Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2003.10.027

Several chemical modifications in the N¹-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxymethyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively active against COX-2 enzyme in vitro.

Full text of DOI:10.1016/j.bmcl.2003.10.027

Bioorganic & Medicinal Chemistry Letters 14 (2004) 499–504
Polar substitutions in the benzenesulfonamide ring of celecoxib
afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors§
Sunil K. Singh,a,* P. Ganapati Reddy,a,y K. Srinivasa Rao,a Braj B. Lohray,a,{ P. Misra,b
Shaikh A. Rajjak,a Yeleswarapu K. Raoa,* and A. Venkateswarlua
aDiscovery Chemistry, Discovery Research-Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
bDiscovery Biology, Discovery Research-Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 24 August 2003; revised 10 October 2003; accepted 14 October 2003
Abstract—Several chemical modifications in the N1-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxy-
methyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively
active against COX-2 enzyme in vitro.
# 2003 Elsevier Ltd. All rights reserved.
The conventional non-steroidal anti-inflammatory
drugs (NSAIDs) exert their effect by inhibiting PGH
synthase (Cyclooxygenase/COX, responsible for arachi-
donic acid metabolism) leading to synthesis of pros-
taglandin (PG), a major mediator of inflammation.1
Two isoforms of this enzyme were identified early in the
last decade. While constitutive COX-1 is responsible for
the production of PGs involved in physiological func-
tions such as gastric cytoprotection, renal homeostasis
and platelate aggregation, the inducible COX-2 (pro-
duced by cytokines, mitogens and endotoxins in
inflammatory cells) is responsible for the elevated pro-
duction of prostaglandins during inflammation, causing
pain, fever and inflammatory disorders.2 The conven-
tional NSAIDs, being non selective for these two dif-
ferently acting enzymes, completely block the overall
production of prostaglandins and elicit analgesic, anti-
pyretic in addition to anti-inflammatory activities. But
their long term use often disrupts the beneficial pros-
taglandin regulated processes3 and causes life threaten-
ing gastrointestinal ulcers thereby limiting their
therapeutic potential.4
Though the search for safer NSAIDs has continued
over the years with little success, it took a new turn
when selective COX-2 inhibition was thought to have
exclusive control over inflammation process, leaving
other tissues unharmed even during chronic treatment.5
Proof of this new concept was soon realized when
selective COX-2 inhibitors, celecoxib6 and rofecoxib7
were introduced on the market respectively by Pfizer
and Merck. Soon after their success, other efficacious
COX-2 inhibitors such as valdecoxib,8 parecoxib
sodium9 and etoricoxib10 entered the segment as second
generation therapy. The popularity of COX-2 inhibitors
as anti-inflammatory agents coupled with their increas-
ing application in other ailments such as cancer (colon,
lung, breast, prostate, bladder, pancreatic, skin and
gastric),11 and Alzheimer’s disease12 is still attracting
fresh scientific input in this area.
The two major chemical classes of COX-2 inhibitors on
the market are: the acidic methanesulfonamide
(MeSO2NH) containing diphenyl ethers such as nime-
sulide 113 and sulfonamide (SO2NH2) or methylsulfonyl
(SO2Me) containing vicinal diarylheterocycles such as
celecoxib 2a,6 valdecoxib 4,8 rofecoxib 37 and etoricoxib
510 (Fig. 1).
Keywords: Polar substitutions; Benzenesulfonamide; 1,5-Diarylpyr-
azoles; COX-2 inhibitors.
§DRL Publication No. 283 A.
Though many diaryl heterocycles have been pursued by
different research groups while designing COX-2 inhi-
bitors, we focused our study on hitherto unreported
chemical modification of the N1-benzenesulfonamide
core of celecoxib, a multi billion dollar drug in this area.
By analogy with the enzyme-ligand co-crystal structure
* Corresponding authors. Tel.: +91-40-2304-5439; fax: +91-40-2304-
5438; e-mail: sunilkumarsingh@drreddys.com; koteswarraoy@
drreddys.com
y
Current address: Department of Chemistry, IIT, Madras, Chennai-
600 036, India.
{
Current address: Zydus Research Center, Gandhinagar Sarkhej,
Ahmedabad 380 015, India.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.10.027

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S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 499–504
Figure 1.
describing the binding of the benzenesulfonamide group
in the secondary COX-2 pocket,14 we wished to study
whether additional substitution on this group would
lead to better COX-2 selectivity. To the best of our
knowledge when we initiated the project, there was no
such report wherein the benzenesulfonamide ring at N1
was additionally substituted with polar groups such as
hydroxyalkyl or acylaminoalkyl which could provide
additional steric, electronic or even polar interactions
with the amino acid residues of the COX-2 enzyme
responsible for selectivity.15 Nor did we come across
any report where the entire benzenesulfonamide group
had been replaced by fused heterocycles in which sulfo-
nyl (–SO2–) or sulfamoyl (–HNSO2–) group forms a
part of the ring. Taking these aspects into consideration,
we synthesized two major classes of novel 1,5-dia-
rylpyrazoles, one by introducing hitherto unreported
groups such as CH2OH, MeCHOH, CH2NHAc and
their derivatives adjacent to SO2NH2 and SO2Me (7a)
and the other by replacing the benzenesulfonamide group
by fused heterocycles such as 1,1-dioxo 2,3-dihydro-
benzo[b]thiophen-5-yl, 1,1-dioxo 2,3-dihydrobenzo[d]-
isothiazol-5-yl and 1,1-dioxo-3H-benzo[c][1,2]oxathiol-
5-yl (7b), keeping other substitutions intact as in cel-
ecoxib analogues (Scheme 1).
Scheme 1.
Disconnection for synthesis of chemically modified 1,5-
diarylpyrazoles is depicted in Scheme 1. The basic
requirement for the synthesis of these pyrazoles was the
availability of the suitably modified phenyl hydrazine
hydrochlorides 8–15. The multi step synthesis of these
compounds will be discussed separately.16 Simple cou-
pling of the latter with appropriate 1,3-diketones in
absolute ethanol under heating condition afforded the
desired diarylpyrazoles (Scheme 2).17 Though the regio-
meric bias was normally in favor of 1,5-diarylpyrazoles,
the minor undesired regio isomers were easily elimin-
ated by triturating the product with a mixture of ethyl
acetate–toluene after column chromatography. The 1,3-
diketones were synthesized by Claisen condensation18
using appropriate acetophenones and ethyl tri-
fluoroacetate and slightly modified conditions involving
sodium hydride in dry DMF at a temperature of À5–
30 ꢀC.19 The 1,1-dioxo-2,3-dihydrobenzo[d]isothiazole-
Scheme 2. (a) NaH/DMF, À5–30 ꢀC, 4–5 h. (b) 2N HCl. (c) Absolute
ethanol, 50–60 ꢀC, 12 h.
5-yl pyrazole 28 was alternatively synthesized from
compound 33 by sequential treatment with carbon tet-
rabromide-triphenyl phosphine20 and aqueous NaHCO3
(Scheme 3). The dioxo 3H-benzo[c][1,2]oxathiol-5-yl

S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 499–504
501
Scheme 3. (a) (i) Ar=4-OMe-phenyl, R¼NH2, TPP/CBr4, CH2Cl2, room temperature, 14 h. (ii) aq NaHCO3, room temperature, 0.5 h. (b) (i)
Ar=4-OMe-phenyl, R¼NH2, acetonyl acetone, SOCl2, EtOH, reflux, 2–3 h. (ii) aq NaOH, Bu4NBr, CH2Cl2–H2O (75:25), room temperature, 2 h.
(c) For 21, Ar¼4-Me-phenyl, R¼NH2, propionic anhydride, propionic acid, pyridine, room temperature, 12–14 h. (d) For 24, Ar=4-Me-phenyl,
R¼Me, propionic anhydride, TEA, CH2Cl2, reflux, 4–5 h. (e) Ar¼4-OMe-phenyl, R¼ Me, PCC, CH2Cl2, room temperature, 2–3 h.
pyrazole 29 was prepared from 33 after converting to
2,5-dimethylpyrrole-1-sulfonyl derivative and treating it
with aq NaOH in CH2Cl2–H2O (75:25) in presence of
Bu4NBr (TBAB). While O-propionyl derivative 24 was
prepared by refluxing a corresponding hydroxymethyl
compound (not reported here) with propionic anhydride
in CH2Cl2 in presence of TEA, compound 21 was syn-
thesized by the selective O-acylation of 16 using pro-
pionic anhydride and pyridine in propionic acid solvent.
Aldehyde 25 was obtained by PCC oxidation of hydroxy-
methyl group of compound 22 in CH2Cl2 at room tem-
perature (Scheme 3). The methylsulfonyl (SO2Me)
derivative 38 was synthesized by H2O2 oxidation of
methylsulfanyl (SMe) analogue 36 in acetic acid at 70–
80 ꢀC. All the compounds reported herein were character-
ized spectroscopically.21 Additionally, the structure of the
most potent series was confirmed by single crystal X-ray
diffraction studies of one of the O-acylated derivative.22
capable of forming additional hydrogen bonds (either
donor or acceptor) with amino acid residues of the
COX-2 secondary pocket, exhibited COX-2 selectivity,
e.g. acetylaminomethyl derivatives 18–19, ethoxy-
carbonylmethyl derivative 21 and hydroxymethyl deri-
vative 22 showed considerable COX-2 selectivity
whereas others, e.g. 23–25 were found almost inactive or
nonselective. In the second series where benzenesulfo-
namide group was completely replaced by fused hetero-
cycles such as 1,1-dioxo 2,3-dihydrobenzo[b]thiophen-5-
yl in compounds 26–27, 1,1-dioxo 2,3-dihy-
drobenzo[d]isothiazol-5-yl in compound 28 and 1,1-
dioxo-3H-benzo[c][1,2]oxathiol-5-yl in compound 29 led
to COX-1 selectivity. This is presumably because of the
larger volume of these N1-substituted groups which may
not be able to enter the COX-2 pocket.
Since hydroxymethyl group introduction as observed in
compound 16 was found to be an effective modification,
a few analogues of this compound in which the C-5
phenyl substituent was varied, were also synthesized.
The in vitro COX-1/COX-2 inhibitory activity of these
analogues is depicted in Table 2. The 4-OMe analogue
33 and 4-SMe analogue 36 were found to be the most
potent among ethers and thioethers. The COX-2
potency decreases with the introduction of either bulkier,
hydrophilic or electron withdrawing groups at this posi-
tion which is clearly shown by compounds 30, 31, 34,
37, 35 and 38. The potency of compounds halogenated
at this position was found to be in the reverse order of
electronegativity and 4-Br analogue 41 was found to be
the best among all. Compounds substituted at position-
3 of this phenyl ring were observed to be almost equi-
potent to those substituted at position-4, e.g. 3-Me
analogue 44 exhibited similar activity as compound 16,
but position-2 behaved quite differently as 2-OMe ana-
logue 47 lost potency when compared to compound 33.
Initially, all the compounds were screened for their
ability to inhibit recombinant human COX-2 enzyme,
expressed in sf-9 cells infected with baculovirus, at 100
mM concentration. The compounds exhibiting more
than 60% COX-2 inhibition were screened for inhibi-
tion of COX-1 enzyme, obtained from microsomal
fraction of Ram Seminal Vesicles. The enzyme activity
was measured by the TMPD method and IC50s were
calculated using non-linear regression analysis of per-
cent inhibitions.23
Compound 16, incorporating our first modification
wherein the hydroxymethyl group was introduced adja-
cent to sulfonamide in celecoxib (Table 1), was found to
be COX-2 selective. Though the COX-2 inhibitory
potency (0.76 mM) of this compound was not at par
with celecoxib (0.036 mM), it was still considered suffi-
ciently active to warrant further studies. A few other
groups, e.g. in compounds 17–25 were also studied at
this position but they were not as effective as compound
16. It was observed that only such groups which were
Docking the potent COX-2 inhibitors 33, 36 and 2b
(SC-558)14 into COX-2 active site (6COX) generated

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S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 499–504
Table 1. 1,5-Diarylpyrazoles with additionally substituted benzene-
sulfonamide and methylsulfonyl groups
Table 2. 1,5-Diarylpyrazoles with hydroxymethyl group adjacent to
sulfonamide
Compd
R
Ar
IC50 in mMa
IC50 in mMa
COX-1 COX-2
Compd
Ar
COX-1
COX-2
16
4-Me-phenyl
278
0.76
16
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
4-Me-phenyl
4-Et-phenyl
4-iso-Butyl-phenyl
Phenyl
4-OMe-phenyl
4-OEt-phenyl
4-OH-phenyl
4-SMe-phenyl
4-SEt-phenyl
4-SO2Me-phenyl
4-F-phenyl
4-Cl-phenyl
4-Br-phenyl
3-F-phenyl
3-Cl-phenyl
3-Me-phenyl
2-F-phenyl
278.0
500.0
4c
1085.0
63.0
135.0
0b
59.7
300.0
68c
500.0
336.0
230.0
1000.0
465.0
327.0
500.0
512.0
1150.0
0.760
1.380
14c
3.450
0.365
0.901
19b
0.235
51.200
29c
1.990
0.712
0.592
7.050
1.950
0.728
3.300
6.300
28.600
17
18
19
20
21
22
23
24
4-SMe-phenyl
4-OMe-phenyl
4-Cl-phenyl
6b
100
100
4.62
34.6
300
0b
50b
2.8
5
4-Me-phenyl
4-Me-phenyl
4-OMe-phenyl
4-SMe-phenyl
4-Me-phenyl
6.85
0.57
3.2
45b
0c
2-Cl-phenyl
2-OMe-phenyl
a Mean of three determinations with standard deviation of < Æ10%.
b % Inhibition at 10 mM concentration (average of two experiments
with standard deviation < Æ12%).
c % Inhibition at 100 mM concentration (average of two experiments
with standard deviation < Æ12%).
various structures with different orientations. The
orientation and hydrogen bonding interaction of the
most energetically favored conformation in the COX-2
complex is depicted in Figure 2. The hydroxymethyl
substituted benzenesulfonamide group of compounds
33 and 36 enters the COX-2 secondary pocket in a
similar manner as that of 2b (SC-558) showing little
variation in hydrogen bonding pattern (Fig. 2b). While
hydrogen bonding interactions of the sulfonamide in 2b
(SC-558) with COX-2 residues are His90 (NH....O¼S,
3.370 A), Gln192 (C¼O....H–N, 3.174 A) and Phe518
(NH....O¼S, 2.947 A), that for compound 33 are His90
(N....H–O, 2.880 A), Gln192 (C¼O....H–N, 3.069 A) and
Phe518 (NH. . ..O¼S, 2.921 A) and for compound 36 are
Ser353 (NH. . ..H–O, 2.804 A) and Leu352 (C¼O. . ..N–H,
2.919 A). Though there is no intramolecular hydrogen
bond observed in compound 36 in the free state, it
becomes significant between the hydroxyl group of
CH2OH and one of the oxygens of the sulfonamide in
its complex (Fig. 2a). In addition, one of the nitrogen
atoms of its pyrazole ring also forms a hydrogen bond
with Arg120 (NH. . .N2, 3.649 A). In general, the hydroxy-
methyl group introduced in these inhibitors competes
with SO2NH2 in forming hydrogen bonds with His90
and binds in the polar region formed by His90, Gln192
and Arg513 through electrostatic interaction. The fluor-
ine atoms of CF3 act as acceptors and form hydrogen
bonds with the side chain of Arg120. The CF3 group of
9c
25
4-OMe-phenyl
92b
c,d
100b
44c
26
27
4-OMe-phenyl
4-Me-phenyl
86b
90b
36b
10b
28
4-OMe-phenyl
85b
12b
29
4-OMe-phenyl
—
92b
36b
Celecoxib
—
10.7
0.036
a Mean of three determinations with standard deviation of < Æ10%.
b % Inhibition at 100 mM concentration (average of two experiments
with standard deviation < Æ12%).
c % Inhibition at 10 mM concentration (average of two experiments
with standard deviation < Æ12%).
d Not determined.

S. K. Singh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 499–504
503
Figure 2. (a) Compound 36-COX-2 complex. The hydrogen bonding interactions are shown as broken lines. The ligand is shown in ball and stick
rendering (C-Orange). (b) Superposition of compound 33 (C-Green), 36 (C-Orange) and 2b (SC-558, C-gray) in the binding site of COX-2. All
protein hydrogens are removed for clarity.
References and notes
all these compounds invariably lies in a pocket formed
by Met113, Val116, Arg120, Val349, Tyr355, Leu359, Val523
and Leu531 through hydrophobic interactions. Similarly,
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N1-benzenesulfonamide ring of celecoxib, the one with a
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1
cmÀ1. H NMR (CDCl3) d 8.00 (d, J=8.6 Hz, 1H), 7.65
(d, J=2.0 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 7.20 (d,
J=5.2 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 6.75 (s, 1H), 5.45
(bs, 2H), 5.05 (d, J=4.6 Hz, 2H), 2.60 (bs, 1H), 2.40 (s,
3H). MS 411 (M+), 393, 376, 330. HPLC (System 1)
98.3%. Anal. (C18H16F3N3O3S) C, H, N.
18. (a) Popic, V. V.; Korneev, S. M.; Nikolaev, V. A.; Koro-
bitsyna, I. K. Synthesis 1991, 195. (b) Anselme, J. P. J.
Org. Chem. 1967, 32, 3716.
19. Representative procedure for 1, 3-Diketones. 40-Methyl-
acetophenone (5.0 g, 37.3 mmol) was dissolved in 25 mL
of dry DMF under argon atmosphere and 60% NaH
(1.86 g, 46.6 mmol) was added in three lots maintaining
the temperature between À5 and 0 ꢀC. After stirring at
this temperature for 0.5 h, ethyl trifluoroacetate (6.62 g,
46.6 mmol) was injected and the reaction mixture was
allowed to stir at ambient temperature for 4–5 h. The
reaction mixture was poured into ice water, acidified with
2N HCl and extracted with ethyl acetate. The combined
organic layer was washed with water, dried and evapo-
rated leaving a residue which was washed with pet-ether,
decanted, dried under high vacuum to provide a gummy
mass of 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butane-
dione (7.72 g, 90%) which was used as such in the final
step.6 IR (Neat) 3340, 1611, 1407 cmÀ1 1H NMR
.
(CDCl3) d 7.84 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.0 Hz,
2H), 6.54 (s, 1H), 2.43 (s, 3H). MS 230 (M+), 215, 161,
119, 91.
20. Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. J. Am.
Chem. Soc. 1970, 92, 2139.
21. Melting points (uncorrected) were determined on Veego
apparatus. IR, 1H NMR (200 MHz) and 13C NMR
(50 MHz), Mass spectra and Elemental analysis (C, H, N)
were respectively obtained using Perkin–Elmer FT-IR
1650, Varian Gemini 200, HP-5989A and Perkin–Elmer
2400 series II CHN-O analyzer. The purity of the final
compounds was determined by HPLC using either ‘‘Sys-
tem 1’’ consisting column, Hichrom RPB (250 mm) and
mobile phase, 0.01 M KH2PO4/CH3CN (50:50) or, ‘‘Sys-
tem 2’’ comprising column, Intersil ODS 3V (250 mm)
and mobile phase, H2O/CH3CN (50:50), both running at
1.0 mL/min with UV detection at respective l max.
22. Unpublished results.
16. Unpublished results.
17. Representative procedure for compound 16. 4-Hydrazino-
2-hydroxymethyl-1-benzenesulfonamide 816 (2.0 g, 9.21
mmol) was dissolved in MeOH (10 mL) under argon
atmosphere and acidified to pH 1–2 using IPA-HCl. The
reaction mixture was stirred at room temperature for 0.5
h and solvent was completely removed under high
vacuum at 40–50 ꢀC. The solid obtained was dissolved in
absolute alcohol (15 mL) and an ethanolic solution of
4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione (2.01
g, 8.75 mmol) was added at room temperature. After
heating the reaction mixture at 50–60 ꢀC for 10–12 h
under argon atmosphere, it was cooled to room tempera-
23. Chan, C. C.; Boyce, S.; Brideau, C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J.; Ford-Hutchinson,
A. W.; Forrest, M. J.; Gauthier, J. Y.; Gordon, R.; Gres-
ser, M.; Guay, J.; Kargman, S.; Kennedy, B.; Leblanc, Y.;
Leger, S.; Mancini, J.; O’Neill, G. P.; Ouellet, M.; Patrick,
D.; Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I.;
Tagari, P.; Therien, M.; Vickers, P.; Visco, D.; Wang, Z.;
Webb, J.; Wong, E.; Xu, L. J.; Young, R. N.; Zamboni,
R.; Riendeau, D. J. Pharmacol. Exp. Ther. 1999, 290, 551.