Heteroaromatic analogues of 1,5-diarylpyrazole class as anti-inflammatory agents

Article abstract of DOI:10.1007/s00044-011-9898-4

A novel series of heteroaromatic analogues of known anti-inflammatory (AI) drug celecoxib replacing the benzenesulfonamide moiety with 6- sulfonamidobenzothiazol-2-yl moiety was synthesized. Regioselective synthesis of the target compounds 2a-i having 1,5

Full text of DOI:10.1007/s00044-011-9898-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3757–3766
DOI 10.1007/s00044-011-9898-4
ORIGINAL RESEARCH
Heteroaromatic analogues of 1,5-diarylpyrazole class
as anti-inflammatory agents
•
Pawan K. Sharma Nisha Chandna Surender Kumar
•
•
•
•
•
Pawan Kumar Satish Kumar Pawan Kaushik
Dhirender Kaushik
Received: 18 February 2011 / Accepted: 8 November 2011 / Published online: 6 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of heteroaromatic analogues of
known anti-inflammatory (AI) drug celecoxib replacing the
benzenesulfonamide moiety with 6-sulfonamidobenzothia-
zol-2-yl moiety was synthesized. Regioselective synthesis of
the target compounds 2a–i having 1,5-diaryl relationship
was achieved by exploring reaction conditions. All the newly
synthesized compounds (2a–i and 8) were screened for their
in vivo AI activity using carrageenan-induced rat paw edema
assay. Five compounds (2c–f and 2i) were found to possess
good AI activity (C60% inhibition), 3 h after the carra-
geenan injection when compared to that of standard drug
indomethacin (78%), whereas the remaining four com-
pounds (2a–b and 2g–h) with 1,5-diaryl relationship have
shown moderate activity with 49–56% inhibition after 3 h.
However, pyrazole 8 having 1,3-diaryl relationship failed to
show appreciable AI activity.
Introduction
The development of an effective therapeutic agent for the
management of inflammation has undergone continual
evolution leading to the emergence of more efficacious
classes of drugs. Since the discovery of aspirin, much
efforts have been devoted to the development of non-ste-
roidal anti-inflammatory (AI) drugs (NSAIDs). Their
mechanism of action involves the inhibition of the pro-
duction of prostaglandins (PGs) by the enzyme cyclooxy-
genase (COX) (Vane, 1971). PGs are important biological
mediators of inflammation originating from biotransfor-
mation of arachidonic acid catalyzed by COX (Cashman,
1996). It has been well established that the enzyme exists
in two isoforms, one constitutive (COX-1) and the other
inducible (COX-2) (Xie et al., 1991). COX-1 is constitu-
tively present in platelets and all tissues and produces PGs
involved in physiological functions, such as gastric
mucosal cytoprotection, renal homeostasis, and platelet
aggregation (Ormrod et al., 2002). Although constitutive in
a few tissues, COX-2 isozyme is transiently induced by
proinflammatory stimuli to generate PGs that mediate the
inflammatory response (Kanapure and Letts, 2004). Con-
ventional NSAIDs owing to their indiscriminate inhibition
of both isoforms of COX, are associated with well-known
side effects at the gastrointestinal (GI) level as well as at
the renal level (Meyer-Irchrath and Schror, 2000). There-
fore, currently, there is a considerable therapeutic interest
in developing selective COX-2 inhibitors based on the
hypothesis that these compounds will reduce pain, fever,
and inflammation without causing GI injury (Dannhardt
and Keifer, 2001). This drug design concept has been
validated by the induction of a blockbuster drug celecoxib
(Penning et al., 1997) (1) which has shown excellent AI
activity with reduced GI side effects.
Keywords 1,5-Diarylpyrazoles ꢀ
Benzothiazolesulfonamide ꢀ Anti-inflammatory activity ꢀ
Inflammation ꢀ NSAID
P. K. Sharma (&) ꢀ N. Chandna ꢀ S. Kumar ꢀ P. Kumar ꢀ
S. Kumar
Department of Chemistry, Kurukshetra University, Kurukshetra
136119, Haryana, India
e-mail: pksharma@kuk.ac.in
P. Kaushik ꢀ D. Kaushik
Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra 136119, Haryana, India
123

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Med Chem Res (2012) 21:3757–3766
H N
O2S
2
H N
O2S
2
N
N
S
N
N
N
F
C
F
C
3
3
H
3C
R
1
2
Thiazolesandtheirderivativesare alsoknown toexhibit AI
activity (Kalkhambkar et al., 2007; Kouatly et al., 2009; Giri
et al., 2009). Since the combination of pharmacophores on the
same scaffold is a well-established approach to the synthesis
of more potent drugs (Pillai et al., 2003; Venkatachalam et al.,
2006), coupled with our ongoing interest (Kumar et al., 2011;
Sharma and Sawhney, 1993, 1997; Sharma et al., 1998, 2010,
2011a, b; Sawhney and Sharma, 1993) in the synthesis of
novel heterocyclic analogues as AI agents led us to focus our
attention on the modification of the most celebrated drug
celecoxib (1) belonging to the 1,5-diarylpyrazole class. Thus,
we decided to study the effects on the AI activity of replacing
the benzenesulfonamide moiety with benzothiazolesulfona-
mide moiety in the 1,5-diarylpyrazole class. We now report
the synthesis and in vivo AI activity data for some heteroar-
omatic analogues (2) of celecoxib.
aminosulfonylbenzothiazole (6). Scheme 1 depicts the
three-step conversion of 4-aminobenzenesulfonamide (3)
into 6. Unfortunately, the conventional method of prepar-
ing 2-aminobenzothiazoles in a single step (Kaufmann
et al., 1928) from appropriate anilines by treatment with
Br2/KSCN failed to give 2-amino-6-aminosulfo-
nylbenzothiazole (5). Therefore, the required aminoben-
zothiazole (5) (Kaufmann and Buckmann, 1941) was
prepared from 3 through the corresponding thiourea
derivative (4). Oxidative cyclization of thiourea (4) with
Br2 gave 2-amino-6-aminosulfonylbenzothiazole (5) which
on treatment with hydrazine hydrate in ethylene glycol
under acidic conditions afforded the required hydra-
zinobenzothiazole (6) in 53% overall yield from 3.
The hydrazine 6 was then treated with unsymmetrical
trifluoromethyl-b-diketones (Singh et al., 2005) in an effort
to synthesize target 1,5-diarylpyrazoles (2) as shown in
Scheme 2. First of all, the attempts were made toward the
synthesis of 2a, the closest analogue of celecoxib having a
benzothiazolesulfonamide moiety in place of benzenesul-
fonamide moiety.
Results and discussion
Chemistry
Accordingly, a solution of 2-hydrazinobenzothiazole-6-
sulfonamide (6) and 4,4,4-trifluoro-1-(4-methylphenyl)butane-
1,3-dione (7a) in ethanol containing a few drops of
The basic requirement for the synthesis of these pyrazoles
was the availability of hitherto unknown 2-hydrazino-6-
SO2NH2
SO2NH2
NH4SCN, dil. HCl
KSCN, Br2
AcOH
NHCSNH2
NH2
3
4
×
1. Br2, reflux
2. H2SO3
NH2NH2.H2O
Ethylene glycol
N
N
NHNH2
NH2
conc. HCl
S
S
H2NO2S
H2NO2S
5
6
Scheme 1 Synthesis of hydrazine 6
123

Med Chem Res (2012) 21:3757–3766
3759
5'
5'
H2NO2S
H2NO2S
6'
6'
4'
4'
O
O
EtOH, H
7'
7'
N
2'
N
2'
+
+
6
CF3
S
S
2"
2
2
N
N
N
N
3"
2"
5
5
3"
4"
F3C
3
CF3
3
7a
4
4
4"
6"
5"
6"
5"
2a
8
Scheme 2 Attempted synthesis of target pyrazoles 2 in ethanol under acidic conditions
concentrated HCl was refluxed on water bath for 3 h following
the procedure of Penning et al. (1997) for the synthesis of
celecoxib. However, NMR of the isolated solid indicated a
mixture of compounds presumably containing hydroxypyraz-
oline and pyrazole. Considering that the hydroxypyrazoline did
not dehydrate completely under the reaction conditions used,
the ethanolic solution of isolated mixture was refluxed in the
presence of acetic acid and concentrated H2SO4 to force
dehydration (Singh et al., 1997). After achieving the dehydra-
tion completely the reaction mixture was reduced to one-third
of its original volume and allowed to cool to obtain a solid
material which was characterized as 8 on the basis of its spectral
data in 45% yield. 19F NMR and and 13C NMR spectroscopy
had been used as an elegant tool in the past to study the position
of CF3 on the pyrazole ring so as to distinguish between the
regioisomeric pyrazole derivatives (Singh et al., 1997, 1999,
2006; Song and Zhu, 2001). 19F NMR spectrum of isolated
productdisplayed a singlet at d-59.0 which is characteristic for
CF3 located at C5 of pyrazole ring (Singh et al., 1997, 1999,
2006; Song and Zhu, 2001). 13C NMR spectrum gave further
credence to our assignment to the structure of the product as 8
by displaying a quartet due to the carbon bearing CF3 group at
d 132.5 (2JCF = 41.8 Hz) which is in the characteristic region
for the C5-carbon of pyrazole ring bearing CF3 group (Singh
et al., 1997, 1999, 2006; Song and Zhu, 2001). Low yield and
isolation of unwanted isomer forced us to further investigate the
reaction. In our next attempt, ethanolic solution of hydrazine 6
and b-diketone 7a was refluxed for 12 h in the presence of
concentrated H2SO4. On completion of reaction, solvents were
removed, and the resulting crude was purified by usingsilica gel
column chromatography to isolate both regioisomeric pyra-
zoles i.e., 1,3-diarylpyrazole (8)asthemajorproduct(60%)and
the preferred 1,5-diarylpyrazole (2a) as minor product (11%).
The structure of regioisomer 2a wasassignedonthebasisof19F
the solubility of our starting 2-hydrazinobenzothiazole 6 in
ethanol was so poor that 100 ml of ethanol is required to dis-
solve only 500 mg of the hydrazine. This observation led us to
try various other polar solvents. The solubility of our hydrazine
was very poor in 1,4-dioxane, methanol, acetone, as well as
acetonitrile, but the hydrazine 6 was reasonably soluble in
DMF. Using DMF as the reaction solvent and following the
procedure of Gosselin et al. (2006), we obtained the preferred
1,5-diarylpyrazole 2a in 62% yield, and no 1,3-diarylpyrazole
was obtained (Scheme 3). Although it is difficult to comment
on the reasons for achieving regioselectivity in DMF, it can be
ascribed to higher polarity of DMF. A proper investigation into
the role of solvent polarity versus regioselectivity of the reac-
tion could not be undertaken owing to the poor solubility of the
starting hydrazine in other polar solvents. The other derivatives
(2b–i) were synthesized in moderate-to-good yields following
the same procedure.
Interestingly, in the case of reaction of hydrazine 6 with
4,4,4-trifluoro-1-(4-fluorophenyl)-1,3-butanedione (7d), a
more polar product was also isolated, besides the preferred
pyrazole 2d (55%), which was assumed to be hydroxypy-
razoline 9d or 10d (Fig. 1). We were able to fully assign the
structure of this more polar product as 9d on the basis of a
rigorous spectral analysis. The IR spectrum of 9d displayed
an absorption band at 3,574 cm-1 indicating the presence of
O–H besides characteristic absorption bands at 3,371 and
3,271 cm-1 (N–H stretch), and 1,319 and 1,157 cm-1 (SO2
stretch). The 1H NMR spectrum of 9d displayed a typical AB
system of two sets of doublets of one proton each at d 3.70
and d 4.12 with a coupling constant of 19.2 Hz. This par-
ticular pattern is expected from the two methylene protons
(CHAHB) at position-4 of 5-hydroxypyrazolines (Singh
et al., 1997). Compound 9d also exhibited exchangeable
signals at *d 7.40 (NH2) and 8.39 (OH) indicating the
presence of the NH2 (SO2NH2) and OH protons. Further
support for the structure of 9d was provided by 13C NMR
spectrum, which exhibited signals at d 45.67, 93.45 (as a
quartet, 2JCF = 33.4 Hz), and 154.7 ppm corresponding to
carbons C4, C5, and C3, respectively. Appearance of a fluo-
rine-coupled quartet at d 93.45 is possible only for structure
NMR and 13C NMR spectroscopy. A signal at d -61.5 in 19
F
NMR spectrum and at d 144.4 (2JCF = 38.4 Hz) in 13C NMR
spectrum of 2a indicate that the CF3 is attached at C3 of pyra-
zole ring (Singh et al., 1997, 1999, 2006; Song and Zhu, 2001).
This failure prompted us to search for appropriate conditions to
synthesize 2 as major or exclusive product. We observed that
123

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Med Chem Res (2012) 21:3757–3766
5'
H2NO2S
6'
4'
O
O
7'
N
S
N
2'
DMF, H
NHNH2
+
R
CF3
S
R
2
N
H2NO2S
N
5
6
7
3
CF3
4
2
2,7,
R
a
b
c
d
e
f
g
h
i
4-CH3-Ph Ph
4-OCH3-Ph
4-F-Ph
4-Cl-Ph
4-Br-Ph
2-naphthyl
2-thienyl
2-furyl
Scheme 3 Synthesis of target pyrazoles 2 in DMF under acidic conditions
Fig. 1 Proposed structure of
more polar product 9d or 10d
5'
H2NO2S
5'
6'
7'
4'
H2NO2S
6'
7'
4'
N
N
2'
S
2'
S
2
2
5N
N
HO
N
HO
N
5
3
2"
5"
2"
4
3
3"
4"
CF3
4
3"
6H" B
F3C
HA
HB
F
6"
4"
HA
5"
F
9d
10d
9d as it confirms the presence of CF3 group at C5 of 5-hy-
droxypyrazoline in conformity with literature reports where
it has been unambiguously established that a structure like
10d would show a quartet for C3 around d 140–142 (Singh
et al., 1997, 1999; Song and Zhu, 2001; Kumar et al., 2006;
Aggarwal et al., 2009). Finally, the 19F NMR spectrum gave
further credence to structure 9d as it displayed a signal at
d -76.8, which is typical for a C5–CF3 of 5-hydroxypyraz-
oline rather than a C3–CF3 which should have appeared
at *d -67 (Singh et al., 1997, 1999; Song and Zhu, 2001;
Kumar et al., 2006; Aggarwal et al., 2009).
10 mg/kg, i.p. The AI activity was then calculated at
hourly intervals 1–4 h after induction, and the results are
presented in Table 1 as the mean paw volume (ml) as well
as the percentage AI activity (AI%).
Among ten compounds (2a–i and 8) tested, five com-
pounds (2c–f and 2i) showed consistently good AI activity
(C60% inhibition) 3 h after the carrageenan injection
compared to that of the standard drug indomethacin (78%),
whereas the remaining compounds have shown moderate
activity with 49–56% inhibition after 3 h. However, none
of the compound showed appreciable AI activity 4 h after
the carrageenan injection. All the compounds containing a
halogen substituent (2d–f) showed better activity as com-
pared to non-halogen-containing compounds. The best
compound 2d in terms of AI activity after 3 h contains a
fluoro (F) substituent at position-4 of the phenyl ring that is
attached to the C-5 of the pyrazole moiety. Compound 2c
containing a methoxy substituent also showed good AI
activity (60% inhibition) after 3 h. These results are in
accordance with our earlier observations (Sharma and
Sawhney, 1997; Sharma et al., 1998) that the compounds
with halogen and methoxy substituents show higher
activity. Loss of AI activity after 4 h suggests that these
compounds get easily metabolized in the system. The
Biological evaluation
In vivo AI activity
All the newly synthesized compounds 2a–i and 8 were
evaluated for their in vivo AI activity by carrageenan-
induced rat paw edema method (Winter et al., 1962). The
protocol of animal experiments has been approved by the
Institutional Animal Ethics Committee. Each test com-
pound was dosed orally (50 mg/kg body weight) 30 min
before induction of inflammation by carrageenan injection.
Indomethacin was used as a reference AI drug at a dose of
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Med Chem Res (2012) 21:3757–3766
3761
Table 1 In vivo AI of compounds 2a–i
Compounda
Volume of edema (ml)b and %AIc
1 h
2 h
3 h
4 h
Control
0.68 0.14
0.20 0.01**
(70)c
0.96 0.02
0.21 0.02**
(78)
1.86 0.03
0.40 0.03**
(78)
1.95 0.02
0.49 0.02**
(75)
Indomethacin
2a
2b
2c
2d
2e
2f
0.44 0.07
(35)
0.60 0.14
(38)
0.81 0.08**
(56)
0.94 0.06**
(52)
0.46 0.06
(32)
0.50 0.02*
(48)
0.85 0.13**
(54)
1.61 0.17
(17)
0.39 0.05
(42)
0.66 0.03
(31)
0.75 0.07**
(60)
0.91 0.04**
(53)
0.31 0.07*
(54)
0.49 0.15*
(48)
0.66 0.02**
(64)
0.96 0.20**
(50)
0.38 0.04
(44)
0.56 0.17
(42)
0.73 0.06**
(61)
1.13 0.19**
(42)
0.37 0.05
(45)
0.42 0.09*
(56)
0.74 0.02**
(60)
1.11 0.24**
(43)
2g
2h
2i
0.47 0.11
(30)
0.70 0.04
(27)
0.87 0.16**
(53)
1.58 0.03
(20)
0.64 0.13
(05)
0.71 0.2
(26)
0.95 0.15**
(49)
1.65 0.13
(15)
0.48 0.08
(27)
0.52 0.03
(46)
0.73 0.06**
(61)
0.88 0.16**
(54)
* Significantly different compared to respective control values, P \ 0.05
** Significantly different compared to respective control values, P \ 0.01
a
Dose levels: test compounds (50 mg/kg body wt.), indomethacin (10 mg/kg body wt.)
b
Values are expressed as mean SEM and analyzed by ANOVA
c
Values in parentheses (percentage AI activity, AI%)
pyrazole 8 with 1,3-diaryl relationship failed to show any
appreciable AI activity. 1,5-diarylpyrazole 2a, the closest
relative of celecoxib failed to show the expected AI
potential. A plausible reason for this might be the bulky
nature of the benzothiazole moiety at N-1 position of
pyrazole which prevents it from binding in the secondary
pocket of COX-2.
position is detrimental to the AI properties of 1,5-diary-
lpyrazole class.
Experimental protocols
Melting points were determined in open capillaries in
electrical apparatus and are uncorrected. IR spectra were
recorded on a Buck Scientific IR M500 instrument. The 1H
NMR, 13C NMR, and 19F NMR spectra were recorded on a
Bruker instrument at 300, 75.5 and 282.4 MHz, respec-
tively. Numbering of carbons and protons in the spectral
assignment of newly synthesized compounds is as men-
tioned in Schemes 2 and 3. However, the aromatic protons
of the ‘R’ group in compounds 2a–i and 9d are indicated
by double primes. The d values are given in ppm relative to
tetramethylsilane as internal standard (for 1H and 13C
NMR). Mass spectra (direct analysis in real time, DART-
MS) were recorded on a JEOL-AccuTOF JMS-T100LC
Mass spectrometer having a DART source in ES? mode.
Conclusion
Ten new compounds including nine 1,5-diarylpyrazoles
(2a–i) and one 1,3-diarylpyrazole (8) were synthesized and
evaluated for their in vivo AI activity. Five (2c–f, 2i) of the
nine 1,5-diarylpyrazoles (2a–i) showed moderate AI
activity (C60% inhibition) 3 h after the carrageenan
injection when compared with the standard drug indo-
methacin with 78% inhibition. 1,3-diarylpyrazole 8 failed
to show any appreciable AI activity. It can be concluded
from the present study that increasing the bulkiness at N-1
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Med Chem Res (2012) 21:3757–3766
Exchangeable (ex) protons were detected by disappear-
ance of peaks upon D2O addition. The purity of the
compounds was checked by 1H NMR and thin layer
chromatography (TLC). Iodine or UV lamp was used as a
visualizing agent for TLC. All the newly synthesized
compounds (2a–2i, 6, 8) were subjected to microanalysis
and gave satisfactory analytical results (within 0.4% of
the calculated values).
J = 1.80, 8.24 Hz, Ar), 7.57 (s, 2H, NH2), 7.36 (d, 1H,
J = 8.24 Hz, Ar), 7.05 (s, 1H, NH), 6.70 (s, 2H, NH2); m/z
245 ([M ? H]?, C7H8N4O2S2 H? calcd. 245).
Attempted synthesis of target pyrazoles in ethanol
under acidic conditions
2-Hydrazino-1,3-benzothiazole-6-sulfonamide (6, 500 mg,
2.0 mmol) was dissolved in ethanol (100 ml) by warming,
and 1-(4-methylphenyl)-4,4,4-trifluoromethyl-1,3-butane-
dione (7a, 510 mg, 2.2 mmol) was added to it while stir-
ring. To the resulting mixture, a few drops of concentrated
sulfuric acid were added and the contents were refluxed for
12 h whereupon solvents were evaporated off to afford the
crude which was purified by silica gel chromatography
(0–20% EtOAc in pet ether) to afford 8 (0.54 g, 60%) and
2a (100 mg, 11%).
Synthesis of 2-hydrazino-1,3-benzothiazole-6-
sulfonamide (6)
The novel hydrazine (6) was prepared in three steps from
sulfanilamide as per the procedure given below:
4-[(Aminocarbothioyl)amino]benzenesulfonamide (4)
Sulfanilamide (34.4 g, 200.0 mmol) was dissolved in a
mixture of conc. HCl (18 ml) and water (50 ml) by
warming. The solution was cooled, and ammonium thio-
cyanate (15.2 g, 200.0 mmol) was added. The mixture was
heated on water bath for 3 h and then cooled. The sepa-
rated product was filtered, washed with water, and crys-
tallized from aqueous ethanol. M.p. 190–191°C (Lit. m.p.
206°C) (Shingare and Ingle, 1977), yield 42.9 g (93%).
2-[3-(4-Methylphenyl)-5-(trifluoromethyl)-1H-pyrazol-
1-yl]-1,3-benzothiazole-6-sulfonamide (8)
M.p. 284–285°C, yield 60%; IR (KBr) cm-1: 3,370 and
3,248 (N–H stretch), 1,541 (N–H bend), 1,316 and 1,150 (s,
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.67 (d,
1H, J = 1.50 Hz, H-70), 8.10 (d, 1H, J = 8.70 Hz, H-40),
7.99 (s, 1H, pyrazole H-4), 7.97 (dd, 1H, J = 1.50,
8.70 Hz, H-50), 7.91 (d, 2H, J = 8.10 Hz, H-200, H-600),
7.51 (s, ex, 2H, SO2NH2), 7.35 (d, 2H, J = 8.10 Hz, H-300,
H-500), 2.37 (s, 3H, CH3); 13C NMR (75.5 MHz, DMSO-
d6): d 161.4, 153.5, 152.1, 141.0, 139.8, 133.0, 132.5 (q,
2JCF = 41.8 Hz, C-5), 129.7, 126.7, 126.1, 124.6, 123.0,
2-Amino-1,3-benzothiazole-6-sulfonamide (5)
To a suspension of 4-aminosulfonylphenylthiourea (4,
29.0 g, 125.5 mmol) in chloroform (100 ml), bromine
(10 ml) in chloroform (100 ml) was added dropwise for
1 h, and the resultant mixture was refluxed for 15 min.
Chloroform (100 ml) was distilled off and the semi-solid
product thus obtained was treated with sulfurous acid till
the brown color was discharged. The solution was refluxed
and treated with aqueous ammonia. The precipitated solid
was filtered, washed with water, dried, and crystallized
from ethanol. M.p. 268–270°C (Lit. m.p. 277°C) (Kauf-
mann and Buckmann, 1941), yield 19.8 g (69%).
1
120.9, 119.1 (q, JCF = 264.6 Hz, C5–CF3), 111.9, 20.9
(CH3); 19F NMR (DMSO-d6, 282.4 MHz) -d 59.0 (C5–
CF3); m/z 439 ([M ? H]?, C18H13F3N4O2S2 H? calcd.
439).
2-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]-1,3-benzothiazole-6-sulfonamide (2a)
M.p. 238–240°C, yield 11%; IR (KBr) cm-1: 3,371 and
3,271 (N–H stretch), 1,535 (N–H bend), 1,319 and 1,157 (s,
2-Hydrazino-1,3-benzothiazole-6-sulfonamide (6)
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.66 (d,
To hydrazine hydrate (10 g, 200.0 mmol) was added conc.
HCl (10 ml) dropwise with stirring at 5–10°C. Ethylene
glycol (40 ml) was then added followed by 2-Amino-1,3-
benzothiazole-6-sulfonamide (5, 11.5 g, 50.2 mmol) in
portions to the above reaction mixture and the resulting
mixture was heated under reflux for 4 h. A fine crystalline
solid, which separated out on cooling, was filtered, washed
with water, and crystallized from ethanol. M.p. 250–253°C,
yield 8.86 g (83%); IR (KBr) cm-1: 3,346 and 3,254 (N–H
1H, J = 1.50 Hz, H-70), 7.94 (dd, 1H, J = 1.80, 8.70 Hz,
H-50), 7.88 (d, 1H, J = 8.70 Hz, H-40), 7.52 (d, 2H,
J = 8.40 Hz, H-200, H-600), 7.49 (s, ex, 2H, SO2NH2),
7.28–7.30 (m, 3H, pyrazole H-4, H-300, H-500), 2.35 (s, 3H,
CH3); 13C NMR (75.5 MHz, DMSO-d6): d 162.4, 151.9,
147.4, 144.4 (q, 2JCF = 38.4 Hz, C-3), 141.6, 139.9, 133.9,
129.8, 129.0, 125.2, 124.8, 123.6, 121.1, 120.9 (q,
1JCF = 265.8 Hz, C3–CF3), 109.0, 21.2 (CH3); 19F NMR
(DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3); m/z 439
([M ? H]?, C18H13F3N4O2S2 H? calcd. 439).
1
stretch), 1,552 (N–H bend); H NMR (300 MHz, DMSO-
d6): d 8.08 (d, 1H, J = 1.80 Hz, Ar), 7.64 (dd, 1H,
123

Med Chem Res (2012) 21:3757–3766
3763
1
Representative procedure for the synthesis of target
pyrazoles in DMF under acidic conditions
stretch); H NMR (300 MHz, DMSO-d6): d 8.66 (d, 1H,
J = 1.50 Hz, H-70), 7.84–7.92 (m, 2H, H-40, H-50), 7.70–75
(m, 2H, H-200, H-600), 7.48 (s, ex, 2H, SO2NH2), 7.37 (s, 1H,
pyrazole H-4), 7.34 (m, 2H, H-300, H-500); 13C NMR
(75.5 MHz, DMSO-d6): d 170.8, 163.4 (d, 1JCF = 245.2 Hz),
To a solution of 2-Hydrazino-1,3-benzothiazole-6-sulfo-
namide (6, 500 mg, 2.0 mmol) and 1-(4-methylphenyl)-
4,4,4-trifluoromethyl-1,3-butanedione (7a, 510 mg, 2.2 mmol)
in DMF (15 ml) was added concentrated hydrochloric acid
(1 ml). The reaction mixture was stirred at 50°C for 3 h,
whereupon few drops of concentrated sulfuric acid were
added, and the content was stirred again for 6 h at 90°C.
The reaction mixture was allowed to cool and poured into
ice-cold water to obtain a solid which was filtered and dried
to afford crude material. The crude material was purified
by silica gel chromatography (0–20% EtOAc in pet ether)
to afford 2a (560 mg, 62%).
2
162.6, 152.1, 146.3, 144.5 (q, JCF = 38.2 Hz, C-3), 141.7,
3
133.8, 132.7 (d, JCF = 9.0 Hz), 124.9, 123.7, 121.2, 120.9
1
2
(q, JCF = 269.5 Hz, C3–CF3), 115.6 (d, JCF = 21.7 Hz),
109.6; 19F NMR (DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3);
m/z 441([M - H]?, C17H10F4N4O2S2 H? calcd. 441).
2-[3-(4-Fluorophenyl)-5-hydroxy-5-(trifluoromethyl)-
4,5-dihydro-1H-pyrazol-1-yl]-1,3-benzothiazole-6-
sulfonamide (9d)
M.p. 254–256°C, yield 6%; IR (KBr) cm-1: 3,573 (O–H),
3,364 and 3,271 (N–H stretch), 1,535 (N–H bend), 1,319
2-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1,3-
1
benzothiazole-6-sulfonamide (2b)
and 1,157 (s, SO2 stretch); H NMR (300 MHz, DMSO-
d6): d 8.63 (d, 1H, J = 1.50 Hz, H-70), 8.39 (bs, 1H, 5-OH,
exchangeable), 7.90–7.93 (m, 2H, H-200, H-600),7.80–7.81
(m, 2H, H-300, H-500), 7.36–7.42 (m, 4H (exchangeable 2H),
M.p. 234–236°C, yield 64%; IR (KBr) cm-1: 3,370 and
3,268 (N–H stretch), 1,535 (N–H bend), 1,317 and 1,155 (s,
SO2 stretch); 1H NMR (300 MHz, DMSO-d6): d 8.67 (d, 1H,
J = 1.50 Hz, H-70), 7.91 (dd, 1H, J = 1.50, 8.70 Hz, H-50),
7.83 (d, 1H, J = 8.70 Hz, H-40), 7.62–65 (m, 2H, H-200,
H-600), 7.45–7.53 (m, 5H, SO2NH2, H-300, H-400, H-500), 7.36
(s, 1H, pyrazole H-4); 13C NMR (75.5 MHz, DMSO-d6): d
162.1, 152.1, 147.4, 144.0 (q, 2JCF = 38.5 Hz, C-3), 141.7,
134.0, 130.3, 130.1, 129.6, 128.6, 128.4, 126.6, 124.9, 123.7,
SO NH , H-40, H-50), 4.12 (J
= 19.2 Hz, 4-HA), 3.70
HAꢁHB
2
2
(d, 1H, JH ꢁH = 19.2 Hz, JH ꢁCF = 1.2 Hz, 4-HB); 13C
4
A
B
B
3
NMR (75.5 MHz, DMSO-d6):
d
164.93, 164.0 (d,
1JCF = 249.1 Hz), 154.7, 152.8, 138.6, 131.9, 129.6 (d,
3JCF = 9.0 Hz), 126.83, 126.7, 122.5 (q, 1JCF = 271.8 Hz,
2
C5–CF3), 120.0, 116.6 (d, JCF = 21.7 Hz), 93.5 (q,
2JCF = 33.9 Hz, C-5), 45.7 (C-4); 19F NMR (DMSO-d6,
282.4 MHz) -d 76.8 (C3–CF3), 109(F); m/z 461([M ? H]?,
C17H12F4N4O3S2 H? calcd. 461).
1
121.3, 121.0 (q, JCF = 269.5 Hz, C3–CF3), 111.9; 19F
NMR (DMSO-d6, 282.4 MHz) –d 61.5 (C3–CF3); m/z 425
([M ? H]?, C17H11F3N4O2S2 H? calcd. 425).
2-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
2-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-
1-yl]-1,3-benzothiazole-6-sulfonamide (2e)
pyrazol-1-yl]-1,3-benzothiazole-6-sulfonamide (2c)
M.p. 236–238°C, yield 60%; IR (KBr) cm-1: 3,365 and
3,271 (N–H stretch), 1,535 (N–H bend), 1,319 and 1,137 (s,
M.p. 236–238°C, yield 62%; IR (KBr) cm-1: 3,394 and
3,286 (N–H stretch), 1,535 (N–H bend), 1,342 and 1,134 (s,
SO2 stretch); 1H NMR (300 MHz, DMSO-d6): d 8.66 (d, 1H,
J = 1.50 Hz, H-70), 7.88–7.91 (m, 2H, H-40, H-50), 7.58 (d,
2H, J = 8.70 Hz, H-200, H-600), 7.50 (s, ex, 2H, SO2NH2, Ar),
7.27 (s, 1H, pyrazole H-4), 7.03 (d, 2H, J = 8.70 Hz, H-300,
H-500), 3.83 (s, 3H, OCH3); 13C NMR (75.5 MHz, DMSO-
d6): d 162.7, 160.9, 152.2, 147.4, 144.5 (q, 2JCF = 37.8 Hz,
C-3), 141.7, 134.0, 131.7, 124.9, 123.7, 121.2, 120.4, 121.0
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.66 (d,
1H, J = 1.50 Hz, H-70), 7.88–7.90 (m, 2H, H-40, H-50),
7.70 (d, 2H, J = 8.10 Hz, H-200, H-600), 7.57 (d, 2H,
J = 8.10 Hz, H-300, H-500), 7.49 (s, ex, 2H, SO2NH2), 7.40
(s, 1H, pyrazole H-4); 13C NMR (75.5 MHz, DMSO-d6): d
162.6, 152.1, 146.1, 144.5 (q, 2JCF = 38.2 Hz, C-3), 141.7,
135.2, 133.8, 132.1, 129.7, 128.6, 128.4, 127.3, 124.9,
1
123.7, 121.2, 120.9 (q, JCF = 269.5 Hz, C3–CF3), 109.9;
19F NMR (DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3); m/z
458 ([M - H]?, C17H10ClF3N4O2S2 H? calcd. 458).
(q, 1JCF = 271.8 Hz, C3–CF3), 114.0, 108.9, 55.7 (CH3); 19
F
NMR (DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3); m/z 453
([M - H]?, C18H13F3N4O3S2 H? calcd. 453).
2-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-
2-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl]-1,3-benzothiazole-6-sulfonamide (2f)
1-yl]-1,3-benzothiazole-6-sulfonamide (2d)
M.p. 245–247°C, yield 65%; IR (KBr) cm-1: 3,394 and
3,279 (N–H stretch), 1,528 (N–H bend), 1,335 and 1,165 (s,
M.p. 234–236°C, yield 55%; IR (KBr) cm-1: 3,364 and 3,271
(N–H stretch), 1,535 (N–H bend), 1,319 and 1,157 (s, SO2
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.65 (d,
123

3764
Med Chem Res (2012) 21:3757–3766
M.p. 223–225°C, yield 64%; IR (KBr) cm-1: 3,393 and
3,276 (N–H stretch), 1,525 (N–H bend), 1,339 and 1,163 (s,
1H, J = 1.50 Hz, H-70), 7.87–7.91 (m, 2H, H-40, H-50), 7.70
(d, 2H, J = 8.70 Hz, H-200, H-600), 7.62 (d, 2H, J = 8.70 Hz,
H-300, H-500), 7.49 (s, ex, 2H, SO2NH2), 7.40 (s, 1H, pyrazole
H-4); 13C NMR (75.5 MHz, DMSO-d6): d 162.6, 152.1,
146.18, 144.5 (q, 2JCF = 37.8 Hz, C-3), 141.7, 133.8, 132.3,
131.5, 127.7, 124.9, 126.3, 123.9, 123.7, 121.2, 120.9 (q,
1JCF = 268.5 Hz, C3–CF3), 116.0, 109.9; 19F NMR
(DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3); m/z 503
([M ? H]?, C17H10BrF3N4O2S2 H? calcd. 503).
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.69 (d,
1H, J = 1.50 Hz, H-50), 8.07 (d, 1H, J = 8.70 Hz, H-40),
7.97 (dd, 1H, J = 1.50, 8.70 Hz, H-50), 7.84 (dd, 1H,
J = 0.90 Hz, 4.80 Hz, H-300), 7.74 (dd, 1H, J = 0.90,
3.90 Hz, H-500), 7.52 (s, 2H, SO2NH2), 7.50 (s, 1H, pyra-
zole H-4), 7.22 (dd, 1H, J = 3.90, 4.80 Hz, H-400); 13C
NMR (75.5 MHz, DMSO-d6): d 161.9, 151.5, 144.2 (q,
2JCF = 38.1 Hz, C-3), 141.5, 140.7, 133.8, 131.8, 130.2,
1
127.5, 120.4 (q, JCF = 269.7 Hz, CF3), 124.6, 123.8,
2-[5-(2-Naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-
123.4, 121.0, 109.1; 19F NMR (DMSO-d6, 282.4 MHz): d
-62.3 (C3–CF3); 19F NMR (DMSO-d6, 282.4 MHz) -d
61.5 (C3–CF3); m/z 431 ([M ? H]?, C15H9F3N4O2S3 H?
calcd. 431).
yl]-1,3-benzothiazole-6-sulfonamide (2g)
5'
H2NO2S
6'
4'
7'
2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
N
2'
1,3-benzothiazole-6-sulfonamide (2i)
S
2
N
N
3"
4"
5
5'
H2NO2S
6'
5"
2"
CF3
3
4'
4
1"
6"
7'
N
8"
7"
S
2'
2
N
2g
N
O
M.p. 238–240, yield 58%; IR (KBr) cm-1: 3,394 and 3,280
(N–H stretch), 1,531 (N–H bend), 1,335 and 1,157 (s, SO2
stretch); 1H NMR (300 MHz, DMSO-d6): d 8.67(d, 1H,
J = 1.50 Hz, H-70), d 8.27 (s, 1H, H-100), 7.97–8.02 (m, 3H,
H-400, H-500, H-800), 7.87 (dd, 1H, J = 1.50, 8.70 Hz, H-500),
7.76 (d, 1H, J = 8.70 Hz, H-40), 7.55–7.70 (m, 3H, H-300,
H-600, H-700), 7.50 (s, ex, 2H, SO2NH2), 7.47 (s, 1H, pyrazole
H-4); 13C NMR (75.5 MHz, DMSO-d6): d 162.7, 152.2,
147.4, 144.7 (q, 2JCF = 38.5 Hz, C-3), 141.7, 133.9, 133.65,
132.8, 129.8, 128.85, 128.2, 127.8, 127.7, 127.5, 127.2, 126.0,
5
5"
CF3
2"
3
4
4"
3"
2i
M.p. 237–239, yield 57%; IR (KBr) cm-1: 3,394 and
3,278 (N–H stretch), 1,535 (N–H bend), 1,342 and 1,128 (s,
1
SO2 stretch); H NMR (300 MHz, DMSO-d6): d 8.70 (d,
1H, J = 1.80 Hz, H-70), 8.18 (d, 1H, J = 8.70 Hz, H-40),
7.99 (dd, 1H, J = 1.80, 8.70 Hz, H-50), 7.97 (dd, 1H,
J = 0.90, 3.60 Hz, H-300), 7.66 (dd, 1H, J = 0.90, 1.8 Hz,
H-500), 7.53 (s, ex, 2H, SO2NH2, Ar),7.50 (s, 1H, pyrazole
H-4), 6.76 (dd, 1H J = 1.8, 3.60 Hz, H-400); 13C NMR
(75.5 MHz, DMSO-d6): d 162.7, 152.2, 145.9, 144.75 (q,
2JCF = 38.25 Hz, C-3), 141.9, 141.6, 137.8, 133.9, 125.1,
1
124.9, 123.7, 122.8, 121.0 (q, JCF = 271.8 Hz, C3–CF3),
109.9; 19F NMR (DMSO-d6, 282.4 MHz) -d 61.5 (C3–CF3);
m/z 475 ([M ? H]?, C21H13F3N4O2S2 H? calcd. 475).
1
2-[5-(2-Thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
123.9, 121.4, 120.9 (q, JCF = 267.8 Hz, C3–CF3), 115.6,
112.7, 107.8; 19F NMR (DMSO-d6, 282.4 MHz) -d 61.5
(C3–CF3); m/z 415 ([M ? H]?, C15H9F3N4O3S2 H? calcd.
415).
1,3-benzothiazole-6-sulfonamide (2h)
5'
H2NO2S
6'
4'
7'
N
Biological evaluation
S
2'
2
N
N
In vivo AI activity
S
5
5"
CF3
2"
3
4
Male Wistar albino rats weighing 200–250 g were used
throughout the study. They were kept in the animal house
4"
3"
2h
123

Med Chem Res (2012) 21:3757–3766
3765
Kalkhambkar RG, Kulkarni GM, ShivKumar H, Rao RN (2007)
Synthesis of novel triheterocyclic thiazoles as anti-inflammatory
and analgesic agents. Eur J Med Chem 42:1272–1276
Kanapure SP, Letts LG (2004) The eicosanoids. Wiley, London,
pp 131–162
under standard conditions of light and temperature with
free access to food and water. Food was withdrawn 12 h
before and during experimental hours. The animals were
randomly divided into groups each consisting of six rats.
One group of six rats was kept as control and received
tween 80 (95:5). Another group received the standard drug
indomethacin at a dose of 10 mg/kg body weight ip. Other
groups of rats were administered the test compounds at a
dose of 50 mg/kg body weight orally. A mark was made on
the left hind paw just beyond the tibiotarsal articulation, so
that every time the paw was dipped up to the fixed mark, a
constant paw volume was ensured. Paw volumes were
measured using a plethysmometer (model 7140, Ugo Ba-
sile, Italy). Thirty minutes after administration of test
compounds and standard drug, 0.1 ml of 1% w/v of car-
rageenan suspension in normal saline was injected into sub
planter region of the left hind paw of all the animals. The
initial paw volume was measured within 30 s of the
injection and remeasured again 1, 2, 3, and 4 h after
administration of carrageenan. The edema was expressed
as an increase in the volume of paw and the percentage of
edema inhibition for each rat and each group was obtained
as follows:
¨
Kaufmann HP, Buckmann HJ (1941) Uber die rhodanierung des
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Kaufmann HP, Oehring W, Clauberg A (1928) Die bildung von
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(2009) Adamantane derivatives of thiazolyl-N-substituted amide,
as possible non-steroidal anti-inflammatory agents. Eur J Med
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Kumar V, Singh SP, Aggarwal R (2006) The reaction of hydroxyl-
amine with aryl trifluoromethyl-b-diketones: synthesis of
5-hydroxy-5-trifluoromethyl-D2-isoxazolines and their dehydra-
tion to 5-trifluoromethylisoxazoles. J Fluor Chem 127:880–888
Kumar P, Chandak N, Kaushik P, Sharma C, Kaushik D, Aneja KR,
Sharma PK (2011) Synthesis and biological evaluation of some
pyrazole derivatives as anti-inflammatory–antibacterial agents.
Med Chem Res. doi:10.1007/s00044-011-9853-4
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The edema was expressed as an increase in the volume
of paw, and the percentage of edema inhibition for each rat
and each group was obtained as follows:
Penning TD, Talley JJ, Bertneshaw SR, Carten JS, Collins PW,
Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM,
Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG,
Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K,
Veenhuizen AW, Zhang YY, Isakson PC (1997) Synthesis and
biological evaluation of the 1,5-diarylpyrazole class of cycloox-
ygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-
3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635,
celecoxib). J Med Chem 40:1347–1365
%
Inhibition = (Vt - V0)control - (Vt -V0)tested
compound/(Vt - V0)control 9 100
where Vt is the volume of edema at specific time inter-
val and V0 is the volume of edema at zero time interval.
Pillai AD, Rathod PD, Franklin PX, Patel M, Nivsarkar M, Vasu KK,
Padh H, Sudarsanam V (2003) Novel drug designing approach
for dual inhibitors as anti-inflammatory agents: implication of
pyridine template. Biochem Biophys Res Commun 301:183–187
Sawhney SN, Sharma PK (1993) Synthesis and antiinflammatory
activity of some 3-heterocycle-1,2-benzisothiazoles. Bioorg Med
Chem Lett 3:1551–1554
Acknowledgments This research study was funded by the Defence
Research and Development Organization (DRDO), Ministry of
Defence, India (Grant no. ERIP/ER/0803739/M/01/1154). The
authors thank the faculty of the Sophisticated Analytical Instrument
Facility, Central Drug Research Institute, Lucknow, for assistance
with Mass spectral facility.
Sharma PK, Sawhney SN (1993) Synthesis and antiinflammatory
activity of some 1,4-dihydro-3-methyl-1-(2-thiazolyl)pyrazol-
o[4,3-c][1,2]benzothiazine 5,5-dioxides. Bull Chem Soc Jpn 66:
3843–3846
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