Synthesis of 4-alkyl-1,2-diphenyl-3,5-dioxopyrazolidines possessing aryl methylsulfonyl and sulfonamide pharmacophores for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1002/jhet.5570390631

A group of 1,2-diphenyl-3,5-dioxopyrazolidines possessing a methylsulfonyl (11) or sulfonamide (15) substituent at the para position of the N¹-phenyl ring, in conjunction with a hydrogen, methyl or fluoro substituent at the para position of the

Full text of DOI:10.1002/jhet.5570390631

Nov-Dec 2002 Synthesis of 4-Alkyl-1,2-diphenyl-3,5-dioxopyrazolidines Possessing
Aryl Methylsulfonyl and Sulfonamide Pharmacophores for Evaluation
as Selective Cyclooxygenase-2 (COX-2) Inhibitors
1309
M. Abdur Rahim, P. N. Praveen Rao, and Edward E. Knaus*
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
Received May 13, 2002
A group of 1,2-diphenyl-3,5-dioxopyrazolidines possessing a methylsulfonyl (11) or sulfonamide (15)
substituent at the para position of the N1-phenyl ring, in conjunction with a hydrogen, methyl or fluoro sub-
stituent at the para position of the N2-phenyl ring, and a C-4 n-butyl, methyl or spiro-cyclopropyl substituent
were synthesized for evaluation as potential cyclooxygenase-2 (COX-2) selective inhibitor antiinflammatory
agents. The title compounds 11and 15 were synthesized using a four-step and a three-step reaction sequence,
respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative
(6, 12) gave the corresponding azobenzene product (8, 13) which was reduced with zinc dust in the presence
of ammonium chloride to yield the corresponding hydrazobenzene (9, 14). Base-catalyzed condensation of9
and 14 with a malonyl dichloride (10) afforded the target 3,5-dioxopyrazolidine product (11, 15). 4-n-Butyl-
1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioxopyrazolidine (11a) was a selective COX-1 inhibitor (COX-1
IC50 = 8.48 mM). In contrast, 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyrazolidine (11b,
COX-2 IC50 = 11.45 mM) and 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-dioxopyrazoli-
dine (11c, COX-2 IC50 = 9.86 mM) were about 46-fold and 20-fold less selective COX-2 inhibitors respec-
tively, relative to the reference drug celecoxib.
J. Heterocyclic Chem., 39, 1309(2002).
Introduction.
meloxicam, celecoxib and rofecoxib are 2.0, 6.6 and 35.5,
respectively [1]. The sulfonamido and methylsulfonyl
pharmacophores present in celecoxib and rofecoxib are
believed to induce COX-2 selectivity by insertion into the
secondary pocket present in the COX-2 binding site that is
absent in COX-1. This secondary pocket present in COX-2
is formed by a conformational change attributed to the
The design of agents to relieve pain and inflammation
associated with arthritic diseases has undergone continual
evolution resulting in the development of more efficacious
classes of drugs that exhibit fewer adverse side effects. In
this regard, structure-activity data for a 1,3-dicarbonyl
class of compounds illustrated by the discontinued drug
phenylbutazone 1 was used for the subsequent design of a
new enolic class of drugs called "oxicams" represented by
meloxicam 2 with reduced gastrointestinal ulcerogenic
effects [1]. A single cyclooxygenase (COX) enzyme,
which catalyzed the bioconversion of arachidonic acid to
prostaglandins and thromboxanes, was originally believed
to be responsible for both the therapeutic and adverse gas-
tric ulceration effects associated with the use of non-
steroidal antiinflammatory drugs (NSAIDs) prior to the
discovery that there are two COX isozymes currently
called COX-1 and COX-2 [2,3]. Thus, the synthesis of
COX-2 is induced by mitogenic and proinflammatory
stimulants [4] that leads to inflammatory processes [5]
whereas, the constitutively expressed COX-1 isozyme is
implicated in important physiological processes that
include gastroprotection and vascular homeostasis [6].
These observations suggested that a drug which selectively
inhibits the COX-2 isozyme would retain the desired clini-
cal antiinflammatory effect, but be devoid of the ulcero-
genic side effects associated with inhibition of COX-1, by
non-selective NSAIDs that inhibit both COX-1 and COX-
2. This drug design concept has been validated by post-
market clinical studies that attest to the efficacy and
improved safety of the selective COX-2 inhibitors cele-
coxib 3 and rofecoxib 4 [7,8]. The COX-2 selectivity
indices (COX-1/COX-2 isozyme inhibition ratio) for
523
presence of isoleucine (Ile ) in COX-1 relative to the
523
smaller valine (Val ) in COX-2 [9]. It was anticipated
that incorporation of a methylsulfonyl or sulfonamido sub-
stituent at the para-position of one of the phenyl rings of
phenylbutazone may confer COX-2 selectivity and reduce
the adverse gastrointestinal effects of phenylbutazone. We
now report the synthesis, in vitro COX-1/COX-2 enzyme
inhibition data and some in vivo antiinflammatory and

1310
M. A. Rahim, P. N. P. Rao, and E. E. Knaus
Vol. 39
analgesic activity data for a class of 1,2-diphenyl-3,5-diox-
opyrazolidines possessing a C-4 methyl, n-butyl or spiro-
cyclopropyl substituent in conjunction with either a para-
methylsulfonyl or sulfonamido substituent on one phenyl
ring and either a para-hydrogen, methyl or fluoro sub-
stituent on the other phenyl ring.
moiety (8a-c) using zinc dust in the presence of ammo-
nium chloride afforded the corresponding 4-methylsul-
fonylhydrazobenzene products 9a-c. Condensation of the
1
4-methylsulfonylhydrazobenzene compounds 9a-c (R =
H, Me, F) with either 2-n-butylmalonyl dichloride (10a),
or 2-methylmalonyl dichloride (10b), in the presence of
pyridine afforded the respective 4-alkyl-1-(4-methylsul-
fonylphenyl)-2-phenyl-3,5-dioxopyrazolidine products
11a-f (32-61 % range). In contrast, the related compounds
11g-i possessing a C-4 spiro-cyclopropyl ring system
could not be prepared using pyridine as a base for the con-
densation-cyclization reaction. Alternatively, reaction of
the 4-methylsulfonylhydrazobenzenes 9a-c with 1,1-
cyclopropanedicarbonyl chloride (10c) using solid potas-
sium carbonate as a base afforded the target products 11g-i
in moderate yields (15-20 % range).
Chemistry.
A group of 1-(4-methylsulfonylphenyl)-2-phenyl-4-
alkyl-3,5-dioxopyrazolidines were synthesized using a
modification of literature procedures [10-12] by the reac-
tion sequence illustrated in Scheme 1. Accordingly, the
acid catalyzed condensation of the nitrosobenzene com-
pounds 5a-c with 4-(methylthio)aniline (6) afforded the
respective 4-methylthioazobenzene products 7a-c.
Oxidation of the methylthio group (7a-c) using potassium
peroxymonosulfate gave the corresponding methylsul-
fonyl derivatives (8a-c). Subsequent reduction of the azo
[a] Reagents and conditions: (i) AcOH, 100 °C, 20 minutes; (ii) zinc dust,
saturated aqueous NH Cl, acetone:MeOH (1:1, v/v); (iii) pyridine, ben-
4
zene, reflux, 2 hours.
The structurally related 1-(4-aminosulfonylphenyl)-2-
phenyl-3,5-dioxo-4-n-butylpyrazolidines 15a-b, that pos-
sess a sulfonamide COX-2 pharmacophore, were prepared
using the reaction sequence illustrated in Scheme 2 where
sulfanilamide (12) was used to prepare the 4-aminosul-
fonylazobenzene intermediates 13a-b.
[a] Reagents and conditions: (i) AcOH, 100 °C, 20 minutes; (ii) OxoneÒ
(potassium peroxymonosulfate), MeOH, H O, 25 °C, 16 hours; (iii) zinc
2
dust, saturated aqueous NH Cl, acetone:MeOH (1:1, v/v); (iv) pyridine,
4
benzene, reflux, 2 hours (11a-f), K CO , benzene, reflux, 2 hours (11g-i).
2
3

Nov-Dec 2002
Synthesis of 4-Alkyl-1,2-diphenyl-3,5-dioxopyrazolidines
1311
Biological Results.
compounds 11d-f are inactive COX inhibitors. The para
2
1
N -phenyl substituent (R = hydrogen, methyl, fluoro) was
a determinant of COX-1 or COX-2 selectivity when one of
the COX isozymes was inhibited. For example, in the
methylsulfonyl group of compounds, compound 11a hav-
A group of 1,2-diphenyl-3,5-dioxopyrazolidines were
prepared to investigate the effect of methylsulfonyl (11)
and sulfonamido (15) substitution at the para-position of
1
the N -phenyl ring, in conjunction with a hydrogen,
2
1
ing a N -phenyl substituent (R = hydrogen) was a selec-
1
methyl or fluoro substituent (R ) at the para-position of
1
tive COX-1 inhibitor whereas, compounds 11b-c (R =
2
the N -phenyl ring and a C-4 n-butyl, methyl or spiro-
methyl, fluoro) were selective COX-2 inhibitors. The
2
cyclopropyl substituent (R ), on in vitro COX-1 and COX-
1
nature of the para N -phenyl substituent was also a deter-
2 inhibitory activities and COX-2 selectivity (see Table 1),
and in vivo antiinflammatory and analgesic activities.
Structure-activity relationships acquired for the methyl-
sulfonyl group of compounds showed that a C-4 n-butyl
substituent (11a-c) was required for inhibition of COX-1
or COX-2 since compounds possessing a C-4 methyl (11d-
f), or spiro-cyclopropyl (11g-i), did not inhibit the COX-1
or COX-2 isozyme at a test compound concentration of
100 mM (see data in Table 1). The 3,5-dioxopyrazolidine
minant of COX selectivity since the methylsulfonyl com-
pound 11b was a selective COX-2 inhibitor while the cor-
responding sulfonamide compound 15b was an inactive
COX-2 inhibitor (IC > 100 mM).
50
The two selective COX-2 inhibitors 4-n-butyl-1-(4-
methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyrazolidine
(11b, COX-2 selectivity index > 8.73) and 4-n-butyl-1-(4-
methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-dioxopyra-
zolidine (11c, COX-2 selectivity index > 20.27) were eval-
uated as antiinflammatory agents at three and five hours
post drug administration using a carrageenan-induced rat
paw edema assay. Compound 11b exhibited moderate anti-
inflammatory activity where inflammation was inhibited
by 11.1 ± 0.1% and 19.9 ± 3.8% at 3 and 5 hours post drug
administration respectively, relative to the reference drug
celecoxib (79.9 ± 1.9 and 58.2 ± 1.8 % inhibition at 3 and
5 hours post drug administration, respectively) for a 50
mg/kg oral dose. In contrast, the more selective COX-2
inhibitor 11c did not exhibit oral antiinflammatory activity.
However, 4-n-butyl-1-(4-methylsulfonylphenyl)-2-
phenyl-3,5-dioxopyrazolidine (11a, COX-1 selectivity
index = 8.48) enhanced inflammation by 7.0 ± 1.0 and 19.0
± 2.5% at 3 and 5 hours post drug administration, respec-
tively. This induction of inflammation by 11a could be
attributed to oxidative damage caused by the generation of
phenylbutazone radicals formed via the peroxidase action
of the COX enzyme. This explanation is consistent with
the observation that factors not involved in the COX path-
way are involved in aggravating inflammatory conditions
2
ring system, which has a single alkyl substituent at C-4 (R
= n-butyl, methyl) also possesses an acidic C-4H which
could give rise to an enolic tautomer, may resemble the
enolic moiety in meloxicam (2). In this regard, one could
rationalize the inability of the C-4 spiro-cyclopropyl com-
pounds 11g-i, which cannot form an enolic tautomer, to
inhibit COX-1 or COX-2. However, the requirement of an
enolizable C-4H is unclear since the C-4 butyl compounds
11a-c inhibit the COX enzyme, but the C-4 methyl
Table 1
In Vitro COX-1 and COX-2 Enzyme Inhibition Data
IC , mM [a]
COX-1
COX-2
S.I.[b]
1
50
[13]. Compounds 15a-b having a N -(4-aminosul-
1
2
Compound
R
R
COX-2
fonylphenyl) substituent were also inactive antiinflamma-
tory agents in this assay.
11a
H
n-Bu
n-Bu
n-Bu
Me
Me
Me
CP[c]
CP
CP
n-Bu
n-Bu
8.48
> 100
11.45
9.86
¾
11b
11c
Me
F
> 100
> 200
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 10.73
22.9
> 8.73
> 20.27
Compounds 11b and 11c were also evaluated as anal-
gesic agents using a rat 4% sodium chloride-induced
abdominal constriction assay employing a 50 mg/kg
intraperitoneal dose. Compound 11b was an active anal-
gesic agent where abdominal constriction was inhibited by
68.6 ± 7.0 and 16.2 ± 6.9% at 30 and 60 minutes post drug
administration, respectively relative to the reference drug
celecoxib (31.7 ± 9.6 and 62.0 ± 7.3% inhibition at 30 and
60 minutes post drug administration, respectively).
Compound 11c was a less potent analgesic agent (22.2 ±
9.0 and 18.9 ± 9.5% inhibition at 30 and 60 minutes,
respectively).
11d
11e
11f
H
Me
F
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
0.0567
¾
¾
¾
¾
¾
¾
¾
¾
11g
H
11h
11i
Me
F
15a
H
15b
Celecoxib
Me
404
[a] Values are mean values of two determinations where the deviation
from the mean is < 10% of the mean value; [b] In vitro COX-2 selectivity
index (IC COX-1/COX-2); [c] CP = spiro-cyclopropyl.
50

1312
M. A. Rahim, P. N. P. Rao, and E. E. Knaus
Vol. 39
EXPERIMENTAL
nitrogen, washed with water (50 ml), and dried under a stream of
nitrogen to yield 9a (0.59 g, 75%); mp 180-181 °C, Lit mp 179
°C [10]; ir (potassium bromide): 3325 (NH), 1300, 1142 (SO2)
Melting points were determined using a Buchi capillary appa-
ratus and are uncorrected. Infrared (IR) spectra were recorded
using a Nicolet 550 Series II Magna FT-IR spectrometer. Nuclear
magnetic resonance (1H nmr, 13C nmr) spectra were recorded on
a Bruker AM-300 spectrometer. 13C nmr was acquired using the
J modulated spin echo technique where methyl and methine car-
bons appear as positive peaks and methylene and quaternary car-
bon resonances appear as negative peaks. Elemental analyses
were performed for C, H, and N (Micro Analytical Service
Laboratory, Department of Chemistry, University of Alberta).
Silica gel column chromatography was performed using Merck
silica gel 60 ASTM (70-230 mesh). 4-(Methyl)nitrosobenzene
(5b) and 4-(fluoro)nitrosobenzene (5c) were prepared according
to a literature procedure [14]. 2-n-Butylmalonyl dichloride (10a),
2-methylmalonyl dichloride (10b) and 1,1-cyclopropanedicar-
bonyl chloride (10c) were prepared according to a literature pro-
cedure [15]. All other reagents were purchased from Aldrich
Chemical (Milwaukee, WI). In vitro COX-1 and COX-2 inhibi-
tion assays were performed using enzyme immunoassay (EIA)
kits purchased from Cayman Chemical, Ann Arbor, MI. Male
Sprague-Dawley rats, used in the anti-inflammatory and anal-
gesic screens, were supplied by Animal Health Services,
University of Alberta. All experiments involving animals were
carried out using protocols approved by the Animal Welfare
Committee, University of Alberta.
1
cm-1; H nmr (deuteriochloroform): d 3.02 (s, 3H, SO2CH3),
5.76 (s, 1H, NH), 6.05 (s, 1H, NH), 6.81 (d, J = 8.6 Hz, 2H,
Harom), 6.90 (dd, J = 6.1 Hz, 6.1 Hz, 1H, Harom), 6.96 (d, J = 8.9
Hz, 2H, Harom), 7.22-7.27 (m, 2H, Harom), 7.76 (d, J = 8.6 Hz,
2H, Harom).
The physical and spectral data for compounds 9b-c, which
were prepared according to the procedure described above for the
synthesis of 9a except that 4-(methyl)nitrosobenzene (5b) and 4-
(fluoro)nitrosobenzene (5c) were used in place of nitrosobenzene
(5a), are listed below.
4-Methylsulfonyl-4'-methylhydrazobenzene (9b).
Compound 9b was obtained by reduction of 8b in 77% yield;
mp 150-151 °C, Lit mp 147 °C [10]; ir (potassium bromide):
3490 (NH), 1293, 1145 (SO2) cm-1; 1H nmr (deuteriochloroform
+ DMSO-d6): d 2.19 (s, 3H, CH3), 2.93 (s, 3H, SO2CH3), 5.98 (s,
1H, NH), 6.65 (d, J = 8.5 Hz, 2H, Harom), 6.83 (s, 1H, NH), 6.87
(d, J = 8.9 Hz, 2H, Harom), 6.95 (d, J = 8.5 Hz, 2H, Harom), 7.63
(d, J = 8.9 Hz, 2H, Harom). Compound 9b was used immediately
for the preparation of 11b, 11e or 11h as it decomposes slowly on
standing.
4-Methylsulfonyl-4'-fluorohydrazobenzene (9c).
Compound 9c was obtained by reduction of 8c in 69% yield;
mp 159-160 °C; ir (potassium bromide): 3342 (NH), 1300, 1146
(SO2) cm-1; 1H nmr (deuteriochloroform): d 3.02 (s, 3H,
SO2CH3), 5.72 (s, 1H, NH), 6.07 (s, 1H, NH), 6.74-6.80 (m, 2H,
Harom), 6.90-6.98 (m, 4H, Harom), 7.76 (d, J = 8.9 Hz, 2H, Harom).
Compound 9c was used immediately for the preparation of 11c,
11f or 11i as it decomposes slowly on standing.
4-Methylthioazobenzene (7a).
Nitrosobenzene (1.07 g, 10.0 mmole) was dissolved in glacial
acetic acid (10.0 ml) with slight warming and this solution was
added to 4-(methylthio)aniline (1.39 g, 10.0 mmole) in glacial
acetic acid (4.0 ml). The reaction was allowed to proceed with
gentle heating on a steam bath for 20 minutes, the reaction mix-
ture was poured into water (50 ml), the solid was collected by fil-
tration after 5 minutes and washed with water (15 ml),
Recrystallization from aqueous ethanol gave 7a (1.72 g, 75%);
mp 81-82 ºC, Lit mp 83-84 ºC [16]; ir (potassium bromide): 1488
(N=N) cm-1; 1H nmr (deuteriochloroform): d 2.69 (s, 3H, SCH3),
7.39 (d, J = 8.9 Hz, 2H, Harom), 7.49-7.57 (m, 3H, Harom), 7.89-
7.95 (m, 4H, Harom).
4-n-Butyl-1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioxopyra-
zolidine (11a).
Pyridine (0.5 ml), and then 2-n-butylmalonyl dichloride (0.45 g,
2.3 mmole), was added consecutively to a solution of 9a (0.50 g,
1.9 mmole) in benzene (10 ml) with stirring. The reaction was
allowed to proceed for 30 minutes at room temperature, and then at
reflux for 4 hours. The cold reaction mixture was washed with 1 N
HCl (10 ml) and extracted with saturated NaHCO3 solution (3 x 20
ml). This aqueous extract was then acidified with 2 N hydrochloric
acid to afford a solid precipitate which was recrystallized from
ethanol to yield 11a (0.31 g, 42%); mp 159-160 °C; ir (potassium
bromide): 1728 (CO), 1304, 1147 (SO2) cm-1; 1H NMR (deuteri-
ochloroform): d 0.91 (t, J = 7.3 Hz, 3H, CH2CH3), 1.35-1.41 (m,
4H, CH2CH2CH2CH3), 2.05-2.09 (m, 2H, CH2CH2CH2CH3),
3.02 (s, 3H, SO2CH3), 3.45 (t, J = 5.8 Hz, 1H, H-4), 7.22–7.40 (m,
5H, Harom), 7.54 (d, J = 9.1 Hz, 2H, Harom), 7.90 (d, J = 9.1 Hz, 2H,
Harom); 13C nmr (deuteriochloroform): d 13.68 (CH2CH3), 22.43,
27.96 (CH2), 44.48 (SO2CH3), 46.15 (C-4), 121.80, 122.00,
127.22, 128.38, 129.31 (Carom-H), 135.84 (Carom-SO2CH3),
137.82, 140.13 (Carom-N), 170.05, 170.37 (CO).
4-Methylsulfonylhydrazobenzene (9a).
A solution of oxone (6.15 g, 10.0 mmole) in water (30 ml) was
added slowly to a solution of 7a (1.14 g, 5.0 mmole) in methanol
(10 ml) at 0 °C, and the reaction mixture was stirred for 16 hours
at room temperature. Removal of the solvent in vacuo, dissolu-
tion of the residue in water (20 ml), extraction with ethyl acetate
(30 ml), washing the organic layer consecutively with water (30
ml) and brine (30 ml), drying the ethyl acetate fraction (sodium
sulfate), and removal of the solvent in vacuo gave 4-methylsul-
fonylazobenzene (8a) as a light brown solid (1.04 g, 80%) which
was used without further purification in the next step. Compound
8a (0.80 g, 3.0 mmole) was dissolved in a minimum volume of
acetone-methanol (1:1, v/v), a saturated aqueous solution of
ammonium chloride (2.0 ml) was added, and additional acetone-
methanol (1:1, v/v) was added to dissolve compound 8a that had
precipitated. A sufficient quantity of zinc dust was added with
stirring to produce a colorless solution, the reaction mixture was
filtered, and the filtrate was poured into ice-water (50 ml). The
white solid that precipitated was collected by filtration under
Anal. Calcd. for C20H22N2O4S: C, 62.16; H, 5.74; N, 7.25.
Found: C, 62.08; H, 5.71; N, 7.26.
Compounds 11b-f, for which physical and spectral data are
listed below, were prepared by reaction of a 4-(methylsul-
fonylphenyl)hydrazobenzene (9a-c) with a malonyl dichloride
(10a-c) using a procedure similar to that described above for the
synthesis of 11a.

Synthesis of 4-Alkyl-1,2-diphenyl-3,5-dioxopyrazolidines
1313
4-n-Butyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopy-
razolidine (11b).
Anal. Calcd. for C17H15FN2O4S.H2O: C, 53.67; H, 4.51; N,
7.36. Found: C, 53.72; H, 4.39; N, 7.10.
Compound 11b was obtained by the reaction of 9b with 2-n-
butylmalonyl dichloride in 51% yield; mp 144-145 °C; ir (potas-
sium bromide): 1727 (CO), 1296, 1153 (SO2) cm-1; 1H nmr (deu-
teriochloroform): d 0.90 (t, J = 7.0 Hz, 3H, CH2CH3), 1.26-1.46
(m, 4H, CH2CH2CH2CH3), 2.06-2.13 (m, 2H, CH2CH2CH2CH3),
2.31 (s, 3H, tolyl-CH3), 3.02 (s, 3H, SO2CH3), 3.43 (t, J= 5.8 Hz,
1H, H-4), 7.13-7.19 (m, 4H, Harom), 7.53 (d, J = 8.9 Hz, 2H,
Harom), 7.89 (d, J = 8.9 Hz, 2H, Harom).
5-(4-Methylsulfonylphenyl)-6-phenyl-5,6-diazaspiro[2.4]hep-
tane-4,7-dione (11g).
Potassium carbonate (1.0 g), and then cyclopropane-1,1-dicar-
bonyl dichloride (10c, 0.77 g, 4.6 mmole), was added to a solution
of 9a (1.0 g, 3.8 mmole) in benzene (20 ml) with stirring, and the
reaction was allowed to proceed for 4 hours at reflux. The cooled
mixture was quenched with water (20 ml), extracted with ethyl
acetate (50 ml), the organic layer was washed with brine (20 ml),
the organic fraction was dried (sodium sulfate), filtered, and the
solvent was removedin vacuo. The crude product was purified by
silica gel column chromatography using ethyl acetate:hexane (1:1,
v/v) as eluant to afford 11g as a colorless solid (0.27 g, 20 %
yield); mp 101-103 °C; ir (potassium bromide): 1728 (CO), 1304,
1154 (SO2) cm-1; 1H nmr (deuteriochloroform): d 1.98 (s, 4H,
CH2), 3.02 (s, 3H, SO2CH3), 7.21-7.28 (m, 2H, Harom), 7.34-7.41
(m, 3H, Harom), 7.59 (d, J = 8.9 Hz, 2H, Harom), 7.91 ( d, J = 8.9
Hz, 2H, Harom); 13C nmr (deuteriochloroform): d 22.63 (CH2),
26.91 (C-4), 44.50 (SO2CH3), 121.60, 121.80, 126.94, 128.37,
129.25 (Carom-H), 136.40 (Carom-SO2CH3), 137.51, 140.70
(Carom-N), 170.82, 171.20 (CO).
Anal. Calcd. for C21H24N2O4S: C, 62.98; H, 6.04; N, 6.99.
Found: C, 63.26; H, 6.10; N, 7.01.
4-n-Butyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-
dioxopyrazolidine (11c).
The title compound 11c was synthesized by the reaction of 9c
with 2-n-butylmalonyl dichloride in 61% yield; mp 75-76 °C; ir
1
(potassium bromide): 1732 (CO), 1300, 1153 (SO2) cm-1; H
nmr (deuteriochloroform): d 0.91 (t, J = 7.3 Hz, 3H, CH2CH3),
1.31-1.51 (m, 4H, CH2CH2CH2CH3), 2.07-2.14 (m, 2H,
CH2CH2CH2CH3), 3.04 (s, 3H, SO2CH3), 3.45 (t, J = 5.8 Hz,
1H, H-4), 7.04-7.10 (m, 2H, Harom), 7.27-7.33 (m, 2H, Harom),
7.53 (d, J = 8.9 Hz, 2H, Harom), 7.92 (d, J = 8.9 Hz, 2H, Harom).
Anal. Calcd. for C20H21FN2O4S•1/2H2O: C, 58.09; H, 5.32;
N, 6.77. Found: C, 58.05; H, 5.02; N, 6.69.
Anal. Calcd. for C18H16N2O4S•1/2H2O: C, 59.16; H, 4.65; N,
7.67. Found: C, 59.17; H, 4.22; N, 7.48.
Compounds 11h-i, for which physical and spectral data are
listed below, were prepared by reaction of a 4-(methylsul-
fonylphenyl)hydrazobenzene (9b-c) with cyclopropane-1,1-
dicarbonyl dichloride (10c) using a procedure similar to that
described for the synthesis of 11g above.
4-Methyl-1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioxopyra-
zolidine (11d).
Compound 11d was obtained by reaction of 9a with 2-methyl-
malonyl dichloride in 46% yield; mp 104-105 °C; ir (potassium bro-
-1 1
mide): 1721 (CO), 1320, 1162 (SO2) cm ; H nmr (deuteriochloro-
5-(4-Methylsulfonylphenyl)-6-(4-tolyl)-5,6-diazaspiro[2.4]hep-
tane-4,7-dione (11h).
form): d 1.62 (d, J = 7.6 Hz, 3H, C-4 CH3), 3.02 (s, 3H, SO2CH3),
3.48 (q, J = 7.6 Hz, 1H, H-4), 7.22-7.40 (m, 5H, Harom), 7.54 (d, J =
8.9 Hz, 2H, Harom), 7.90 (d, J = 8.9 Hz, 2H, Harom); 13C nmr (deu-
teriochloroform): d 11.94 (C-4 CH3), 41.07 (SO2CH3), 44.32 (C-4),
The title compound was synthesized by reaction of 9b with
10c in 15% yield; mp 98-100 °C; ir (potassium bromide): 1732
1
(CO), 1300, 1171 (SO2) cm-1; H nmr (deuteriochloroform): d
121.76, 121.96, 127.10, 128.21, 129.19 (Carom-H), 135.85 (Carom
-
1.97 (s, 4H, CH2), 2.32 (s, 3H, tolyl-CH3), 3.02 (s, 3H, SO2CH3),
7.16 (d, J = 8.6 Hz, 2H, Harom), 7.23 (d, J = 8.6 Hz, 2H, Harom),
7.58 (d, J = 8.5 Hz, 2H, Harom), 7.90 (d, J = 8.5 Hz, 2H, Harom).
Anal. Calcd. for C19H18N2O4S.2/3H2O: C, 59.67; H, 4.50; N,
7.32. Found: C, 59.30; H, 4.84; N, 6.84.
SO2CH3), 137.79, 140.09 (Carom-N), 170.30, 170.67 (CO).
Anal. Calcd. for C17H16N2O4S.3/4H2O: C, 57.04; H, 4.89; N,
7.82. Found: C, 57.16; H, 4.55; N, 7.41.
4-Methyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyra-
zolidine (11e).
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-5,6-diaza-
spiro[2.4]heptane-4,7-dione (11i).
Compound 11e was obtained by reaction of 9b with methyl-
malonyl dichloride in 32% yield; mp 198-199 °C; ir (potassium
1
bromide): 1720 (CO), 1304, 1153 (SO2) cm-1; H nmr (deuteri-
Compound 11i was obtained by reaction of9c with 10c in 19%
yield; mp 105-107 °C; ir (potassium bromide): 1732 (CO), 1300,
ochloroform): d 1.61 (d, J = 7.6 Hz, 3H, C-4 CH3), 2.32 (s, 3H,
tolyl-CH3), 3.02 (s, 3H, SO2CH3), 3.45 (q, J = 7.6 Hz, 1H, H-4),
7.12-7.20 (m, 4H, Harom), 7.54 (d, J = 8.9 Hz, 2H, Harom), 7.90
(d, J = 8.9 Hz, 2H, Harom).
Anal. Calcd. for C18H18N2O4S: C, 60.32; H, 5.06; N, 7.82.
Found: C, 60.48; H, 4.94; N, 7.82.
1
1153 (SO2) cm-1; H nmr (deuteriochloroform): d 1.99 (s, 4H,
CH2), 3.03 (s, 3H, SO2CH3), 7.05-7.10 (m, 2H, Harom), 7.23-7.58
(m, 2H, Harom), 7.57 (d, J = 8.6 Hz, 2H, Harom), 7.92 (d, J = 8.6
Hz, 2H, Harom).
Anal. Calcd. for C18H15N2O4: C, 57.75; H, 4.04; N, 7.48.
Found: C, 57.60; H, 4.36; N, 7.25.
4-Methyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-
dioxopyrazolidine (11f).
4-Aminosulfonylazobenzene (13a).
The title compound 11f was synthesized by the reaction of 9c
Nitrosobenzene (2.14 g, 20.0 mmole) was dissolved in glacial
acetic acid (20 ml) with slight warming, this solution was added to
4-aminobenzenesulfonamide (12, 3.44 g, 20.0 mmole) in glacial
acetic acid (8.0 ml), the reaction was allowed to proceed with gen-
tle heating on a steam bath for 20 minutes, and the cool reaction
mixture was poured into water (100 ml). After standing for 5 min-
utes, the solid was collected by filtration, washed with water, and
with methylmalonyl dichloride in 35% yield; mp 110-112 °C; ir
1
(potassium bromide): 1731 (CO), 1300, 1153 (SO2) cm-1; H
nmr (deuteriochloroform): d 1.63 (d, J = 7.6 Hz, 3H, C-4 CH3),
3.03 (s, 3H, SO2CH3), 3.47 (q, J = 7.6 Hz, 1H, H-4), 7.04-7.08
(m, 2H, Harom), 7.27-7.32 (m, 2H, Harom), 7.53 (d, J = 8.9 Hz,
2H, Harom), 7.92 (d, J = 8.9 Hz, 2H, Harom).

1314
M. A. Rahim, P. N. P. Rao, and E. E. Knaus
Vol. 39
recrystallized from aqueous ethanol to afford 13a (3.92 g, 75%);
mp 219-220 °C, Lit mp 220-221 °C [17]; ir (potassium bromide):
3325, 3280 (NH), 1307, 1153 (SO2) cm-1; 1H nmr (deuteriochlo-
roform + DMSO-d6): d 6.57 (s, 2H, NH2), 7.34-7.43 (m, 3H,
Harom), 7.78-7.82 (m, 2H, Harom), 7.84 (d, J = 8.6, 2H, Harom),
7.93 (d, J = 8.6 Hz, 2H, Harom); 13C nmr (deuteriochloroform +
DMSO-d6): d 110.10, 111.60, 118.00, 127.07, 128.50 (Carom–H),
131.94 (Carom-SO2NH2), 148.83, 152.50 (Carom-N).
according to the method previously reported [18].
Antiinflammatory Assay.
The test compounds were evaluated using the in vivo rat car-
rageenan-induced foot paw edema model reported previously [19].
Analgesic Assay.
Analgesic activity was determined using the 4% sodium chlo-
ride-induced writhing (abdominal constriction) assay as
described previously [20].
4-n-Butyl-1-(4-aminosulfonylphenyl)-2-phenyl-3,5-dioxopyra-
zolidine (15a).
Acknowledgements.
4-Aminosulfonylazobenzene (13a, 3.13 g, 12.0 mmole) was dis-
solved in a minimum quantity of acetone-methanol (1:1, v/v), and a
saturated solution of ammonium chloride (1.2 ml) was added with
stirring. Additional acetone-methanol (1:1, v/v) was added to dis-
solve13a that had precipitated. Zinc dust was added to this solution
with stirring until the solution turned colorless, and the reaction
mixture was filtered into ice-water. The white precipitate was col-
lected by filtration under nitrogen, washed with water and dried to
yield 14a (2.81 g, 89%), which was used without further purifica-
tion in the next reaction. Pyridine (1.0 ml), and then 2-n-butyl-
malonyl dichloride (1.0 g, 5.0 mmole), was added to a solution of
14a (1.0 g, 3.8 mmole) in benzene (20.0 ml), and the reaction mix-
ture was heated at reflux for 2 hours. The cooled reaction mixture
was quenched with water (20 ml), extracted with ethyl acetate (50
ml), the organic layer was washed with brine (20 ml), the organic
layer was dried (sodium sulfate), filtered, and the solvent was
removed in vacuo. The residue obtained was purified by silica gel
column chromatography using ethyl acetate:hexane (1:1, v/v) as
eluant to afford 15a as a colorless solid (0.77 g, 52% yield); mp 98-
99 °C; ir (potassium bromide): 3356, 3253 (NH), 1721 (CO), 1320,
We are grateful to the Canadian Institutes of Health Research
(MOP-14712) for financial support of this research and to
Rx&D-HRF/CIHR for a postdoctoral fellowship (to A.R.) and a
graduate scholarship (to P.R.).
REFERENCES AND NOTES
*
Correspondence to: E. E. Knaus, Email: eknaus@pharmacy.
ualberta.ca
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1
1162 (SO2) cm-1; H nmr (deuteriochloroform): d 0.82 (t, J = 7.3
Hz, 3H, CH2CH2CH2CH3), 1.27-1.41 (m, 4H, CH2CH2CH2CH3),
1.98-2.05 (m, 2H, CH2CH2CH2CH3), 3.35 (t, J = 5.8 Hz, 1H, H-4),
4.69 (s, 2H, SO2NH2), 7.12-7.30 (m, 5H, Harom), 7.57 (d, J = 8.9
Hz, 2H, Harom), 7.79 (d, J = 8.9 Hz, 2H, Harom).
Anal. Calcd. for C19H21N3O4S: C, 58.90; H, 5.46; N, 10.85.
Found: C, 58.74; H, 5.48; N, 10.46.
The physical and spectral data for compound 15b, which was
prepared using the same procedure described above for the
preparation of 15a except that 4-methylnitrosobenzene (5b) was
used in place of nitrosobenzene (5a), is listed below.
4-n-Butyl-1-(4-aminosulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyra-
zolidine (15b).
Compound 15b was obtained by reaction of 14b with 10a in 38
% yield; mp 172-173 °C; ir (potassium bromide): 3363, 3261
(NH), 1721 (CO), 1328, 1155 (SO2) cm-1; 1H nmr (deuteriochlo-
roform): d 0.91 (t, J = 7.0 Hz, 3H, CH2CH2CH2CH3), 1.31-1.51
(m, 4H, CH2CH2CH2CH3), 2.05-2.13 (m, 2H, CH2CH2CH2CH3),
2.31 (s, 3H, tolyl-CH3), 3.43 (t, J = 5.8 Hz, 1H, H-4), 4.80 (s, 2H,
SO2NH2), 7.13-7.20 (m, 4H, Harom), 7.48 (d, J = 8.9 Hz, 2H,
Harom), 7.87 (d, J = 8.9 Hz, 2H, Harom).
Anal. Calcd. for C20H23N3O4S: C, 59.83; H, 5.77; N, 10.47.
Found: C, 59.63; H, 5.76; N, 10.14.
Cyclooxygenase (COX) Inhibition Assays.
The in vitro ability of the test compounds to inhibit COX-1 and
COX-2 was determined using a COX-(ovine) inhibitor screening
kit (catalog no. 560101, Cayman Chemical, Ann Arbor, MI)
[19] P. Kumar and E. E. Knaus, Drug Design Del., 2, 145 (1987).
[20] J. K. Buolamwini and E. E. Knaus, Drug Design Del., 7, 19
(1990).