR υmax/cm : 3354 (NH), 3061,
2-Methyl-1-[4-(methylsulfanyl)phenyl]prop-2-en-
1-one (3a)
1H
−
1
−
/cm : 3100, 3060 (CH 3003 (CH aromatic), 2966, 2927, 2872 (CH aliphatic),
max
1
Yellow oil, yield 81%, IR
υ
1
aromatic), 2984, 2938, 2885, 2838, 2788 (CH aliphatic), 1350, 1149 (SO ). H-NMR (CDCl ):
δ
1.05 (d, 3H,
2
3
1
1666 (C=O). H-NMR (CDCl ):
δ 2.06 (s, 3H, CH ), 2.52 CHCH , J = 6.6 Hz), 1.18-1.33 (m, 1H, CHCH ), 3.03
3 3 3
3
(s, 3H, SCH ), 5.56 (d, 1H, CCH ,
3 2
J = 1.5 Hz), 5.84 (d, (s, 3H, SO CH ), 3.15 (d, 2H, CHCH , J = 6.9 Hz), 5.25
2 3 2
1H, CCH ,
2
J = 1.5 Hz), 7.24-7.99 (m, 4H, aromatic H). (s, 1H, pyrazole NH, (D O exch.)), 7.26-8.11 (m, 4H,
2
+ +
MS, m/z (%): M 192 (0.41%), 98 (100%). Anal. Calcd. aromatic H). MS, m/z (%): M 238 (100). Anal. Calcd.
for C H OS (192.06): C, 68.71; H, 6.29. Found: C, for C H N O S (238.08): C, 55.44; H, 5.92; N, 11.76.
11 12 11 14 2 2
68.50; H, 6.55.
Found: C, 55.70; H, 5.69; N, 11.48.
2-Methyl-1-[4-(methylsulfonyl)phenyl]prop-2-en-
1-one (3b)
General method for preparation of compounds
5a-d
−
1
Yellow oil, yield 70%, IR υmax/cm : 3040, 3030 (CH
The appropriate benzyl chloride (4.9 mmol) was

810
N. M. A.-E. Gawad et al.
+
added to a stirred solution of 3,4-disubstituted 4,5- 7.27-8.01 (m, 8H, aromatic H). MS, m/z (%): M 362
+
H-pyrazole 4a,b (4.9 mmol) in absolute etha- (40.82), [M+2] 364 (12.63), 125 (100%). Anal. Calcd.
dihydro-1
nol (80 mL) and anhydrous potassium carbonate (0.25 for C H ClN O S (362.09): C, 59.58; H, 5.28; N, 7.72.
18 19 2 2
gm, 1.76 mmol). The reaction mixture was heated Found: C, 59.88; H, 5.49; N, 7.58.
under reflux for 15 h on a water bath. The solvent was
evaporated under reduced pressure and then extract-
ed with methylene chloride (2 × 30 mL). The organic
layer was washed with water (2 × 30 mL) and dried
over anhydrous sodium sulfate to give yellow oil.
General method for preparation of compounds
6a-d
The appropriate phenacyl bromide (4.9 mmol) was
added to a stirred solution of 3,4-disubstituted 4,5-
dihydro-1
nol (80 mL) and anhydrous potassium carbonate (0.25
gm, 1.76 mmol). The reaction mixture was heated
Yellow oil, yield 55%, IR υmax/cm : 3067, 3050, 3022 under reflux for 15 h on a water bath. The solvent was
H-pyrazole 4a,b (4.9 mmol) in absolute etha-
1-Benzyl-4-methyl-3-[4-(methylsulfanyl)phenyl]-
4,5-dihydro-1H-pyrazole (5a)
−
1
1
(CH aromatic), 2968, 2920, 2873 (CH aliphatic). H evaporated under reduced pressure and then extracted
NMR (CDCl ): δ 1.16 (d, 3H, CHCH , J = 6.6 Hz), with methylene chloride (2 × 30 mL). The organic layer
3 3
1.18-1.29 (m, 1H, CHCH ), 2.50 (s, 3H, SCH ), 2.61 (d, was washed with water (2 × 30 mL) and dried over
3 3
2H, CHCH , J = 6.9 Hz), 2.70 (s, 2H, CH ), 7.21-7.95 anhydrous sodium sulfate to give yellow oil.
2 2
+
(m, 9H, aromatic H). MS, m/z (%): M 296 (41.5), 91
(100%). Anal. Calcd. for C H N S (296.13): C, 72.93; 2-{4-Methyl-3-[4-(methylsulfanyl)phenyl]-4,5-di-
18 20
2
H, 6.80; N, 9.45. Found: C, 73.06; H, 6.59; N, 9.69.
hydro-1
Yellow oil, yield 50%, IR
aromatic), 2971, 2830 (CH aliphatic), 1692 (C=O). H-
NMR (CDCl ): 1.18 (d, 3H, CHCH , J = 6.6 Hz), 1.24-
H-pyrazol-1-yl}-1-phenylethanone (6a)
−
1
υ
max
/cm : 3088, 3060 (CH
1
1-Benzyl-4-methyl-3-[4-(methylsulfonyl)phenyl]-
4,5-dihydro-1
Yellow oil, yield 56%, IR
tic), 2970, 2925 (CH aliphatic), 1303, 1147 (SO ). H- CHCH , J = 6.9 Hz), 3.45 (s, 2H, COCH ), 7.26-8.01
H-pyrazole (5b)
δ
3
3
−
/cm : 3068 (CH aroma- 1.27 (m, 1H, CHCH ), 2.50 (s, 3H, SCH ), 2.61 (d, 2H,
3 3
1
υ
max
1
2
2
2
+
δ 1.15 (d, 3H, CHCH , J = 6.6 Hz), (m, 9H, aromatic H). MS, m/z (%): [M-1] 323, 105
3
NMR (CDCl ):
3
1.20-1.34 (m, 1H, CHCH ), 2.62 (d, 2H, CHCH , J
3 2
=
(100%). Anal. Calcd. for C H N OS (324.13): C, 70.34;
19 20 2
6.9 Hz), 3.01 (s, 3H, SO CH ), 3.07 (s, 2H, CH ), 7.26- H, 6.21; N, 8.63. Found: C, 70.25; H, 5.95; N, 8.28.
2 3 2
+
7.95 (m, 9H, aromatic H). MS, m/z (%): M 328 (5.09),
91 (100%). Anal. Calcd. for C H N O S (328.12): C, 2-{4-Methyl-3-[4-(methylsulfonyl)phenyl]-4,5-di-
18 20 2 2
65.83; H, 6.14; N, 8.53. Found: C, 65.60; H, 5.91; N, hydro-1H-pyrazol-1-yl}-1-phenylethanone (6b)
−
1
Yellow oil, yield 51%, IR υmax/cm : 3080, 3040 (CH
8.19.
aromatic), 2971, 2830 (CH aliphatic), 1692 (C=O), 1306,
1
1148 (SO ). H NMR (CDCl ): δ 1.17 (d, 3H, CHCH , J
2 3 3
1-(4-Chlorobenzyl)-4-methyl-3-[4-(methylsulfanyl)
phenyl]-4,5-dihydro-1
Yellow oil, yield 43%, IR
aromatic), 2928, 2850 (CH aliphatic), 1090 (Cl). H COCH ), 7.26-7.94 (m, 9H, aromatic H). Anal. Calcd.
H-pyrazole (5c)
= 6.6 Hz), 1.20-1.25 (m, 1H, CHCH ), 3.00 (s, 3H,
3
−
/cm : 3090, 3070 (CH SO CH ), 3.06 (d, 2H, CHCH , J = 6.9 Hz), 3.42 (s, 2H,
2 3 2
1
υ
max
1
2
NMR (CDCl ):
3
δ 1.19 (d, 3H, CHCH , J = 6.6 Hz), 1.21- for C H N O S (356.12): C, 64.02 ; H, 5.66; N, 7.86.
3 19 20 2 3
1.29 (m, 1H, CHCH ), 2.52 (s, 3H, SCH ), 2.55 (d, 2H, Found: C, 64.16; H, 5.50; N, 7.66.
3 3
CHCH , J = 6.9 Hz), 2.77 (s, 2H, CH ), 7.24-7.41 (m,
2 2
+
8H, aromatic H). MS, m/z (%): M 330 (42.29), [M+2]
+
1-(4-Chlorophenyl)-2-{4-methyl-3-[4-(methylsulfan-
-pyrazol-1-yl}ethanone
332 (15.01), 98 (100%). Anal. Calcd. for C H ClN S yl)phenyl]-4,5-dihydro-1
18 19 2
H
(330.87): C, 65.34; H, 5.79; N, 8.47. Found: C, 65.60; (6c)
−
1
Yellow oil, yield 51%, IR υmax/cm : 3066, 3050 (CH
H, 5.49; N, 8.36.
aromatic), 2971, 2928 (CH aliphatic), 1692 (C=O),
1
1091 (Cl). H NMR (CDCl ): δ 1.19 (d, 3H, CHCH , J =
3 3
1-(4-Chlorobenzyl)-4-methyl-3-[4-(methylsulfonyl)
phenyl]-4,5-dihydro-1
Yellow oil, yield 39.5%, IR
aromatic), 2927, 2869 (CH aliphatic), 1350, 1145 (SO ), 7.26-7.89 (m, 8H, aromatic H). MS, m/z (%): M 358
H-pyrazole (5d)
6.6 Hz), 1.22-1.34 (m, 1H, CHCH ), 2.50 (s, 3H, SCH ),
3
3
−
/cm : 3088, 3040 (CH 2.75 (d, 2H, CHCH , J = 6.9 Hz), 3.14 (s, 2H, COCH ),
2 2
1
υ
max
+
2
1
1089 (Cl). H-NMR (CDCl ): δ 1.21 (d, 3H, CHCH , J = (0.63), M+2 360 (0.23), 204 (100%). Anal. Calcd. for
3
3
6.6 Hz), 1.23-1.27 (m, 1H, CHCH ), 2.62 (d, 2H, CHCH
3
,
2
C H ClN OS (358.08): C, 63.59; H, 5.34; N, 7.81.
19 19 2
J
= 6.9 Hz), 3.05 (s, 3H, SO CH ), 3.11 (s, 2H, CH ), Found: C, 63.41; H, 5.53; N, 7.63.
2 3 2

New Pyrazoles as Potential Anti-inflammatory Agents
811
1-(4-Chlorophenyl)-2-{4-methyl-3-[4-(methylsulfon-
aromatic), 2967, 2922 (CH aliphatic), 1692 (C=O),
1
yl)phenyl]-4,5-dihydro-1
(6d)
Yellow oil, yield 48%, IR υmax/cm : 3088, 3040 (CH 3.92 (d, 2H, CHCH ,
H
-pyrazol-1-yl}ethanone
1091 (Cl). H-NMR (CDCl ): δ 1.16 (d, 3H, CHCH , J =
3
3
6.6 Hz), 1.29-1.36 (m, 1H, CHCH ), 2.50 (s, 3H, SCH ),
3
3
−
1
J
= 6.9 Hz), 7.24-7.97 (m, 8H,
2
+
aromatic), 2971, 2928 (CH aliphatic), 1688 (C=O), 1344, aromatic H). MS, m/z (%): M 344 (22.67), M+2 346
1
1146 (SO ), 1011 (Cl). H-NMR (CDCl ):
δ 1.18 (d, 3H, (7.02), 139 (100%). Anal. Calcd. for C H ClN OS
18 17 2
2
3
CHCH , J = 6.6 Hz), 1.20-1.33 (m, 1H, CHCH ), 3.03 (344.08): C, 62.69; H, 4.97; N, 8.12. Found: C, 62.45;
3 3
(s, 3H, SO CH ), 3.09 (d, 2H, CHCH , J = 6.9 Hz), 3.98 H, 4.90; N, 7.94.
2 3 2
(s, 2H, COCH ), 7.25-7.97 (m, 8H, aromatic H). MS,
2
m/z (%): M+1 391 (13.89%), 139 (100%). Anal. Calcd. (4-Chlorophenyl){4-methyl-3-[4-(methylsulfonyl)
for C H ClN O S (390.08): C, 58.38; H, 4.90; N, 7.17. phenyl]-4,5-dihydro-1 -pyrazol-1-yl}methanone
H
19 19
2
3
Found: C, 58.58; H, 5.21; N, 7.34.
(7d)
−
1
Yellow oil, yield 44%, IR υmax/cm : 3094, 3070 (CH
aromatic), 2998, 2976, 2916 (CH aliphatic), 1689 (C=O),
General method for preparation of compounds
7a-d
1
1311, 1145 (SO ), 1088 (Cl). H-NMR (CDCl ):
δ 1.14
2
3
The appropriate benzoylchloride (4.9 mmol) was (d, 3H, CHCH , J = 7.2 Hz), 1.24-1.27 (m, 1H, CHCH ),
3 3
added to a stirred solution of 3,4-disubstituted 4,5- 3.06 (s, 3H, SO CH ), 3.86 (d, 2H, CHCH , J = 6.9 Hz),
2 3 2
13
H-pyrazole 4a, b (4.9 mmol) in absolute 7.52-8.01 (m, 8H, aromatic H). C-NMR (DMSO-d ): δ
6
dihydro-1
ethanol (80 mL) and anhydrous potassium carbonate 9.70 (CHCH ), 37.44 (CHCH ), 43.36 (SO CH ), 53.48
3 3 2 3
(0.25 gm, 1.76 mmol). The reaction mixture was heated (CHCH ), 120.73, 127.27, 127.45, 127.67, 127.85, 128.59,
2
under reflux for 15 h on a water bath. The solvent was 128.92, 131.34, 132.75, 134.89, 135.65 and 141.57 (C
evaporated under reduced pressure and then extracted aromatic), 159.95 (C=N olefinic), 164.88 (C=O). MS,
+
with methylene chloride (2 × 30 mL). The organic m/z (%): M 376 (12.02), M+2 378 (11.17), 139 (100%).
layer was washed with water (2 × 30 mL) and dried Anal. Calcd. for C H ClN O S (376.06): C, 57.37; H,
18 17 2 3
over anhydrous sodium sulfate to give yellow oil.
4.55; N, 7.43. Found: C, 57.21; H, 4.85; N, 7.66.
{4-Methyl-3-[4-(methylsulfanyl)phenyl]-4,5-dihy-
General method for preparation of compounds
8a,b
dro-1H-pyrazol-1-yl}(phenyl)methanone (7a)
−
1
Yellow oil, yield 53%, IR υmax/cm : 3070, 3055 (CH
4-Chlorosulfonyl chloride (1.03 gm, 4.9 mmol) was
1
aromatic), 2971, 2923 (CH aliphatic), 1687 (C=O). H- added to a stirred solution of 3,4-disubstituted 4,5-
NMR (CDCl ): 1.18 (d, 3H, CHCH , J = 6.6 Hz), dihydro-1 -pyrazole 4a (4.9 mmol) in absolute etha-
1.20-1.36 (m, 1H, CHCH ), 2.50 (s, 3H, SCH ), 3.44 (d, nol (80 mL) and anhydrous potassium carbonate (0.25
δ
H
,b
3
3
3
3
2H, CHCH , J = 6.9 Hz), 7.23-7.99 (m, 9H, aromatic gm, 1.76 mmol). The reaction mixture was heated
2
+
H). MS, m/z (%): M 310 (10.67), 193 (100%). Anal. under reflux for 15 h on a water bath. The solvent was
Calcd. for C H N OS (310.41): C, 69.65; H, 5.84; N, evaporated under reduced pressure and then extracted
18 18 2
9.02. Found: C, 69.69; H, 5.78; N, 8.83.
with methylene chloride (2 × 30 mL). The organic
layer was washed with water (2 × 30 mL) and dried
over anhydrous sodium sulfate. The organic layer was
concentrated under vacuum to give solid, which was
{4-Methyl-3-[4-(methylsulfonyl)phenyl]-4,5-dihy-
dro-1
Yellow oil, yield 54%, IR
aromatic), 2968, 2919 (CH aliphatic), 1692 (C=O), respectively.
H-pyrazol-1yl}(phenyl)methanone (7b)
−
1
υ
max
/cm : 3080, 3024 (CH re-crystallized from ethanol to give the products 8a,b,
1
1310, 1146 (SO ). H-NMR (CDCl ):
δ
1.17 (d, 3H,
2
3
CHCH , J = 6.6 Hz), 1.23-1.27 (m, 1H, CHCH ), 3.05 1-[(4-Chlorophenyl)sulfonyl]-4-methyl-3-[4-(me-
3 3
(s, 3H, SO CH ), 3.92 (d, 2H, CHCH , J = 6.9 Hz), thylsulfanyl)phenyl]-4,5-dihydro-1H-pyrazole (8a)
2 3 2
+ o
7.27-8.11 (m, 9H, aromatic H). MS, m/z (%): M 342 Yellow crystals, m.p. 65-68 C, yield 43%, IR
−
/cm :
max
1
υ
(6.07), 105 (100%). Anal. Calcd. for C H N O S 3100, 3080 (CH aromatic), 2969, 2927, 2815 (CH
18 18 2 3
1
(342.10): C, 63.14; H, 5.30; N, 8.18. Found: C, 63.00; aliphatic), 1365, 1157 (SO ), 1090 (Cl). H-NMR (CDCl ):
2
3
H, 5.21; N, 8.50.
δ 1.16 (d, 3H, CHCH , J = 6.6 Hz), 1.21-1.42 (m, 1H,
3
CHCH ), 2.49 (s, 3H, SCH ), 3.06 (d, 2H, CHCH ,
3 3 2
J = 6.9
+
(4-Chlorophenyl){4-methyl-3-[4-(methylsulfanyl) Hz), 7.20-7.88 (m, 8H, aromatic H). MS, m/z (%): M 380
phenyl]-4,5-dihydro-1 -pyrazol-1-yl}methanone (11.57), 130 (100%). Anal. Calcd. for C H ClN O S
(7c)
Yellow oil, yield 40%, IR υmax/cm : 3070, 3045 (CH H, 4.78; N, 7.60.
H
17 17
2
2 2
(380.04): C, 53.60; H, 4.50; N, 7.35. Found: C, 53.81;
−
1

812
N. M. A.-E. Gawad et al.
1-[(4-Chlorophenyl)sulfonyl]-4-methyl-3-[4-(meth-
(NHCNH amidinic). Anal. Calcd. for C H N O S
2 12 16 4 2
ylsulfonyl)phenyl]-4,5-dihydro-1H-pyrazole (8b)
(280.10): C, 51.41; H, 5.75; N, 19.98. Found: C, 51.21;
o
Brown crystals, m.p. 72-75 C, yield 45%, IR
−
1
υ
max
/cm : H, 5.91; N, 20.01.
3092, 3070 (CH aromatic), 2971, 2927 (CH aliphatic),
1
1370, 1340, 1150, 1146 (2SO ), 1088 (Cl). H-NMR
General method for preparation of compounds
11a,b
2
(CDCl ):
3
δ 1.20 (d, 3H, CHCH , J = 6.6 Hz), 1.24-1.29
3
(m, 1H, CHCH ), 3.03 (s, 3H, SO CH ), 3.08 (d, 2H,
3 2 3
Sodium hydride (0.614 gm, 25.6 mmol) was added
CHCH , J = 6.9 Hz), 7.27-7.97 (m, 8H, aromatic H). slowly to a stirred solution of the previously synthesiz-
2
Anal. Calcd. for C H ClN O S (412.03): C, 49.45; H, ed propiophenones, 2a,b (12.8 mmol) in dry toluene
17 17 2 4 2
o
4.15; N, 6.78. Found: C, 49.25; H, 4.44; N, 6.59.
(15 mL), at 60 C and the reaction mixture was left to
stir for 10 min. Then diethyl oxalate (1.89 mL, 13.95
mmol) was added to the previously stirred solu-
General method for preparation of compounds
10a,b
tion and the reaction mixture was left for two hours at
o
Methyl carbamimidothioate
was added to a magnetically stirred solution of 3,4- acid (2-5 drops), washed with diethyl ether (30 mL)
disubstituted 4,5-dihydro-1 -pyrazole 4a (4.83 and the organic layer was extracted with methylene
9 (1 gm, 5.55 mmol) 60 C. The resulting mixture was acidified with acetic
H
,b
mmol) in pyridine (10 mL) and left under reflux at chloride (2 × 30 mL) over anhydrous sodium sulfate.
110°C for 1 h. After one night standing at room tem- The organic layer was concentrated under vacuum to
perature, diethyl ether was added and the precipitate give yellow oil.
was collected by filtration and washed with diethyl
ether (3 × 20 mL) to afford a brown solid that was Ethyl 2-methyl-3-[4-(methylsulfanyl)phenyl]-3-
dissolved in methanol (20 mL). 2 N sodium hydroxide oxopropanoate (11a)
−
1
solution (12 mL) and water (200 mL) were successively Yellow oil, yield 61%, IR υmax/cm : 3080, 3036 (CH
added to the previous suspension. The formed precipi- aromatic), 2980, 2926 (CH aliphatic), 1764, 1712, 1695
1
tate was collected by filtration, washed with diethyl (C=Os). H-NMR (CDCl ):
δ 1.18 (t, 3H, CH CH , J =
2 3
3
ether (2 × 20 mL) and dried to yield the products 7.2 Hz), 1.34 (d, 3H, CHCH , J = 6.9 Hz), 2.50 (s, 3H,
3
10a,b, respectively.
SCH ), 4.32 (q, 1H, CHCH , J = 7.2 Hz), 4.37 (q, 2H,
3 3
CH CH , J = 7.2 Hz), 7.22-7.96 (m, 4H, aromatic H).
2 3
+
MS, m/z (%): M 280 (3.62), 151 (100%). Anal. Calcd.
4-Methyl-3-[4-(methylsulfanyl)phenyl]-4,5-dihy-
dro-1 -pyrazole-1-carboximidamide (10a)
Orange powder, m.p. 223-225 C, yields 42%, IR
H
for C H O S (280.08): C, 59.98; H, 5.75. Found: C,
14 16 4
o
υ
max
/
59.93; H, 5.87.
−
1
cm : 3300, 3208 (NH, NH ), 3066 (CH aromatic), 2971,
2
1
2921 (CH aliphatic). H NMR (CDCl ):
δ
1.02 (d, 3H, Ethyl 2-methyl-3-[4-(methylsulfonyl)phenyl]-3-
3
CHCH , J = 6.1 Hz), 1.16-1.21 (m, 1H, CHCH ), 2.49 oxopropanoate (11b)
3 3
−
1
(s, 3H, SCH ), 2.74 (d, 2H, CHCH , J = 6.0 Hz), 7.27- Yellow oil, yield 50%, IR υmax/cm : 3100, 3080 (CH
3
2
7.79 (m, 4H, aromatic H), 7.82, 8.29 (2s, 3H, NH and aromatic), 2981, 2927 (CH aliphatic), 1740, 1714, 1693
+ 1
NH , D O exch.). MS, m/z (%): [M-1] 247 (28.35%), (C=Os), 1315, 1153, (SO ). H-NMR (CDCl ):
δ
1.13 (t,
2
2
2
3
157 (100%). Anal. Calcd. for C H N S (248.11): C, 3H, CH CH , J = 6.3 Hz), 1.38 (d, 3H, CHCH , J = 6.9
12 16 4 2 3 3
58.04; H, 6.49; N, 22.56. Found: C, 57.89; H, 6.19; N, Hz), 3.00 (s, 3H, SO CH ), 4.24 (q, 1H, CHCH , J = 7.2
2 3 3
22.90.
Hz), 4.33 (q, 2H, CH CH , J = 7.2 Hz), 7.87-8.18 (m, 4H,
2 3
+
aromatic H). MS, m/z (%): M 312 (0.48), 213 (100%).
4-Methyl-3-[4-(methylsulfonyl)phenyl]-4,5-dihy- Anal. Calcd. for C H O S (312.07): C, 53.84; H, 5.16.
14 16 6
dro-1H-pyrazole-1-carboximidamide (10b)
Found: C, 54.10; H, 5.00.
o
Red powder, m.p. 199-201 C, yield 59%, IR υmax/cm :
−
1
3300, 3222 (NH, NH ), 3030 (CH aromatic), 2971, 2928
2
General method for preparation of compounds
12a-d
1
(CH aliphatic), 1330, 1145 (SO ). H-NMR (CDCl ):
δ
2
3
1.15 (d, 3H, CHCH , J = 6.1 Hz), 1.16-1.34 (m, 1H,
3
Phenyl hydrazine or 4-methoxyphenyl hydrazine
CHCH ), 3.02 (s, 3H, SO CH ), 3.09 (d, 2H, CHCH , J (3.6 mmol) was added slowly to a mixture of the
3 2 3 2
= 6.0 Hz), 7.26-8.02 (m, 4H, aromatic H), 8.08, 8.10 previously synthesized butyric acid ethyl ester 11a,b
13
(2s, 3H, NH and NH , D O exch.). C-NMR (DMSO- (3.6 mmol) and triethylamine (3-5 drops) in absolute
2
2
d ): 9.67 (CCH ), 14.55 (SCH ), 38.22 (CHCH ), 43.34 ethanol (20 mL). The reaction mixture was left to stir
6 3 3 3
(CHCH ), 120.65, 125.39, 125.97, 127.12, 127.76 and at reflux for 24 h. It was then cooled, washed with brine
2
128.56 (C aromatic), 157.87 (C=N olefinic), 168.40 and extracted with methylene chloride. The organic

New Pyrazoles as Potential Anti-inflammatory Agents
813
layer was then separated, dried over anhydrous
General method for preparation of compounds
14a,b
sodium sulfate and evaporated under vacuum to give
yellow oily products, 12a-d.
4-Hydrazino-benzenesulfonamide 13 (0.67 gm, 3.6
mmol) was added slowly to a mixture of the previously
Ethyl 4-methyl-5-[4-(methylsulfanyl)phenyl]-1- synthesized butyric acid ethyl ester 11a
phenyl-1 -pyrazole-3-carboxylate (12a) and triethylamine (3-5 drops) in absolute ethanol (20
Yellow oil, yield 79%, IR υmax/cm : 3080, 3060 (CH mL). The reaction mixture was left to stir at reflux for
,b (3.6 mmol)
H
−
1
1
aromatic), 2978, 2922 (CH aliphatic), 1709 (C=O). H- 24 h. It was then cooled, washed with brine and extract-
NMR (DMSO- ): 1.20 (t, 3H, CH CH , J = 7.2 Hz), ed with methylene chloride. The organic layer was then
d
6
δ
2
3
1.41 (s, 3H, CCH ), 2.52 (s, 3H, SCH ), 4.33 (q, 2H, separated, dried over anhydrous sodium sulfate and
3 3
CH CH , J = 6.9 Hz), 7.21-7.96 (m, 9H, aromatic H). evaporated under vacuum to give solid products, 14a,b
2 3
+
MS, m/z (%): M 352 (2.91), 137 (100%). Anal. Calcd. respectively.
for C H N O S (352.12): C, 68.16; H, 5.72; N, 7.95.
20 20
2
2
Found: C, 67.89; H, 5.48; N, 7.93.
Ethyl 4-methyl-5-[4-(methylsulfanyl)phenyl]-1-(4-
sulfamoylphenyl)-1 -pyrazole-3-carboxylate (14a)
Ethyl 4-methyl-5-[4-(methylsulfonyl)phenyl]-1- Yellow crystals, m.p. 95-98 C, yield 75%, IR υmax/cm :
phenyl-1 -pyrazole-3-carboxylate (12b) 3320, 3280 (NH stretching), 3065, 3020 (CH aromatic),
Yellow oil, yield 72%, IR
aromatic), 2979, 2927 (CH aliphatic), 1715 (C=O), 1360, (SO ). H NMR (DMSO-d ):
H
o
−
1
H
2
−
1
υ
max
/cm : 3100, 3080 (CH 2969, 2922 (CH aliphatic), 1709 (C=O), 1368, 1160
1
δ
1.08 (t, 3H, CH CH , J =
2 3
2
6
1
1148, (SO ). H-NMR (CDCl ):
δ
1.23 (t, 3H, CH CH
2
,
3
7.2 Hz), 1.96 (s, 3H, CCH ), 2.52 (s, 3H, SCH ), 4.36 (q,
3 3
2
3
J
= 7.2 Hz), 1.45 (s, 3H, CCH ), 3.04 (s, 3H, SO CH ), 2H, CH CH , J = 7.2 Hz), 7.04-7.84 (m, 8H, aromatic
3 2 3 2 3
13
4.42 (q, 2H, CH CH , J = 6.9 Hz), 7.22-8.25 (m, 9H, H), 10.08 (s, 2H, NH , D O exch.). C-NMR(DMSO-
2
3
2
2
+
aromatic H). MS, m/z (%): M 384 (0.58), 303 (100%).
d ): δ 9.31 (CCH ), 10.60 (CH CH ), 14.07 (SCH ),
6 3 2 3 3
Anal. Calcd. for C H N O S (384.45): C, 62.48; H, 45.47 (CH CH ), 123.73, 123.92, 125.50, 125.73, 125.91,
20 20 2 4 2 3
5.24; N, 7.29. Found: C, 62.42; H, 5.48; N, 7.54.
126.08, 127.07, 127.14, 128.83, 129.40, 129.74, 138.00,
146.90, 148.48 and 151.98 (C aromatic and olefinic),
+
Ethyl 1-(4-methoxyphenyl)-4-methyl-5-[4-(methyl- 169.02 (C=O ester). MS, m/z (%): M 431 (3.34), 163
sulfanyl)phenyl]-1 -pyrazole-3-carboxylate (12c) (100%). Anal. Calcd. for C H N O S (431.10): C,
H
20 21
3
4 2
−
1
Yellow oil, yield 65%, IR υmax/cm : 3080, 3020 (CH 55.67; H, 4.91; N, 9.74. Found: C, 55.71; H, 5.07; N,
aromatic), 3000, 2922, 2880 (CH aliphatic), 1710 9.62.
1
(C=O). H-NMR (DMSO-d ): δ 1.19 (t, 3H, CH CH , J
6 2 3
= 7.2 Hz), 1.42 (s, 3H, CCH ), 2.52 (s, 3H, SCH ), 3.94 Ethyl 4-methyl-5-[4-(methylsulfonyl)phenyl]-1--(4-
3 3
(s, 3H, OCH ), 4.36 (q, 2H, CH CH , J = 6.9 Hz), 7.22- sulfamoylphenyl)-1H-pyrazole-3-carboxylate (14b)
3 2 3
+ o
7.99 (m, 8H, aromatic H). MS, m/z (%): M 382 (14.56), Brown crystals, m.p. 88-91 C, yield 77%, IR
−
/cm :
max
1
υ
151 (100%). Anal. Calcd. for C H N O S (382.14): C, 3300, 3258 (NH stretching), 3098, 3066 (CH aromatic),
21 22 2 3 2
65.95; H, 5.80; N, 7.32. Found: C, 66.19; H, 5.75; N, 2974, 2925 (CH aliphatic), 1703 (C=O), 1340, 1140,
1
(2SO ). H-NMR (DMSO-d ): δ 1.08 (t, 3H, CH CH , J =
2 6 2 3
7.60.
7.2 Hz), 2.08 (s, 3H, CCH ), 3.20 (s, 3H, SO CH ), 4.38
3 2 3
Ethyl 1-(4-methoxyphenyl)-4-methyl-5-[4-(methyl- (q, 2H, CH CH , J = 7.2 Hz), 7.09-8.07 (m, 8H, aromatic
2 3
+
sulfonyl)phenyl]-1
Yellow oil, yield 67%, IR υmax/cm : 3090, 3040 (CH 464 (13.92), 63 (100%). Anal. Calcd. for C H N O S
6 2
H-pyrazole-3-carboxylate (12d)
H), 10.08 (s, 2H, NH , D O exch.). MS, m/z (%): [M+1]
2 2
−
1
20 21
3
aromatic), 2998, 2931 (CH aliphatic), 1711 (C=O), 1360, (463.09): C, 51.82; H, 4.57; N, 9.07. Found: C, 51.70; H,
1
1144 (SO ). H-NMR (DMSO-
d ):
6
δ
1.11 (t, 3H, CH CH ,
2 3
4.60; N, 9.00.
2
J
= 7.2 Hz), 1.45 (s, 3H, CCH ), 3.01 (s, 3H, SO CH ),
3 2 3
3.69 (s, 3H, OCH ), 4.39 (q, 2H, CH CH , J = 6.9
3 2 3
General method for preparation of compounds
15a,b
13
Hz), 7.25-8.04 (m, 8H, aromatic H). C-NMR DMSO-
d ): δ 9.70 (CCH ), 13.9 (CH CH ), 43.11 (SO CH ),
6 3 2 3
Potassium hydroxide (0.24 g, 4.2 mmol) dissolved in
3
2
52.11 (OCH ), 62.22 (CH CH ), 120.30, 127.28, 127.36, methanol (5 mL) was added to a solution of ethyl 4-
3 2 3
128.63, 129.98, 134.00, and 152.50 (C aromatic and methyl-5-[4-(methylsulfanyl)phenyl]-1-(4-sulfamoyl-
+
olefinic), 169.02 (C=O ester). MS, m/z (%):[M+1] 415 phenyl)-1
H-pyrazole-3-carboxylate 14a (0.91 g, 2.1
(4.02), 183 (100%). Anal. Calcd. for C H N O S mmol) or ethyl 4-methyl-5-[4-(methylsulfonyl)phenyl]-
21 22 2 5
(414.12): C, 60.85; H, 5.35; N, 6.76. Found: C, 60.83; 1--(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate 14b
H, 5.59; N, 6.53. (0.97 gm, 2.1 mmol) dissolved in methanol (14 mL).

814
N. M. A.-E. Gawad et al.
The reaction mixture was heated to reflux for 3 h, ene chloride (2 × 30 mL). The organic layer was sep-
cooled, poured into water and filtered. The filtrate was arated, dried over sodium sulfate and re-crystallised
acidified with 10% HCl, the precipitate separated, from ethanol to yield the amide products.
washed with water, dried under vacuum and extract-
ed with methylene chloride (2 × 50 mL) to give the 4-[4-Methy1-5-[(4-(methylsulfanyl)phenyl)-3-(pi-
acid products 15a
,
b
, respectively.
peridine-1-ylcarbonyl)-1
sulfonamide (17a)
Red crystals, m.p. 155-158 C, yield 35%, IR
-pyrazole-3-carboxylic acid (15a) 3400, 3300 (NH ), 3080, 3020 (CH aromatic), 2928,
H-pyrazol-1-yl]benzene-
o
−
/cm :
max
1
4-Methyl-5-[4-(methylsulfanyl)phenyl]-1-(4-sulfa-
moylphenyl)-1
υ
H
2
−
1
Yellow oil, yield 59%, IR υmax/cm : 3298, 3237 (NH ), 2848 (CH aliphatic), 1620 (C=O), 1336, 1145 (SO ).
2
2
1
3080, 3020 (CH aromatic), 2970, 2924 (CH aliphatic),
H-NMR (CDCl ):
3
δ
1.22-2.03 (m, 6H, 3CH ), 2.15 (s,
2
1
2790 (OH), 1691 (C=O), 1368, 1151 (SO ). H-NMR 3H, CCH ), 2.50 (s, 3H, SCH ), 3.03-3.22 (m, 4H,
2
3
3
(DMSO-d ): δ 1.23 (s, 3H, CCH ), 2.52 (s, 3H, SCH ), N(CH ) ), 7.26-8.17 (m, 8H, aromatic H), 9.39 (s, 2H,
6 3 3 2 2
13
7.03-7.97 (m, 8H, aromatic H), 9.79 (s, 1H, COOH, D O NH , D O exch.). C-NMR(DMSO-d ): δ 8.44 (CCH ),
6 3
2
2
2
+
exch.), 10.01 (s, 2H, NH , D O exch.). MS, m/z (%): M
2 2
10.60 (CH CH ), 14.20 (SCH ), 21.46, 21.95 and 34.07
2 3 3
403 (28.04), 349 (100%). Anal. Calcd. for C H N O S
18 17 3 4
(3 piperidine CH ), 40.94, and 43.52 (2 piperidine
2
2
(403.07): C, 53.58; H, 4.25; N, 10.41. Found: C, 53.60; CH ), 125.22, 126.00, 127.34, 128.78, 128.91, 129.57,
2
H, 4.55; N, 10.02.
130.06, 131.02, 140.88, 142.22, and 149.01 (C aromatic
+
and olefinic), 174.00 (C=O amidic). MS, m/z (%): M
4-Methyl-5-[4-(methylsulfonyl)phenyl]-1-(4-sulfa-
470 (35.85), 84 (100%). Anal. Calcd. for C H N O S
23 26 4 3 2
moylphenyl)-1H-pyrazole-3-carboxylic acid (15b) (470.14): C, 58.70; H, 5.57; N, 11.91. Found: C, 58.55;
−
1
Yellow oil, yield 71%, IR υmax/cm : 3330, 3220 (NH ), H, 5.29; N, 11.63.
2
3082 (CH aromatic), 2947, 2929 (CH aliphatic), 2795
1
(OH), 1692 (C=O), 1330, 1141 (2SO ). H-NMR (DMSO- 4-[4-Methyl-5-(4-(methylsulfonyl)phenyl-3-(piper-
2
d ):
6
δ
1.23 (s, 3H, CCH ), 3.15 (s, 3H, SO CH ), 7.07- idine-1-ylcarbonyl)-1H-pyrazol-1-yl]benzenesul-
3 2 3
8.06 (m, 8H, aromatic H), 10.15 (s, 1H, COOH, D O fonamide (17b)
2
+
o
Brown crystals, m.p. 152-155 C, yield 49%, IR
exch.), 10.19 (s, 2H, NH , D O exch.). MS, m/z (%): M
2 2
υ
/
max
−
cm 3308, 3230(NH ), 3090, 3020 (CH aromatic), 2928
2
1
435 (52.53), 77 (100%). Anal. Calcd. for C H N O S
18 17 3 6
2
1
(435.06): C, 49.65; H, 3.93; N, 9.65. Found: C, 49.95; (CH aliphatic), 1639 (C=O), 1335, 1143 (2SO ). H-
2
H, 4.23; N, 10.02.
NMR (CDCl ): δ 1.54-1.74 (m, 6H, 3CH ), 2.17 (s, 3H,
3 2
CCH ), 3.01(s, 3H, SO CH ), 3.04-3.20 (m, 4H, N(CH ) ),
3 2 3 2 2
7.26-8.17 (m, 8H, aromatic H), 9.40 (s, 2H, NH , D O
2 2
General method for preparation of compounds
16a,b
+
exch.). MS, m/z (%):[M+1] 503 (37.70), 63 (100%).
The previously synthesized acids 15a,b (1.24 mmol) Anal. Calcd. for C H N O S (502.61): C, 54.96; H,
23 26 4 5 2
were suspended in thionyl chloride (5 mL) and heated 5.21; N, 11.15. Found: C, 54.55; H, 4.98; N, 11.13.
gently under reflux until a homogenous solution was
obtained then for further 45 min. The solutions were 4-[4-Methy1-5-[(4-(methylsulfanyl)phenyl)-3-(mor-
then evaporated to dryness under vacuum in a water pholin-1-ylcarbonyl)-1
bath to remove excess thionyl chloride. The residues fonamide (17c)
were azeotroped three times with dry benzene (5 mL) Red crystals, m.p. 166-167 C, yield 40%, IR
H-pyrazol-1-yl]benzenesul-
o
−
1
/cm :
υ
max
each, where the last traces of thiony1 chloride were 3380, 3220 (NH ), 3090, 3022 (CH aromatic), 2924,
2
1
removed. The residue was then used directly without 2855 (CH aliphatic), 1620 (C=O), 1336, 1145 (SO ). H-
2
further purification for the next step.
NMR (CDCl ): δ 1.44 (s, 3H, CCH ), 2.50 (s, 3H, SCH ),
3 3 3
3.03-3.36 (m, 4H, N(CH ) ), 3.45-4.01 (m, 4H, O(CH ) ),
2 2 2 2
7.20-8.01 (m, 8H, aromatic H), 10.08 (s, 2H, NH , D O
2 2
General method for preparation of compounds
17a-d
+
exch.). MS, m/z (%): M 472.12 (95.96), 108 (100%).
The acid chlorides 16a,b (1.21 mmol) were dissolved Anal. Calcd. for C H N O S (472.12): C, 55.91; H,
22 24 4 4 2
in dry methylene chloride (5.5 mL) and added drop- 5.12; N, 11.86. Found: C, 56.19; H, 5.01; N, 11.73.
wise to a solution of triethylamine (2-5 drops) and pi-
peridine or morpholine (1.87 mmol) in methylene 4-[4-Methyl-5-(4-(methylsulfonyl)phenyl-3-(mor-
o
chloride (5 mL) maintained at 0 C. The reaction mix- pholin-1-ylcarbonyl)-1
H-pyrazol-1-yl]benzenesul-
ture was stirred at room temperature for 8 h after fonamide (17d)
o
which it was added to brine and extracted with methyl- Brown crystals, m.p. 177-180 C, yield 30%, IR υmax
/

New Pyrazoles as Potential Anti-inflammatory Agents
815
−
1
cm : 3322, 3262 (NH ), 3090, 3077 (CH aromatic),
2
Where Vc is the mean of edema volume of rat paw
2921, 2853 (CH aliphatic), 1639 (C=O), 1341, 1144 after administration of carrageenan in the positive
1
(2SO ). H-NMR (CDCl ):
δ 1.24 (s, 3H, CCH ), 2.84 (s, control group, Vt is the mean of edema volume of rat
3
2
3
3H, SO CH ), 3.03-3.29 (m, 4H, N(CH ) ), 3.62-3.86 paw after administration of the tested compounds or
2 3 2 2
(m, 4H, O(CH ) ), 7.27-8.14 (m, 8H, aromatic H), 10.04 the reference drugs.
2 2
+
(s, 2H, NH , D O exch.). MS, m/z (%): M 504 (43.51),
2
2
71 (100%). Anal. Calcd. for C H N O S (504.11): C,
22 24 4 6 2
Analgesic activity
The analgesic effect of the most active anti-inflam-
matory derivatives 5c 12a 12c 14a, and 17d was
screened using the reported method of -benzoquinone
induced writhing in mice (Okun et al., 1963).
Adult male albino mice weighing 20-25 g were used
52.37; H, 4.79; N, 11.10. Found: C, 52.57; H, 4.73; N,
10.92.
,
,
,
p
Pharmacological screening
The experimental tests on animals have been per-
formed in accordance with the Institutional Ethical in this study. The new tested compounds and the
Committee approval, Faculty of Pharmacy, Cairo Uni- reference drugs indomethacin and celecoxib were pre-
versity.
pared as a suspension in 2% Tween 80. A sensitivity
test was carried out one day before drug administra-
tion, where animals were injected intraperitoneally
Anti-inflammatory activity
The newly synthesized compounds, indomethacin with 0.2-0.25 mL of 0.02% freshly prepared solution of
and celecoxib as reference standards were evaluated -benzoquinone in distilled water (Kurumbail et al.,
for in vivo anti-inflammatory activity using the stand- 1996). Animals showing writhing to -benzoquinone
ard acute carrageenan-induced paw edema method in within 30 min were chosen for studying the analgesic
rats (Winter et al., 1962, 1963). activity.
Wister albino rats (obtained from the animal house On the next day, mice were divided into eight groups
p
p
of Faculty of Pharmacy, Cairo University) of either each of 6 animals. The first group received 2% Tween
sex, pregnant female animals were excluded, weigh- 80 and kept as control while the second and third
ing 120-150 gm were divided into 33 groups of six groups received indomethacin and celecoxib, respecti-
animals each. The initial hind paw volume of rats was vely; in a dose of 25 mg/kg body weight. The rest of the
determined volumetrically. Indomethacin and celecoxib groups received 5c
,
12a
,
12c
,
14a, and 17d in the
-benzo-
(reference standards) and the tested compounds same dose. One hour later, 0.02% solution of
p
suspended in 2% Tween 80, at a dose of 25 mg/kg body quinone was administered intraperitoneally and the
weight, were administered intraperitoneally. The con- animals were observed for 30 min after injection of the
trol group received only 2% Tween 80, 1 h before in- irritant during which the animals showing writhing
duction of inflammation. One percent solution of carra- were counted.
geenan in saline (0.1 mL/rat) was injected subcu-
Writhing is defined as stretch, torsion to one side,
taneously into the right hind paw one hour after the drawing up of hind leg, retraction of the abdomen, so
tested compound had been administered intraperi- that the belly of mouse touches the floor. The mice
toneally. Paw edema volume was measured after 3 showing any of the previous types of reactions are
and 4 h using the plethysmometer 7150 (Ugo Basile) counted as positive responses. The analgesic activity
and compared with the initial hind paw volume of was expressed as the percentage protection against
p-
each rat. Data were collected, checked and revised. benzoquinone induced writhing response in compari-
Quantitative variables from normal distribution were son with the control according to the following equation:
expressed as means S.E. The anti-inflammatory ac-
Number of protected animals×100
-----------------------------------------------------------------------------------------------
=
Total number of animals
tivity was expressed as percentage inhibition of edema
volume in treated animals in comparison with the
control group (Table I). Statistical differences between
the treatments and the control were tested by one-
way analysis of variance (ANOVA) followed by Tukey
% Protection
Acute ulcerogenicity study
Fifty five adult albino rats of either sex (pregnant
female rats were excluded) weighing 120-150 g were
HSD test at a value of
p < 0.05.
The anti-inflammatory activity was expressed as used in this study. Animals were divided into 11
percentage inhibition of edema and was calculated by groups and received the drug orally. The first group
the following equation:
received 2% Tween 80 and kept as control while the
second and third groups received indomethacin and
celecoxib, respectively; in a dose of 25 mg/kg body
% Inhibition = 100 × [Vc
−
Vt/Vc]

816
N. M. A.-E. Gawad et al.
weight. The rest of the groups received 5c
12c 14a 14b
was allowed two hours post administration of the two steps (Burton and Hu, 1948; Almirante et al., 1965;
drugs. Rats received the given dose orally for three Humphries and Finefield, 2006). Compounds 3a
successive days. Two hours following the last dose, rats were synthesized from 2a using Mannich reaction/
were scarified; the stomach of each rat was removed, elimination sequence. Cyclocondensation of 3a with
opened along the greater curvature, rinsed with 0.9% hydrazine hydrate in absolute ethanol under dry ni-
sodium chloride (isotonic solution) and the stomach trogen, to guarantee a complete cyclocondensation
,
8b
,
12a
,
pan-1-one intermediate 2b was prepared according to
,
,
, 15a, and 17b in the same dose. Food the previously reported method from thioanisole 1 in
,b
,b
,b
was stretched on a corkboard using pins. Examination reaction yielded the corresponding pyrazoles 4a
for the presence of ulcers and erosions was done using (Scheme 2).
a magnifying lens (10 × s) (Meshali et al., 1983)
Nucleophilic
The ulcer index was calculated according to the amines 4a
method of Robert et al. (Robert et al., 1968). The degree substituted phenacyl bromides, unsubstituted benzoyl
of ulcerogenic effect was expressed in terms of: chlorides and -chlorosulfonyl chloride that contain
I. Percentage incidence of ulcers in each group of reasonable leaving groups achieved 5a 6a 7a
animals divided by 10 and 8a , respectively. Additionally, amidated products
II. The average number of ulcers per stomach. of compounds 4a have been achieved through the
III. The average severity of ulcers by visual observa- reaction with the previously prepared methyl carba-
tion. mimidothioate 9 (Grosscurt et al., 1979; Alberto et al.,
Finally, the ulcer index was expressed as the sum- 1988) in pyridine to furnish compounds 10a
(Scheme
,b
N-alkylation reactions of secondary
,b with the appropriate aryl halides, un-
p
-
d
,
-
d
,
-d,
,b
,b
,b
mation value of the above three items.
Results are tabulated in Table III.
3).
On the other hand, the reaction of 2a
oxalate under strong alkaline and dry solvent condi-
tions yielded the ester derivatives 11a which were
cyclized with unsubstituted phenylhydrazine or the
previously synthesized 4-hydrazinylbenzenesulfon-
,b with diethyl
,b
RESULTS AND DISCUSSION
Chemistry
The synthetic pathways applied to obtain target com- amide 13 (Organ and Mayer, 2003) to achieve the
pounds are displayed in Schemes 1-5. As described in pyrazole-3-carboxylic acid ethyl esters 12a and
Scheme 1, the known 1-[4-(methylsulfonyl)phenyl]pro- 14a (Scheme 4).
-d
,b
Reagents and conditions: (a) Propionyl chloride, AlCl , dichloromethane,
3
o
0-5 C, 16 h; (
b) 30% Hydrogen peroxide, glacial acetic acid, reflux, 8 h.
Scheme 1. Synthesis of the key intermediates 2a and 2b
.
Reagents and conditions:
(a) 37% Aq. formaldehyde, piperidine, glacial acetic
acid, reflux, 12 h; (b) Hydrazine hydrate, absolute ethanol, reflux, 3 h.
Scheme 2. Synthesis of the key intermediates 3a,b and 4a,b.

New Pyrazoles as Potential Anti-inflammatory Agents
817
Reagents and conditions:
(a) Benzyl chloride or 4-chlorobenzyl chloride, K CO , absolute ethanol, reflux, 15 h;
2 3
(b) Phenacyl bromide or 4-chlorophenacyl bromide, K CO , absolute ethanol, reflux, 15 h; (c) Benzoyl chloride or
2 3
4-chlorobenzoyl chloride, K CO , absolute ethanol, reflux, 15 h; (d) P-chlorosulfonyl chloride, K CO , absolute
2 3 2 3
ethanol, reflux, 15 h; (e) Pyridine, reflux, 1 h.
Scheme 3. Synthesis of compounds 5a-d
,
6a-d, 7a-d, 8a,b, and 10a,b.
As illustrated in scheme 5, base catalyzed hydrolysis These derivatives 16a
of the previously synthesized ester derivatives 14a without further purification with secondary amines,
has been carried out via refluxing them with potassium named piperidine or morpholine, in the presence of a
hydroxide in methanol to produce the expected corres- catalytic amount of triethylamine to yield the amide
ponding free acids 15a , respectively. Furthermore, derivatives 17a . The structures of the newly syn-
compounds 15a reacted with thionyl chloride to thesized compounds were elucidated by elemental
yield the unstable acid chloride derivatives 16a
,b were reacted directly in situ,
,b
,b
-d
,b
1
13
,
b
.
analyses and spectral data [IR, H-NMR, C-NMR

818
N. M. A.-E. Gawad et al.
o
Reagents and conditions:
zine or 4-methoxyphenylhydrazine, triethylamine, absolute ethanol, reflux 24 h; (
hydrazinylbenzenesulfonamide, triethylamine, absolute ethanol, reflux 24 h.
(
a
) Diethyl oxalate, NaH, dry toluene, 60 C, 2 h; (
b
) Phenylhydra-
c) 4-
Scheme 4. Synthesis of compounds 11a,b, 12a-d, and 14a,b.
and mass spectra].
Concerning the dihydropyrazole derivatives
and 10 it has been noticed that the 4-chlorophenyl
compounds 5c 6c 6d, and 8b have shown consider-
5, 6, 8
,
,
Anti-inflammatory activity
The newly synthesized compounds, indomethacin able anti-inflammatory effect compared to their unsub-
and celecoxib as reference standards were evaluated stituted analogues. Moreover, the sulfonyl derivatives
for in vivo anti-inflammatory activity at a 25 mg/kg 6d 8b, and 10b have shown more anti-inflammatory
,
body weight single dose using the standard acute car- effect than their sulfanyl analogues. On the other
rageenan-induced paw edema method in rats reported hand, the reverse was true for the sulfanyl derivatives
by Winter et al. (Winter et al., 1962, 1963). The employ- 5c and 6c, which have shown better anti-inflamma-
ed technique is based on the ability of the tested com- tory effect than their sulfonyl analogues.
pounds to inhibit the edema produced in the hind paw
of the rat after injection of carrageenan.
As for the pyrazole derivatives 12
, 14, 15 and 17, it
has been noticed that the sulfonyl derivatives 14b
,
The inhibitory effect of the tested compounds on the 17b, and 17d have shown better anti- inflammatory
carrageenan induced edema in rats was illustrated in effect than their sulfanyl analogues. Moreover, the
Table I in comparison with indomethacin and celecoxib incorporation of the sulfonamide moiety in compounds
which were used as reference drugs. From the obtained 14b
results, it has been revealed that eleven compounds inflammatory activity more than the methoxy moiety
5c 6c 6d 8b 10b 12a 12c 14a 14b 17b, and 17d and even more than the unsubstituted phenyl ana-
showed anti-inflammatory activity comparable to or logues, a concept that was derived from one of the
slightly lower than the reference drugs. used reference drug, celecoxib.
, 17b, and 17d made a positive impact on the anti-
,
,
,
,
,
,
,
,
,

New Pyrazoles as Potential Anti-inflammatory Agents
819
Reagents and conditions:
(a) KOH, methanol, reflux, 3 h; (b) Thionyl chloride, CH Cl ,
2 2
gentle reflux, 45 min; (c) piperidine or morpholine, TEA, CH Cl , 8 h, R.T.
2 2
Scheme 5. Synthesis of compounds 15a,b, 16a,b, and 17a-d.
reported method by Meshali et al. (Meshali et al.,
The analgesic effect of the most active anti-inflam- 1983). The ulcer index was calculated according to the
matory derivatives 5c 12a 12c 14a, and 17d was method of Robert et al. (Robert et al., 1968).
screened using the reported method of -benzoqui- The results of the ulcer index of the reference drugs
none induced writhing in mice by Okun et al. (Okun and the tested compounds were tabulated in Table III.
et al., 1963). It was noticed that compounds 5c 8b 12a 12c 14a
Analgesic activity
,
,
,
p
,
,
,
,
,
The results were recorded in Table II. From the ob- and 14b have shown a considerable gastric safety
tained data, it was noticed that all the tested com- profile when compared to celecoxib as a reference
pounds have shown good analgesic activity, equal to or drug, yet all the tested compounds have shown less
even higher than indomethacin or equal to celecoxib.
gastric ulcer than indomethacin. Furthermore, the
sulfanylphenyl pyrazole derivatives with a protective
ester side chain 12a 12c, and 14a have displayed
remarkable gastric protection. On the other hand, the
15a, and 17b as well as indome- sulfanylphenyl pyrazole derivative 15a has shown the
thacin and celecoxib was evaluated following the highest ulcer index value, which may be attributed to
,
Acute ulcerogenicity study
The ulcerogenic liability of compounds 5c
, 7c, 8b,
12a 12c 14a 14b
,
,
,
,

820
N. M. A.-E. Gawad et al.
Table I. Percentage inhibition of indomethacin, celecoxib
and the new pyrazole derivatives on carragenan-induced
edema of the hind paw rats (n = 6)
Table III. Ulcerogenic effect of indomethacin, celecoxib
and some new pyrazole derivatives in rats (25 mg/kg b.wt,
n = 5)
% Inhibition
% Incidence Average no. Average Ulcer
Cpd. No.
Cpd.
No.
Dose
divided by 10
of ulcer
severity index
mg/kg
3 h
4 h
0
Control
Indomethacin
Celecoxib
5c
0
10
8
0
0
0
Control
Indomethacin
Celecoxib
4a
0
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
c
5.7
2
1
16.7
11.2
10.8
10.9
6.1
61.86
85.06
22.29
41.87
62.05
47.47
89.64
53.43
45.90
65.18
41.93
58.80
27.83
40.72
65.24
39.04
53.31
59.16
41.57
84.22
66.27
38.31
87.65
40.48
78.73
85.36
74.52
61.27
38.92
73.01
41.39
63.96
c
1.2
1
80.07
30.28
10.19
8
1.8
1.8
0.8
0.8
1.2
1.8
3.6
3
8b
8
1.1
1.3
1
4b
b
12a
4
5a
56.41
a
12c
4
5.8
5b
42.06
c
14a
6
1.1
1.2
1.3
1.2
8.3
5c
82.26
a
14b
8
11
5d
42.39
a
15a
10
10
14.9
14.2
6a
40.03
b
17b
6b
55.86
c
6c
65.17
c
6d
70.76
16.76
29.24
the presence of an acidic carboxylic side chain.
In conclusion, eleven compounds 5c 6c 6d
10b 12a 12c 14a 14b 17b, and 17d showed anti-
7a
,
,
, 8b,
7b
,
,
,
,
,
b
7c
55.26
inflammatory activity comparable to or slightly lower
than the reference drugs, reaching about 82% inhibi-
tion with a considerable gastric safety profile. The
compounds that showed significant anti-inflammatory
activity possessed also an excellent analgesic activity,
7d
33.30
a
8a
45.62
c
8b
76.62
10a
10b
12a
12b
12c
12d
14a
14b
15a
15b
17a
17b
17c
17d
22.67
c
69.99
especially compounds 5c, 12a, 12c, 14a, and 17c.
c
65.22
31.76
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67.80
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